Você está na página 1de 45

Bonus images for this chapter can be found online at

http://www.expertconsult.com

Cutaneous Vascular Diseases

Raynaud phenomenon and Raynauds disease


Raynaud phenomenon occurs in the presence of an associated
disease, usually collagen vascular disease, and often systemic
sclerosis/scleroderma. This is also called secondary Raynauds
phenomenon. Raynauds disease (or primary Raynauds
disease) occurs in the absence of such disease. In a series of
165 patients with Raynaud, 51 had primary disease (Raynauds
disease). A defined connective tissue disease was present in
about one-third of the remaining patients, but 54 had undefined connective tissue disease (35 with positive antinuclear
antibody [ANA] titer). In another study of 142 patients with
idiopathic Raynaud phenomenon followed for more than 10
years, 14% progressed to a definite connective tissue disease.
The initial presence of ANAs, thickening of fingers, older age
at onset, and female sex were predictors of connective tissue
disease. In a larger study of 586 patients with Raynaud, followed by sequential nailfold capillary microscopy and auto
antibody determinations, these two investigations were able,
in 80% of cases, to identify the 12.6% of patients who went on
to develop systemic sclerosis. The absence of nailfold capillaroscopic findings is also predictive of primary Raynauds
disease (no associated systemic disease). Laser Doppler perfusion imaging may enhance the evaluation of vascular
damage from Raynauds. Technetium digital blood flow scintigraphy may aid in the early diagnosis of Raynauds of either
the primary or the secondary type.
Many of the studies on pathogenesis and therapy in Raynaud
are conducted on patients with systemic sclerosis/scleroderma,
so it may not be possible to translate these findings to patients
with Raynauds disease. However, it appears that cold exposure is a major trigger of vasospasm in all Raynauds patients.
There appears to be an exaggerated sympathetic response to
cold. This may be due to both excessive vasoconstrictor tone
and a weak systemic vasodilatation process, centrally mediated at least in part. The abnormal sympathetic response may
also explain why some patients say that stress triggers
Raynaud attacks. High homocysteine levels have been detected
in patients with both primary and secondary Raynauds
disease. Patients with systemic sclerosis and Raynauds phenomenon have elevated levels of endothelin (ET-1), and this
correlated with both nailfold capillaroscopic findings and
more advanced disease.

Raynaud phenomenon
Raynaud phenomenon is produced by an intermittent constriction of the small digital arteries and arterioles. The digits
have sequential pallor, cyanosis, and rubor. The involved
parts are affected in paroxysms by the attacks of ischemia,
which cause them to become pale, cold to the touch, and
numb. The phenomenon is more frequently observed in cold
weather. When exposed to cold, the digits become white

35

(ischemic), then blue (cyanotic), and finally red (hyperemic).


In time, the parts may fail to regain their normal circulation
between attacks and become persistently cyanotic and painful.
If this phenomenon persists over a long period, punctate
superficial necrosis of the fingertips develops (Fig. 35-1); later,
even gangrene may occur.
Raynaud phenomenon occurs most frequently in young to
middle-aged women. It occurs with scleroderma, dermato
myositis, lupus erythematosus, mixed connective tissue
disease (MCTD), Sjgren syndrome, rheumatoid arthritis, and
paroxysmal hemoglobinuria. Scleroderma was the underlying
diagnosis in more than half of patients in one series. Occlusive
arterial diseases, such as embolism, thromboangiitis obliterans, arteriosclerosis obliterans, and large-vessel vasculitis
(Takayasus disease), may be present. In addition, various diseases of the nervous system, including cervical rib, scalenus
anticus syndrome, and complex regional pain syndrome
(reflex sympathetic dystrophy), may produce the disorder.
Physical trauma, such as hand-transmitted vibration as occurs
with pneumatic hammer operation, can induce a syndrome
identical to Raynauds and has been termed vibration white
finger or handarm vibration syndrome. Pianists and
typists may also develop this phenomenon. Raynauds is a
well-recognized complication following cold injury, especially
frostbite. Pharmacological agents, such as bleomycin, ergot,
-blockers (including eyedrops), cyclosporine, interferon
(IFN)- and , vinyl polychloride exposure, and cocaine, may
also be the cause. The clumping of red blood cells is believed
to be responsible for the induction of Raynaud phenomenon,
with high titers of circulating cold agglutinins. It may occur in
cryoglobulinemia and polycythemia vera. Patients with cancer
may develop Raynauds as a paraneoplastic phenomenon.
Endocrine disorders, such as acromegaly, pheochromocytoma,
carcinoid, and hypothyroidism, may present with or be associated with Raynauds. Raynauds of the nipple is a variant of
Raynauds that is difficult to diagnose. It presents with severe
pain during lactation, and must be distinguished from nipple
candidiasis and eczema. Patients report the onset of symptoms
during pregnancy, and when asked, will say that the symptoms are triggered by cold and accompanied by biphasic or
triphasic color changes of the nipple. Nifedipine can be highly
effective in this condition and is safe for use during lactation,
since little is found in the breast milk.
Simple tests and physical examination will generally distinguish between Raynauds disease and Raynaud phenomenon.
Sclerodactyly, digital pitted scars, puffy fingers with telangiectases, positive ANA, subcutaneous calcifications,
basilar lung fibrosis, and changes on nailfold capillary
microscopy (avascular skip areas with irregularly dilated
capillary loops) are signs of connective tissue disease. An
anticentromere antibody is an indicator of CREST (Calcinosis,
Raynauds syndrome, Esophageal dysmotility, Sclerodactyly,
Telangiectasia) syndrome. Measuring rewarming after cold
exposure can distinguish handarm vibration syndrome

Cutaneous Vascular Diseases

35

Fig. 35-1 Raynaud phenomenon with fingertip necrosis.

(HAVS) from Raynauds. HAVS patients will all rewarm their


hand temperature by >2.2C in the first 30 seconds, and will
rewarm their hand temperature by 5C in the same time period
as normal persons (less than 5min 30sec); in Raynauds
patients, rewarming averages 7min and is always longer than
5min 30sec.

Raynauds disease (primary Raynauds disease)


Raynauds disease is a primary disorder of cold sensitivity
primarily seen in young women. The intermittent attacks of
pallor, cyanosis, hyperemia, and numbness of the fingers are
identical to those in Raynaud phenomenon. The disease is
usually bilateral, and gangrene occurs in less than 1% of cases.
The diagnosis requires the absence of the diseases enumerated under Raynaud phenomenon. Although some suggest
that Raynauds disease should be present for 2 years before
being classified as a primary process, it may take as long as
11 years for some systemic disorders to manifest. Overall,
fewer than half of patients presenting with Raynaud symptoms will prove to have a connective tissue disease. The prognosis is good for primary Raynauds disease.

Treatment

802

Treatments have often been studied only in patients with


Raynauds phenomenon and digital ulceration, so not all treatments can be assumed to be effective in primary Raynauds
disease or Raynauds secondary to other causes. If an underlying cause if found, treatment of that associated condition will
often lead to improvement of the Raynauds. In both primary
and secondary Raynauds, exposure to cold should be avoided.
This includes avoidance of exposure to cold not only of the
extremities but also of other parts of the body, since vaso
spasm may be induced by reduction of core body temperature.
Warm gloves should be worn whenever possible. Residence
in a warm climate is helpful. Trauma to the fingertips should
be avoided. Smoking is absolutely contraindicated. An attack
of Raynauds may be broken at times by swinging the affected
arm in a wide circle from the shoulderthe windmill
maneuver. The use of standard nitroglycerin paste has had
minimal efficacy and can produce systemic side effects. A new
form of topical nitroglycerin, known as MQX-503, has been
reported to improve Raynauds while having the same side
effects as placebo. Alternative treatments, including ginkgo
and other herbal medications, have limited efficacy when compared to the standard treatments below, and cannot be recommended for patients with significantly symptomatic disease.

Calcium channel-blockers are the first-line therapy used in


Raynauds due to their efficacy and low side-effect profile.
Prolonged-release amlodopine or nifedipine is usually recommended. Two-thirds of treated patients will respond favorably. The phosphodiesterase inhibitor sildenafil has been
effective in both reducing the frequency of Raynauds episodes and in healing digital ulcers. It has become the secondline agent of choice. Tadalafil has not been compared to
sildenafil, but has not been effective in secondary Raynauds
in scleroderma, and substitution of tadalafil for sildenafil for
cost savings may not be appropriate in the treatment of
Raynauds. An angiotensin II-receptor type I antagonist (losartan) or selective serotonin-reuptake inhibitors (fluoxetine or
venlafaxine) may be useful in refractory cases. Quinapril is not
effective, suggesting that not all angiotensin-converting
enzyme (ACE) inhibitors are effective in Raynauds.
Intravenous biweekly N-acetylcysteine has been effective in
reducing the number of attacks and was relatively side effectfree. The use of statins (specifically atorvastatin) in patients
with Raynauds due to systemic sclerosis/scleroderma was
associated with a reduction in Raynauds-associated symptoms. This may be through the vasoprotective actions of
statins, since statin administration was associated with reduction of circulating markers of vascular injury, which are commonly elevated in scleroderma patients. Bosentan, an
endothelin receptor (ETA and ETB) antagonist, significantly
reduces the frequency of Raynauds attacks and reduces new
digital ulcers. Iloprost, a prostaglandin analog, has substantial
efficacy in scleroderma-associated Raynauds and digital
ulceration, when given intravenously but not orally. Oral cisaprost has minimal or no efficacy. Treprostinil and epoprostenol have preliminary data supporting their benefit.
In cases that are refractory to the medical treatments outlined above, surgical modalities can be considered. If single
digits are involved, botulinum toxin injections in the palm
around each involved neurovascular bundle may lead to dramatic and, at times, immediate pain reduction. Ulcerations of
the affected digits heal following the injections. The duration
of response is often months to years, and can be repeated with
similar efficacy. Local digital sympathectomy can be effective,
and avoids amputation of chronically ulcerated digits. Cervical
sympathectomy and endoscopic thoracic sympathectomy may
give initial relief, but Raynauds symptoms often recur after
1 year to 18 months. However, despite the return of the
Raynauds symptoms, digital ulceration is markedly reduced.
Compensatory hyperhidrosis is a common complication of
thoracic sympathectomy.
Allen D, et al: Paraneoplastic Raynauds phenomenon in a breast
cancer survivor. Rheumatol Int 2009 Jun 11 (Epub ahead of print).
Anderson JE, et al: Raynauds phenomenon of the nipple: a treatable
cause of painful breastfeeding. Pediatrics 2004; 113:e360.
Batthish M: Raynauds phenomenon as a presenting feature of
hypothyroidism in an 11-year-old girl. J Rheumatol 2009; 36:203.
Blagojevic J, Matucci-Cerinic M: Are statins useful for treating vascular
involvement in systemic sclerosis? Nat Clin Pract Rheumatol 2009;
5:70.
Bovenzi M: A longitudinal study of vibration white finger, cold response
of digital arteries, and measure of daily vibration exposure. Int Arch
Occup Environ Health 2009 Sep 4 (Epub ahead of print).
Brueckner CS, et al: Effect of sildenafil on digital ulcers in systemic
sclerosisanalysis from a single centre pilot study. Ann Rheum Dis
2009 Nov 8 (Epub ahead of print).
Choi WS, et al: To compare the efficacy and safety of nifedipine
sustained release with Ginkgo biloba extract to treat patients with
primary Raynauds phenomenon in South Korea: Korean Raynaud
study (KOARA study). Clin Rheumatol 2009; 28:553.
Chung L, et al: MQX-503, a novel formulation of nitroglycerin,
improves the severity of Raynauds phenomenon. Arthritis Rheum
2009; 60:870.
De Angelis R, et al: Raynauds phenomenon: clinical spectrum of 118
patients. Clin Rheumatol 2003; 22:279.

Schiopu E, et al: Randomized placebo-controlled crossover trial of


tadalafil in Raynauds phenomenon secondary to systemic sclerosis.
J Rheumatol 2009; 36:2264.
Sulli A, et al: Raynauds phenomenon and plasma endothelin:
correlations with capillaroscopic patterns in systemic sclerosis. J
Rheumatol 2009; 36:1235.
Sunderkotter C, et al: Comparison of patients with and without digital
ulcers in systemic sclerosis: detection of possible risk factors. Br J
Dermatol 2009; 160:835.
Wasserman A, Brahn E: Systemic sclerosis: bilateral improvement of
Raynauds phenomenon with unilateral digital sympathectomy. Semin
Arthritis Rheum 2009 Oct 29 (Epub ahead of print).
Wu YJ, et al: Vascular response of Raynauds phenomenon to
nifedipine or herbal medication (duhuo-tisheng tang with danggui-sini
tang): a preliminary study. Chang Gung Med J 2008; 31:492.
Ziegler S, et al: Long-term outcome of primary Raynauds phenomenon
and its conversion to connective tissue disease: a 12-year
retrospective patient analysis. Scand J Rheumatol 2003; 32:343.

Erythromelalgia

Delgado S, et al: Bacterial analysis of breast milk: a tool to differentiate


Raynauds phenomenon from infectious mastitis during lactation. Curr
Microbiol 2009; 59:59.
Dorafshar AH, et al: Reoperative digital sympathectomy in
refractory Raynauds phenomenon. Plast Reconstr Surg 2009;
123:36e.
Fregene A, et al: Botulinum toxin type A: a treatment option for digital
ischemia in patients with Raynauds phenomenon. J Hand Surg Am
2009; 34:446.
Friedman EA, et al: The effects of tadalafil on cold-induced
vasoconstriction in patients with Raynauds phenomenon. Clin
Pharmacol Ther 2007; 81:503.
Funauchi M, et al: Effects of bosentan on the skin lesions: an
observational study from a single center in Japan. Rheumatol Int 2009;
29:769.
Gargh K, et al: A retrospective clinical analysis of pharmacological
modalities used for symptomatic relief of Raynauds phenomenon in
children treated in a UK paediatric rheumatology centre. Rheumatology
(Oxford) 2009 Oct 1 (Epub ahead of print).
Gayraud M: Raynauds phenomenon. Joint Bone Spine 2007; 74:e1.
Gliddon AE, et al: Prevention of vascular damage in scleroderma and
autoimmune Raynauds phenomenon: a multi-center, randomized,
double-blind, placebo-controlled trial of the angiotensin-converting
enzyme inhibitor quinapril. Arthritis Rheum 2007; 56:3837.
Herrick AL: A local approach to Raynaud phenomenon. Nat Rev
Rheumatol 2009; 5:246.
Heymann WR: Sildenafil for the treatment of Raynauds phenomenon.
J Am Acad Dermatol 2006 Sep; 55:501.
Khan MI, et al: Efficacy of cervicothoracic sympathectomy versus
conservative management in patients suffering from incapacitating
Raynauds syndrome after frost bite. J Ayub Med Coll Abbottabad
2008; 20:21.
Koenig M, et al: Autoantibodies and microvascular damage
are independent predictive factors for the progression of
Raynauds phenomenon to systemic sclerosis. Arthritis Rheum 2008;
58:3902.
Kuwana M, et al: Long-term beneficial effects of statins on vascular
manifestations in patients with systemic sclerosis. Mod Rheumatol
2009; 19:530.
Kwon SR, et al: Diagnosis of Raynauds phenomenon by (99m)
Tc-hydroxymethylene diphosphonate digital blood flow scintigraphy
after one-hand chilling. J Rheumatol 2009; 36:1663.
Lambova SN, Muller-Ladner U: The role of capillaroscopy in
differentiation of primary and secondary Raynauds phenomenon in
rheumatic diseases: a review of the literature and two case reports.
Rheumatol Int 2009; 29:1263.
Lazzerini PE, et al: Homocysteine and Raynauds phenomenon: a
review. Autoimmun Rev 2009 Aug 15 (Epub ahead of print).
Malenfant D, et al: The efficacy of complementary and alternative
medicine in the treatment of Raynauds phenomenon: a literature
review and meta-analysis. Rheumatology (Oxford) 2009; 48:791.
Mariotti A, et al: Finger thermoregulatory model assessing functional
impairment in Raynauds phenomenon. Ann Biomed Eng 2009 Sep 4
(Epub ahead of print).
Mondelli M, et al: Sympathetic skin response in primary Raynauds
phenomenon. Clin Auton Res 2009; 19:355.
Morino C, et al: Raynauds phenomenon of the nipples: an elusive
diagnosis. J Hum Lact 2007; 23:191.
Nagy Z, et al: Nailfold digital capillaroscopy in 447 patients with
connective tissue disease and Raynauds disease. J Eur Acad
Dermatol Venereol 2004; 18:62.
Neumeister MW, et al: Botox therapy for ischemic digits. Plast Reconstr
Surg 2009; 124:191.
Pope J, et al: Iloprost and cisaprost for Raynauds phenomenon in
progressive systemic sclerosis. Cochrane Database Syst Rev 2000;
(2):CD000953.
Rosato E, et al: Laser Doppler perfusion imaging is useful in the study
of Raynauds phenomenon and improves the capillaroscopic
diagnosis. J Rheumatol 2009; 36:2257.
Rosato E, et al: The treatment with N-acetylcysteine of Raynauds
phenomenon and ischemic ulcers therapy in sclerodermic patients: a
prospective observational study of 50 patients. Clin Rheumatol 2009;
28:1379.
Salem KM, et al: Analysis of rewarming curves in Raynauds
phenomenon of various aetiologies. J Hand Surg Eur Vol 2009;
34:621.

Erythromelalgia
Also called erythermalgia and acromelalgia, erythromelalgia
is a not uncommon condition. The population-based incidence
is 1.3 per 100 000 per year: 2.0 per 100 000 in women and
0.6 per 100 000 in men per year. Erythromelalgia is an easily
recognized clinical syndrome characterized by paroxysmal
vasodilation affecting the feet, with burning, localized pain,
redness, and high skin temperature. Infrequently, the hands
(Fig. 35-2), face, and ears may be involved. The burning paroxysms may last from a few minutes to several days, and are
usually triggered by an increase in environmental temperature
or exercise. The average patient has 12 attacks per week, but
in some patients, the attacks are much more frequent. Often,
relief can only be obtained by immersing the burning feet in
ice water. Over 20% of patients will have evidence of cold
injury, and more than 1% will suffer gangrene or undergo
amputation. Quality of life is severely impacted by this
condition.
Erythromelalgia can be considered primary, secondary, and
familial. For treatment purposes, secondary cases of erythro
melalgia should be carefully divided into those associated
with myeloproliferative diseases, often with elevated platelets,
and others. Myeloproliferative diseases complicated by
erythromelalgia include polycythemia vera, thrombotic
thrombocytopenic purpura, and various forms of thrombocythemia. Administration of romiplostim, a thrombopoiesisstimulating protein, has resulted in erythromelalgia. Low-dose
aspirin is effective therapy for erythromelalgia associated with
platelet abnormalities. If this fails, other methods to reduce the
platelet count should be considered.

Fig. 35-2 Erythromelalgia of the hands (normal hands lateral to the


patients).

803

Cutaneous Vascular Diseases

35

804

Acquired erythromelalgia has been reported secondary to


topical exposure to isopropyl alcohol and after mushroom
poisoning with Clitocybe acromelalga and Clitocybe amoenolens.
Medications that have induced erythromelalgia include
calcium channel-blockers (both nifedipine and verapamil),
ergot derivatives such as bromocriptine and pergolide, and
cyclosporine. There may be a long period of treatment (years)
with these agents before the appearance of the erythromelalgia. Stopping the offending medication usually leads to
improvement of symptoms within weeks.
In the vast majority of cases seen by dermatologists, erythro
melalgia is probably a neurological disorder. It can be seen in
various neurological conditions or diseases associated with
neurological sequelae, such as peripheral neuropathy, myelitis, multiple sclerosis, autoimmune small-fiber axonopathy, or
diabetes mellitus. Two patients with autoimmune disease and
idiopathic thrombocytopenic purpura developed erythromelal
gia and responded to intravenous immunoglobulin (IVIG)
therapy. Erythromelalgia is sometimes associated with
Raynaud phenomenon, both disorders of abnormal neurovascular function. In many cases, no associated neurological
disease may be detected by routine neurological examination,
but careful neurological testing will reveal evidence of a smallfiber neuropathy in the majority of such cases.
Inherited, familial, or hereditary erythromelalgia usually
has its onset in childhood or adolescence (early or late onset).
Familial cases have an autosomal-dominant inheritance
pattern. Familial erythromelalgia is now known to be an
inherited neuronal ion channelopathy. The mutation is in
the gene SCN9A, which encodes a peripheral sodium channel
NaV1.7. This is a mainly peripheral sodium channel with
robust expression in dorsal root ganglion neurons and sympathetic ganglion neurons, especially those with nociceptive
function. This sodium channel acts as a threshold channel
and sets the gain in nociceptors. Many mutations in the
affected gene have been mapped. Gene mutations causing
erythromelalgia occur in areas that affect the structure of
the actual channel by substituting amino acids in this critical
location. The mutations causing erythromelalgia are gain-offunction mutations. The amount of gain of function correlates
with the age of onset of the disease, more significant mutations
having earlier onset. The nature of the mutation also affects
the binding of medications to the channel, so various mutations may have different responses to same medication,
depending on whether that mutation allows the drug to bind
to the channel. Other gain-of-function mutations in the SCN9A
gene cause paroxysmal extreme pain disorder (formerly
called familial rectal pain syndrome). This disorder has prominent autonomic manifestations that include skin flushing
(sometimes with only half of the face turning red [harlequin
color change]), syncope with bradycardia, and severe burning
painmost commonly rectal, ocular, or mandibular. One
mutation in NaV1.7 produced a clinical syndrome with features of both erythromelalgia and paroxysmal extreme pain
disorder. Autosomal-recessive nonsense mutations that cause
loss of function of the NaV1.7 channel result in the inability to
sense pain. These patients are otherwise neurologically normal.
When severe, erythromelalgia is a life-altering disease, and
aggressive management is warranted. Patients may benefit
from referral to special clinics for pain management or pain
rehabilitation. At times, simple measures such as immersion
in cool water may stop pain crises. Biofeedback can be of
benefit. In general, no more than 50% of patients with erythro
melalgia of the neuropathic type will respond to any one
medication, so the treatment must be tailored to each patient,
and often combinations of agents are used. Topical amitriptyline 1% and ketamine 0.5% in a gel are safe topical options, and
are especially reasonable for affected thin-skinned areas, such

as the face or ears, where penetration would be optimal. Oral


amitriptyline, sertraline, nortriptyline, and venlafaxine have
shown benefit in some multiple patients. Oral magnesium in
extremely high doses (>1g per day in liquid form) was beneficial in one patient. Mexiletine, carbamazepine, and the combination of carbamazepine and gabapentin are also reported to
be effective in individual patients. Neurosurgical intervention
has been used in the most severely affected, carefully selected
cases that have failed medical management.

Red ear syndrome


Red ear syndrome describes a rarely reported disorder characterized by relapsing attacks of redness and burning affecting
both ears, but usually only one ear at a time. The attacks are
more common in the winter and are precipitated by touching,
movements, and exposure to warmth. Associated conditions
include neural disorders of the trigeminal and glossopharyngeal nerves, migraines, and lupus erythematosus. It is unclear
if red ear syndrome is a disease sui generis or is actually
erythromelalgia of the ears. Treatment with oral and topical
tricyclics has been beneficial. Red ear syndrome must be distinguished from the springtime variant of polymorphous light
eruption seen in young males with cold exposure, relapsing
polychondritis (the lobe is also involved in red ear syndrome),
cellulitis, and borrelial lymphocytoma.
Badeloe S, et al: Secondary erythromelalgia involving the ears probably
preceding lupus erythematosus. Int J Dermatol 2007; 46:6.
Berk DR, Eisen AZ: Erythromelalgia of the ears: an unusual variant and
response to therapy. J Drugs Dermatol 2008; 7:285.
Berlin AL, et al: Coexistence of erythromelalgia and Raynauds
phenomenon. J Am Acad Dermatol 2004; 50:456.
Brill TJ, et al: Red ear syndrome and auricular erythromelalgia: the
same condition? Clin Exp Dermatol 2009 Jun 1 (Epub ahead of print).
Buttaci CJ: Erythromelalgia: a case report and literature review. Pain
Med 2006; 7:534.
Catterall WA, et al: Inherited neuronal ion channelopathies: new
windows on complex neurological diseases. J Neurosci 2008;
28:11768.
Chan MK, et al: Erythromelalgia: an endothelial disorder responsive to
sodium nitroprusside. Arch Dis Child 2002; 87:229.
Cheng X, et al: Mutation l136V alters electrophysiological properties of
the Na(v)1.7 channel in a family with onset of erythromelalgia in the
second decade. Mol Pain 2008; 4:1.
Choi JS, et al: Mexiletine-responsive erythromelalgia due to a new
Nav1.7 mutation showing use-dependent current fall-off. Exp Neurol
2009; 21:383.
Cohen JS: High-dose oral magnesium treatment of chronic, intractable
erythromelalgia. Ann Pharmacother 2002; 36:255.
Cohen JS: Transdermal therapy for erythromelalgia. Arch Dermatol
2006; 142:1508.
Coppa LM, et al: Erythromelalgia precipitated by acral erythema in the
setting of thrombocytopenia. J Am Acad Dermatol 2003; 48:973.
David MD, et al: Thermoregulatory sweat testing in patients with
erythromelalgia. Arch Dermatol 2006; 142:1583.
Davis MD, et al: Erythromelalgia: vasculopathy, neuropathy, or both? A
prospective study of vascular and neurophysiologic studies in
erythromelalgia. Arch Dermatol 2003; 139:1337.
DiCaudo DJ, et al: Alleviation of erythromelalgia with venlafaxine. Arch
Dermatol 2004; 140:621.
Drenth JP, et al: Primary erythermalgia as a sodium channelopathy:
screening for SCN9A mutations: exclusion of a causal role of SCN10A
and SCN11A. Arch Dermatol 2008; 144:320.
Durosaro O, et al: Intervention for erythromelalgia, a chronic pain
syndrome: comprehensive pain rehabilitation center, Mayo Clinic. Arch
Dermatol 2008; 144:1578.
Estacion M, et al: Nav1.7 gain-of-function mutations as a continuum:
A1632E displays physiological changes associated with
erythromelalgia and paroxysmal extreme pain disorder mutations and
produces symptoms of both disorders. J Neurosci 2008; 28:11079.
Firmin D, et al: Treatment of familial erythromelalgia with venlafaxine. J
Eur Acad Dermatol Venereol 2007; 21:836.

Livedo reticularis, livedo racemosa


Livedo reticularis is the term used to describe a netlike, mottled
or reticulated, pink or reddish-blue discoloration of the skin,
mostly on the extremities, especially the legs. It is more prominent with exposure to cold, and may vanish with warming. It
is commonly seen on the lower extremities in young children
and women. The pathogenic basis is reduced blood flow
through and lowered oxygen tension in the venous plexus of
the skin. Cutis marmorata is another name for livedoid physio
logic mottling of skin exposed to cold. For clinical purposes,
it is best to separate livedo reticularis (a benign condition in
most cases) from fixed livedo reticularis, better known as
livedo racemosa. Livedo racemosa forms irregular networks,
and broken circular segments that are fixed and do not vary
appreciably with temperature changes (Fig. 35-3). The lesions
are usually asymptomatic. If necrosis or purpura occurs over
the livedoid areas, the terms necrotizing livedo and retiform

Livedo reticularis, livedo racemosa

Fisher TZ, et al: A novel Nav1.7 mutation producing carbamazepineresponsive erythromelalgia. Ann Neurol 2009; 65:733.
Han C, et al: Early- and late-onset inherited erythromelalgia: genotypephenotype correlation. Brain 2009; 132:1711.
Iqbal J, et al: Experience with oral mexiletine in primary erythromelalgia
in children. Ann Saudi Med 2009; 29:316.
Jackson AL, Oates JA: A patient with adult erythermalgia: evidence
suggesting an autoimmune etiology. Am J Med Sci 2008; 335:320.
Kalgaard OM, et al: Prostacyclin reduces symptoms and sympathetic
dysfunction in erythromelalgia in a double-blind randomized pilot
study. Acta Derm Venereol 2003; 83:442.
Kluger N, et al: Romiplostim-induced erythromelalgia in a patient with
idiopathic thrombocytopenic purpura. Br J Dermatol 2009; 161:482.
Lampert A, et al: A pore-blocking hydrophobic motif at the cytoplasmic
aperture of the closed-state Nav1.7 channel is disrupted by the
erythromelalgia-associated F1449V mutation. J Biol Chem 2008;
283:24118.
Lampert A, et al: Erythromelalgia mutation L823R shifts activation and
inactivation of threshold sodium channel Nav1.7 to hyperpolarized
potentials. Biochem Biophy Res Commun 2009; 390:319.
Michiels JJ, et al: Platelet-mediated erythromelalgic, cerebral, ocular
and coronary microvascular ischemic and thrombotic manifestations in
patients with essential thrombocythemia and polycythemia vera: a
distinct aspirin-responsive and coumadin-resistant arterial
thrombophilia. Platelets 2006; 17:528.
Misery L, et al: Severe neurological complications of hereditary
erythermalgia. J Eur Acad Dermatol Venereol 2007; 21:1446.
Mork C, et al: The prostaglandin E1 analog misoprostol reduces
symptoms and microvascular arteriovenous shunting in
erythromelalgiaa double-blind, crossover, placebo-compared study.
J Invest Dermatol 2004; 122:587.
Nanayakkara PWB, et al: Verapamil-induced erythermalgia. Neth J Med
2007; 65:349.
Natkunarajah J, et al: Treatment with carbamazepine and gabapentin of
a patient with primary erythermalgia (erythromelalgia) identified to have
a mutation in the SCN9A gene, encoding a voltage-gated sodium
channel. Clin Exp Dermatol 2009 Jun 17 (Epub ahead of print).
Paticoff J, et al: Defining a treatable cause of erythromelalgia: acute
adolescent autoimmune small-fiber axonopathy. Anesth Analg 2007;
104:438.
Pipili C, Cholongitas E: Erythromelalgia in a diabetic patient managed
with gabapentin. Diabetes Res Clin Pract 2008; 79:e15.
Reed KB, Davis MDP: Incidence of erythromelalgia: a population-based
study in Olmsted County, Minnesota. J Eur Acad Dermatol Venereol
2009; 23:13.
Saviuc PF, et al: Erythromelalgia and mushroom poisoning. J Toxicol
Clin Toxicol 2001; 39:403.
Sheets PL, et al: A Nav1.7 channel mutation associated with hereditary
erythromelalgia contributes to neuronal hyperexcitability and displays
reduced lidocaine sensitivity. J Physiol 2007; 581:1019.
Thami GP, et al: Erythromelalgia induced by possible calcium channel
blockade by cyclosporin. BMJ 2003; 326:910.
Young FB: When adaptive processes go awry: gain-of-function in
SCN9A. Clin Genet 2008; 73:34.

Fig. 35-3 Livedo racemosa.

purpura respectively may be used. Livedo racemosa and


livedo with purpura or necrosis are almost always associated
with significant systemic disease that requires treatment.
Unfortunately, the literature does not always accurately separate these entities, and patients may present with variable
livedo (resembling livedo reticularis) and later develop more
fixed lesions. In addition, some patients who have more variable livedo may have serious underlying disease that may
require evaluation and treatment. These patients may not be
easily identifiable initially on physical examination features
alone. In this section, the term livedo will be used to describe
this cutaneous finding and its association with other conditions. When livedo reticularis is seen, the clinician should consider the following categories of diseases as possibly causal:
physiologic, hypercoagulable states (including myelodysplasias, cancer, and antiphospholipid and Sneddon syndromes),
vasculitis (especially medium- and large-vessel), emboli, medications, and neurologic disorders.
Drugs may cause livedo. Amantadine (Symmetrel) may be
not uncommonly associated with livedo reticularis. Quinidine
and quinine may be associated with a photosensitivity that is
livedoid in appearance, but on biopsy an interface dermatitis
will be present. Minocycline can cause livedo, and this is a
marker for the development of an antineutrophil cytoplasmic
antibody (ANCA)-positive vasculitis in these patients. The
medication must be stopped immediately. Other medications
associated with livedo include gemcitabine, heparin (perhaps
associated with heparin-induced antiplatelet antibodies), IFN, and bismuth.
Neurological disorders can create livedo reticularis by altering innervation and consequently blood flow in the skin. Brain
injury, multiple sclerosis, diabetes mellitus, poliomyelitis, and
Parkinsons disease are some examples.
Many of the syndromes with fixed livedo (livedo racemosa)
have important systemic implications. These conditions can be
either primary thrombotic processes or vascular inflammatory
processes. If the vessels of the skin are affected, are the vessels
in other organs, specifically the central nervous system (CNS)
and kidneys, at risk? Sneddon syndrome usually occurs in
young to middle-aged women. They present with livedo, and
then develop cerebrovascular infarcts. The prognosis is poor.
805

Cutaneous Vascular Diseases

35

Frequently, patients have antiphospholipid antibodies (up to


85%) and may have enough features to be diagnosed
with systemic lupus erythematosus (SLE). They would be
accurately diagnosed as having antiphospholipid antibody
syndrome. Other connective tissue diseases, such as dermatomyositis, rheumatoid arthritis, and systemic sclerosis, may
have antiphospholipid/anticardiolipin antibodies and hence
feature livedo. For this reason, patients with SLE and livedo
are apt to have more severe disease manifestations, such as
renal disease, vasculitis, and anticardiolipin antibodies, even
in the absence of fullblown Sneddon syndrome. Headache
may be the presenting symptom in these patients, and the
misdiagnosis of migraine may initially be entertained. Not all
patients with Sneddon syndrome can be diagnosed as having
antiphospholid antibody syndrome, however, and their
optimal evaluation and management is unclear. Other significant disorders with livedo as a skin manifestation include
thrombotic processes (hypercoagulable states, type I cryoglobulinemia), microangiopathic hemolytic anemias (thrombotic
thrombocytopenic purpura, hemolytic uremic syndrome,
and disseminated intravascular coagulopathy), medium- and
large-vessel vasculitides, and septicemia. Moyamoya disease
is a rare, chronic cerebrovascular occlusive condition characterized by progressive stenosis of the arteries in the circle of
Willis. Patients present with ischemic strokes or cerebral hemorrhages. Both idiopathic moyamoya disease and disease connected with factor V Leiden mutation have been associated
with livedo reticularis. Divryvan Bogaert syndrome, with
livedo racemosa, seizures, and significant CNS disease, may
be related to moyamoya or Sneddon syndrome.
Oxalosis may lead to livedo reticularis from deposition of
oxalate crystals in and around blood vessel walls. The characteristic crystals are seen on biopsy. Calciphylaxis, with calcium
deposits in vessels and tissue, may cause livedo by a still
unclear mechanism. Other possible causes of livedo include
cryofibrinogenemia, Graves disease (associated with anticardiolipin antibodies), atrial myxoma, tuberculosis (perhaps as
a complication of vascular inflammationvascular-based
tuberculid), and syphilis.
Asherson RA, et al: Unusual manifestations of the antiphospholipid
syndrome. Clin Rev Allergy Immunol 2003; 25:61.
Gibbs MB, et al: Livedo reticularis: an update. J Am Acad Dermatol
2005; 52:1009.
Kraemer M, et al: The spectrum of differential diagnosis in neurological
patients with livedo reticularis and livedo racemosa. A literature review.
J Neurol 2005; 252:1155.
Miesbach W, et al: Recurrent life-threatening thromboembolism and
catastrophic antiphospholipid syndrome in a patient despite sufficient
oral anticoagulation. Clin Rheumatol 2004; 23:256.
Richards KA, et al: Livedo reticularis in a child with moyamoya disease.
Pediatr Dermatol 2003; 20:124.
Shoenfeld Y, et al: Features associated with epilepsy in the
antiphospholipid syndrome. J Rheumatol 2004; 31:1344.
Sladden MJ, et al: Livedo reticularis induced by amantadine. Br J
Dermatol 2003; 149:656.
Tebbe B: Clinical course and prognosis of cutaneous lupus
erythematosus. Clin Dermatol 2004; 22:121.
Tektonidou MG, et al: Antiphospholipid syndrome nephropathy in
patients with systemic lupus erythematosus and antiphospholipid
antibodies: prevalence, clinical associations, and long-term outcome.
Arthritis Rheum 2004; 50:2569.
Tietjen GE, et al: Migraine is associated with livedo reticularis: a
prospective study. Headache 2002; 42:263.
Tietjen GE, et al: Livedo reticularis and migraine: a marker for stroke
risk? Headache 2002; 42:352.

Cholesterol emboli
Cholesterol emboli resulting from severe atherosclerotic
disease, usually of the abdominal aorta, may cause unilateral
806

Fig. 35-4 Livedo reticularis secondary to cholesterol emboli.

or bilateral livedo of the lower extremities. The livedo may not


be present with the patient supine, and may only be present
when the legs are dependent. Patients frequently have concomitant cyanosis (blue toes), purpura, nodules, ulceration, or
gangrene (Fig. 35-4). Pain often accompanies the skin lesions.
Acute renal failure occurs in up to 75% and about one-third of
patients will have characteristic skin lesions. An eosinophilia
on complete blood count is present in 80% of cases. Older men
with severe atherosclerotic disease are at greatest risk. They
are often on anticoagulant therapy, and many have recently
undergone vascular surgery or instrumentation. Slightly more
than 1% of left heart catheterizations are complicated by cholesterol emboli. The differential diagnosis includes vasculitis,
septic staphylococcal emboli resulting from endocarditis or
an infected aneurysm, and periarteritis nodosa. Mortality is
around 75% at 1 year. Deep biopsy with serial sections may
demonstrate the characteristic cholesterol clefts within
thrombi. Frozen section evaluation with polarized microscopy
is particularly sensitive. Livedo reticularis of recent onset in
an elderly person warrants consideration of this diagnosis.
Fukumoto Y, et al: The incidence and risk factors of cholesterol
embolization syndrome, a complication of cardiac catheterization: a
prospective study. J Am Coll Cardiol 2003; 42:211.
Hagiwara N, et al: Renal cholesterol embolism in patients with carotid
stenosis: a severe and underdiagnosed complication following
cerebrovascular procedures. J Neurol Sci 2004; 222:109.

Evaluation of the patient with possible cutaneous


vascular disorders
In the evaluation of patients who present with livedo, purpura,
or ulceration, a broad differential diagnosis must be considered. Among the diseases considered should be primary
pathology of the cutaneous vasculature. In general, these vascular disorders of the skin are divided into two main groups:
vasculitis and vasculopathy. Vasculitis includes disorders in
which the primary damage in the blood vessels occurs due to
inflammatory cells infiltrating and damaging the vessel walls.
As a consequence of inflammation within vessels, the clotting
cascade is triggered and thrombosis may be seen adjacent
to and in the late stages of healing vasculitic lesions. In
vasculopathy, the primary process is thrombosis. This is
usually due to a hypercoagulable state. Once thrombosis
occurs, inflammatory cells enter the vessel and vessel wall in
an attempt to re-establish local circulation. Thus late in the
process of a primary thrombotic process, vascular inflammation is seen and can be misinterpreted as a vasculitis. Emboli
can be considered thrombotic events and late lesions from
embolic lesions may also be inflammatory and misleading
histologically. All these processesvasculitis, vasculopathy,

Livedoid vasculopathy
Synonyms for livedoid vasculopathy include livedoid vasculitis, atrophie blanche, segmental hyalinizing vasculitis, livedo
reticularis with summer/winter ulceration, and PURPLE
(painful purpuric ulcers with reticular pattern of the lower
extremities). The vasculopathy is characterized clinically by
early focal, painful purpuric lesions of the lower extremities
that frequently ulcerate and heal slowly (Fig. 35-5). The ulcers
heal, with small, stellate and reticulated, white scars, referred
to as atrophie blanche (Fig. 35-6). The ulcers may be ringed by
telangiectasis and hemosiderin-induced hyperpigmentation.
Livedo racemosa may be present on the affected extremity or
be more widespread. About two-thirds to three-quarters of the
patients are female; the mean age of onset is 45 years. The
condition is bilateral in 80% of patients and ulceration occurs
in 70%.
Histologically, livedoid vasculopathy is characterized by
hyaline thrombi within small and at times medium vessels
in the dermis. Perivascular hemorrhage may be present.
Leukocytoclastic vasculitis is not found, and the biopsies can
be described as showing intravascular thrombosis without
inflammation. Focal lymphocytic intravascular and perivascular inflammation may be seen, but this is considered second-

Fig. 35-5 Livedoid vasculopathy.

ary to the thrombotic process, rather than a primary and


pathogenic component of the disease. By direct immunofluorescence, fibrin, C3, and IgM are often found in the vessel
walls, but these are again considered secondary to the thrombosis. In biopsies of older lesions, recanalizing vessels may
demonstrate endothelial proliferation. Biopsy of the atrophie
blanche-like lesions may show lobular vascular proliferation,
as observed in chronic stasis dermatitis. In about 15% of
patients, an initial biopsy does not reveal diagnostic histology
and a second biopsy is required. After two biopsies, diagnostic
pathology is found in 98% of patients.
The pathogenic etiology is considered to be a hypercoagulable state that results in spontaneous thrombosis of superficial
skin vessels. The thrombosis results in low tissue oxygen
tension, with local hypoxia and skin damage. However, the
hypercoagulable state can be identified with current testing
technology in only about 40% of patients. In livedoid vasculopathy, testing should include anticardiolopin antibody,
lupus anticoagulant, factor V Leiden gene mutation (usually
heterozygous), protein C, S, or antithrombin III heterozygous
deficiency, prothrombin G20210A gene mutation, cryoproteins, and homocysteine level. The finding of methylene
tetrahydrofolate reductase (MTHFR) deficiency with or
without hyperhomocysteinemia has been reported in livedoid
vasculopathy, but the pathogenic significance of this is unclear.
Plasminogen activator inhibitor-1 (PAI-1) mutation with
increased PAI-1 plasma levels has been found in some patients
with livedoid vasculopathy. PAI-1 is an important inhibitor of
fibrinolysis, and elevated levels are associated with an
increased risk of thrombosis.
Not surprisingly, underlying connective tissue disease, carcinomas, myeloma, lymphoma, venous insufficiency, deep
venous thrombosis, and cerebrovascular accident have been
seen in association with livedoid vasculopathy. These are all
conditions associated with a prothrombotic state in some
patients. Mononeuropathy multiplex has been reported in
association with livedoid vasculopathy.
There is a broad differential diagnosis for livedoid vasculopathy, since many conditions can cause livedo reticularis
with ulceration of the lower extremity. The conditions that
must be excluded include small-vessel vasculitis (especially

Livedoid vasculopathy

and embolialter cutaneous blood flow and can be accompanied by livedo. If vessels lose competence they may leak, creating purpura, and if vasculitis, vasculopathy, or emboli are
severe enough or affect a large enough vessel, the viability of
the overlying skin is compromised, and necrosis and ulceration may occur. Complicating this situation is the fact that
patients may have both a vasculitis and a hypercoagulable
state, resulting in biopsies that, at times, are pathogenically
discordant. A patient with an inherited or acquired disorder
of coagulation and a drug-induced cutaneous vasculitis would
be a not uncommon example. The above discussion makes it
clear that this area of differential diagnosis is a difficult one
for even the most skilled dermatologist. Careful sampling of
early lesions, with large and deep biopsies if necessary, may
be required to find the primary vascular pathology. Since
vasculitis may be a focal process, step sections may be required
to find the diagnostic features. In addition, the diagnosis proposed must be interpreted in the context of other elements of
the patients medical condition, such as medications, infections, underlying diseases, and involvement of other organ
systems besides the skin.

Fig. 35-6 Atrophie blanche.

807

Cutaneous Vascular Diseases

35

that associated with hepatitis C virus and essential mixed


cryoglobulinemia or a connective tissue disease), microscopic
polyarteritis, polyarteritis nodosa (PAN) (both cutaneous and
systemic), peripheral vascular disease, erythema induratum
mimicking PAN, and hydroxyurea-associated leg ulceration.
The treatment of livedoid vasculopathy is directed at treating the hypercoagulable state. About one-third of patients are
smokers, and this should be stopped. Patients with venous
insufficiency should be managed with elevation, compression,
and bandaging as appropriate. These patients may improve
with this local therapy alone. If venous insufficiency ulcerations with an atrophie blanche appearance are slow to heal,
consideration for treatment with the livedoid vasculopathy
therapeutic ladder should be considered. Agents demonstrated to be effective in livedoid vasculopathy (in order of
their recommended use) include: low-dose aspirin, oral pent
oxifylline, oral dipyridamole, folic acid and a B complex multi
vitamin (in patients with MTHFR mutation and elevated
homocysteine), danazol or stanazol (to increase endogenous
antithrombotic proteins), heparin (low molecular weight or
regular), and warfarin. Warfarin may be slightly superior to
heparin. No treatment is universally beneficial in all patients,
and treatment may need to be tailored to individual response
and disease activity. In patients with connective tissue diseases (and antiphospholipid antibodies) hydroxychloroquine
may be beneficial. In refractory cases, tissue plasminogen activator infusion, IVIG, and rituximab can be considered.
Hyperbaric oxygen may accelerate ulcer healing. Other treatments that have been reported as effective include PUVA,
niacin, iloprost, and ketanserin. Systemic immunosuppressives usually are of no benefit in cases with true livedoid
vasculopathy. If there is a dramatic response to steroids,
another diagnosis should be sought.
Anavekar ND, Kelly R: Heterozygous prothrombin gene mutation
associated with livedoid vasculopathy. Australas J Dermatol 2007;
48:120.
Boyvat A, et al: Livedoid vasculopathy associated with heterozygous
protein C deficiency. Br J Dermatol 2000; 143:840.
Browning CE, Callen JP: Warfarin therapy for livedoid vasculopathy
associated with cryofibrinogenemia and hyperhomocysteinemia. Arch
Dermatol 2006; 142:75.
Calamia KT, et al: Livedo (livedoid) vasculitis and the factor V Leiden
mutation: additional evidence for abnormal coagulation. J Am Acad
Dermatol 2002; 46:133.
Callen JP: Livedoid vasculopathy: what it is and how the patient should
be evaluated and treated. Arch Dermatol 2006; 142:1481.
Cardoso R, et al: Livedoid vasculopathy and hypercoagulability in a
patient with primary Sjgrens syndrome. Int J Dermatol 2007; 46:431.
Davis MD, Wysokinski WE: Ulcerations caused by livedoid vasculopathy
associated with a prothrombotic state: response to warfarin. J Am
Acad Dermatol 2008; 58:512.
Deng A, et al: Livedoid vasculopathy associated with plasminogen
activator inhibitor-1 promoter homozygosity (4G/4G) treated
successfully with tissue plasminogen activator. Arch Dermatol 2006;
142:1466.
Frances C, Barete S: Difficult management of livedoid vasculopathy.
Arch Dermatol 2004; 140:1011.
Gotlib J, et al: Heterozygous prothrombin G20210A gene mutation in a
patient with livedoid vasculitis. Arch Dermatol 2003; 139:1081.
Hairston BR, et al: Treatment of livedoid vasculopathy with lowmolecular-weight heparin: report of 2 cases. Arch Dermatol 2003;
139:987.
Hairston BR, et al: Livedoid vasculopathy. Arch Dermatol 2006; 142:1413.
Irani-Hakime NA, et al: Livedoid vasculopathy associated with combined
prothrombin G20210A and factor V (Leiden) heterozygosity and
MTHFR C677T homozygosity. J Thromb Thrombolysis 2008; 26:31.
Juan WH, et al: Livedoid vasculopathy: long-term follow-up results
following hyperbaric oxygen therapy. Br J Dermatol 2006; 154:251.
Kavala M, et al: A case of livedoid vasculopathy associated with factor
V Leiden mutation: successful treatment with oral warfarin. J
Dermatolog Treat 2008; 19:121.

808

Magy N, et al: Livedoid vasculopathy with combined thrombophilia:


efficacy of iloprost. Rev Med Interne 2002; 23:554.
Meiss F, et al: Livedoid vasculopathy: the role of
hyperhomocysteinemia and its simple therapeutic consequences. Eur
J Dermatol 2006; 16:159.
Mimouni D, et al: Cutaneous polyarteritis nodosa in patients presenting
with atrophie blanche. Br J Dermatol 2003; 148:789.
Ravat FE, et al: Response of livedoid vasculitis to intravenous
immunoglobulin. Br J Dermatol 2002; 147:166.
Toth C, et al: Mononeuropathy multiplex in association with livedoid
vasculitis. Muscle Nerve 2003; 28:634.
Tsai TF, et al: Polymorphisms of MTHFR gene associated with livedoid
vasculopathy in Taiwanese population. J Dermatol Sci 2009; 54:214.
Zeni P, et al: Successful use of rituximab in a patient with recalcitrant
livedoid vasculopathy. Ann Rheum Dis 2008; 67:1055.

Calciphylaxis
Calciphylaxis is an increasingly reported syndrome that is
potentially fatal. It occurs most commonly in the setting of
chronic renal failure, often with type 2 diabetes, and obesity.
Women outnumber men 3:1 to 4:1. About 14% of patients
on hemodialysis and 4% of patients on peritoneal dialysis
develop calciphylaxis. About half of calciphylaxis patients are
diabetic and more than half have a body mass index (BMI) of
>30. Every gain in the BMI of 1 point over 30 increases the risk
for calciphylaxis by 10%. Calciphylaxis occurs on the background of extensive calcification of the media of mediumsized and small arterioles. Parathyroid hormone (PTH) levels
are often abnormal (either high or low), and calciphylaxis may
also be seen in the setting of primary hyperparathyroidism,
as well as secondary hyperparathyroidism of renal failure.
Tumors may also produce PTH-related proteins and be associated with calciphylaxis. In about 20% of calciphylaxis patients,
the Ca X PO4 product will be greater than 70, a sensitive but
not specific marker for calciphylaxis. The arteriolar calcification is a chronic process due to many metabolic factors and
signaling molecules that cause vascular smooth-muscle cells
to transform to an osteogenic phenotype. Thus the vascular
calcification in calciphylaxis and most cases of calcific uremic
arteriolopathy is due to local deposition of calcium in the
blood vessels by the vascular smooth muscles cells. It is not
metastatic or dystrophic calcification. Liver disease and systemic corticosteroid therapy increase the risk for development
of calciphylaxis by 23-fold.
Calciphylaxis begins as fixed livedo reticularis (livedo
racemosa). Areas within the livedo become increasingly
violaceous and eventually purpuric, bullous, and necrotic.
Subcutaneous nodules may herald the onset of the livedo and
be associated with it. Affected tissue in calciphylaxis has
reduced tissue oxygenation. Lesions affect the legs below the
knees in 90% of cases. More proximal lesions, and lesions of
the fatty areas of the thighs, buttocks, and abdomen occur in
about two-thirds of cases. Severe pain is a cardinal feature
of calciphylaxis, often requiring narcotic analgesia for
control. Ischemic myopathy may occur in severe cases,
and muscle pain may precede the appearance of the skin
lesions. Necrotic skin lesions are very resistant to healing and
infection of open wounds with septicemia is a common cause
of death. The 1-year survival of all calciphylaxis patients is
about 40%, and only 10% in patients with both proximal and
distal disease.
An optimum biopsy to confirm the diagnosis of calciphylaxis should be adjacent to the necrotic area where there is
erythema or early purpura. Ideally, it should be deep and large
enough to identify diagnostic features. This may require an
incisional rather than a simple punch biopsy. Since vascular
calcification is common in all patients with chronic renal
failure, this alone cannot confirm the diagnosis. In addition,

Al-Absi AI, et al: Case report: medial arterial calcification mimicking


temporal arteritis. Am J Kidney Dis 2004; 44:e73.
Asobie N, et al: Calciphylaxis in a diabetic patient provoked by warfarin
therapy. Clin Exp Dermatol 2008; 33:342.
Funabiki M, et al: Sudden onset of calciphylaxis: painful violaceous
livedo in a patient with peritoneal dialysis. Clin Exp Dermatol 2009;
34:622.
Guldbakke KK, Khachemoune A: Calciphylaxis. Int J Dermatol 2007; 46:231.
Hackett BC, et al: Calciphylaxis in a patient with normal renal function:
response to treatment with sodium thiosulfate. Clin Exp Dermatol
2009; 34:39.
Hanafusa T, et al: Intractable wounds caused by calcific uremic
arteriolopathy treated with bisphosphonates. J Am Acad Dermatol
2007; 57:1021.
Hayden MR, et al: Vascular ossificationcalcification in metabolic
syndrome, type 2 diabetes mellitus, chronic kidney disease, and
calciphylaxiscalcific uremic arteriolopathy: the emerging role of
sodium thiosulfate. Cardiovasc Diabetol 2005; 4:4.
Hussein MR, et al: Calciphylaxis cutis: a case report and review of
literature. Exp Mol Pathol 2009; 86:134.
Kalajian AH, et al: Calciphylaxis with normal renal and parathyroid
function: not as rare as previously believed. Arch Dermatol 2009;
145:451.

Kyritsis I, et al: Combination of sodium thiosulphate cinacalcet, and


paricalcitol in the treatment of calciphylaxis with hyperparathyroidism.
Int J Artif Organs 2008; 31:742.
Li JZ, Huen W: Images in clinical medicine. Calciphylaxis with arterial
calcification. N Engl J Med 2007; 357:1326.
Mwipatayi BP, et al: Calciphylaxis: emerging concept in vascular
patients. Eur J Dermatol 2007; 17:73.
Nigwekar SU, et al: Calciphylaxis from nonuremic causes: a systematic
review. Clin J Am Soc Nephrol 2008; 3:1139.
Ohta A, et al: Penile necrosis by calciphylaxis in a diabetic patient with
chronic renal failure. Intern Med 2007; 46:985.
Pallure V, et al: Cinacalcet as first-line treatment for calciphylaxis. Acta
Derm Venereol 2008; 88:62.
Schliep S, et al: Successful treatment of calciphylaxis with pamidronate.
Eur J Dermatol 2008; 18:554.
Weenig RH, et al: Calciphylaxis: natural history, risk factor analysis, and
outcome. J Am Acad Dermatol 2007; 56:569.
Woods M, et al: Penile calciphylaxis. J Am Acad Dermatol 2006; 54:736.

Purpura

there should be evidence of tissue damage (necrosis), extravascular calcification, and thrombosis in the arterioles of the
dermis and subcutaneous tissue.
The pathogenesis of calciphylaxis is still being elucidated. In
most cases, it occurs on the background of extensive calcification of arterioles of the skin. The calcification triggers intimal
proliferation and narrows the arterioles. Gradually or rather
suddenly, the patient will develop areas of livedo and necrosis. This heralds the onset of vascular thrombosis. The mechanism that triggers this thrombotic phase of calciphylaxis and
the appearance of the skin lesions is unclear. Some of these
may be prothrombotic states, such as female gender, warfarin
administration, trauma, the presence of cancer, edema, and
anatomic location. The skin overlying fatty areas, such as the
medial thighs, abdomen, and breasts of women, is particularly
susceptible to thrombotic diseases such as diffuse dermal angiomatosis and warfarin and heparin necrosis. This may be
caused by low blood flow or the reduced circulation due to
tethering and kinking of vessels due to gravity. In some
patients, low protein C levels are identified. Human immunodeficiency virus (HIV) infection and cryofibrinogenemia have
also been associated. A useful model to consider pathogenically is that calciphylaxis is analogous to atherosclerotic myocardial disease. There is a gradual and progressive abnormality
of the vasculature, with narrowing of the vessel lumen (by
plaque in the case of atherosclerosis and by intimal calcification in the case of calciphylaxis). The acute symptomatology
is triggered by thrombosis of the narrowed vessel, leading to
occlusion of the vessel and downstream anoxia and necrosis.
As in atherosclerotic disease, treatment for calciphylaxis
should be directed at early prevention of intimal calcification.
Unlike atherosclerosis, however, it is unclear how to prevent
intimal calcification in the setting of renal disease.
Penile calciphylaxis is a particularly painful variant. The
glans penis develops a deep necrotic ischemic ulceration. The
risk factors are diabetes and renal failure. Penectomy is often
required for pain management. One case resembled temporal
arteritis.
Much of the treatment for calciphylaxis is directed at altering abnormal calcium metabolism. Low calcium dialysis, oral
phosphate binders, cinacalcet, bisphosphonates, and intra
venous sodium thiosulfate have all been used with some
success. Once the ulcerations are present, gentle debridement
is associated with healing and increased survival. Painful
ulcers may also respond to hyperbaric oxygen therapy.
Parathyroidectomy is best reserved for cases refractory to the
above regimens and a marked elevation of PTH.

MarshallWhite syndrome and Bier spots


The marbled mottling produced in the forearm and hand by
occluding the brachial artery with a tight sphygmomanometer
cuff is characterized initially, and chiefly, by pale macules
12cm in diameter. These were described by Bier in 1898 and
are known as Bier spots. Wilkin re-examined this phenomenon
with laser Doppler velocimetry and concluded that the red
spots on the hand are caused by relative vasodilation, with
vasoconstriction in the pale areas.
Wilkin JK, et al: Biers spots reconsidered: a tale of two spots, with
speculation on a humerus vein. J Am Acad Dermatol 1986; 14:411.

Purpura
Purpura is the term used to describe extravasation of blood
into the skin or a mucous membrane. It presents as distinctive
brownish-red or purplish macules a few millimeters to many
centimeters in diameter. Several terms are used to describe
various clinical manifestations of purpura.
Petechiae are superficial, pinhead-sized (<3mm), round,
hemorrhagic macules, bright red at first, then brownish or
rust-colored. They are most commonly seen in the dependent
areas, are evanescent, occur in crops, regress over a period of
days, and most often imply a disorder of platelets rather than
a coagulation factor disorder. These disorders typically give
rise to ecchymoses or hematomas rather than petechiae.
Petechiae may also be a sign of vasculitis.
Ecchymoses are better known as bruises or black and blue
marks. These extravasations signify a deeper and more extensive interstitial hemorrhage, which forms a flat, irregularly
shaped, bluish-purplish patch. Such patches gradually turn
yellowish and finally fade away. They are characteristic of
scurvy.
Vibices (singular, vibex) are linear purpuric lesions.
Hematoma designates a pool-like collection of extravasated
blood in a dead space in tissue that, if of sufficient size, produces a swelling that fluctuates on palpation. Hematomas are
usually walled off by tissue planes.

Pathogenesis
Purpura may result from hyper- and hypocoagulable states,
vascular dysfunction, and extravascular causes, including idio
pathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation (DIC),
drug-induced thrombocytopenia, bone marrow failure, congenital or inherited platelet function defects, acquired platelet
function defects (aspirin, renal or hepatic disease, or gammopathy), and thrombocytosis secondary to myeloproliferable
809

Cutaneous Vascular Diseases

35

diseases. Most of these disorders produce findings of nonpalpable purpura. Ecchymosis predominates in procoagulant
defects, such as hemophilia, anticoagulants, vitamin K deficiency, and hepatic disease resulting in poor procoagulant
synthesis. There is often a component of trauma. Increased
frequency of ecchymotic skin can be the result of poor dermal
support of blood vessels, most often localized to the area of
trauma, and may result from actinic (senile) purpura, topical or
systemic corticosteroid therapy, scurvy, systemic amyloidosis,
EhlersDanlos syndrome, or pseudoxanthoma elasticum.
Primarily prothrombotic disorders form characteristic retiform purpura or purpura associated with livedo reticularis.
These include disorders in which fibrin, cryoglobulin, or
other material occludes vessels. Representative causes include
monoclonal cryoglobulinemia, cryofibrinogenemia, DIC,
purpura fulminans, protein C/S deficiency, warfarin-induced
necrosis, heparin necrosis, cholesterol emboli, oxalate crystal
occlusion, and antiphospholipid syndrome.

Evaluation
A history and physical examination are often all that is necessary. A family history of bleeding or thrombotic disorders,
duration of symptoms, use of drugs and medications that
might affect platelet function and coagulation, as well as a
review of medical conditions that may result in altered coagulation, should be documented. Physical examination should
stress the size, type, and distribution of purpura; a search for
telangiectases; a joint examination; and an evaluation of skin
elasticity, unusual scars, and unusual body habitus. Correlation
of purpura morphology with pathogenesis allows for a more
focused approach.
A complete blood cell count and differential can be used to
assess for microangiopathic anemia, screen for myeloproliferative disorders, and assess the number and morphology of
platelets. A bleeding time is the preferred method of assessing
platelet function. The partial thromboplastin time (PTT) and
the prothrombin time (PT) are tests to evaluate abnormal coagulation states.

Thrombocytopenic purpura
Thrombocytopenic purpura may be classified into two large
categories: states resulting from accelerated platelet destruction and states resulting from deficient platelet production.
Accelerated platelet destruction may be immunologic or nonimmunologic. The former may be due to antibodies (auto
immune or drug-induced thrombocytopenia), isoantibodies
(congenital or post-transfusion), immune complex disease, or
other immunologic processes, such as erythroblastosis fetalis,
neonatal lupus, scleroderma, other connective tissue diseases,
or acquired immunodeficiency syndrome (AIDS). The group
of thrombocytopenias with accelerated platelet destruction
includes thrombotic thrombocytopenic purpura and DIC.
Deficient platelet production may be related to diseases such
as aplastic anemia and leukemia.

Immune thrombocytopenic purpura


(immune thrombocytopenia)

810

Immune thrombocytopenic purpura (ITP) was also known as


idiopathic thrombocytopenic purpura or Werlhofs disease.
It is an autoimmune disease characterized by an isolated
thrombocytopenia (platelet count <100 000). The causative
antibodies are directed at molecules on the platelet surface,
leading to their premature sequestration and destruction,
primarily in the spleen. ITP is called primary in the absence of
another cause, or secondary if there is a causal association, e.g.

Fig. 35-7 Oral hemorrhagic bullae as the presenting complaint in


immune thrombocytopenic purpura.

secondary ITP (SLE-associated). Bleeding symptoms are


minimal or absent in a large proportion of cases. Cutaneous
manifestations can include an acute or gradual onset of
petechiae or ecchymoses in the skin and mucous membranes,
especially in the mouth. Epistaxis, conjunctival hemorrhages,
hemorrhagic bullae in the mouth (Fig. 35-7), and gingival
bleeding may occur. Melena, hematemesis, and menorrhagia
are also present, and the latter may be the first sign of this
disease in young women. Chronic leg ulcers occasionally
develop.
Bleeding can occur when the platelet count drops below
50 000/mm3. Post-traumatic hemorrhage, spontaneous hemorrhage, and petechiae may appear. The risk of serious hemorrhage is greatly increased at levels below 10 000/mm3. The
gravest complication is intracranial hemorrhage. ITP may be
fatal, but most mortality in adults occurs secondary to treatment complications. Bleeding time is usually prolonged and
coagulation time is normal, whereas the clot retraction is
abnormal and capillary fragility is increased. Increased
numbers of megakaryocytes are found in the bone marrow.
The age of onset determines the clinical manifestations and
course. In children the onset is often acute and follows a viral
illness in 5060% of patients. Parvovirus B19 is frequently
complicated by thrombocytopenia, which may be ITP or
simply a consequence of reduced bone marrow production of
platelets. The average lag between purpura and the preceding
infection is usually 2 weeks (range 14). Most of these cases
resolve spontaneously. Since children are at much less risk of
developing serious hemorrhagic complications, a more conservative management approach may be taken. A few patients
will develop chronic thrombocytopenia, and deaths, usually
from cerebral hemorrhage, have been reported. In a series of
332 children with ITP, 58 (17%) had episodes of major hemorrhage. One death resulted from sepsis. In another series of 427
cases, 323 (72%) had mild to benign disease. Roughly 85% of
children who undergo splenectomy experience remission.
More than half of the remaining patients spontaneously remit
within 15 years.
The chronic form occurs most often in adults, is persistent,
and has a female to male ratio of between 2:1 and 4:1. Secondary
ITP is more common in adults. HIV, hepatitis C, and auto
immune disease are the most common associated diseases.
Treatment of the associated disease may lead to improvement
of the thrombocytopenia. Breast cancer has been associated
with ITP, with a parallel course in one-third of cases. Other
malignancies have also been associated with ITP. Helicobacter
pylori infection as a cause of ITP is controversial, but testing
for H. pylori antibodies and treatment for infection have limited
toxicity so could be considered.

Aktepe OC, et al: Human parvovirus B19 associated with idiopathic


thrombocytopenic purpura. Pediatr Hematol Oncol 2004; 21:421.
Aledort LM, et al: Prospective screening of 205 patients with ITP,
including diagnosis, serological markers, and the relationship between
platelet counts, endogenous thrombopoietin, and circulating
antithrombopoietin antibodies. Am J Hematol 2004; 76:205.
Daou S, et al: Idiopathic thrombocytopenic purpura in elderly patients: a
study of 47 cases from a single reference center. Eur J Intern Med
2008; 19:447.
de Latour RP, et al: Breast cancer associated with idiopathic
thrombocytopenic purpura: a single center series of 10 cases. Am J
Clin Oncol 2004; 27:333.
George JN: Definition, diagnosis and treatment of immune
thrombocytopenic purpura. Haematologica 2009; 94:759.
Kuter DJ, et al: Efficacy of romiplostim in patients with chronic immune
thrombocytopenic purpura: a double-blind randomised controlled trial.
Lancet 2008; 371:395.
Maloisel F, et al: Danazol therapy in patients with chronic idiopathic
thrombocytopenic purpura: long-term results. Am J Med 2004;
116:590.
Rodeghiero F, et al: Standardization of terminology, definitions and
outcome criteria in immune thrombocytopenic purpura of adults and
children: report from an international working group. Blood 2009;
113:2386.
Vesely SK, et al: Management of adult patients with persistent
idiopathic thrombocytopenic purpura following splenectomy: a
systematic review. Ann Intern Med 2004; 140:112.

Drug-induced thrombocytopenia
Thrombocytopenic purpura resulting from drug-induced
antiplatelet antibodies may be caused by drugs such as
heparin, sulfonamides (antibiotics and hydrochlorthiazide),
digoxin, quinine, quinidine, chlorothiazides, penicillin,
cephalosporins, minocycline, acetaminophen, nonsteroidal
anti-inflammatory drugs (NSAIDs), statins, fluconazole,
protease inhibitors, H2 blockers, antiplatelet agents, rifampin,
and lidocaine.
Heparin-induced thrombocytopenia (HIT) is associated
with life-threatening arterial and venous thrombosis and, to a
lesser extent, hemorrhagic complications. The platelet count

usually begins to fall 414 days after starting heparin, more


commonly in a patient with prior exposure to the medication.
Platelet counts drop to about 50% of their pre-HIT level,
usually with a nadir of about 50 000, and rarely 10 000. HIT is
mediated by an antibody to the platelet factor 4 (PF4)heparin
complex. The antibody cross-links FcRII receptors on the
platelet surface, resulting in platelet activation, aggregation,
and simultaneous activation of blood-coagulation pathways.
Tests for HIT antibodies include immunoassays (such as
enzyme-linked immunoassay [ELISA]) and functional tests.
Treatment for drug-induced thrombocytopenia consists of
removal of the offending agent. Corticosteroids are helpful in
moderately high dosage (60mg/day prednisone) and are
usually only necessary as a brief course. When a clinical diagnosis of HIT is made, heparin should be stopped immediately
and treatment with an alternative anticoagulant should be
started, if required. In patients with thrombosis, warfarin
therapy can begin when the platelet count has normalized.

Thrombotic microangiopathy

ITP in the elderly is more difficult to manage. Patients more


frequently have major bleeding complications, more complications from immunosuppressive agents, especially corticosteroids, and more complications from splenectomy. Corticosteroids
have a particularly low response rate in elderly ITP patients.
Danazol has demonstrated reasonable safety and efficacy in
the elderly.
The differential diagnosis of ITP includes drug-induced
thrombocytopenia, myelodysplasia, thrombotic thrombocytopenic purpura, and congenital/hereditary thrombocytopenia.
The goal of treatment for ITP is to raise the platelet count
above 20 000 to 30 000 and to stop all bleeding symptoms.
Platelet transfusions are indicated if there is significant bleeding or if the platelet count is dangerously low. If the platelet
count is above 20 00030 000, the patient may be closely monitored. The treatment of ITP has changed with the availability
of new treatment approaches. Initial treatment is a short course
of corticosteroids, either for 12 weeks or as monthly pulses.
IVIG or anti-D may be given with this treatment. If the patient
relapses or has persistent symptoms, systemic corticosteroids
are given with any of the following: rituximab, anti-D, IVIG,
or a thrombopoietin agonist. Splenectomy can be considered
a second-line treatment, although age >60 years makes this
treatment less desirable. Danazol can be added as a secondline agent, especially in the elderly. When second-line treatments have failed in patients with chronic and persistent or
worsening disease, immunosuppression with mycophenolate
mofetil, azathioprine, cyclosporine, vincristine, lymphomatype chemotherapeutic regimens, and even autologous transplantation could be considered.

Blackmer AB, et al: Fondaparinux and the management of heparininduced thrombocytopenia: the journey continues. Ann Pharmacother
2009; 43:1636.
Chong BH, Isaacs A: Heparin-induced thrombocytopenia: what clinicians
need to know. Thromb Haemost 2009; 101:279.
Grossjohann B, et al: Ceftriaxone causes drug-induced immune
thrombocytopenia and hemolytic anemia: characterization of targets
on platelets and red blood cells. Transfusion 2004; 44:1033.
Picker SM, et al: Pathophysiology, epidemiology, diagnosis and
treatment of heparin-induced thrombocytopenia (HIT). Eur J Med Res
2004; 9:180.
Russell KN, et al: Acute profound thrombocytopenia associated with
readministration of eptifibatide: case report and review of the literature.
Pharmacotherapy 2009; 29:867.
Selleng K, et al: Heparin-induced thrombocytopenia in intensive care
patients. Semin Thromb Hemost 2008; 34:425.
Shantsila E, et al: Heparin-induced thrombocytopenia: a contemporary
clinical approach to diagnosis and management. Chest 2009; 135:1652.
Syed S, Reilly RF: Heparin-induced thrombocytopenia: a renal
perspective. Nat Rev Nephrol 2009; 5:501.
Wirth SM, et al: Evaluation of a clinical scoring scale to direct early
appropriate therapy in heparin-induced thrombocytopenia. J Oncol
Pharm Pract 2009 Aug 19 (Epub ahead of print).
Zondor SD, et al: Treatment of drug-induced thrombocytopenia. Expert
Opin Drug Saf 2002; 1:173.

Thrombotic microangiopathy
The diagnosis of a thrombotic microangiopathy is made in the
presence of a microangiopathic hemolytic anemia and thrombo
cytopenia in the absence of another plausible explanation.
Thrombotic thrombocytopenic purpura and hemolytic uremic
syndrome are the two major diseases in this group. Certain
drugs, such as cyclosporine, quinine, ticlopidine, clopidogrel,
mitomycin C, docetaxel, trastuzumab, and bleomycin, have
been associated with a thrombotic microangiopathy.

Thrombotic thrombocytopenic purpura


Also known as Moschcowitz syndrome, thrombotic thrombocytopenic purpura (TTP) was in the past diagnosed with the
pentad of thrombocytopenia, hemolytic anemia, renal abnormalities, fever, and disturbances of the CNS. Many cases,
however, do not have renal disease, and CNS findings are not
required for the diagnosis. The diagnosis of TTP requires only
a Coombs-negative hemolytic anemia and thrombocytopenia
with platelet aggregation in the microvasculature. Most
patients will develop neurological findings. Fever is present in
75%. Multiple ecchymoses and retiform purpura may be found
on the skin. The presence of schistocytes on a blood smear is
the morphologic hallmark of the disease, and a schistocyte
count of greater than 1% in the absence of other known causes
of thrombotic microangiopathy strongly suggests a diagnosis

811

Cutaneous Vascular Diseases

35

of TTP. Tests may show a decreased hematocrit and decreased


platelets, an elevated lactate dehydrogenase, and elevated
indirect bilirubin. A delay in diagnosis may lead to a mortality
rate as high as 90%.
Biopsies demonstrate hemorrhage and fibrin occlusion of
vessels. Inflammation is absent. Studies of plasma samples
from patients with active TTP have often shown the presence
of unusually large von Willebrand factor (VWF) multimers.
The underlying cause of TTP is a congenital or acquired deficiency of the VWF cleaving protease, ADAMTS13. VWF is
secreted by the endothelial cell in long multimers, which
should be cleaved into monomers by ADAMTS13 and released
into the circulation. Instead, multimers circulate and extend
from the surface of the endothelial cells in the microvasculature. Platelets adhere to these multimers and the surface of the
endothelial cell, leading to microvascular thrombosis.
TTP is divided into two forms, idiopathic and congenital
(UpshawSchulman syndrome). Congenital TTP is less
common (<10% of cases), and usually presents in infancy or
childhood with jaundice and thrombocytopenia. Some patients
with a congenital deficiency of ADAMTS13 do not present
until adulthood or may even remain asymptomatic. The course
is frequently relapsing TTP at regular intervals. Idiopathic TTP
is a rare disease (about 10 per million per year). Females represent 70% of cases and black people have a nine-fold risk of
developing idiopathic TTP. Idiopathic TTP is due to an auto
antibody directed against ADAMTS13 that can be detected in
up to 85% of cases. Neurological symptoms are the most frequent presentation, and range from confusion to seizures or
coma.
Until exchange plasmapheresis was instituted as the treatment of choice, 80% of these patients died; now, 80% survive.
Plasma exchange therapy is the primary treatment. It clears
the VWF multimers, reduces the autoantibody, and replenishes the inhibited ADAMTS13. Plasma exchange is usually
continued daily until clinical symptoms improve and the
platelet count is above 150 000. In conjunction with plasma
exchange, glucocorticoids may be given, although their success
is variable. Cyclosporine and rituximab have been used in
refractory cases, with promising results. Splenectomy may be
used in refractory cases. Congenital TTP is usually much
easier to treat, with only small amounts of normal plasma
infusion required to provide the missing ADAMTS13 and stop
the clotting.

Hemolytic uremic syndrome


Hemolytic uremic syndrome (HUS) has many similarities to
TTP but is now considered a distinct entity, both clinically and
pathogenically. HUS is most commonly a disease of childhood. Patients have a microangiopathic hemolytic anemia,
often following a diarrheal illness caused by Shiga toxin (Stx)producing Escherichia coli. The annual incidence is 6.1 cases per
100 000. It is the most common cause of acute renal injury
requiring transplantation in children aged 15. Streptococcus
pneumoniae infection can also be followed by HUS. Cases of
HUS not following such infections are called atypical HUS.
Fever is usually absent in HUS cases. Renal insufficiency
occurs in all patients and is the hallmark of HUS. Neurological
disease can occur but affects less than half of cases.
The pathogenic mechanism of typical HUS is endothelial
damage due to the bacterial toxin and subsequent complement
activation on the endothelial surface. The affected vessels are
thickened, endothelial cells are detached, and the vascular
lumen is narrowed and occluded by platelet thrombi. The
renal vessels are at particular risk, since the subendothelial
membrane is exposed and this membrane is particularly at risk
for complement-mediated damage. In atypical and familial
812

HUS, similar complement activation via the alternative


pathway (through C3b) occurs on endothelial surfaces, leading
to endothelial damage and intravascular thrombosis.
In atypical and familial HUS, mutations in the alternative
complement cascade have been identified. Complement factor
H (CFH) mutations are most common and many patients are
heterozygotes. The abnormal CFH complexes with the normal
CFH, inactivating it. CFH is the major downregulator of the
alternative complement cascade as it degrades C3b. Loss of
CFH activity allows for unopposed C3b activity and complement activation. Other mutations are in complement factor I
(CFI), which cleaves c3B and C4b. Mutations in membrane
cofactor protein (MCP), a cofactor for CFI, in C3 itself, in complement factor B (a component of C3b), and in thrombomodulin can also cause atypical HUS. The type of mutation
determines the clinical course of atypical HUS, with CFH, CFI,
CFB, and thrombomodulin mutations having rates of death or
end-stage renal disease of more than 50%. Recurrence of HUS
occurs in more than three-quarters of patients with CFH and
CFI mutations. Some patients are compound heterozygotes
with mutations in two different genes noted above. About 6%
of patients have an autoantibody to CFH and have auto
immune HUS.
Although HUS is a disorder caused by a genetic deficiency
in most cases, onset may not occur until middle age. About
67% of atypical HUS occurs during childhood, with almost all
patients with anti-CFH antibodies diagnosed before age 16.
Oral contraceptives may trigger HUS in 8% of patients with
CFH and 20% of patients with CFI mutations.
HUS is treated with plasma exchange as soon as the diagnosis is made. Corticosteroids, azathioprine, mycophenolate
mofetil, and rituximab may be used in atypical HUS. The role
of cadaver kidney transplantation in atypical HUS is unclear
due to the high rate of recurrence and loss of the graft. The
likelihood for a successful outcome following transplantation
is dependent on mutation type.
Bouw MC, et al: Thrombotic thrombocytopenic purpura in childhood.
Pediatr Blood Cancer 2009; 53:537.
Burns ER, et al: Morphologic diagnosis of thrombotic thrombocytopenic
purpura. Am J Hematol 2004; 75:18.
Cataland SR, et al: Demographic and ADAMTS13 biomarker data as
predictors of early recurrences of idiopathic thrombotic
thrombocytopenic purpura. Eur J Haematol 2009 Aug 10 (Epub ahead
of print).
Davies M, et al: Successful vaginal delivery in a patient with extreme
thrombotic thrombocytopenic purpura at term. J Obstet Gynaecol
2009; 29:765.
De S, et al: Severe atypical HUS caused by CFH S1191Lcase
presentation and review of treatment options. Pediatr Nephrol 2009
Oct 24 (Epub ahead of print).
Elliott MA, et al: Rituximab for refractory and or relapsing thrombotic
thrombocytopenic purpura related to immune-mediated severe
ADAMTS13-deficiency: a report of four cases and a systematic review
of the literature. Eur J Haematol 2009; 83:365.
Ferrari S, et al: IgG subclass distribution of anti-ADAMTS13 antibodies
in patients with acquired thrombotic thrombocytopenic purpura. J
Thromb Haemost 2009; 7:1703.
Feys HB, et al: ADAMTS13 in health and disease. Acta Haematol 2009;
121:183.
Feys HB, et al: Mutation of the H-bond acceptor S119 in the ADAMTS13
metalloprotease domain reduces secretion and substrate turnover in a
patient with congenital thrombotic thrombocytopenic purpura. Blood
2009; 114:4749.
Itala M, et al: Excellent response of refractory life-threatening
thrombotic thrombocytopenic purpura to cyclosporine treatment. Clin
Lab Haematol 2004; 26:65.
Jhaveri KD, et al: Treatment of refractory thrombotic thrombocytopenic
purpura using multimodality therapy including splenectomy and
cyclosporine. Transfus Apher Sci 2009; 41:19.
Kamiya K, et al: Rituximab was effective on refractory thrombotic
thrombocytopenic purpura but induced a flare of hemophagocytic

Nonthrombocytopenic purpura
(dysproteinemic purpura)
Cryoglobulinemia and cryofibrinogenemia
The term cryoglobulinemia refers to the presence in the serum
of proteins that precipitate at temperatures below 37C and
redissolve on rewarming. These tend to be chronic conditions,
unless the underlying disease process is treated. Abnormal
serum proteins behaving as cryoglobulins and cryofibrinogens
may be IgG, IgM, or both. Type I cryoglobulinemia occurs
most frequently in multiple myeloma and macroglobulinemia,
and is of a monoclonal IgM, IgG, or Bence Jones cryoglobulin
form. Type II cryoglobulins are monoclonal and have rheumatoid factor-like activity. They are autoantibodies to the constant region of IgG. They occur in many connective tissue
diseases and may also be due to the B-cell proliferation seen
in hepatitis C virus (HCV) infection. Mixed cryoglobulinemia
(type III), in which the cryoglobulins are of various classes, are
associated with HCV infection in more than 90% of cases.
Purpura is most apt to occur on exposed surfaces after cold
exposure. It may be of sudden onset and may clear rapidly
once the patient is kept warm. Marked brown hyperpigmentation of the dorsal feet, at times in a livedoid pattern, may
suggest this diagnosis. Cryoglobulinemia can be the cause of
chronic leg ulcers (Fig. 35-8). An unusual clinical presentation
of type I cryoglobulinemia in association with multiple
myeloma is follicular hyperkeratosis of the central face, especially the nose.
In monoclonal disease, the biopsy reveals amorphous, jellylike, eosinophilic material in the vessel lumen. In types II and
III cryoglobulinaemia, a skin biopsy reveals classic leukocytoclastic vasculitis, and less commonly features of polyarteritis
nodosa.
Treatment of type I cryoglobulinemia is to address the associated myeloproliferative disorder. Thalidomide was beneficial in one patient with a type I cryoglobulin, retiform purpura
and clonal plasma cell expansion. For cryoglobulinemia associated with HCV or connective tissue disease, options include
plasmapheresis, IVIG, systemic steroids, immunosuppressors,
and colchicine. Simple plasma exchange can be helpful, but
cryofiltration apheresis is the best method to remove cryoproteins in the treatment of cryoprecipitate-induced diseases.

Fig. 35-8 Cryoglobulinemia.

Nonthrombocytopenic purpura (dysproteinemic purpura)

syndrome in a patient with systemic lupus erythematosus. Mod


Rheumatol 2009 Sep 26 (Epub ahead of print).
Kremer Hovinga JA, et al: Splenectomy in relapsing and
plasma-refractory acquired thrombotic thrombocytopenic purpura.
Haematologica 2004; 89:320.
Lotta LA, et al: ADAMTS13 mutations and polymorphisms in congenital
thrombotic thrombocytopenic purpura. Hum Mutat 2009 Oct 21 (Epub
ahead of print).
Marques MB: Thrombotic thrombocytopenic purpura and heparininduced thrombocytopenia: two unique causes of life-threatening
thrombocytopenia. Clin Lab Med 2009; 29:321.
Noris M, Remuzzi G: Atypical hemolytic-uremic syndrome. N Engl J Med
2009; 361:1676.
Patel A, et al: Thrombotic thrombocytopenic purpura: the masquerader.
South Med J 2009; 102:504.
Prestidge C, Wong W: Ten years of pneumococcal-associated
haemolytic uraemic syndrome in New Zealand children. J Paediatr
Child Health 2009 Oct 26 (Epub ahead of print).
Siau K, Varughese M: Thrombotic microangiopathy following docetaxel
and trastuzumab chemotherapy: a case report. Med Oncol 2009 Oct
22 (Epub ahead of print).
van Goor H, et al: Adamalysins in biology and disease. J Pathol 2009;
219:277.
Yomtovian R, et al: Rituximab for chronic recurring thrombotic
thrombocytopenic purpura: a case report and review of the literature.
Br J Haematol 2004; 124:787.

Reduction of the HCV viral load is the long-term solution in


HCV-associated cases and can result in disappearance of the
cryoglobulins. IFN treatment produced an exacerbation of
vasculitis in one reported patient. Mixed cryoglobulinemia
with renal, neurologic, and cardiac disease refractory to other
treatments can respond to rituximab.
In contrast to cryoglobulinemia, cryofibrinogenemia is
rarely symptomatic. The precipitating cryofibrinogen is a cold
insoluble complex of fibrin, fibrinogen, and fibrin split products with albumin, cold insoluble globulin, factor VIII, and
plasma proteins. Associated collagenvascular disorders,
infections, and malignancies are significantly more frequent in
patients with combined cryofibrinogen and cryoglobulin than
in those with isolated cryofibrinogenemia. Cryofibrinogen has
been associated with calciphylaxis in the setting of renal
disease, and livedoid vasculopathy when accompanied by
other prothrombotic risks. Familial primary cryofibrinogen
emia manifests as painful purpura with slow-healing ulcerations and edema of both feet during the winter months.
Amdo TD, et al: An approach to the diagnosis and treatment of
cryofibrinogenemia. Am J Med 2004; 116:332.
Auzerie V, et al: Leg ulcers associated with cryoglobulinemia: clinical
study of 15 patients and response to treatment. Arch Dermatol 2003;
139:391.
Batisse D, et al: Sustained exacerbation of cryoglobulinemia-related
vasculitis following treatment of hepatitis C with peginterferon alfa. Eur
J Gastroenterol Hepatol 2004; 16:701.
Blain H, et al: Cryofibrinogenaemia: a study of 49 patients. Clin Exp
Immunol 2000; 120:253.
Cavallo R, et al: Rituximab in cryoglobulinemic peripheral neuropathy. J
Neurol 2009; 256:1076.
Charles ED, Dustin LB: Hepatitis C virus-induced cryoglobulinemia.
Kidney Int 2009; 76:818.
da Silva Fucuta Pereira P, et al: Long-term efficacy of rituximab in
hepatitis C virus-associated cryoglobulinemia. Rheumatol Int 2009 Aug
25 (Epub ahead of print).
De Rosa FG, Agnello V: Observations on cryoglobulin testing: I. The
association of cryoglobulins containing rheumatoid factors with
manifestation of cryoglobulinemic vasculitis. J Rheumatol 2009;
36(9):1953.
De Rosa FG, et al: Observations on cryoglobulin testing: II. The
association of oligoclonal mixed cryoglobulinemia with cirrhosis in
patients infected with hepatitis C virus. J Rheumatol 2009; 36:1956.

813

Cutaneous Vascular Diseases

35

Della Rossa A, et al: Hyperviscosity syndrome in cryoglobulinemia:


clinical aspects and therapeutic considerations. Semin Thromb
Hemost 2003; 29:473.
Ferri C, et al: Mixed cryoglobulinemia: demographic, clinical, and
serologic features and survival in 231 patients. Semin Arthritis Rheum
2004; 33:355.
Harati A, et al: Skin disorders in association with monoclonal
gammopathies. Eur J Med Res 2005; 10:93.
Lo KY, et al: Hepatitis C virus-associated type II mixed cryoglobulinemia
vasculitis complicated with membranous proliferative
glomerulonephritis. Ren Fail 2009; 31:149.
Rayhill SC, et al: Positive serum cryoglobulin is associated with worse
outcome after liver transplantation for chronic hepatitis C.
Transplantation 2005; 80:448.
Requena L, et al: Follicular spicules of the nose: a peculiar cutaneous
manifestation of multiple myeloma with cryoglobulinemia. J Am Acad
Dermatol 1995; 32:834.
Resnik KS: Intravascular eosinophilic depositswhen common
knowledge is insufficient to render a diagnosis. Am J Dermatopathol
2009; 31:211.
Rongioletti F, et al: The histological and pathogenetic spectrum of
cutaneous disease in monoclonal gammopathies. J Cutan Pathol
2008; 35:705.
Sampson A, Callen JP: Thalidomide for type 1 cryoglobulinemic
vasculopathy. Arch Dermatol 2006; 142:972.
Siami FS, et al: Cryofiltration apheresis in the treatment of
cryoprecipitate induced diseases. Ther Apher 1997; 1:58.
Tallarita T, et al: Successful combination of rituximab and plasma
exchange in the treatment of cryoglobulinemic vasculitis with skin
ulcers: a case report. Cases J 2009; 2:7859.

Waldenstrm hyperglobulinemic purpura


(purpura hyperglobulinemica)
Waldenstrm hyperglobulinemic purpura presents with episodic showers of petechiae occurring mainly on the lower
extremities. The dorsum of the feet is intensely involved,
and the petechiae diminish on the ascending parts of the feet
(Fig. 35-9). A diffuse peppery distribution is commonly
noted, resembling Schambergs disease. The petechiae may be
induced or aggravated by prolonged standing or walking, or
by wearing constrictive garters or stockings.
Serum protein electrophoresis demonstrates a broad-based
peak (polyclonal hypergammaglobulinemia). The bulk of the
protein increase is IgG, though occasionally increased amounts
of IgA are also found. IgM is usually normal or decreased.
Rheumatoid factor in varying amounts is present in almost all

Fig. 35-9 Waldenstrm hyperglobulinemic purpura.

814

patients. Antithyroglobulins, increased erythrocyte sedimentation rate (ESR), leukopenia, antinuclear factors, and proteinuria may be found. Almost 80% of patients with
hypergammaglobulinemic purpura of Waldenstrm have
antibodies to Ro/SSA.
Hyperglobulinemic purpura occurs most commonly in
women and is frequently seen with Sjgren syndrome and
rheumatoid arthritis. Adverse fetal outcomes in these women
may be associated with the associated autoantibodies (SSA/
SSB). Hyperglobulinemic purpura may also be a primary
chronic benign illness. When it is associated with hepatitis C,
it has a predilection for men, and has manifestations that
usually last longer than those associated with Sjgren
syndrome.
In about one-third of patients, leukocytoclastic vasculitis is
present. Patients with leukocytoclastic vasculitis have a higher
prevalence of articular involvement, peripheral neuropathy,
Raynaud phenomenon, renal involvement, ANA, rheumatoid
factor, and anti-Ro/SSA antibodies. The course of the disease
is essentially benign, but chronic. Rare deaths are related to
associated cryoglobulin disease. Hyperglobulinemic purpura
may be a manifestation or harbinger of connective tissue or
hematopoietic diseases, and rarely, progression to myeloma
has been reported.
Patients often improve with support stockings. Steroids
should be reserved for severe disease. Indomethacin and
hydroxychloroquine may be of value in the treatment of
milder disease, especially in patients who have connective
tissue disease or are SSA/B (Ro/La)-positive. Aspirin and colchicine have been used with some success.
Al-Mayouf SM, et al: Hypergammaglobulinaemic purpura associated
with IgG subclass imbalance and recurrent infection. Clin Rheumatol
2000; 19:499.
Jolly EC, et al: Benign hypergammaglobulinemic purpura is not
benign in pregnancy. Clin Rheumatol 2009; 28:S11.
Maeda-Tanaka M, et al: Juvenile-onset hypergammaglobulinemic
purpura and fetal congenital heart block. J Dermatol 2006; 33:714.
Malaviya AN, et al: Hypergammaglobulinemic purpura of Waldenstrm:
report of 3 cases with a short review. Clin Exp Rheumatol 2000; 18:518.
Ramos-Casals M, et al: Cutaneous vasculitis in primary Sjgren
syndrome: classification and clinical significance of 52 patients.
Medicine (Baltimore) 2004; 83:96.

Waldenstrm macroglobulinemia
Waldenstrm macroglobulinemia (WM) is a lymphoplasmacytic lymphoma of B lymphocytes, with proliferation of monoclonal lymphocytes in bone marrow, lymph nodes, and spleen.
Lymphadenopathy, hepatosplenomegaly, and anemia are
characteristic. Elevated levels of IgM in the circulation define
this unique and rare lymphoproliferative disease, and the IgM
is responsible for some of the skin manifestations of this disorder. Elderly men are predominately affected, and there is a
strong familial predisposition. The cutaneous manifestations
of WM can be divided into two categories: nonspecific and
specific. Nonspecific manifestations are related to the hyperviscosity syndrome created by the circulating IgM, and include
purpura of the skin and mucous membranes. The purpura
may be surmounted by giant tense bullae. Bleeding of the
gums and epistaxis can occur. The IgM may behave as a cryo
globulin, resulting in purpura, livedo, cutaneous ulcerations,
and vasculitis. Urticaria (some patients satisfying the diagnostic criteria for Schnitzlers syndrome), disseminated xanthoma,
and amyloid deposition can be seen. Specific skin lesions are
of two types: specific skin deposits of aggregates of the IgM
(IgM storage lesions), and cutaneous infiltrates with neoplastic
lymphoid cells. The specific skin lesions usually occur once the
diagnosis of WM is already known, but uncommonly the skin

Abdallah-Lotf M, et al: Cutaneous manifestations as initial presentation


of Waldenstrms macroglobulinemia. Eur J Dermatol 2003; 13:90.
Autier J, et al: Cutaneous Waldenstrms macroglobulinemia with
deck-chair sign treated with cyclophosphamide. J Am Acad
Dermatol 2005; 52:45.
Chan I, et al: Cutaneous Waldenstrms macroglobulinaemia. Clin Exp
Dermatol 2003; 28:491.
Ciccarelli BT, et al: Soluble CD27 is a faithful marker of disease burden
and is unaffected by the rituximab-induced IgM flare, as well as by
plasmapheresis, in patients with Waldenstrms macroglobulinemia.
Clin Lymphoma Myeloma 2009; 9:56.
Colvin JH, et al: Cutaneous lymphoplasmacytoid lymphoma
(immunocytoma) with Waldenstrms macroglobulinemia mimicking
rosacea. J Am Acad Dermatol 2003; 49:1159.
Harnalikar M, et al: Keratotic vascular papules over the feet: a case of
Waldenstrms macroglobulinaemia-associated cutaneous
macroglobulinosis. Clin Exp Dermatol 2009 Oct 23 (Epub ahead of
print).
Libow LF, et al: Cutaneous Waldenstrms macroglobulinemia: report of
a case and overview of the spectrum of cutaneous disease. J Am
Acad Dermatol 2001; 45(6 Suppl):S202.
Murota H, et al: Improvement of recurrent urticaria in a patient with
Schnitzler syndrome associated with B-cell lymphoma with
combination rituximab and radiotherapy. J Am Acad Dermatol 2009;
61:1070.
Pascal L, et al: Bortezomib and Waldenstrms macroglobulinemia.
Expert Opin Pharmacother 2009; 10:909.
Rajkumar SV, et al: Monoclonal gammopathy of undetermined
significance, Waldenstrm macroglobulinemia, AL amyloidosis, and
related plasma cell disorders: diagnosis and treatment. Mayo Clin Proc
2006; 81:693.
Rongioletti F, et al: The histological and pathogenetic spectrum of
cutaneous disease in monoclonal gammopathies. J Cutan Pathol
2008; 35:705.
Stone MJ: Waldenstrms macroglobulinemia: hyperviscosity syndrome
and cryoglobulinemia. Clin Lymphoma Myeloma 2009; 9:97.
Tedeschi A, et al: Fludarabine-based combination therapies for
Waldenstrms macroglobulinemia. Clin Lymphoma Myeloma 2009;
9:67.

Treon SP: How I treat Waldenstrm macroglobulinemia. Blood 2009;


114:2375.
Wolgamot GM, et al: Firm papules on lower extremities of 52-year-old
male. Am J Dermatopathol 2005; 27:313.
Yokote T, et al: Cutaneous infiltration with Waldenstrm
macroglobulinemia. Leuk Res 2006; 30:1207.

Purpura secondary to clotting disorders


Hereditary disorders of blood coagulation usually result from
a deficiency or qualitative abnormality of a single coagulation
factor, as in hemophilia or von Willebrands disease. Acquired
disorders commonly result from multiple coagulation factor
deficiencies, as in liver disease, biliary tract obstruction, malabsorption, or drug ingestion. Acquired clotting disorders
may also involve platelet abnormalities, as in DIC. Hemorrhagic
manifestations are common and may be severe, especially in
hereditary forms. Ecchymoses and subcutaneous hematomas
are common, especially on the legs. Severe hemorrhage may
follow trauma, and hemarthrosis is frequent. Other hemorrhagic manifestations include respiratory obstruction resulting from hemorrhage into the tongue, throat, or neck; epistaxis;
gastrointestinal and genitourinary tract bleeding; and, rarely,
CNS hemorrhage.

Drug- and food-induced purpura

lesions are the first clue to the diagnosis. The specific IgM
deposits present clinically as subepidermal blisters (clinically
and histologically resembling bullous amyloidosis) or translucent 13mm papules. They are found most commonly on the
lower extremity, even on the sole. Slight hyperkeratosis may
be seen over the papules. Histologically, the papules are composed of dermal nodular homogenous and fissured pink
deposits with a tendency to involve newly formed vessels.
They are periodic acid-Schiff (PAS)-positive, but negative for
Congo red. Direct immunofluorescence will identify the
dermal globules as being composed of IgM and is a useful
diagnostic approach. When WM results in specific cutaneous
lymphoid aggregates, the presentation is very nonspecific.
Small redbrown to violaceous macules, papules, nodules, or
plaques may be present, usually on the face. Rosacea is often
initially entertained as a diagnosis. Widespread skin involvement with a deck-chair sign (sparing the abdominal skin
folds) has been reported.
The natural history of WM is that of an indolent myelodysplasia. Treatment is directed at reducing the volume of neoplastic cells and should be managed by an oncologist. Most
indolent and asymptomatic patients are followed or treated
only when clinical disease occurs. Given the risk of secondary
neoplasms, fludarabine is avoided, unless other options are
not possible. Combinations of cyclophosphamide, systemic
steroids, and rituximab or bortezomib, systemic steroids and
rituximab are initial therapeutic options. Plasmapheresis can
be effective in controlling acute symptoms of hyperviscosity
syndrome. Rituximab is not used as a monotherapy in WM
patients with hyperviscosity, as they may experience a flare of
their disease. Soluble CD27 can be used as a marker to determine response to therapy.

Harley JR: Disorders of coagulation misdiagnosed as nonaccidental


bruising. Pediatr Emerg Care 1997; 13:347.
Sham RL, et al: Evaluation of mild bleeding disorders and easy
bruising. Blood Rev 1994; 8:98.

Drug- and food-induced purpura


Drug-induced purpura may be related to platelet destruction,
vessel fragility, interference with platelet function, or vasculitis. Drug-induced thrombocytopenic purpura was discussed
earlier in this chapter. Examples of purpurogenic drugs
are: aspirin and other NSAIDs, allopurinol, thiazides, gold,
sulfonamides, cephalosporins, hydralazine, phenytoin,
quinidine, ticlopidine, and penicillin. Combinations of
diphenhydramine and pyrithyldione can induce purpuric
mottling and areas of necrosis. Cocaine-induced thrombosis
with infarctive skin lesions is associated with skin popping.
Topical EMLA cream can induce purpura within 30min of
application, a result of a toxic effect on the capillary endothelium. Agave ingestion can induce purpura and vasculitic-like
lesions due to a direct toxic effect on the endothelium. Purpura
has been associated with the use of acetaminophen in patients
afflicted with infectious mononucleosis. Small-vessel vasculitis, including urticarial vasculitis, has been caused by the
ingestion of tartrazine dye. Pseudoephedrine can induce a
pigmented purpura-like reaction. Patch testing reproduced
the eruption. Purpuric contact dermatitis is rare and usually
caused by rubber chemical or textile dyes.
Aster RH: Can drugs cause autoimmune thrombocytopenic purpura?
Semin Hematol 2000; 37:229.
DAddario SF, et al: Minocycline-induced immune thrombocytopenia
presenting as Schambergs disease. J Drugs Dermatol 2003; 2:320.
Diaz-Jara M, et al: Pigmented purpuric dermatosis due to
pseudoephedrine. Contact Dermatitis 2002; 46:300.
Dlott JS, et al: Drug-induced thrombotic thrombocytopenic purpura/
hemolytic uremic syndrome: a concise review. Ther Apher Dial 2004;
8:102.
Neri I, et al: Purpura after application of EMLA cream in two children.
Pediatr Dermatol 2005; 22:566.
OFlynn G, et al: Evaluation of a cocktail of three bacteriophages for
biocontrol of Escherichia coli O157:H7. Appl Environ Microbiol 2004;
70:3417.
Verma GK, et al: Purpuric contact dermatitis from footwear. Contact
Dermatitis 2007; 56:362.

815

Cutaneous Vascular Diseases

35

Purpura fulminans
Also known as purpura gangrenosa, this is a severe, rapidly
fatal reaction. There are three forms of the disease:
1. that associated with infection and DIC
2. hereditary deficiency of protein C or S
3. that which follows a febrile illness that leads to an
acquired protein S deficiency.
The most common form is that which is associated with an
infectious illness, usually bacterial septicemia, but sometimes
a viral infection (varicella). Asplenic patients, who are at risk
for pneumococcal or meningococcal sepsis, are also predisposed to purpura fulminans. Neonates with homozygous
protein C or protein S deficiencies may suffer purpura fulminans (Fig. 35-10). Some patients develop transient deficiencies
of proteins C and S in response to infection. A number of cases
of purpura fulminans associated with infections and factor V
Leiden mutation, with normal protein C and protein S levels,
have been reported. Meningococcemia, streptococcal sepsis,
Capnocytophaga sepsis (from dog bite), staphylococcal septicemia, and urosepsis are the most common causes. Rickettsial
disease and malaria may present as purpura fulminans. Active
HHV-6 replication with acquired protein S deficiency and
purpura fulminans has been described. Purpura fulminans
presents as the sudden appearance of large ecchymotic areas,
especially prominent over the extremities, progressing to acral
hemorrhagic skin necrosis. (Fig. 35-11). The term symmetrical
peripheral gangrene is used to describe cases when acral
gangrene is present. Fever, shock, and DIC usually accompany
the skin lesions, which on biopsy show noninflammatory

necrosis, with plateletfibrin thrombi occluding the blood


vessels.
Other disease, such as the fibrinolysis syndrome, may have
purpura fulminans as part of the symptom complex. An
acquired form has been reported secondary to alcohol and
acetaminophen ingestion, as well as from diclofenac or propylthiouracil. When purpura fulminans occurs in the setting
of SLE, the catastrophic antiphospholipid antibody syndrome
(CAPS) must be considered (Fig. 35-12). Purpura fulminans
has been reported as a presenting feature of the ChurgStrauss
syndrome and other ANCA-positive vasculitides.
Management is usually supportive, with treatment of the
underlying disease process (antibiotics for the septicemia) and
replacement therapy using fresh frozen plasma. Protein C and
antithrombin replacement is useful in treating patients shown
to have deficiencies. Plasmapheresis has been used in nonbacterial cases. Heparin anticoagulation can be used. Despite
these measures, amputations (often multiple extremities) and
deaths continue to occur in patients with severe disease. The
use of pressors to maintain blood pressure during the septic
episode may contribute to reduced peripheral circulation and
peripheral tissue damage. Fasciotomy during the initial management of these patients may reduce the depth of soft-tissue
involvement and the extent of amputations.
Akman A, et al: Unusual location of purpura fulminans associated with
acquired protein C deficiency and administration of propylthiouracil.
Clin Exp Dermatol 2009; 34:e463.
Betrosian AP, et al: Meningococcal purpura fulminans in a patient with
systemic lupus erythematosus: a mimic for catastrophic
antiphospholipid antibody syndrome? Am J Med Sci 2004; 327:373.
Boccara O, et al: Nonbacterial purpura fulminans and severe
autoimmune acquired protein S deficiency associated with human
herpesvirus-6 active replication. Br J Dermatol 2009; 161:181.
Culpeper KS, et al: Purpura fulminans. Lancet 2003; 361:384.
Davis MD, et al: Presentation and outcome of purpura fulminans
associated with peripheral gangrene in 12 patients at Mayo Clinic. J
Am Acad Dermatol 2007; 57:944.
de Souza AL, et al: Purpura fulminans without meningitis: a rare
condition? Am J Med 2007; 120:e17.
Dhainaut JF, et al: Protein C/activated protein C pathway: overview of
clinical trial results in severe sepsis. Crit Care Med 2004; 32(5
Suppl):S194.

Fig. 35-10 Neonatal purpura fulminans secondary to homozygous


protein C deficiency.

Fig. 35-11 Purpura fulminans.

816

Fig. 35-12 Catastrophic antiphospholipid antibody syndrome.

Disseminated intravascular coagulation


Up to two-thirds of patients with disseminated intravascular
coagulation (DIC) have skin lesions, which may be the initial
manifestation of the syndrome. Minute, widespread petechiae,
ecchymoses, ischemic necrosis of the skin, and hemorrhagic
bullae are the usual findings. Purpura fulminans may supervene and progress to symmetrical peripheral gangrene. DIC
may be initiated by a variety of disorders, including septicemic
hypotension, hypoxemia, acidosis, malignancies, chemotherapy, obstetric crises, antiphospholipid antibody syndrome,
SLE, arthropod envenomation, and leukemia. Long-term treatment with granulocyte colony-stimulating factor (G-CSF) has
also been reported to precipitate DIC. Children with kaposiform hemangioendotheliomas are at risk for consumptive
coagulopathy (KasabachMerritt syndrome).
DIC is the result of widespread intravascular coagulation
in which certain coagulation factors are consumed faster
than they can be replaced. Laboratory findings include
decreased platelets, decreased fibrinogen (only in severe
cases; normal in 57% of cases), elevated PT/PTT (5060% of
cases), and increased fibrin degradation products and
D-dimers. Control of the underlying disease is the paramount
consideration, and often antibiotics or surgical drainage of
loculated infection may lead to spontaneous resolution of
DIC. Bleeding is treated with platelet transfusion in the presence of thrombocytopenia and fresh frozen plasma to correct
coagulation factor abnormalities. Heparin is considered when
thrombosis in the form of venous, arterial, or widespread
microvascular thrombosis (purpura fulminans) is present.
Protein C concentrate may benefit patients with severe sepsis
and DIC.
Levi M, et al: Guidelines for the diagnosis and management of
disseminated intravascular coagulation. British Committee for
Standards in Haematology. Br J Haematol 2009; 145:24.

Okabayashi K, et al: Hemostatic markers and the sepsis-related organ


failure assessment score in patients with disseminated intravascular
coagulation in an intensive care unit. Am J Hematol 2004; 76:225.

Congenital fibrinogen disorders


Deficiencies of fibrinogen are classified as reductions in quantity (afibrinogenemia or hypofibrinogenemia) or in quality
(dysfibrinogenemia). Afibrinogenemia occurs at a rate of about
1 per million in the population. It may present at birth with
umbilical cord bleeding. Epistaxis, menorrhagia, hemarthrosis
(but much less than in hemophilia and with far fewer musculo
skeletal sequelae), trauma, and surgery-related bleeding can
occur. The severity of the bleeding tendency is highly variable
from patient to patient, some suffering no bleeding problems
at all. Pregnancy complications include recurrent miscarriage
and peripartum hemorrhage. Ironically, due to the loss of the
antithrombotic effect of fibrinogen, thrombotic events are
increased in afibrinogenemia. Arterial and venous thrombosis
can occur. Patients with hypofibrinogenemia are more numerous, and in general are less symptomatic and only occasionally
require treatment. Hypofibrinogenemia can be associated with
pregnancy losses and rarely liver disease due to accumulation
of abnormal fibrinogen in the endoplasmic reticulum of
hepatocytes. Dysfibrinogenemia is asymptomatic in 55% of
cases, 25% exhibit bleeding tendencies, and 20% have a tendency to thrombosis. This represents only 0.8% of patients
with deep venous thrombosis, so screening for this condition
is not cost-effective, unless there is a family history. Mutations
in the fibrinogen gene cluster cause all three of these fibrinogen disorders.

Blueberry muffin baby

Edlich RF, et al: Modern concepts of the diagnosis and treatment of


purpura fulminans. J Environ Pathol Toxicol Oncol 2008; 27:191.
Fourrier F, et al: Combined antithrombin and protein C supplementation
in meningococcal purpura fulminans: a pharmacokinetic study.
Intensive Care Med 2003; 29:1081.
Ghosh SK, et al: Symmetrical peripheral gangrene: a prospective study
of 14 consecutive cases in a tertiary-care hospital in eastern India.
J Eur Acad Dermatol Venereol 2009 Jun 9 (Epub ahead of print).
Ghosh SK, et al: Purpura fulminans: a cutaneous marker of
disseminated intravascular coagulation. West J Emerg Med 2009;
10:41.
Hassan Z, et al: Purpura fulminans: a case series managed at a
regional burn center. J Burn Care Res 2008; 29:411.
Jaconelli T, Psirides A: Medical image. A fulminant rash: purpura
fulminans. N Z Med J 2009; 122:3558.
Kato Y, et al: Purpura fulminans: an unusual manifestation of severe
falciparum malaria. Intensive Care Med 2007; 33:1168.
Krzelj V: Response to hyperbaric oxygen therapy for purpura fulminans.
Pediatr Emerg Care 2005; 21:485.
Lalitha AV, et al: Spectrum of purpura fulminans. Indian J Pediatr 2009;
76:87.
Regnault V, et al: Anti-protein S antibodies following a varicella infection:
detection, characterization and influence on thrombin generation. J
Thromb Haemost 2005; 3:1243.
Staquet P, et al: Detection of Neisseria meningitidis DNA from skin
lesion biopsy using real-time PCR: usefulness in the aetiological
diagnosis of purpura fulminans. Intensive Care Med 2007; 33:1168.
Stein RH, et al: Purpura fulminans. Int J Dermatol 2003; 42:130.
Warner PM, et al: Current management of purpura fulminans: a
multicenter study. J Burn Care Rehabil 2003; 24:119.
Watt SG, et al: Purpura fulminans in paroxysmal nocturnal
haemoglobinuria. Br J Haematol 2007; 137:271.
Zenz W, et al: Use of recombinant tissue plasminogen activator in
children with meningococcal purpura fulminans: a retrospective study.
Crit Care Med 2004; 32:1777.

Asselta R, et al: Molecular genetics of quantitative fibrinogen disorders.


Cardiovasc Hematol Agents Med Chem 2007; 5:163.
de Moerloose P, Neerman-Arbez M: Congenital fibrinogen disorders.
Semin Thromb Hemost 2009; 35:356.
Vu D, Neerman-Arbez M: Molecular mechanisms accounting for
fibrinogen deficiency: from large deletions to intracellular retention of
misfolded proteins. J Thromb Haemost 2007; 5:125.

Blueberry muffin baby


Originally coined to describe the characteristic appearance of
the purpuric lesions observed in newborns with congenital
rubella, the term blueberry muffin baby is associated with
many disorders that produce extramedullary erythropoiesis.
The eruption consists of generalized dark blue to magenta,
nonblanchable, indurated, round to oval, hemispheric papules
ranging from 1 to 7mm. Lesions favor the head, neck, and
trunk.
Etiologic factors include congenital infections (toxoplasmosis, rubella, cytomegalovirus, and parvovirus B19), hemolytic
disease of the newborn (Rh incompatibility, blood group
incompatibility), hereditary spherocytosis, twin transfusion
syndrome, neuroblastoma, rhabdomyosarcoma, Langerhans
cell histiocytosis, and congenital leukemia. Patients with
multiple vascular disorders, such as hemangiopericytoma,
hemangioma, blue rubber bleb nevus, and glomangioma, may
be mistaken for blueberry muffin baby. Evaluation should
include a peripheral blood cell count, hemoglobin level,
TORCH serologies, viral cultures, and a Coombs test. A skin
biopsy may also be helpful in determining the cause.
Brisman S, et al: Blueberry muffin rash as the presenting sign of
AicardiGoutieres syndrome. Pediatr Dermatol 2009; 26:432.
Gaffin JM, Gallagher PG: Picture of the month. Blueberry muffin baby
(extramedullary hematopoiesis) due to congenital cytomegalovirus
infection. Arch Pediatr Adolesc Med 2007; 161:1102.
Holland KE, et al: Neonatal violaceous skin lesions: expanding the
differential of the blueberry muffin baby. Adv Dermatol 2005; 21:153.

817

Cutaneous Vascular Diseases

35

Mehta V, et al: Blueberry muffin baby: a pictorial differential diagnosis.


Dermatol Online J 2008; 14:8.
Sankilampi U, et al: Congenital Langerhans cell histiocytosis mimicking
a blueberry muffin baby. J Pediatr Hematol Oncol 2008; 30:145.

Miscellaneous purpuric manifestations


Deep venous thrombosis
Deep venous thrombosis (DVT) is a common medical condition that can result in immediate (pulmonary embolism) or
long-term consequences (venous insufficiency, postphlebitic
syndrome). Risk factors include female gender, obesity, immobilization, low atmospheric pressure, winter season, and the
presence of cancer. In 35% of cancer-associated cases, the
thrombosis is the first sign of the cancer. The use of
erythropoiesis-stimulating agents doubles the risk of venous
thromboembolism (VTE) for cancer patients. Hereditary mutations that result in a hypercoagulable state also increase the
risk for VTE. The left leg is more often affected than the right.
The mean age is 52 years. Significant superficial vein thrombosis is considered a risk factor for DVT. The risk of pulmonary embolism from DVT is the major concern. Treatment
includes preventive strategies (exercise, weight control, and
prophylaxis for high-risk settingspostoperative, post-stroke,
and immobilized cancer patient).
Bates SM, et al: Clinical practice. Treatment of deep-vein thrombosis. N
Engl J Med 2004; 351:268.
Brown HK, et al: The influence of meteorological variables on the
development of deep venous thrombosis. Thromb Haemost 2009;
102:676.
Canonico M, Scarabin PY: Hormone therapy and risk of venous
thromboembolism among postmenopausal women. Climacteric
2009:12:76.
Coss E, et al: 57-year-old woman with acute lower extremity pain and
swelling. Mayo Clin Proc 2009; 84:e1.
Doggen CJ: High coagulant factors & venous thrombosis. Blood 2009;
114:2854.
Fanikos J, et al: Long-term complications of medical patients with
hospital-acquired venous thromboembolism. Thromb Haemost 2009;
102:688.
Hershman DL, et al: Patterns of use and risks associated with
erythropoiesis-stimulating agents among Medicare patients with
cancer. J Natl Cancer Inst 2009; 101:1633.
Kucher N, et al: Lack of prophylaxis before the onset of acute venous
thromboembolism among hospitalized cancer patients: the SWIss
Venous ThromboEmbolism Registry (SWIVTER). Ann Oncol 2009 Oct
14 (Epub ahead of print).
Lyman GH, Khorana AA: Cancer, clots and consensus: new
understanding of an old problem. J Clin Oncol 2009; 27:4821.
Millar JA: Selection of medical patients for prophylaxis of venous
thromboembolism based on analysis of the benefithazard ratio. Intern
Med J 2009; 39:606.
Pai N, et al: Differences in etiological and clinical manifestations in
upper extremity and lower limb deep venous thrombosis patients from
India. Clin Appl Thromb Hemost 2009 Nov 10 (Epub ahead of print).
Piazza G, Goldhaber SZ: Physician alerts to prevent venous
thromboembolism. J Thromb Thrombolysis 2009 Nov 4 (Epub ahead
of print).
Shrier I, et al: Effect of early physical activity on long-term outcome
after venous thrombosis. Clin J Sport Med 2009; 19:487.
Spyropoulos AC, et al: Rates of venous thromboembolism occurrence in
medical patients among the insured population. Thromb Haemost
2009; 102:951.
Vedantham S: Deep venous thrombosis: the opportunity at hand. Am J
Roetgenol 2009; 193:922.

818

Fig. 35-13 Superficial migratory thrombophlebitis.

superficial venous thrombosis (Fig. 35-13). Patients may also


exhibit indurated subcutaneous nodules and overlying
purpura or brown discoloration indicative of postinflammatory hyperpigmentation.
Primary hypercoagulable states that may be associated with
superficial thrombophlebitis include deficiencies of antithrombin III, heparin cofactor II, protein C, protein S, and
factor XII; disorders of tissue plasminogen activator; abnormal
plasminogen; dysfibrinogenemia; and lupus anticoagulant.
Secondary hypercoagulable states include varicosities, malignancy (Trousseau syndrome), pregnancy, oral contraceptive
use, infusion of prothrombin complex concentrates, Behets
disease, thromboangiitis obliterans, acute thrombophlebitis of
superficial veins of the breast (Mondors disease), septic
thrombophlebitis, psittacosis, secondary syphilis, intravenous
catheters, intravenous drugs (sugar solutions, protein hydrolysates, calcium, potassium, hypertonic concentrates,
diazepam, nitrogen mustard, acridinylaniside, dacarbazine,
and carmustine), and street drugs (cocaine, bulking agents
such as paregoric, quinine, dextrose, sucrose, and lactose).
In the evaluation of superficial thrombophlebitis, one should
consider the possibility of underlying deep venous disease.
Superficial femoral vein involvement should alert the physician to underlying deep venous disease requiring anticoagulation. Lesser saphenous vein thrombophlebitis is also frequently
associated with underlying DVT. Elliptic biopsies across the
palpable cord may be required to exclude other considerations
such as sarcoidal granulomas, cutaneous polyarteritis nodosa,
Kaposi sarcoma, and vasculotropic metastasis.
Treatment is directed at the underlying cause. Leg elevation
and local heat will help to promote the dissolution of clots,
which may take up to 812 weeks to resolve. Heparin therapy
may reduce the incidence of thromboembolic complications in
high-risk individuals.

Superficial thrombophlebitis

Mondors disease

Painful induration with erythema, often in a linear or branching configuration forming cords, is the classic presentation of

Mondors disease occurs three times more frequently in


women than in men, and most patients are between 30 and 60

Miscellaneous purpuric manifestations


Fig. 35-14 Mondors disease.

years of age. The sudden appearance of a cordlike thrombosed


vein along the anteriorlateral chest wall is characteristic (Fig.
35-14). It is at first red and tender and subsequently changes
into a painless, tough, fibrous band. There are no systemic
symptoms. Both sides of the chest have the same rate of
involvement. Mondors disease may be associated with strenuous exercise, pregnancy, intravenous drug abuse, jellyfish
stings, breast cancer, and breast surgery. The condition represents a localized thrombophlebitis of the veins of the thoraco
epigastric area. The veins involved are the lateral thoracic,
thoracoepigastric, and superior epigastric. In the end stage, a
thick-walled vein remains that has a hard, ropelike appearance
and, on occasion, may result in a furrowing of the breast.
Exceptionally, a vein coursing up the inside of the upper arm
and across or into the axilla may be thrombosed, leading to
the axillary web syndrome. Similar string-like phlebitis findings have been described in the penis, antecubital fossa, groin,
and abdomen.
Treatment is symptomatic, with hot, moist dressings and
analgesics or NSAIDs. The disease process runs its course in
3 weeks to 6 months.
Craythorne E, et al: Axillary web syndrome or cording, a variant of
Mondor disease, following axillary surgery. Arch Dermatol 2009;
145:1199.
de Godoy JM, et al: The association of Mondors disease with protein S
deficiency: case report and review of literature. J Thromb Thrombolysis
2002; 13:187.
Kraus S, et al: Mondors disease of the penis. Urol Int 2000; 64:99.
Samlaska CS, James WD: Superficial thrombophlebitis. I. Primary
hypercoagulable states. J Am Acad Dermatol 1990; 22:975.
Samlaska CS, James WD: Superficial thrombophlebitis. II. Secondary
hypercoagulable states. J Am Acad Dermatol 1990; 23:1.

Postcardiotomy syndrome
Between 2 and 3 weeks after pericardiotomy, fever, pleuritis,
pericarditis, or arthritis may appear, together with petechiae
on the skin and palate. This syndrome may be confused with
infectious mononucleosis and bacterial endocarditis.

Orthostatic purpura (stasis purpura)


Prolonged standing or even sitting with the legs lowered
(as in a bus, airplane, or train) may produce edema and a
purpuric eruption on the lower extremities. Elevation of the

Fig. 35-15 Child abuse, purpura of the face from the sole of a shoe.

legs and the use of elastic stockings are helpful preventive


strategies.

Obstructive or traumatic purpura


Purpura may be evoked by mechanical obstruction to the circulation, with resulting stress on the small vessels. This may
be encountered in cardiac decompensation, or after convulsions, vomiting episodes, the Valsalva maneuver, pertussis, or
sexual climax. Nonpalpable purpura has been reported in
association with the use of a mucus-clearing device, which
requires the patient to exhale forcefully through a flutter
valve (flutter valve purpura). Local obstruction of the blood
flow with purpura may result from compression of the
veins by tumors or a gravid uterus or by occlusions from
thrombosis.
Purpuric lesions in children bring into question the possibility of the battered child (Fig. 35-15). Bruises and ecchymoses
on the genital area, buttocks, or hands are suggestive of an
abused child. Linear lesions on accessible areas raise the question of factitial disease. Ecchymoses of bizarre shapes may also
correspond to trauma inflicted during religious rituals or cultural practices. Coin-rubbing and cupping performed as remedies for common diseases are examples. Passion purpura
on the palate may result from fellatio, or on the neck or upper
arms (a hickey) from biting and sucking. Facial, cheek, and
periorbital purpura can be postictal and may be mistaken for
spousal abuse. Bathtub suction-induced purpura occurs on the
lower back location in a U-shaped distribution. It may be
mistaken for abuse.
Baselga E, et al: Purpura in infants and children. J Am Acad Dermatol
1997; 37:673.
Ely SF, et al: Asphyxial deaths and petechiae: a review. J Forensic Sci
2000; 45:1274.
Jaffe FA: Petechial hemorrhages. A review of pathogenesis. Am J
Forensic Med Pathol 1994; 15:203.
Knoell KA, et al: Flutter valve purpura. J Am Acad Dermatol 1998;
9:292.
Landers MC, et al: Bathtub suction-induced purpura. Pediatr Dermatol
2004; 21:146.
Reis JJ, et al: Postictal hemifacial purpura. Seizure 1998; 7:337.

819

Cutaneous Vascular Diseases

35

Paroxysmal nocturnal hemoglobinuria (PNH)


This acquired intravascular hemolytic anemia usually occurs
in young adults, median age 40 years. It is an acquired clonal
disorder resulting from a somatic mutation in a multipotent
hematopoietic stem cell that produces all the bone marrowderived cell lines (neutrophils, lymphocytes, platelets, and
erythrocytes). The clinical manifestations are intravascular
hemolysis, smooth muscle dystonia due to depletion of tissue
nitric oxide (abdominal pain, esophageal spasm, fatigue, erectile dysfunction), and life-threatening venous thrombosis.
Some cases occur after recovery from aplastic anemia.
Widespread cutaneous thrombosis, with initial erythematous
cutaneous plaques progressing to hemorrhagic bullae, can
occur. Vascular thrombi are found on biopsy. The cause of
PNH is a mutation in an X-linked gene, phosphatidylinositol
glycan class A (PIGA). The product of this gene is the first step
in the biosynthesis of all GPI anchors on the surface of hemato
poietic cells. Erythrocytes in PNH lack two GPI-anchored proteins, CD55 and CD59, which prevent complement activation
on the erythrocyte surface. CD55 accelerates the rate of breakdown of membrane-bound C3 convertase, and CD59 reduces
the number of membrane attack complexes that are formed.
The diagnosis of PNH can be made by detecting the loss of
CD55 and CD59 through monoclonal antibody tests. The
FLAER (fluorescent aerolysin) flow cytometry test is now commonly used to diagnose PNH. Hematopoietic stem-cell transplantation may be curative, after either ablative or non-ablative
conditioning regimens. Eculizumab, a humanized monoclonal
antibody against C5, inhibits terminal complement activation.
It stabilizes hemoglobin levels and reduces transfusion requirements in PNH patients.
Brodsky RA: Narrative review. Paroxysmal nocturnal hemoglobinuria: the
physiology of complement-related hemolytic anemia. Ann Intern Med
2008; 148:587.
Haspel RL, Hillmen P: Which patients with paroxysmal nocturnal
hemoglobinuria (PNH) should be treated with eculizumab? ASH
evidence-based review 2008. Hematology Am Soc Hematol Educ
Program 2008:35.
Hillmen P: The role of complement inhibition in PNH. Hematology Am
Soc Hematol Educ Program 2008:166.
Parker CJ: Bone marrow failure syndromes: paroxysmal nocturnal
hemoglobinuria. Hematol Oncol Clin North Am 2009; 23:333.
White JM, et al: Haemorrhagic bullae in a case of paroxysmal nocturnal
haemoglobinuria. Clin Exp Dermatol 2003; 28:504.

Paroxysmal hand hematoma (Achenbach syndrome)

receptor. Sebastian syndrome consists of giant platelets, leuko


cyte inclusions, and thrombocytopenia. Fechtner syndrome is
a rare type of familial thrombocytopenia associated with large
platelets, leukocyte inclusions, and features of Alport syndrome. The MayHegglin anomaly consists of easy bruising
with giant platelets and Dohle-like cytoplasmic inclusions in
granulocytes. The inclusions appear as electron-dense long
rods and needles oriented along the long axis of the spindle.
All four of these syndromes are due to abnormalities in the
MYH-9 gene. Glanzmann thrombasthenia, with dysfunctioning alphaIIbeta3 receptor, is a platelet storage pool defect
causing similar clinical findings.
Balderramo DC, et al: Sebastian syndrome: report of the first case in a
South American family. Haematologica 2003; 88:ECR17.
Hadjkacem B, et al: BernardSoulier syndrome: novel nonsense
mutation in GPIbbeta gene affecting GPIbIX complex expression. Ann
Hematol 2009; 88:465.
Matzdorff AC, et al: Perioperative management of a patient with
Fechtner syndrome. Ann Hematol 2001; 80:436.
Nurden AT, et al: Genetic testing in the diagnostic evaluation of
inherited platelet disorders. Semin Thromb Hemost 2009; 35:204.
Nurden P, Nurden AT: Congenital disorders associated with platelet
dysfunctions. Thromb Haemost 2008; 99:253.
Sachs UJ, et al: BernardSoulier syndrome due to the homozygous
Asn-45Ser mutation in GPIX: an unexpected, frequent finding in
Germany. Br J Haematol 2003; 123:127.
Salles II, et al: Inherited traits affecting platelet function. Blood Rev
2008; 22:155.
Simon D, et al: Platelet function defects. Haemophilia 2008; 14:1240.

Painful bruising syndrome (autoerythrocyte


sensitization, GardnerDiamond syndrome,
psychogenic purpura)
Painful bruising syndrome is a distinctive localized purpuric
reaction occurring primarily in young to middle-aged women
who usually manifest personality disorders. There may be
depression, anxiety, hysterical or masochistic character traits,
or inability to deal with hostile feelings. A recurrent type of
eruption, it is characterized by extremely painful and tender,
ill-defined ecchymoses about the extremities (Fig. 35-16) and
sometimes on the face or trunk. The lesions evolve in a few
hours and resolve within 58 days. New lesions may appear
in crops. Emotional upsets are generally associated with the
appearance of these painful purpuric lesions. Some patients
will report a premonition as to when they will develop new

Spontaneous focal hemorrhage into the palm or the volar


surface of a finger may result in transitory localized pain,
followed by rapid swelling and localized bluish discoloration.
The lesion resolves spontaneously within a few days.
Spontaneous hemorrhage from an arteriole appears to be
responsible. The acute nature, purpuric findings, and rapid
resolution are distinguishing features of Achenbach syndrome.
Robertson A, et al: Paroxysmal finger haematomas (Achenbachs
syndrome) with angiographic abnormalities. J Hand Surg [Br] 2002;
27:391.

Easy bruising syndromes


Young women who bruise easily despite normal coagulation
profiles and normal platelet counts may have antiplatelet antibodies. Otherwise, specific platelet function defects should be
suspected. BernardSoulier syndrome is a rare inherited disorder characterized by giant platelets, thrombocytopenia, and
a prolonged bleeding time. It is caused by genetic defects of
the glycoprotein IbIX complex that constitutes the VWF
820

Fig. 35-16 GardnerDiamond syndrome.

Archer-Dubon C, et al: Two cases of psychogenic purpura. Rev Invest


Clin 1998; 50:145.
Datta S, et al: A case of psychogenic purpura in a female child. J
Indian Med Assoc 2009; 107:104.
Moll S: Psychogenic purpura. Am J Hematol 1997; 55:146.
Panconesi E, et al: Stress, stigmatization and psychosomatic purpuras.
Int Angiol 1995; 14:130.
Uthman IW, et al: Autoerythrocyte sensitization (GardnerDiamond)
syndrome. Eur J Haematol 2000; 65:144.
Yucel B, et al: Dissociative identity disorder presenting with
psychogenic purpura. Psychosomatics 2000; 41:279.

Pigmentary purpuric eruptions (progressive


pigmentary dermatosis, progressive pigmenting
purpura, purpura pigmentosa chronica)
The pigmented purpuric eruptions (PPE) are a group of
common dermatoses of unknown pathogenesis.
The most common variant of progressive pigmentary dermatosis is Schambergs disease. The typical lesions are
thumbprint-sized and composed of aggregates of pinheadsized petechiae resembling grains of cayenne pepper on a
background of golden-brown hemosiderin staining. The
lesions commonly begin on the lower legs, with slow proximal
extension (Fig. 35-17). These lesions seldom itch. The favored
sites are around the lower shins and ankles, but lesions may
be more widespread and occasionally affect the upper extremities or trunk.
Majocchis disease is also known as purpura annularis telangiectodes. The early lesions are 13cm annular patches
composed of dark red telangiectases with petechiae and hemosiderin staining. Central involution and peripheral extension
produce ringed, semicircular, target-like, or concentric rings,
such as are seen on the cross-cut section of a tree trunk. The
eruption begins symmetrically on the lower extremities,
spreads up the legs, and may extend on to the trunk and arms.
Involution of individual patches is slow and, because new
lesions continue to form, may continue indefinitely. The
lesions are asymptomatic.
GougerotBlum syndrome (pigmented purpuric lichenoid
dermatitis) is characterized by minute, rust-colored to violaceous, lichenoid papules that tend to fuse into plaques of
various hues between red, violaceous, and brown (purpura
with lichenoid dermatitis). Favorite locations are the legs,
thighs, and lower trunk. The chief difference between this and
Schambergs disease is the deeper color and the presence of

Pigmentary purpuric eruptions

lesions a few hours ahead of time by the tingling and burning


sensation at the site of a future lesion. Extracutaneous somatic
symptoms are common, such as headache, paresthesias, transient paresis, syncope, diplopia, abdominal distress, diarrhea,
nausea and vomiting, and arthralgia.
Gardner and Diamond reported that intracutaneous injections of erythrocyte stroma evoked typical lesions. Since then,
many have reported similar reactions to autologous whole
blood, packed or washed red cells, or fractions of erythrocyte
stroma. These are hard to assess, because similar reactions
have been reported to substances as diverse as hemoglobin,
phosphatidyl serine, histamine, histidine, trypsin, purified
protein derivative (PPD), autologous serum, and platelets.
Blinded, controlled testing, trying to avoid factitial trauma, has
given mixed responses. Abnormalities in tissue plasminogen
activator-dependent fibrinolysis, thrombocytosis, and anticardiolipin antibodies have also been implicated. Most now
believe this syndrome is psychosomatic and artifactual. The
most effective treatment is to address the underlying psychological dysfunction. Improvement of the underlying psychopathology usually leads to disappearance of the cutaneous
manifestations.

Fig. 35-17 Schambergs disease.

induration, both of which relate to the presence of a lichenoid


band of lymphoid inflammation. Similar lesions have also
occurred during IFN therapy for hepatitis C.
Ducas and Kapetanakis pigmented purpura is scaly and
eczematous. The eczematous patches also demonstrate
petechiae and hemosiderin staining. Pruritus is common, and
the lesions are often more extensive than the other pigmented
purpuras. It is distinguished histologically by the presence of
spongiosis. Purpuric pityriasis rosea may resemble Ducas and
Kapetanakis purpura.
Lichen aureus is characterized by the sudden appearance of
one or several golden or rust-colored, closely packed macules
or lichenoid papules. The macules may be grouped into a
patch and may occur on any part of the body, but the vast
majority of lesions occur on the feet or lower leg. The patches
are usually solitary and asymptomatic, but may occasionally
be painful. Adults predominate, but children may also be
affected.
Rare variants of the pigmented purpuric dermatoses are the
linear or zosteriform type and the transitory type. These tend
to be more transient than the other variants. A single case of
evolution to linear morphea has been reported.
Histologically, all forms of pigmenting purpura demonstrate superficial perivascular lymphocytic (and at times granulomatous) infiltrate associated with extravasation of red cells
and, in later lesions, hemosiderin deposition. The degree of
hemosiderin deposition may be variable and insufficient to
confirm the diagnosis histologically. The infiltrating cells are
primarily CD4+ lymphocytes. There may be a lichenoid band
of lymphoid inflammatory cells (GougerotBlum type) or
spongiosis (Ducas and Kapetanakis type). An iron stain (Perl,
Prussian blue, ferricyanide) is sometimes used to demonstrate
the hemosiderin deposition.
Cutaneous T-cell lymphoma may begin with clinical lesions
that resemble pigmented purpura. In addition, lesions of pigmented purpuric dermatosis may demonstrate clonality.
Patients with more widespread lesions above the knee are
much more likely to have clonal infiltrates and eventually
meet histological criteria for the diagnosis of cutaneous T-cell
lymphoma.
821

Cutaneous Vascular Diseases

35

In most cases of pigmented purpuric dermatosis, the etiology is unknown. Patients with stasis dermatitis and venous
insufficiency may develop lesions that bear a superficial clinical resemblance to Schambergs disease. Their lesions are more
diffuse and do not form well-circumscribed macules. Oral
medications can induce eruptions that closely resemble
DucasKapetanakis purpura. These include acetaminophen,
aspirin, glipizide, IFN-, and medroxyprogesterone injections.
Stopping the offending medication will lead to resolution of
the eruption. Pigmented purpuric contact dermatitis may simulate a PPE. Inciting allergens include nickel sulfate, fragrance
mix, and Disperse Blue dyes. Patch testing on the back may be
negative, but a positive response may be seen when the offending allergen is applied to a lesion. As with pigmenting drug
eruptions, pigmented purpuric contact dermatitis should be
suspected when the lesions are more widespread (sites other
than the legs) and especially if they have an eczematous
character.
Anecdotal reports of benefit from topical steroids make a
therapeutic trial for 46 weeks reasonable. Oral rutoside,
50mg twice a day, and ascorbic acid, 500mg twice a day, have
cleared a few patients. PUVA and narrow-band ultraviolet
(UV) B have demonstrated efficacy and should be considered
when the above modalities fail. Immunosuppressive therapy
with cyclosporine and methotrexate has also been effective,
but is usually not warranted in such a pauci-symptomatic
disorder. If immunosuppression is considered, CTCL (cutaneous T-cell lymphoma) must be excluded, and patch testing and
drug withdrawal should have been undertaken.
Abe M, et al: Transitory pigmented purpuric dermatoses in a young
Japanese female. J Dermatol 2008; 35:525.
Bell HK, et al: Localized morphoea preceded by a pigmented purpuric
dermatosis. Clin Exp Dermatol 2003; 28:369.
Engin B, et al: Patch test results in patients with progressive pigmented
purpuric dermatosis. J Eur Acad Dermatol Venereol 2009; 23:209.
Georgala S, et al: Persistent pigmented purpuric eruption associated
with mycosis fungoides: a case report and review of the literature. J
Eur Acad Dermatol Venereol 2001; 15:62.
Gupta G, et al: Capillaritis associated with interferon-alfa treatment of
chronic hepatitis C infection. J Am Acad Dermatol 2000; 43(5 Pt
2):937.
Hamada T, et al: A case of zosteriform pigmented purpuric dermatosis.
Arch Dermatol 2007; 143:1599.
Hoesly FJ, et al: Purpura annularis telangiectodes of Majocchi: case
report and review of the literature. Int J Dermatol 2009; 48:1129.
Komericki P, et al: Pigmented purpuric contact dermatitis from Disperse
Blue 106 and 124 dyes. J Am Acad Dermatol 2001; 45:456
Lin W-L, et al: Granulomatous variant of chronic pigmented purpuric
dermatoses: report of four new cases and an association with
hyperlipidaemia. Clin Exp Dermatol 2007; 32:513.
Magro CM, et al: Pigmented purpuric dermatosis. Am J Clin Pathol
2007; 128:218.
Rose RF, et al: Pigmented purpuric dermatosis as a delayed reaction to
medroxyprogesterone acetate. J Eur Acad Dermatol Venereol 2008;
22:1150.
Sardana K, et al: Pigmented purpuric dermatoses: an overview. Int J
Dermatol 2004; 43:482.
Ugajin T, et al: Mycosis fungoides presenting as pigmented purpuric
eruption. Eur J Dermatol 2005; 15:489.

Purpuric agave dermatitis


Agave americana is a large, thick, long-leaved, subtropical plant
with a striking bluegray color. It is commonly used in ornamental beddings in the southwestern US. The plant grows up
to 2 metres in diameter and may overgrow the surrounding
landscape. As these plants are very deep-rooted and difficult
to remove, some individuals have attempted removal with the
help of a chain saw. A striking purpuric dermatosis occurs in
a pattern corresponding to the splatter of the plants sap.
822

Histologically, there is vascular damage at the level of the


capillary and postcapillary venule, with a sparse infiltrate of
neutrophils and karyorrhectic debris, suggesting low-grade
leukocytoclastic vasculitis. Papulovesicular lesions have also
been described. The plants sap contains calcium oxalate crystals, as well as various acrid oils and saponins. The causative
component is unknown.
Cherpelis BS, et al: Purpuric irritant contact dermatitis induced by Agave
americana. Cutis 2000; 66:287.
Ricks MR, et al: Purpuric agave dermatitis. J Am Acad Dermatol 1999;
40(2 Pt 2):356.

VASCULITIS
Vasculitis is a clinicopathologic process characterized by
inflammation and necrosis of blood vessels. Since the clinical
morphology correlates with the size of the affected blood
vessel(s), these disorders are classified by the blood vessel(s)
affected. Diseases may involve vessels of overlapping size. In
general, small-vessel disease (affecting postcapillary venules)
causes urticarial lesions and palpable purpura; small-artery
disease manifests as subcutaneous nodules; medium-sized
arteries with necrosis of major organs, livedo, purpura, and
mononeuritis multiplex; and large-vessel disease with symptoms of claudication and necrosis.

Classification
Numerous classification schemes have been proposed, all of
which have limitations. It is important to remember that infectious and thrombotic conditions, which classically show
thrombosis of vessels histologically, may also at times show
true leukocytoclastic vasculitis. Hence, infectious, embolic,
and thrombotic causes of vessel damage must always be considered before unequivocally diagnosing a case as an inflammatory vasculitis. Leukocytoclastic vasculitis is also
commonly seen adjacent to suppurative folliculitis and at the
base of chronic ulcers. The discovery of the association of some
forms of small- and medium-vessel vasculitides with positive
ANCAs has made their diagnosis and classification much
easier (Box 35-1).
Carlson JA, Chen KR: Cutaneous vasculitis update: small vessel
neutrophilic vasculitis syndromes. Am J Dermatopathol 2006; 28:486.
Fiorentino DF: Cutaneous vasculitis. J Am Acad Dermatol 2003; 48:311.
Grzeszkiewicz TM, Fiorentino DF: Update on cutaneous vasculitis. Semin
Cutan Med Surg 2006; 25:221.
Sunderkotter C, Sindrilaru A: Clinical classification of vasculitis. Eur J
Dermatol 2006; 16:114.

Small-vessel vasculitis
Cutaneous small-vessel vasculitis (cutaneous
leukocytoclastic vasculitis)
The vast majority of cases of cutaneous leukocytoclastic vasculitis (LCV) follow an acute infection or exposure to a new
medication. Palpable purpura is the hallmark of this disease,
with lesions ranging from pinpoint to several centimeters in
diameter (Fig. 35-18). Annular, vesicular, bullous, or pustular
lesions may develop. Small ulcerations may develop, but
when ulceration is prominent, one must suspect either a vasculitis of larger vessels (small to medium arterioles) or the
presence of both a vasculitis and a hypercoagulable state.
Lesions of LCV predominate on the ankles and lower legs,
affecting mainly dependent areas or areas under local pressure. Edema, especially of the ankles, is usually noted. In the
hospitalized or bedridden patient, the buttocks and posterior

Box 35-1 Classification of vasculitis


I. Cutaneous small-vessel (postcapillary venule)
Idiopathic cutaneous small-vessel vasculitis
HenochSchnlein purpura
Acute hemorrhagic edema of infancy
Urticarial vasculitis
Cryoglobulinemic vasculitis
Erythema elevatum diutinum
Granuloma faciale
Other diseases with leukocystoclastic vasculitis: druginduced vasculitis, malignancy (lymphoreticular more
common than solid tumor), connective tissue diseases,
hyperglobulinemic purpura, inflammatory bowel disease,
bowel-associated dermatitisarthritis syndrome (bowel
bypass), HIV infection, and neutrophilic dermatoses
(Behet; Sweet; erythema nodosum leprosum; septic
vasculitis; autoinflammatory conditionsfamilial
Mediterranean fever, and serum sickness)

Small-vessel vasculitis

A.
B.
C.
D.
E.
F.
G.
H.

II. Medium-vessel
A. Polyarteritis nodosa
1. Benign cutaneous forms
2. Systemic form

III. Mixed size (medium and small) vessel disease


A. Connective tissue disease associated (usually
rheumatoid vasculitis)
B. Septic vasculitis
C. ANCA-associated
1. Microscopic polyangiitis
2. Wegener granulomatosis
3. Allergic granulomatosis (ChurgStrauss)
4. Occasional drug-induced (most are postcapillary
venule only)

IV. Large-vessel vasculitis


A. Giant-cell arteritis
B. Takayasu arteritis

thighs are dependent areas and may be the initial or primary


site of involvement. Mild pruritus, fever, and malaise may
occur. Arthralgias or, less commonly, frank arthritis may be
seen. Other systemic involvement is rare and should raise the
consideration of another diagnosis. Although, in general, systemic involvement is not found or is minimal, serious systemic
disease can accompany cutaneous LCV and should be looked
for in every patient.
The lesions usually resolve within 34 weeks, with residual
postinflammatory hyperpigmentation. Ten percent of cases of
cutaneous LCV may have recurrences. A persistent underlying cause must be sought in cases that are chronic.

Histology
There is angiocentric segmental inflammation of the postcapillary venule, with expansion of the vessel wall, fibrin deposition, and infiltration by neutrophils that show fragmentation
of their nuclei (karyorrhexis or leukocytoclasia). Endothelial
cell swelling is common, but endothelial necrosis suggests
more serious illness (including septic vasculitis, ANCAassociated vasculitis). Vascular thrombosis may be present.
The presence of tissue eosinophilia favors a medication as the
cause. Immunofluorescence and ultrastructural studies have
shown the presence of immunoglobulins, complement components, and fibrin deposits within postcapillary venule walls if
the biopsy is taken within the first 24h. Later, fibrin is prominent, but immunoglobulin deposits may have been destroyed.
An important exception is HenochSchnlein purpura, which

Fig. 35-18 Leukocytoclastic vasculitis, palpable purpura.

usually demonstrates prominent IgA deposits, even in more


advanced lesions.

Pathogenesis
Cutaneous small-vessel vasculitis is felt to be caused by circulating immune complexes. These complexes lodge in vessel
walls and activate complement. Various inflammatory mediators are produced, contributing to endothelial injury. Cocaine
use may cause or exacerbate small-vessel vasculitis.

Etiology
Most cases of cutaneous LCV are post-infectious or druginduced. Drugs in virtually every class have been reported as
causing LCV, and the time from when the medication was
started to the onset of the eruption may be hours to years,
making any ingested agent a possible cause. A host of infectious agents, such as -hemolytic Streptococcus group A,
Mycoplasma, and rarely Mycobacterium tuberculosis may cause
palpable purpura. Patients with lymphoproliferative neoplasms, as well as solid tumors (lung, colon, genitourinary,
and breast cancer) may experience cutaneous small-vessel vasculitis at some time during the course of their disease. A recurrence of the LCV may mark the return of a treated malignancy.
Cutaneous LCV may be the initial manifestation of a medium
or mixed-vessel vasculitis.

Clinical evaluation
The clinical evaluation is critical in separating those cases of
benign cutaneous vasculitis (usually following an infection or
induced by a medication) from those cases associated with
more serious underlying disease or which have significant
systemic involvement. It may not be possible on initial physical examination to separate the more benign-behaving cases
from those associated with more serious disease. The history
823

Cutaneous Vascular Diseases

35

should focus on possible infectious disorders, prior associated


diseases, drugs ingested, and a thorough review of systems.
Screening laboratory tests may help to elucidate the underlying cause or extent of organ involvement. When the history
suggests a recent drug and the patient is clinically well, nothing
more than a urinalysis may be required. A complete blood
count, urinalysis, strep throat culture or ASO titer, hepatitis B
and C serologies, and ANA and rheumatoid factor are a reasonable initial screen for patients with no obvious cause for
their vasculitis. Serum protein electrophoresis, serum complements, ANCAs, and cryoglobulins may be required in some
cases. A skin biopsy should be performed to confirm the diagnosis of LCV. Direct immunofluorescence should be performed to identify HenochSchnlein purpura.

Treatment
The initial treatment of most cases of leukocytoclastic vasculitis in patients who are clinically well and have a normal urin
alysis should be nonaggressive, since the majority of cases
are acute and self-limited, affect only the skin, and do not
threaten progressive deterioration of internal organs. Rest and
elevation of the legs is likely to be helpful. Analgesics and
avoidance of trauma and cold are prudent general measures.
An identified antigen or drug should, of course, be eliminated
and any identified infectious, connective tissue, or neoplastic
disease treated.
A variety of systemic treatments may be required for severe,
intractable, or recurrent disease, especially if significant organ
involvement is present. For disease limited to the skin, NSAIDs
can be considered for the arthralgias. Colchicine, 0.6mg 23
times a day, or dapsone, 50200mg/day, as trials of 23 weeks
each, may be useful for chronic vasculitis. Low doses of colchicine and dapsone may be combined, if either medication
alone is unsuccessful or effective doses of either drug cannot
be reached. Although one controlled trial suggested that colchicine was ineffective in LCV, even in that trial a portion of
the patients did respond and flared when the drug was
stopped. Oral antihistamines, by blocking the vasodilation
induced by histamine, may reduce immune complex trapping
and improve LCV. Systemic corticosteroids, in doses ranging
from 60 to 80mg/day, are recommended for patients with
serious systemic manifestations or necrotic lesions. Usually, a
brief course leads to resolution, and chronic treatment is rarely
required. In refractory patients immunosuppressive agents,
such as mycophenolate mofetil, 23g/day; methotrexate,
525mg/week; or azathioprine, 50200mg/day (23.5mg/
kg/day), may be considered. Azathioprine dosing is based on
thiopurine methyltransferase levels. In more difficult cases,
cyclophosphamide, monthly intravenous pulses of steroids or
cyclophosphamide, or cyclosporine, 35mg/kg/day, may be
effective. The tumor necrosis factor (TNF)-blockers, especially
infliximab and to a lesser degree etanercept, may be effective
in cutaneous small-vessel vasculitis. These agents may also
cause vasculitis. Rituximab has been effective in refractory
cases.

824

Bahrami S, et al: Tissue eosinophilia as an indicator of drug-induced


cutaneous small-vessel vasculitis. Arch Dermatol 2006; 142:155.
Drago F, et al: Cutaneous vasculitis induced by cyclo-oxygenase-2
selective inhibitors. J Am Acad Dermatol 2004; 51:1029.
Fain O, et al: Vasculitides associated with malignancies: analysis of
sixty patients. Arthritis Rheum 2007; 57:1473.
Fiorentino DF: Cutaneous vasculitis. J Am Acad Dermatol 2003; 48:311.
Greco F, et al: Cutaneous vasculitis associated with Mycoplasma
pneumoniae infection: case report and literature review. Clin Pediatr
(Phila) 2007; 46:451.
Kim HM, et al: Cutaneous leukocytoclastic vasculitis with cervical
tuberculous lymphadenitis: a case report and literature review.
Rheumatol Int 2006; 26:1154.
Mang R, et al: Therapy for severe necrotizing vasculitis with infliximab. J
Am Acad Dermatol 2004; 51:321.

McCain ME, et al: Etanercept and infliximab associated with cutaneous


vasculitis. Rheumatology 2002; 41:116.
McIlwain L, et al: Hypersensitivity vasculitis with leukocytoclastic
vasculitis secondary to infliximab. J Clin Gastroenterol 2003; 36:411.
Nousari HC, et al: Annular leukocytoclastic vasculitis associated with
monoclonal gammopathy of unknown significance. J Am Acad
Dermatol 2000; 43:955.
Sais G, et al: Colchicine in the treatment of cutaneous leukocytoclastic
vasculitis. Results of a prospective, randomized controlled trial. Arch
Dermatol 1995; 131:1399.
Solans-Laque R, et al: Paraneoplastic vasculitis in patients with solid
tumors: report of 15 cases. J Rheumatol 2008; 35:294.

Cutaneous vasculitis and connective tissue disease


Patients with various connective tissue diseases (SLE, Sjgrens
syndrome, rheumatoid arthritis [RA], and dermatomyositis)
may develop cutaneous vasculitic lesions. Vasculitis in the
setting of connective tissue disease may be associated with
significant internal organ involvement, especially of the
peripheral and central nervous system and the kidneys
(glomerulonephritis). Ischemic digital infarcts are seen in
addition to palpable purpura. Ulceration of vasculitic lesions
is not uncommon and may be particularly difficult to manage
in the patient with RA. The prevalence of vasculitis in patients
with RA has decreased with improved treatment of RA.
Treatment is the same as for cutaneous LCV, along with management of the underlying connective tissue disease.
Genta MS, et al: Systemic rheumatoid vasculitis: a review. Semin
Arthritis Rheum 2006; 36:88.
Piqu E, et al: Leukocytoclastic vasculitis presenting as an erythema
gyratum repens-like eruption on a patient with systemic lupus
erythematosus. J Am Acad Dermatol 2002; 47:S254.

Subtypes of small-vessel vasculitis


HenochSchnlein purpura
HenochSchnlein purpura (HSP) is characterized by purpura,
arthralgias, and abdominal and renal disease. Typically,
mottled purpura appears on the extensor aspects of the
extremities, which become hemorrhagic within a day and start
to fade in about 5 days (Fig. 35-19). New crops may appear
over a period of a few weeks. Urticarial lesions, vesicles,
necrotic purpura, and hemangioma-like lesions may also be
present at some stages. It occurs primarily in male children,
with a peak age between 4 and 8 years; however, adults may
also be affected. A viral infection or streptococcal pharyngitis
is the usual triggering event. H. pylori infection has been implicated in some childhood and adult cases.
In about 40% of cases, the cutaneous manifestations are
preceded by mild fever, headache, joint symptoms, and

Fig. 35-19 HenochSchnlein purpura.

Blanco R, et al: HenochSchnlein purpura as clinical presentation of a


myelodysplastic syndrome. Clin Rheumatol 1997; 16:626.
Egan CA, et al: Relapsing HenochSchnlein purpura associated with
Pseudomonas aeruginosa pyelonephritis. J Am Acad Dermatol 1999;
41:381.
Hoshino C: Adult onset SchnleinHenoch purpura associated with
Helicobacter pylori infection. Intern Med 2009; 48:847.
Mytinger JR, et al: HenochSchnlein purpura associated with
Helicobacter pylori in a child. Pediatr Dermatol 2008; 25:630.
Paller AS, et al: Pulmonary hemorrhage: an often fatal complication of
HenochSchoenlein purpura. Pediatr Dermatol 1997; 14:299.
Piette WW: What is SchnleinHenoch purpura, and why should we
care (editorial)? Arch Dermatol 1997; 133:438.
Reinauer S, et al: SchnleinHenoch purpura associated with gastric
Helicobacter pylori infection. J Am Acad Dermatol 1995; 33:876.

Tancrede-Bohin E, et al: SchnleinHenoch purpura in adult patients.


Arch Dermatol 1997; 133:438.
Trapani S, et al: Severe hemorrhagic bullous lesions in Henoch
Schnlein purpura: three pediatric cases and review of the literature.
Rheumatol Int 2009 Jul 16 (Epub ahead of print).
Zurada JM, et al: HenochSchnlein purpura associated with
malignancy in adults. J Am Acad Dermatol 2006; 55:S65.

Acute hemorrhagic edema of infancy


Also known as Finkelsteins disease, Seidlmayer syndrome,
medallion-like purpura, infantile postinfectious iris-like
purpura and edema, and purpura en cocarde avec oedme,
acute hemorrhagic edema (AHE) of infancy affects children
under the age of 2 with a recent history of an upper respiratory
illness (75%), a course of antibiotics, or both. The children are
often nontoxic in appearance. There is abrupt onset of large
cockade, annular, or targetoid purpuric lesions involving the
face, ears, and extremities (Fig. 35-20). Scrotal purpura may
also occur. Early in the course there may first be acral edema,
with subsequent proximal spread. The edema is nontender
and may be asymmetrical. A low-grade fever is common, and
involvement of internal organ systems (joint pains, gastrointestinal symptoms, and renal involvement) is rare. Routine
laboratory tests are unremarkable. Spontaneous recovery
without sequelae occurs within 1220 days. The differential
diagnosis includes HSP, meningococcemia, erythema multiforme, urticaria, and Kawasakis disease. There are some similarities between HSP and AHE (postinfectious, seasonal,
favors males), but it is different in that it favors younger children (<2 years), resolves more quickly, lacks IgA on direct
immunofluorescence in most cases, and is rarely associated
with systemic symptoms. In one family, a child under 4 developed AHE while the sibling aged 16 developed HSP following
the same pharyngitis. From a clinical point of view, the most
urgent need is to exclude the possibility of septicemia, especially meningococcemia.

Small-vessel vasculitis

abdominal pain for up to 2 weeks. Arthralgia progressing to


arthritis produces periarticular swelling around the knees and
ankles. There may be pulmonary hemorrhage, which can be
fatal. Abdominal pain and gastrointestinal bleeding may occur
at any time during the disease; severe abdominal pain may
even suggestor portendan acute surgical abdomen.
Paralytic ileus may occur. Vomiting, rebound tenderness, and
distension are other manifestations. Gastrointestinal radiographs may show spiking or a marbled cobble-stone
appearance. Renal involvement manifests as microscopic or
even gross hematuria, and may occur in 25% or more of
patients. The long-term prognosis in children with gross hematuria is very good; however, progressive glomerular disease
and renal failure may develop in a small percentage, so that
careful follow-up is necessary for those with hematuria.
IgA, C3, and fibrin depositions have been demonstrated in
biopsies of both involved and uninvolved skin by immuno
fluorescence techniques. Since IgA immune complexes persist
longer in vasculitis, they are easier to identify than the IgG/Mcontaining immune complexes in other forms of LCV. In
patients with abdominal pain suggestive of HSP but with no
skin lesions, one can inject histamine (as used as a control by
the allergists) into the skin and biopsy the area 4h later. This
histamine trap test may identify IgA in vessels and confirm
the diagnosis of HSP.
In adults, HSP is not rare. Adult patients have IgA glomerulo
nephritis or other renal abnormalities in more than 50% of
cases. Purpura above the waist in adults was more common
in patients with glomerulonephritis. In adult patients with
HSP and upper gastrointestinal symptoms (gastritis), a search
for H. pylori infection should be undertaken. If an association
with H. pylori can be confirmed, treatment of the gastrointestinal infection may lead to resolution of the HSP. HSP in adults
can be associated with an underlying malignancy. Males represent 90% or more of malignancy-associated HSP cases. Solid
tumors are seen in more than half of cases (especially nonsmall-cell lung cancer, prostate cancer, and renal cancer). Forty
percent of cases have a hematological malignancy. About half
of the cases present within 1 month of the diagnosis of the
malignancy.
Treatment is supportive. The usual duration of illness is
616 weeks. Between 5% and 10% of patients will have per
sistent or recurrent disease. Dapsone, 50 to 200mg/day, or
colchicine, 0.6mg/day to 1.2mg twice a day, can be used
initially if treatment is required and skin lesions are the
primary concern. For abdominal pain, an H2 blocker and/or
corticosteroids (prednisone at 1mg/kg/day) can be effective.
Corticosteroids are more effective for abdominal pain than is
analgesia. The value of systemic corticosteroids in the treatment of renal disease is controversial, but they may be used
preventively or to treat active nephritis. IVIG can be used in
refractory skin disease and persistent abdominal pain, and to
arrest rapidly progressive glomerulonephritis. NSAIDs are
best avoided, as they may cause renal or gastrointestinal
complications.

Goraya JS, Kaur S: Acute infantile hemorrhagic edema and Henoch


Schnlein purpura: is IgA the missing link? J Am Acad Dermatol 1999;
47:801.
Ince E, et al: Infantile acute hemorrhagic edema: a variant of
leukocytoclastic vasculitis. Pediatr Dermatol 1995; 12:224.
Karremann M, et al: Acute hemorrhagic edema of infancy: report of 4
cases and review of the current literature. Clin Pediatr (Phila) 2009;
48:323.

Fig. 35-20 Acute hemorrhagic edema, typical large annular


hemorrhagic plaques.

825

Cutaneous Vascular Diseases

35

Kuroda K, et al: Acute haemorrhagic oedema of infancy associated with


cytomegalovirus infection. Br J Dermatol 2002; 147:1254.
Millard T, et al: Acute infantile hemorrhagic oedema. J Am Acad
Dermatol 1999; 41:837.

Urticarial vasculitis
A significant percentage of patients (reported as high as 510%,
but probably less) with fixed urticarial lesions will have vasculitis histologically. This is termed urticarial vasculitis (Fig.
35-21). This urticarial morphology is maintained throughout
the course of the illness. Microscopic hemorrhage into the
urticarial plaques may occur, resulting in a bruise-like appearance as the lesions fade. Determination of the serum complement levels (CH50, C3, C4, and anti-C1q precipitins) is critical
in the evaluation of urticarial vasculitis. Patients with normal
complement levels usually have a leukocytoclastic vasculitis,
which is idiopathic, limited to the skin, self-resolving, and best
considered a subset of cutaneous small-vessel vasculitis.
Hypocomplementemic urticarial vasculitis is a distinctive syndrome seen virtually always in women. Clinical features
include arthritis (50%), arthralgias, angioedema, eye symptoms, asthma and obstructive pulmonary disease (20%), and
gastrointestinal symptoms (20%). Glomerulonephritis may be
present. A rare subset of patients with hypocomplementemic
urticarial vasculitis has Jaccouds arthropathy and serious valvular heart disease.
Underlying diseases associated with all forms of urticarial
vasculitis include gammopathies (IgG and IgM gammopathy),
SLE, Sjgren syndrome, serum sickness, and viral infections,
especially hepatitis C. Patients with hypocomplementemic
urticarial vasculitis can have anti-C1q antibodies directed
against the collagen-like region of that molecule, a feature used
to define this disease. Patients with SLE may also have these
autoantibodies. Many patients with hypocomplementemic
urticarial vasculitis will have positive ANAs, and up to onequarter will have positive anti-dsDNA antibodies. The vast
majority (96%) will have a positive lupus band test. Over
time, more than 50% will meet the criteria for the diagnosis of
SLE. For this reason, some consider hypocomplementemic
urticarial vasculitis a form of SLE. Patients with HCV infection
may develop hypocomplementemic or normocomplementic
urticarial vasculitis without a detectable cryoglobulin.
Three clinical features distinguish the skin lesions of urticarial vasculitis from true urticaria:
1. The lesions are often painful, rather than pruritic.
2. The lesions last longer than 24h and are fixed, rather
than migrating.

Fig. 35-21 Urticarial vasculitis.

826

3. On resolving, there is postinflammatory purpura or


hyperpigmentation.
More difficult is the distinction of urticarial vasculitis from
neutrophilic urticaria, as patients with the latter condition can
have painful, more persistent lesions. Histologic evaluation is
critical.
Histologically, patients with hypocomplementemic urticarial vasculitis will show both leukocytoclastic vasculitis and
diffuse interstitial neutrophils. Eosinophils are more likely to
be seen in patients with neutrophilic urticaria or normocomplementemic urticarial vasculitis. Sweet syndrome shows a
more intense dermal infiltrate with marked upper dermal
edema. Sweet syndrome and vasculitis share the presence of
karyorrhexis. While virtually all biopsies of idiopathic urticaria demonstrate neutrophils, karyorrhexis is usually distinctly absent. In neutrophilic urticaria, neutrophils will be
found in the dermis and in the vessel walls (moving from the
vascular compartment into the skin). Finding neutrophils in
the vessel walls alone without fibrinoid necrosis of vessel
walls and leukocytoclasia is insufficient to make the diagnosis
of urticarial vasculitis. Most patients with urticarial lesions
with neutrophilic infiltrates and normal complements have
neutrophilic urticaria rather than urticarial vasculitis.
Other neutrophilic disorders that are in the differential diagnosis of urticarial vasculitis include mixed cryoglobulinemia,
Schnitzler syndrome, the autoinflammatory syndromes (CIAS1/NALP-3 mutations), and neutrophilic dermatosis associated
with connective tissue disease. Mixed cryoglobulinemia will be
seen most frequently in the context of HCV infection and may
present with urticarial, purpuric, or even necrotic/ulcerative
lesions. Vasculitis should be seen on biopsy. The other three
conditions all can have cutaneous lesions that are urticarial and
clinically very similar. They tend to have less dermal edema
than is typical of either urticaria or Sweet syndrome.
Histologically, they lack vasculitis but show tissue neutrophilia
with leukocytoclasia. Schnitzler is diagnosed by the finding of
an IgM monoclonal gammopathy. The autoinflammatory syndromes are diagnosed by their characteristic features and
genetic testing. In some patients with adult-onset Still disease
or SLE, transient macules and papules coalescing into plaques
may be seen. This condition has been termed neutrophilic
urticarial dermatitis, but its pathogenesis remains unknown.
In the setting of such neutrophilic urticarial lesions, ferritin
measurement and a workup for SLE are appropriate.
The treatment of hypocomplementemic urticarial vasculitis
is directed at the symptomatology and severity of the disease.
Indomethacin has been particularly effective. Antihistamines,
dapsone, and colchicine may be tried. The addition of pentoxifylline to dapsone may be effective. Antimalarials can be
beneficial, as would be expected in this autoimmune connective tissue disease. Immunosuppressive therapy with prednisone and the steroid-sparing agent mycophenolate mofetil
(2g/day) can be considered in refractory and severe cases.
Amano H, et al: Hypocomplementemic urticarial vasculitis with
Jaccouds arthropathy and valvular heart disease: case report and
review of the literature. Lupus 2008; 17:837.
Chang S, Carr W: Urticarial vasculitis. Allergy Asthma Proc 2007; 28:97.
Davis MDP, et al: Clinicopathologic correlation of hypocomplementemic
and normocomplementemic urticarial vasculitis. J Am Acad Dermatol
1998; 38:899.
Fiorentino DF: Cutaneous vasculitis. J Am Acad Dermatol 2003; 48:311.
Hamid S, et al: Urticarial vasculitis caused by hepatitis C virus infection.
J Am Acad Dermatol 1998; 39:278.
Hunt DP, et al: Pulmonary capillaritis and its relationship to development
of emphysema in hypocomplementaemic urticarial vasculitis
syndrome. Sarcoidosis Vasc Diffuse Lung Dis 2006; 23:70.
Kieffer C, et al: Neutrophilic urticarial dermatosis. Medicine 2009; 88:23.
Nurnberg W, et al: Urticarial vasculitis syndrome effectively treated with
dapsone and pentoxifylline. Acta Derm Venereol 1995; 75:54.

Cryoglobulinemic vasculitis
About 15% of patients with a circulating cryoprecipitable
protein are symptomatic and have cryoglobulinemic vasculitis. They typically have mixed cryoglobulinemia. Mixed cryo
globulinemia follows a benign course in half of cases, but in
about one-third liver or renal failure occurs. Fifteen percent of
cases develop malignancy, usually B-cell lymphoma, and less
frequently hepatocellular or thyroid cancer. By far the most
common cause of cryoglobulinemic vasculitis is HCV infection, but autoimmune diseases and lymphoproliferative disorders can also be associated with cryoglobulinemic vasculitis.
Cryoglobulinemic vasculitis usually presents with macular or
palpable purpura, typically confined to the lower extremities.
Lesions may be limited or severe. Two-thirds of patients show
confluent areas of hemosiderosis of the feet and lower legs,
characteristic of prior episodes of purpura. While only 30% of
patients report an exacerbation with cold exposure, up to 50%
will have Raynaud phenomenon and cold-induced acrocyanosis of the ears. Other morphologies include ecchymoses, livedo
reticularis, urticaria, and ulcerations. Widespread systemic
vasculitis occurs in about 10% of patients. Neuropathy and
other neurologic complications occur in 40% of patients.
Arthralgias, xerostomia, and xerophthalmia are frequent complaints. Laboratory evaluation will reveal a cryoglobulin,
hypocomplementemia (90%), and a positive rheumatoid factor
(70%). ANCAs are rarely positive. A skin biopsy will show
LCV.
The treatment of cryoglobulinemic vasculitis is the treatment of the underlying disease if possible. In the case of HCV
infection, this usually is IFN- plus ribavirin. Cryoglobulinemic
vasculitis associated with HCV may also be flared by IFN
treatment. Colchicine, dapsone, IVIG, infliximab, and rituximab (an anti-CD20 monoclonal antibody) can be attempted. In
severe cases plasmapheresis may be beneficial.
Batisse D, et al: Sustained exacerbation of cryoglobulinaemia-related
vasculitis following treatment of hepatitis C with peginterferon alfa. Eur
J Gastroenterol Hepatol 2004; 16:701.
Cacoub P, et al: Anti-CD20 monoclonal antibody (rituximab) treatment
for cryoglobulinemic vasculitis: where do we stand? Ann Rheum Dis
2008; 67:283.
Chandesris MO, et al: Infliximab in the treatment of refractory vasculitis
secondary to hepatitis C-associated mixed cryoglobulinaemia.
Rheumatology 2004; 43:532.
De Blasi T, et al: Cryoglobulinemia-related vasculitis during effective
anti-HCV treatment with PEG-interferon alfa-2b. Infection 2008; 36:285.
Enomoto M, et al: Entecavir to treat hepatitis B-associated
cryoglobulinemic vasculitis. Ann Intern Med 2008; 149:912.
Farri C, et al: Mixed cryoglobulinemia: demographic, clinical, and
serologic features and survival in 231 patients. Semin Arthritis Rheum
2004; 33:355.
Kawakami T, et al: Remission of hepatitis B virus-related
cryoglobulinemic vasculitis with entecavir. Ann Intern Med 2008;
149:911.
Nemni R, et al: Peripheral neuropathy in hepatitis C virus infections with
and without cryoglobulinaemia. J Neurol Neurosurg Psychiatry 2003;
74:1267.
Roccatello D, et al: Long-term effects of anti-CD20 monoclonal antibody
treatment of cryoglobulinaemic glomerulonephritis. Nephrol Dial
Transplant 2004; 19:3054.

Scarpato S, et al: Plasmapheresis in cryoglobulinemic neuropathy: a


clinical study. Dig Liver Dis 2007; 39:S136.
Tallarita T, et al: Successful combination of rituximab and plasma
exchange in the treatment of cryoglobulinemic vasculitis with skin
ulcers: a case report. Cases J 2009; 2:7859.

Macular lymphocytic arteritis (lymphocytic


thrombophilic arteritis)
This is a rarely reported condition that affects predominantly
non-Caucasian females. It presents with multiple ill-defined
brown macules on the lower legs resembling postinflammatory hyperpigmentation. Histologically, a vessel in the sub
cutaneous fat is infiltrated with lymphocytes but there is no
destruction of the vessels. Neutrophils are absent.

Small-vessel vasculitis

Saadoun D, et al: Anti-C1q antibodies in hepatitis C virus infection. Clin


Exp Immunol 2006; 145:308.
Shaw D, et al: Hypocomplementaemic urticarial vasculitis associated
with non-Hodgkin lymphoma and treatment with intravenous
immunoglobulin. Br J Dermatol 2007; 157:392.
Toprak O, et al: Hypocomplementaemic urticarial vasculitis syndrome
and acute renal failure with cryoglobulin() hepatitis C infection.
Nephrol Dial Transplant 2004; 19:2680.
Worm M, et al: Mycophenolate mofetil is effective for maintenance
therapy of hypocomplementaemic urticarial vasculitis. Br J Dermatol
2000; 143:1324.

Golfers and exercise-related vasculitis


This syndrome, which occurs mostly in hot weather, affects
primarily older men (age >50). Golfing or exercise with prolonged walking is the trigger. The syndrome is characterized
by asymptomatic or pruritic, burning, or stinging, purpuric,
macular or slightly raised papules and plaques, predominately
just above the sock line near the ankles. Mild ankle swelling
may be present. The lesions resolve in under 3 days in most
patients. Histologically, true LCV is not seen, but erythrocytes
and neutrophils are present in the affected tissue. About half
of the patients are on antithrombotic agents. This syndrome
probably represents a form of purpura due to anticoagulation
and prolonged erect posture rather than a true vasculitis.
Kelly RI, et al: Golfers vasculitis. Australas J Dermatol 2005; 46:11.
Saleh Z, Mutasim DF: Macular lymphocytic arteritis: a unique benign
cutaneous arteritis, mediated by lymphocytes and appearing as
macules. J Cutan Pathol 2009; 36:1269.

Erythema elevatum diutinum


A rare condition, erythema elevatum diutinum (EED) is considered to be a chronic fibrosing leukocytoclastic vasculitis.
Classically, multiple orange to yellow papules and plaques
develop over the joints (Fig. 35-22), particularly the elbows,
knees, hands, and feet. Lesions may also involve the buttocks
and areas over the Achilles tendon. Petechiae and purpura can
be associated with early lesions. More rarely, large plaques

Fig. 35-22 Erythema elevatum diutinum.

827

Cutaneous Vascular Diseases

35

with nodules at the periphery may affect the trunk and


extremities. Scattered nodules on the trunk with no acral
lesions constitute another rare variant. With time, the papules
take on a doughy to firm consistency and develop a red or
purple color. In HIV infection, skin-colored or red nodules
affect the soles, producing lesions resembling keloids, Kaposi
sarcoma, or bacillary angiomatosis. Pruritus, arthralgias, and
pain have been reported; however, most patients are asymptomatic. Some patients with EED will develop pyoderma
gangrenosum-like ulcerations, which in one case presented as
a phagedenic penile ulceration. Systemic complications are
rare, but an unusual and potentially rapidly destructive keratitis can lead to blindness. EED has been associated with HIV
infection, SLE, Sjgren syndrome, lymphoma, breast cancer,
lymphoepithelioma-like carcinoma, dermatitis herpetiformis,
and celiac disease. IgA monoclonal gammopathy may be
detected. Chronic and recurrent streptococcal infections cause
exacerbations of the disease in some patients. These may all
represent conditions with persistent circulating immune complexes that might trigger a chronic vasculitis. Pathogenically,
ANCAs (60% IgA and 33% IgG) are found in EED. ANCApositive vasculitides, such as Wegener granulomatosis, have
rarely been reported to have EED-like lesions.
Histologically, early lesions are a leukocytoclastic vasculitis,
but with prominent interstitial neutrophils. Well-formed
lesions are composed of nodular and diffuse mixed infiltrates
of neutrophils and nuclear dust, eosinophils, histiocytes, and
plasma cells that often extend into the subcutaneous fat. The
prominence of eosinophils; the chronicity of the process, which
results in an onion skin-like perivascular fibrosis; and the
admixture of plasma cells and many lymphocytes are the hallmarks of EED. Erythrocyte extravasation may lead to extracellular cholesterol crystals in long-standing cases.
Dapsone is the treatment of choice. Patients with celiac
disease may respond to a gluten-free diet. Tetracycline and
nicotinamide, sulfapyridine, colchicine, antimalarials, and
intralesional or systemic steroids have all been reported as
effective in a limited number of cases. Intermittent plasma
exchange has been used successfully in patients with IgA
paraproteinemia. The interstitial keratitis also responds to
dapsone. Unfortunately, the late nodular lesions may not
resolve with dapsone treatment.
Aldave AJ, et al: Peripheral keratitis associated with erythema elevatum
diutinum. Am J Ophthalmol 2003; 135:389.
Ayaoub N, et al: Antineutrophil cytoplasmic antibodies of IgA class in
neutrophilic dermatoses with emphasis on erythema elevatum
diutinum. Arch Dermatol 2004; 140:931.
Barzegar M, et al: An atypical presentation of erythema elevatum
diutinum involving palms and soles. Int J Dermatol 2009; 48:73.
Chow RK, et al: Erythema elevatum diutinum associated with IgA
paraproteinemia successfully controlled with intermittent plasma
exchange. Arch Dermatol 1996; 132:1360.
Di Giacomo TB, et al: Erythema elevatum diutinum presenting with a
giant annular pattern. Int J Dermatol 2009; 48:290.
Farley-Loftus R, et al: Erythema elevatum diutinum. Dermatol Online J
2008; 14:13.
Futei Y, Konohana I: A case of erythema elevatum diutinum associated
with B-cell lymphoma: a rare distribution involving palms, soles and
nails. Br J Dermatol 2000; 142:116.
Golmia A, et al: The development of erythema elevatum diutinum in a
patient with juvenile idiopathic arthritis under treatment with abatacept.
Clin Rheumatol 2008; 27:105.
Grabbe J, et al: Erythema elevatum diutinumevidence for
disease-dependent leucocyte alterations and response to dapsone.
Br J Dermatol 2000; 143:415.
Hatzitolios A, et al: Erythema elevatum diutinum with rare distribution as
a first clinical sign of non-Hodgkins lymphoma: a novel association?
J Dermatol 2008; 35:297.
High W, et al: Late-stage nodular erythema elevatum diutinum. J Am
Acad Dermatol 2003; 49:764.

828

Kavanagh GM, et al: Erythema elevatum diutinum associated with


Wegeners granulomatosis and IgA paraproteinemia. J Am Acad
Dermatol 1993; 28:846.
Liu TC, et al: Erythema elevatum diutinum as a paraneoplastic
syndrome in a patient with pulmonary lymphoepithelioma-like
carcinoma. Lung Cancer 2009; 63:151.
Mitamura Y, et al: Nodular scleritis and panuveitis with erythema
elevatum diutinum. Am J Ophthalmol 2004; 137:368.
Muratori S, et al: Erythema elevatum diutinum and HIV infection: a
report of five cases. Br J Dermatol 1999; 141:335.
Pai HS, et al: Erythema elevatum diutinum in association with celiac
disease. Int J Dermatol 2009; 48:787.
Shimizu S, et al: Erythema elevatum diutinum with primary Sjgren
syndrome associated with IgA antineutrophil cytoplasmic antibody. Br
J Dermatol 2008; 159:733.
Soubeiran E, et al: Erythema elevatum diutinum with unusual clinical
appearance. J Dtsch Dermatol Ges 2008; 6:303.
Tasanen K, et al: Erythema elevatum diutinum in association with
coeliac disease. Br J Dermatol 1997; 136:624.
Tomasini C, et al: Infantile erythema elevatum diutinum: report of a
vesiculo-bullous case. Eur J Dermatol 2006; 16:683.
Wahl CE, et al: Erythema elevatum diutinum. Am J Dermatopathol 2005;
27:397.
Wayte JA, et al: Pyoderma gangrenosum, erythema elevatum diutinum
and IgA monoclonal gammopathy. Australas J Dermatol 1995; 36:21.
Yoshii N, et al: Erythema elevatum diutinum manifesting as a penile
ulcer. Clin Exp Dermatol 2007; 32:211.

Granuloma faciale
Characterized by brownish-red, infiltrated papules, plaques
(Fig. 35-23), and nodules, granuloma faciale involves the facial
areas, particularly the nose. Healthy, middle-aged (mean
53 years) white men (male to female ratio, 5:1) are most typically affected. Childhood cases have been reported. Extrafacial
disease occurs in up to 20% of cases, usually affecting the
upper trunk and extremities.
The pathology of granuloma faciale is similar to that of EED,
with focal leukocytoclastic vasculitis, diffuse dermal neutrophilia with leukocytoclasia, tissue eosinophilia, and perivascular fibrosis.
A variety of treatment options are available. Intralesional
corticosteroids are the recommended first approach.
Cryotherapy in combination with intralesional corticosteroids
has been shown to be very effective. Topical corticosteroids
may also be useful. Although controlled clinical trials are
lacking, dapsone, colchicine, or antimalarials could be considered if the patient remains unresponsive. Laser treatment with
pulsed dye and argon lasers has been effective in multiple
cases, making it a reasonable consideration as first-line
treatment.

Fig. 35-23 Granuloma faciale.

Polyarteritis nodosa

Ammirati CT, et al: Treatment of granuloma faciale with the 585-nm


pulsed dye laser. Arch Dermatol 1999; 135:903.
Dowlati B, et al: Granuloma faciale: successful treatment of nine cases
with a combination of cryotherapy and intralesional corticosteroid
injection. Int J Dermatol 1997; 36:548.
Marcoval J, et al: Granuloma faciale: a clinicopathological study of 11
cases. J Am Acad Dermatol 2004; 51:269.
van de Kerkhof PC: On the efficacy of dapsone in granuloma faciale.
Acta Derm Venereol 1994; 74:61.
Welsh JH, et al: Granuloma faciale in a child successfully treated with
the pulsed dye laser. J Am Acad Dermatol 1999; 41:351.
Zargari O: Disseminated granuloma faciale. Int J Dermatol 2004;
43:210.

Polyarteritis nodosa
Polyarteritis nodosa (PAN) is characterized by necrotizing
vasculitis affecting primarily the small to medium-sized arteries. There are two major forms, the benign cutaneous and the
systemic, although even long-standing benign cutaneous PAN
can evolve into systemic disease. There are ten diagnostic criteria for systemic PAN:
1. livedo racemosa
2. polymorphonuclear arteritis
3. leg pain/myopathy/weakness
4. mono-/polyneuropathy
5. positive hepatitis B virus (HBV) serology
6. weight loss >4kg
7. testicular pain/tenderness
8. diastolic blood pressure >90mmHg
9. elevated BUN/creatinine
10. arteriographic abnormality.
Separating systemic PAN from microscopic polyangiitis
(MPA) can be difficult, and the skin manifestations clinically
and histologically are of no benefit in this regard.
PAN is 24 times more common in men than in women and
the mean age of presentation is 4550 years. A cutaneous vasculitis identical to PAN has been seen in intravenous drug
abusers (see below) and in association with SLE, inflammatory
bowel disease, hairy cell leukemia, familial Mediterranean
fever, and Cogan syndrome (nonsyphilitic interstitial keratitis
and vestibulo-auditory symptoms). Infectious associations
include hepatitis B, hepatitis C, and antecedent streptococcal
infections. Vascular-based tuberculids (erythema induratum,
nodular tuberculid) may have histology identical to PAN. The
proportion of PAN cases associated with HBV is currently
about 57% of cases overall, but this percentage is falling
with HBV immunization. The identification of associated
hepatitis virus infection has therapeutic and prognostic
implications.
The skin is involved in up to 50% of patients with the systemic form of PAN, with wide-ranging findings. The most
striking and diagnostic lesions (15% of patients) are 510mm
subcutaneous nodules occurring singly or in groups, distributed along the course of the blood vessels, above which the
skin is normal or slightly erythematous (macular arteritis).
These nodules are often painful and may pulsate and, in time,
ulcerate (Fig. 35-24). Common sites are the lower extremities,
especially below the knee. Ecchymoses and peripheral gangrene of the fingers and toes may also be present. Livedo
reticularis in combination with subcutaneous nodules strongly
suggests the diagnosis of PAN. Palpable purpura with histologic features of cutaneous LCV may be seen in PAN in 20%
of patients. Urticaria is present in 6% of cases of PAN. HBVassociated PAN is associated with cutaneous findings in only
30% of cases.

Fig. 35-24 Polyarteritis nodosa with multiple leg ulcerations.

Classic systemic PAN may involve the vessels throughout


the entire body. It has a particular predilection for the
skin, peripheral nerves, gastrointestinal tract, and kidneys.
Hypertension (due to renal involvement in 80%), tachycardia,
fever, edema, and weight loss (>70%) are cardinal signs of the
disease. Arthralgia/arthritis (up to 75%), myocardial and intestinal infarctions, and peripheral neuritis (75%) are also seen.
Mononeuritis multiplex, most often manifested as foot drop,
is a hallmark of PAN. Involvement of the meningeal, vertebral,
and carotid arteries may lead to hemiplegia and convulsions.
The lungs and spleen are rarely involved. Aneurysms develop,
which may result in multiorgan infarcts. A Five Factor Score
(FFS) has been validated, with 1 point each for proteinuria,
renal insufficiency, gastrointestinal tract involvement, CNS
involvement, and cardiomyopathy. The 5-year survival for
patients with FFS scores of 0, 1, and >2 are 88%, 75%, and 54%
respectively. Prior to the use of systemic immunosuppressives,
the mortality for systemic PAN exceeded 90%.
A leukocytosis of as high as 40 000/mm3 may occur, with
neutrophilia to 80%; thrombocytosis, progressive normocytic
anemia, and an elevated sedimentation rate and C-reactive
protein (CRP) may also be found. Hepatitis B and C studies
should be performed. Urinary abnormalities, such as protein
uria, hematuria, and casts, are present in 70% of patients. The
prevalence of ANCA positivity is related to how one diagnoses PAN as opposed to MPA. ANCAs are more commonly
found in MPA than in PAN, and in both diseases p-ANCA is
the predominant type. HBV-associated PAN is rarely, if ever,
ANCA-positive.
The histology is that of an inflammatory necrotizing and
obliterative panarteritis that attacks the small and mediumsized arteries. Focal vasculitis forms nodose swellings that
become necrotic, producing aneurysms and rupture of the
vessels. Hemorrhage, hematoma, and ecchymosis may result.
Obliteration of the lumen may occur, with ischemic necrosis
of surrounding tissue. Characteristically, the arteries are
affected at their branching points.
The mainstay of diagnosis is the presence of these histologic
features and the constellation of clinical findings. The preferable site for biopsy is an accessible area such as skin, muscle,
or testis. If these are not involved, angiography may detect
829

35

aneurysmal dilations as small as 1cm wide in the renal,


hepatic, or other visceral vessels.

Cutaneous Vascular Diseases

Treatment
Untreated classic PAN can be fatal, death usually being due
to renal failure or cardiovascular or gastrointestinal complications. Death generally occurs early in the course of the disease.
Patients with HBV- or HCV-associated PAN should be given
IFN and other antiviral treatments as their initial therapy.
For PAN not associated with HBV or HCV, treatment with
corticosteroids and cytotoxic agents has increased the 5-year
survival rate to more than 75%. Corticosteroids in the range of
1mg/kg/day are given initially. Once the disease remits, the
dose should be reduced. After an average of 36 months, with
the patient in remission, the steroids are slowly tapered to
discontinuation.
Cyclophosphamide is given with steroids or sometimes as a
single agent. Initially, 2mg/kg/day as a single dose is recommended. Twice this amount may be required for severely ill
patients. The oral dose is then adjusted to maintain the white
blood cell count between 3000 and 3500/mm3 and the neutrophil count above 1500 cells/mm3. When the disease has
been quiescent for at least 1 year, the cyclophosphamide may
be tapered and stopped. On average, 1824 months of therapy
are required. Pulsed intravenous cyclophosphamide is associated with a lower incidence of toxicity, especially the longterm risk of malignancy. Plasma exchange may be used for
acute crises or treatment failures with corticosteroids and
cyclophosphamide. Ulcerations in PAN can be very painful
due to the associated neuropathy. They should be managed
like nonhealing leg ulcers.

Cutaneous polyarteritis nodosa


About 10% of patients present with PAN localized to the skin
and with limited systemic involvement. Neuropathy occurs in
20%. Subcutaneous nodules (80%), livedo (70%), and ulceration (44%) are the characteristic cutaneous features that should
lead to suspicion of cutaneous PAN. Atrophie blanche-like
lesions around the ankles may be the sole cutaneous manifestation of cutaneous PAN. Plaques on the trunk and proximal
extremities expanding slowly and centrifugally are another
manifestation. At the periphery of the plaques is a ring of
12cm subcutaneous nodules. Cutaneous PAN has a better
prognosis and will require less aggressive therapy, patients
rarely suffering the systemic renal, gastrointestinal, and cardiovascular complications of systemic PAN. This form of PAN
is the most common childhood pattern of PAN. Whether there
are two clear subsets of patients, cutaneous and systemic PAN,
or rather a spectrum of disease is controversial. Patients with
cutaneous PAN must be followed carefully and regularly
evaluated to exclude the development of systemic involvement, which may appear as long as two decades after the
initial diagnosis.
The diagnosis of cutaneous PAN is made by biopsy of a
subcutaneous nodule. An excisional biopsy is recommended,
as the vasculitis is focal. The affected arteriole is at the junction
of the dermis and subcutaneous tissue or in the subcutaneous
fat. Adjacent to the affected vessel there is an inflammatory
panniculitis, and inadequate evaluation of the biopsy or too
small a sample may lead to the erroneous diagnosis of a panniculitis. Also distal to the affected arteriole, thrombosis
usually occurs. If the biopsy is inadequate in depth or size, this
bland thrombosis without inflammation is seen and the erroneous diagnosis of a vasculopathy will be made. Cutaneous
PAN has been associated with HBV surface antigenemia, HCV
infection, Crohns disease, Takayasu arteritis, relapsing polychondritis, streptococcal infections, tuberculosis, and medica830

tions (minocycline). Typically, the only laboratory abnormality


is an elevated erythrocyte sedimentation rate (ESR) or CRP. In
some cases, a p-ANCA may be present. Most patients respond
well to aspirin, NSAIDs, prednisone, pentoxifylline, sulfapyridine, or methotrexate, alone or in some combination. In
childhood cutaneous PAN, since streptococcal infection is
common, penicillin treatment may be used. In refractory cases,
IVIG may be used.
Asano Y, et al: High-dose intravenous immunoglobulin infusion in
polyarteritis nodosa: report on one case and review of the literature.
Clin Rheumatol 2006; 25:396.
Bauz A, et al: Cutaneous polyarteritis nodosa. Br J Dermatol 2002;
146:694.
Chan PT, et al: Inflammatory plaque with peripheral nodules: a new
specific finding of cutaneous polyarteritis nodosa. J Am Acad Dermatol
2009; 60:320.
Diaz-Perez JL, et al: Cutaneous polyarteritis nodosa. Semin Cutan Med
Surg 2007; 26:77.
Fathalla BM, et al: Cutaneous polyarteritis nodosa in children. J Am
Acad Dermatol 2005; 53:724.
Fein H, et al: Cutaneous arteritis presenting with hyperpigmented
macules: macular arteritis. J Am Acad Dermatol 2003; 49:519.
Fortin PR, et al: Prognostic factors in systemic necrotizing vasculitis of
the polyarteritis nodosa group: a review of 45 cases. J Rheumatol
1995; 22:78.
Guillevin L, et al: Prognostic factors in polyarteritis nodosa and
ChurgStrauss syndrome: a prospective study in 342 patients.
Medicine (Baltimore) 1996; 75:17.
Guillevin L, et al: Short-term corticosteroids then lamivudine and
plasma exchanges to treat hepatitis B virus-related polyarteritis
nodosa. Arthritis Rheum 2004; 51:482.
Komatsuda A, et al: Cutaneous polyarteritis nodosa in a patient with
Crohns disease. Mod Rheumatol 2008; 18:639.
Kumar L, et al: Benign cutaneous polyarteritis nodosa in children below
10 years of age: a clinical experience. Ann Rheum Dis 1995; 54:134.
Matsumura Y, et al: A case of cutaneous polyarteritis nodosa
associated with ulcerative colitis. Br J Dermatol 2000; 142:561.
Mimouni D, et al: Cutaneous polyarteritis nodosa in patients presenting
with atrophie blanche. Br J Dermatol 2003; 148:789.
Pak H, et al: Purpuric nodules and macules on the extremities of a
young woman: cutaneous polyarteritis nodosa. Arch Dermatol 1998;
134:232.
Pennoyer JW, et al: Ulcer associated with polyarteritis nodosa treated
with bioengineered human skin equivalent (Apligraf). J Am Acad
Dermatol 2002; 46:145.
Rogalski C, Sticherling M: Panarteritis cutanea benignaan entity limited
to the skin or cutaneous presentation of a systemic necrotizing
vasculitis? Report of seven cases and review of the literature. Int J
Dermatol 2007; 46:817.
Schaffer JV, et al: Perinuclear antineutrophilic cytoplasmic antibodypositive cutaneous polyarteritis nodosa associated with minocycline
therapy for acne vulgaris. J Am Acad Dermatol 2001; 44:198.
Segelmark M, Selga D: The challenge of managing patients with
polyarteritis nodosa. Curr Opin Rheumatol 2007; 19:33.
Sheth AP, et al: Cutaneous polyarteritis nodosa of childhood. J Am
Acad Dermatol 1994; 31:561.
Siberry GK, et al: Cutaneous polyarteritis nodosa. Arch Dermatol 1994;
130:884.
Soufir N, et al: Hepatitis C virus infection in cutaneous polyarteritis
nodosa. Arch Dermatol 1999; 135:1001.

ANCA-positive small-vessel vasculitides


Antineutrophil cytoplasmic antibodies (ANCAs) have become
an important laboratory finding used in the diagnosis and,
in some cases, the prognosis of systemic vasculitis. ANCAs
occur in three patterns: cytoplasmic (c-ANCA); perinuclear
(p-ANCA); and atypical ANCA. c-ANCA is associated with
antibodies directed against proteinase 3 (PR3). Antibodies
against myeloperoxidase result in the p-ANCA pattern, but
antibodies against other antigens may also give this pattern.
Atypical ANCAs are not directed against myeloperoxidase or

Microscopic polyangiitis
With the advent of ANCA serologies and clarification of the
features of microscopic polyangiitis (MPA), this diagnosis is
becoming increasingly more common. There is a northsouth
gradient in incidence, with southern European countries
having 34 times as many cases. Most patients with MPA have
systemic symptoms, such as fever, weight loss, myalgias, and
arthralgias, which can present with an acute flu-like illness or
can evolve for months to years before a more explosive phase
of their disease. These cases have been termed slowly progressive MPA. Most patients with MPA will have or develop
segmental necrotizing and crescentic glomerulonephritis
(8090%), with pulmonary involvement in 2565% of cases.
Pulmonary capillaritis, which can be complicated by hemorrhage, occurs in 1229% of MPA patients. The skin is involved
in 44% of cases of MPA. Purpura as papules, macules, or
ecchymoses (retiform purpura) is present in 26% of cases and
cutaneous ulceration may result. Urticarial lesions occur in 1%
of cases. Patients with MPA may present with skin lesions as
their initial clinical findings. Livedo is seen in two-thirds of
such patients. Skin biopsies of macules, papules, petechiae, or
sites adjacent to ecchymoses may reveal a necrotizing LCV in
the reticular dermis. Palisading and neutrophilic granulomatous dermatitis was found on a skin biopsy of the elbow of an
MPA patient.
Vasculitic neuropathy is common (58%) and eye disease
may occur. Eosinophilia and asthma are not seen. ANCAs are
positive in 70% of cases, p-ANCA more frequently than
c-ANCA. MPA is separated from PAN by the presence of
glomerulonephritis, pulmonary symptoms, and the absence of
hypertension and microaneurysms. ANCAs are less frequently
positive in PAN.

MPA is managed like other forms of ANCA-SVV, with systemic corticosteroids and often cytotoxic agents from the
disease onset. If the disease is localized, sulfamethoxazole/
trimethoprim with corticosteroids may be considered. In generalized but non-organ-threatening disease, methotrexate may
be added to the corticosteroids. Cyclophosphamide is usually
used in the early induction phase of treatment (612 months)
as monthly pulses (as opposed to daily treatment). Lowertoxicity immunosuppressives (methotrexate, azathioprine,
mycophenolate mofetil) may be used as maintenance or in
milder cases. IVIG and anti-TNF agents (infliximab) may be
considered in refractory cases. Relapses are frequent; the
5-year survival is about 75% and 7-year survival is 62%.
Bosch X, et al: Treatment of antineutrophil cytoplasmic antibodyassociated vasculitis: a systematic review. JAMA 2007; 298:655.
Greenfield JR, et al: ANCA-positive vasculitis induced by thioridazine:
confirmed by rechallenge. Br J Dermatol 2002; 147:1265.
Guilleven L, et al: Microscopic polyangiitis: clinical and laboratory
findings in eighty-five patients. Arthritis Rheum 1999; 42:421.
Irvine AD, et al: Microscopic polyangiitis. Arch Dermatol 1997; 133:474.
Jacobs-Kosmin D, et al: Pantoprazole and perinuclear antineutrophil
cytoplasmic antibody-associated vasculitis. J Rheumatol 2006; 33:629.
Kawakami T, et al: Cutaneous manifestations in patients with
microscopic polyangiitis: two case reports and a minireview. Acta
Derm Venereol 2006; 86:144.
Kawakami T, et al: Clinical and histopathologic features of 8 patients
with microscopic polyangiitis including two with a slowly progressive
clinical course. J Am Acad Dermatol 2007; 57:840.
Kluger N, et al: Comparison of cutaneous manifestations in systemic
polyarteritis nodosa and microscopic polyangiitis. Br J Dermatol 2008;
159:615.
Maejima H, et al: Microscopic polyangiitis presenting urticarial erythema
and HenochSchnlein purpura: two case reports. J Dermatol 2004;
31:655.
Niiyama S, et al: Dermatological manifestations associated with
microscopic polyangiitis. Rheumatol Int 2008; 28:593.
Penas PF, et al: Microscopic polyangiitis: a systemic vasculitis with a
positive p-ANCA. Br J Dermatol 1996; 134:542.
Watz H, et al: Bronchioloalveolar carcinoma of the lung associated with
a highly positive pANCA-titer and clinical signs of microscopic
polyangiitis. Pneumologie 2004; 58:493.

ANCA-positive small-vessel vasculitides

PR3. Most laboratories now perform specific tests to determine


whether positive ANCAs are reactive against myeloperoxidase or PR3. Anti-PR3 antibodies are relatively specific for
Wegener granulomatosis and microscopic polyangiitis.
Antibodies against myeloperoxidase are less specific and can
be found in microscopic polyangiitis, ChurgStrauss syndrome, and drug-induced vasculitis. Usually, either anti
myeloperoxidase or anti-PR3 antibodies are found, but not
both. If both patterns are found, drug-induced vasculitis
should be suspected. ANCAs have been used to delineate a
group of small-vessel vasculitides called ANCA small-vessel
vasculitides or ANCA-SVV. These include microscopic polyangiitis, Wegener granulomatosis, and ChurgStrauss syndrome. These diseases have overlapping features, but
characteristically demonstrate pulmonary hemorrhage and/or
necrotizing glomerulonephritis (pulmonaryrenal syndrome).
Conversely, 60% of patients with the pulmonaryrenal syndrome will have ANCA-SVV. With ANCA testing, ANCASVV can be diagnosed with 85% sensitivity and 98% specificity.
While ANCAs are usually negative in Takayasu arteritis,
giant-cell arteritis, Kawasakis disease, and Behet disease,
positive ANCAs can be found in cryoglobulinemia and other
forms of skin-limited vasculitis, in 20% of patients with SLE,
and in a higher percentage of patients with RA. ANCAs are
used in the setting of vasculitis with systemic features or in
situations where the clinical findings suggest ANCA-SVV.
ANCA testing does not replace other tests or, more importantly, histologic confirmation of the presence of vasculitis.
While the ANCA-SVVs are of unknown etiology, in multiple
cases a solid tumor has been identified at the time of the diagnosis of the vasculitis, and Wegener granulomatosis and
microscopic polyangiitis are the two most frequent forms of
ANCA-positive vasculitis. Thrombophlebitis occurs in about
8% of persons with an ANCA-positive vasculitis.

Wegener granulomatosis
Wegener granulomatosis is a syndrome consisting of necrotizing granulomas of the upper and lower respiratory tract, generalized necrotizing angiitis affecting the medium-sized blood
vessels, and focal necrotizing glomerulitis. By far the most
common initial manifestation, present in 90% of patients, is the
occurrence of rhinorrhea, severe sinusitis, and nasal mucosal
ulcerations, with one or several nodules in the nose, larynx,
trachea, or bronchi. Fever, weight loss, and malaise occur in
these patients, who are usually 4050 years of age and more
often male than female (1.3:1). Obstruction in the nose may
also block the sinuses. The nodules in the nose frequently
ulcerate and bleed. The parenchymal involvement of the lungs
produces cough, dyspnea, and chest pain. Granulomas may
occur in the ear and mouth, where the alveolar ridge becomes
necrotic, and ulceration of the tongue and perforated ulcers of
the palate develop. The combination of nasal and palatal
involvement may lead to saddle-nose deformity. The strawberry gums appearance of hypertrophic gingivitis is characteristic, and biopsy from these lesions may be diagnostic (Fig.
35-25).
Cutaneous findings occur in 45% of patients. Nodules may
appear in crops, especially along the extensor surfaces of the
extremities. The firm, slightly tender, flesh-colored or violaceous nodules may later ulcerate. These may be mistaken
for ulcerating rheumatoid nodules. The necrotizing angiitis
of the skin may present as a palpable purpura, petechial or
831

nasal carriage of Staphylococcus aureus, an accepted trigger of


Wegener granulomatosis. In refractory cases, IVIG and antiTNF therapy (infliximab) may be used. Tacrolimus, 0.1mg/
kg/day, was successful in treating a pyoderma gangrenosumlike ulceration in a patient with Wegener granulomatosis.

Cutaneous Vascular Diseases

35

Fig. 35-25 Wegener granulomatosis, strawberry gingiva.

hemorrhagic pustular eruption, subcutaneous nodules, or


ulcers. Livedo reticularis is rare in Wegener granulomatosis.
Patients may present with pyoderma gangrenosum-like
lesions and several patients have been reported presenting
with features of temporal arteritis. The condition previously
described as malignant pyoderma is now felt to represent
Wegener granulomatosis.
Limited forms involving the upper respiratory tract without
renal involvement may also occur and have a better prognosis.
Cutaneous findings can be associated with limited disease.
Focal necrotizing glomerulitis occurs in 85% of patients. It may
be fulminant from the outset or may become more severe as
the disease progresses. Renal failure was the most frequent
cause of death before cyclophosphamide treatment. Other
organs frequently involved include the joints (arthralgia in
two-thirds); eyes (conjunctivitis, episcleritis, and proptosis) in
58%; and CNS and cardiac involvement in 22% and 12% of
patients, respectively.
Histologically, the cutaneous lesions may demonstrate
an LCV, with or without granulomatous inflammation.
Granulomatous vasculitis may be seen. Palisaded granulomas
with multinucleated giant cells and a central core of neutrophils and debris are a characteristic finding. Often, if the
lesions are ulcerated, they are nonspecific histologically.
Biopsy of another affected organ may be required to confirm
the diagnosis. The early detection of Wegener granulomatosis
has improved with the availability of ANCA testing, as 75
80% of patients are c-ANCA (anti-PR3)-positive.
Untreated Wegener granulomatosis has a mean survival
time of 5 months and a 90% mortality over 2 years.
Cyclophosphamide therapy has dramatically changed the
prognosis. Treatment recommendations are cyclophosphamide, 2mg/kg/day, and prednisone, 1mg/kg/day, followed
by tapering of the prednisone to an alternate-day regimen.
Complete remission is achieved in up to 93% of patients and
lasts an average of 4 years for still living patients. In more
limited disease, patients may respond to methotrexate alone
or methotrexate in combination with prednisone. After initial
induction therapy and a remission, methotrexate, azathioprine, leflunomide, or mycophenolate mofetil may be used
instead of cyclophosphamide. Treatment should be continued
for at least 1 year. Trimethoprimsulfamethoxazole may
decrease the relapse rate and can be considered for long-term
treatment of patients with limited upper respiratory tract
involvement in remission in combination with conventional
immunosuppressive protocols. The benefit of long-term
sulfamethoxazole/trimethoprim is due to its reduction of
832

Bartolucci P, et al: Efficacy of the anti-TNF-alpha antibody infliximab


against refractory systemic vasculitides: an open pilot study on 10
patients. Rheumatology 2002; 41:1126.
De Groot K, et al: Wegeners granulomatosis: disease course,
assessment of activity and extent and treatment. Lupus 1998; 7:285.
Frances C, et al: Wegeners granulomatosis. Arch Dermatol 1994;
130:861.
Grses L, et al: Wegeners granulomatosis presenting as neutrophilic
dermatosis: a case report. Br J Dermatol 2000; 143:207.
Manchanda Y, et al: Strawberry gingiva: a distinctive sign in Wegeners
granulomatosis. J Am Acad Dermatol 2003; 49:335.
Micali G, et al: Cephalic pyoderma gangrenosum (PG)-like lesions as a
presenting sign of Wegeners granulomatosis. Int J Dermatol 1994;
33:477.
Nishino H, et al: Wegeners granulomatosis associated with vasculitis of
the temporal artery. Mayo Clin Proc 1993; 68:194.
Rozin A: Infliximab efficiency in refractory Wegeners granulomatosis.
Rheumatology 2003; 42:1124.
Wenzel J, et al: Successful treatment of recalcitrant Wegeners
granulomatosis of the skin with tacrolimus (Prograf). Br J Dermatol
2004; 151:927.

ChurgStrauss syndrome
ChurgStrauss syndrome (CSS) occurs in three phases. The
initial phase, often lasting many years, consists of allergic
rhinitis, nasal polyps, and asthma. The average age of onset of
the asthma is 35 years in CSS (as opposed to allergic asthma,
which often presents in childhood). After 2 to 12 years, a
debilitated asthmatic begins to experience attacks of fever and
eosinophilia (2090%), with pneumonia and gastroenteritis
(second phase). After a few more months or years, but on
average 3 years after the initial symptoms, a diffuse angiitis
involves the lungs, heart, liver, spleen, kidneys, intestines, and
pancreas. Mononeuritis multiplex is common. Triggers of this
third phase have included vaccination, desensitization, leukotriene inhibitors, azithromycin, inhaled fluticasone, or rapid
discontinuation of corticosteroids. Renal involvement is less
common than in Wegener granulomatosis or microscopic
polyangiitis. A fatal outcome is likely in most untreated
patients, with congestive heart failure resulting from granulomatous inflammation of the myocardium being the most frequent cause of death. Increased rates of arterial and venous
thrombosis are seen in CSS, perhaps related to the dense infiltrates of eosinophils.
Cutaneous lesions are present in two-thirds of patients.
Palpable purpura is seen in nearly 50% of patients. Subcutaneous
nodules on the extensor surfaces of the extremities and on the
scalp are seen in 30%. Firm, nontender papules may be present
on the fingertips. These may resemble lesions seen with septic
emboli or atrial myxoma, but show vasculitis on biopsy.
Urticaria, solar urticaria, and livedo reticularis can occur in
CSS. Plaques with the histologic features of eosinophilic cellulitis (Well syndrome) can be seen.
Laboratory studies are significant for a peripheral eosino
philia, which correlates with disease severity. ANCAs are
frequently positive (5570%), most commonly for antimyeloperoxidase (p-ANCA) and less frequently for anti-PR3
(c-ANCA), and tend to correlate with disease severity.
Histologically, a small-vessel vasculitis is present that
involves not only superficial venules, but also larger and
deeper vessels. The tissue is often diffusely infiltrated with
eosinophils, and granulomas may be present. Palisaded granulomas differ from those in Wegener granulomatosis in that

Abe R, et al: Disseminated subcutaneous nodules alone as


manifestations of ChurgStrauss syndrome. Int J Dermatol 2008;
47:532.
Abe-Matsuura Y, et al: Allergic granulomatosis (ChurgStrauss)
associated with cutaneous manifestations. J Dermatol 1995; 22:46.
Ames PR, et al: Eosinophilia and thrombophilia in ChurgStrauss
syndrome: a clinical and pathogenetic overview. Clin Appl Thromb
Hemost 2009 Oct 14 (Epub ahead of print).
Assaf C, et al: ChurgStrauss syndrome: successful treatment with
mycophenolate mofetil. Br J Dermatol 2004; 150:596.
Black JG, et al: Montelukast-associated ChurgStrauss vasculitis:
another associated report. Ann Allergy Asthma Immunol 2009;
102:351.
Chen KR, et al: Granulomatous arteritis in cutaneous lesions of
ChurgStrauss syndrome. J Cutan Pathol 2007; 34:330.
Davis MDP, et al: Cutaneous manifestations of ChurgStrauss
syndrome. J Am Acad Dermatol 1997; 37:199.
Drage LA, et al: Evidence for pathogenic involvement of eosinophils
and neutrophils in ChurgStrauss syndrome. J Am Acad Dermatol
2002; 47:209.
Fisher K, et al: Cutaneous ChurgStrauss granuloma in a child. J Cutan
Pathol 2009; 36:910.
Govoni M, et al: ChurgStrauss syndrome and Wells syndrome:
coincidence or pathogenetic association? A new case report. Clin Exp
Rheumatol 2007; 25:S41.
Jaworsky C: Leukotriene receptor antagonists and ChurgStrauss
syndrome: an association with relevance to dermatopathology? J
Cutan Pathol 2008; 35:611.
Kranke B, et al: Macrolide-induced ChurgStrauss syndrome in a
patient with atopy. Lancet 1997; 350:1551.
Lee SC, et al: Wells syndrome associated with ChurgStrauss
syndrome. J Am Acad Dermatol 2000; 43:556.
Louthrenoo W, et al: Childhood ChurgStrauss syndrome. J Rheumatol
1999; 26:1387.
Nepal M, Padma H: Fluticasone-associated cutaneous allergic
granulomatous vasculitis: an underrecognized but important cause of
drug-induced cutaneous ChurgStrauss syndrome. South Med J 2008;
101:761.
Oh MJ, et al: ChurgStrauss syndrome: the clinical features and
long-term follow-up of 17 patients. J Korean Med Sci 2006; 21:265.
Shimauchi T, et al: Solar urticaria as a manifestation of ChurgStrauss
syndrome. Clin Exp Dermatol 2007; 32:209.
Tatsis E, et al: Interferon-alpha treatment of four patients with the
ChurgStrauss syndrome. Ann Intern Med 1998; 129:370.
Vanoli M, et al: A case of ChurgStrauss vasculitis after hepatitis B
vaccination. Ann Rheum Dis 1998; 57:256.

Cocaine-associated vasculitis
There are numerous reports of various forms of cutaneous
vasculitis associated with the intravenous or intranasal use of
cocaine. Skin lesions have included typical LCV, as well as
larger-vessel vasculitis resembling PAN. Localized nasal
lesions with vasculitis resembling Wegener granulomatosis
have been observed in patients using inhaled cocaine. This has
been termed cocaine-induced pseudovasculitis or cocaineinduced midline destructive lesions to try to distinguish it
from true Wegener granulomatosis. In addition, patients using
cocaine may develop more widespread cutaneous and sys-

temic vasculitis affecting kidneys, lungs, and testes. The cutaneous lesions resemble LCV, but ecchymotic lesions and skin
necrosis were more prominent in these patients than in the
typical LCV patient. Purpura and necrosis of the earlobe were
especially common and characteristic. Agranulocytosis, not a
typical feature of ANCA-positive vasculitis, was also found.
These patients have an elevated c-ANCA (PR3-ANCA), similar
to patients with true Wegener granulomatosis. However, the
c-ANCA in patients with cocaine-induced vasculitis reacts
with human neutrophil elastase (HNE-ANCA). Patients with
Wegener granulomatosis and microscopic polyangiitis are
negative for HNE-ANCA.
Street cocaine is commonly contaminated with pharmaceutical agents. Surprisingly, levamisole has been found in the
cocaine seized by law enforcement in up to 30% of cases in the
US and 100% in Italy. Levamisole therapy is associated with
ecchymotic purpura and necrosis, with a predilection for the
ears. It also causes agranulocytosis and c-ANCA positivity. It
is therefore unclear whether the vasculitic lesions seen in recreational cocaine users are due to the cocaine or to the levamisole excipient or both. In every patient presenting with a
cutaneous or systemic vasculitis, a detailed history of recreational drug use must be obtained, and toxicology screening
should be considered in any patient with vasculitis having the
features outlined above, especially agranulocytosis or cutaneous necrosis, or failure to respond to appropriate therapy. In
these patients, stopping of the drug may lead to a gradual
improvement of the vasculitis, although initial immunosuppressive therapy may be required. Treatment to eradicate
nasal S. aureus should be considered if there are prominent
nasal findings.

Giant-cell arteritis/temporal arteritis

they generally lack multinucleated giant cells and the core


contains eosinophils. In some patients, flame figures, similar
to those in Well syndrome, are noted in the dermis.
Corticosteroids alone may be used in patients with CSS and
an FFS (see PAN above) of 0. Cyclophosphamide alone or
in combination with corticosteroids should be used in cases
of neuropathy, refractory glomerulonephritis, myocardial
disease, severe gastrointestinal disease, and CNS involvement.
Methotrexate and other immunosuppressives can be used as
a steroid-sparing agent, especially to maintain a remission.
IFN-, mycophenolate mofetil, and the anti-TNF agents (in
fliximab and etanercept) have also been used successfully in
CSS.

Barbano G, et al: Disseminated autoimmune disease during levamisole


treatment of nephrotic syndrome. Pediatr Nephrol 1999; 13:602.
Fucci N: Unusual adulterants in cocaine seized on Italian clandestine
market. Forensic Sci Int 2007; 172:e1.
Kinzie E, et al: Levamisole found in patients using cocaine. Ann Emerg
Med 2009; 53:546.
Menni S, et al: Ear lobe bilateral necrosis by levamisole-induced
occlusive vasculitis in a pediatric patient. Pediatr Dermatol 1997;
14:477.
Neynaber S, et al: PR3-ANCA-positive necrotizing multi-organ vasculitis
following cocaine abuse. Acta Derm Venereol 2008; 88:594.
Rachapalli SM, Kiely PD: Cocaine-induced midline destructive lesions
mimicking ENT-limited Wegeners granulomatosis. Scand J Rheumatol
2008; 37:477.
Rongioletti F, et al: Purpura of the ears: a distinctive vasculopathy with
circulating autoantibodies complicating long-term treatment with
levamisole in children. Br J Dermatol 1999; 140:948.
Wiesner O, et al: Antineutrophil cytoplasmic antibodies reacting with
human neutrophil elastase as a diagnostic marker for cocaine-induced
midline destructive lesions but not autoimmune vasculitis. Arthritis
Rheum 2004; 50:2954.
Zhu NY, et al: Agranulocytosis after consumption of cocaine adulterated
with levamisole. Ann Intern Med 2009; 150:287.

Giant-cell arteritis/temporal arteritis


Giant-cell arteritis is a systemic disease of people over the age
of 50 years (mean age >70), favoring women (2:1). It is uncommon in African Americans and favors whites. Its best-known
location is the temporal artery, where it is known as temporal
arteritis, cranial arteritis, and Hortons disease. It is characterized by a necrotizing arteritis with granulomas and giant cells,
which produce unilateral headache and exquisite tenderness
in the scalp over the temporal or occipital arteries in 5075%
of patients. Temporal headaches are characteristically constant, severe, and boring. Ear and parotid pain and masticationinduced jaw claudication may occur. Fever, anemia, and a
high sedimentation rate (>50) are usually present. Proximal,
833

35
Cutaneous Vascular Diseases

Andonopoulos AP, et al: Experience with infliximab (anti-TNF


monoclonal antibody) as monotherapy for giant cell arteritis. Ann
Rheum Dis 2003; 62:1116.
Botella-Estrada R, et al: Magnetic resonance angiography in the
diagnosis of a case of giant cell arteritis manifesting as scalp necrosis.
Arch Dermatol 1999; 135:769.
Carlson JA, Chen KR: Cutaneous vasculitis update: neutrophilic
muscular vessel and eosinophilic, granulomatous, and lymphocytic
vasculitis syndromes. Am J Dermatopathol 2007; 29:32.
Hamidou MA, et al: Temporal arteritis associated with systemic
necrotizing vasculitis. J Rheumatol 2003; 30:2165.
Marcos O, et al: Tongue necrosis in a patient with temporal arteritis. J
Oral Maxillofac Surg 1998; 56:1203.
Tsianakas A, et al: Scalp necrosis in giant cell arteritis: case report and
review of the relevance of this cutaneous sign of large-vessel
vasculitis. J Am Acad Dermatol 2009; 61:701.

Fig. 35-26 Giant cell arteritis with scalp necrosis.

834

symmetrical, and severe morning and even day-long stiffness,


soreness, and pain occur in 50% of patients (associated polymyalgia rheumatica). It is rarely fatal. Blindness may develop
and is the most feared complication of the disease. Many
patients who develop visual loss have premonitory symptoms
allowing for the diagnosis and intervention, which may
prevent permanent visual loss.
The cutaneous manifestations may be only inflammatory.
The affected artery becomes evident as a hard, pulsating,
tender, tortuous bulge under red or cyanotic skin. Another
manifestation is necrosis of the scalp (Fig. 35-26). The lesions
may first appear as ecchymoses. Later, they may become vesicular or bullous and are followed by gangrene. Urticaria,
purpura, alopecia, tender nodules, prurigo-like nodules, and
livedo reticularis may be seen. Lingual artery involvement
may cause an accompanying red, sore, or gangrenous tongue.
Nasal septal perforation may develop. Actinic granuloma may
be associated. Actinic damage of the arterial elastic tissue of
the temporal artery may be possible due to its superficial location. The elderly Caucasian is at greatest risk, and when lesions
are biopsied, at times only the external half of the artery that
received solar radiation is involved. Temporal arteritis may be
an actinically induced disease.
Polymyalgia rheumatica (PMR) has a significant clinical
association with giant-cell arteritis. Prompt treatment may
forestall serious disease. About 10% of central retinal artery
occlusions are due to giant-cell arteritis. ESRs are elevated in
more than 90% of patients with giant-cell arteritis. Temporal
artery biopsy is generally diagnostic, provided that at least a
2cm segment is provided. Even arteries that are normal to
palpation may show diagnostic findings. Magnetic resonance
angiography is a noninvasive diagnostic method that may aid
in confirming the clinical suspicion and identify the best site to
biopsy. Not all patients with arteritis of the temporal artery
have giant cell arteritis, as temporal arteritis may be a manifestation or part of the systemic vasculitides such as PAN, Wegener
granulomatosis, or microscopic polyarteritis. Pathogenically,
the presence of TNF polymorphisms in patients with PMR and
temporal arteritis suggests a genetic predisposition.
Treatment is usually begun with prednisone, 60mg/day,
and continued for 1 month or until all reversible clinical and
laboratory parameters (such as the ESR) have returned to
normal. The disease is quite steroid-responsive and tapering
to a dose of 7.510mg/day is usually possible. Daily therapy
seems to be important and is usually necessary for a minimum
of 12 years. Most patients achieve complete remission that
is often maintained after therapy is withdrawn. Anti-TNF
agents may be used in refractory cases, but relapses occur
when treatment is stopped, and corticosteroid therapy is
usually required.

Takayasu arteritis
Known also as aortic arch syndrome and pulseless disease,
Takayasu arteritis is a thrombo-obliterative process of the
great vessels stemming from the aortic arch, occurring generally in young women (female to male ratio, 9:1) in the second
or third decade of life. It is more common in Japan, Southeast
Asia, India, and South America. Radial and carotid pulses are
typically obliterated. Most skin changes are due to the disturbed circulation. There may be loss of hair and atrophy
of the skin and its appendages, with underlying muscle
atrophy. Occasional patients with cutaneous necrotizing or
granulomatous vasculitis of small vessels have been reported.
Erythematous nodules with or without livedo, simulating erythema nodosum or erythema induratum, may rarely occur.
Pyoderma gangrenosum-like ulcerations are well described in
Japan. Pyoderma gangrenosum lesions precede the diagnosis
of the arteritis by an average of 3 years. These lesions are more
commonly generalized and in three-quarters of cases occur on
the upper extremities.
Treatment of Takayasu arteritis with prednisone, 1mg/kg/
day tapered in 812 weeks to 20mg/day or less, is recommended. Methotrexate may be used for its steroid-sparing
effects. With active medical and surgical intervention, the
aggressive course of this disease can be modified. The
pyoderma gangrenosum-like lesions are also treated with
systemic steroids, but azathioprine, cyclophosphamide, mycophenolate mofetil, cyclosporine, and tacrolimus have also been
effective.
Ohta Y, et al: Inflammatory diseases associated with Takayasus
arteritis. Angiology 2003; 54:339.
Pascual-Lopez M, et al: Takayasus disease with cutaneous involvement.
Dermatology 2004; 208:10.
Skaria AM, et al: Takayasu arteritis and cutaneous necrotizing vasculitis.
Dermatology 2000; 200:139.
Ujiie H, et al: Pyoderma gangrenosum associated with Takayasus
arteritis. Clin Exp Dermatol 2004; 29:357.

Malignant atrophic papulosis


Papulosis atrophicans maligna, also known as Degos disease,
is a potentially fatal obliterative arteritis syndrome. Some
affected patients have a long benign course with skin lesions
only, while in others, death occurs within a few years. Degos
disease occurs 23 times more frequently in men than in
women, often presenting between the ages of 20 and 40.
Familial kindreds are well reported. In patients with the more
aggressive variant, survival averages 23 years after the
disease has developed.
Skin lesions are usually the first sign of the disease. Clinically,
Degos disease is characterized by the presence of pale rose,
rounded, edematous papules occurring mostly on the trunk.
Similar lesions may occur on the bulbar conjunctiva and oral

Cebeci Z, et al: Degos disease. Ophthalmology 2009; 116:1415.


Chung HY, et al: Degos disease: a rare condition simulating rheumatic
diseases. Clin Rheumatol 2009; 28:861.
Cuchillero RMO, et al: Benign cutaneous Degos disease. Clin Exp
Dermatol 2003; 28:145.
De Breucker S, et al: Inefficacy of intravenous immunoglobulins and
infliximab in Degos disease. Acta Clin Belg 2008; 63:99.
Dyrsen ME, et al: Parvovirus B19-associated catastrophic endothelialitis
with a Degos-like presentation. J Cutan Pathol 2008; 35:20.
Guhl G, et al: Wegeners granulomatosis: a new entity in the growing
differential diagnosis of Degos disease. Clin Exp Dermatol 2009;
34:e1.
High WA, et al: Is Degos disease a clinical and histological end point
rather than a specific disease? J Am Acad Dermatol 2004; 50:895.
Hohwy T, et al: A fatal case of malignant atrophic papulosis (Degos
disease) in a man with factor V Leiden mutation and lupus
anticoagulant. Acta Derm Venereol 2006; 86:245.
Kanekura T, et al: A case of malignant atrophic papulosis successfully
treated with nicotine patches. Br J Dermatol 2003; 149:660.
Katz SK, et al: Malignant atrophic papulosis (Degos disease) involving
three generations of a family. J Am Acad Dermatol 1997; 37:480.
Kim DW, et al: Degos disease (malignant atrophic papulosis) as a fatal
cause of acute abdomen: report of a case. Surg Today 2008; 38:866.
Liu CM, et al: Lesions resembling malignant atrophic papulosis in a
patient with progressive systemic sclerosis. Cutis 2005; 75:101.

Moss C, et al: Degos disease: a new simulator of non-accidental injury.


Dev Med Child Neurol 2009; 51:647.
Powell J, et al: Benign familial Degos disease worsening during
immunosuppression. Br J Dermatol 1999; 141:524.
Requena L, et al: Degos disease in a patient with acquired
immunodeficiency syndrome. J Am Acad Dermatol 1998; 38:852.
Saglik E, et al: Malignant atrophic papulosis: endocardial involvement
and positive anticardiolipin antibodies. J Eur Acad Dermatol Venereol
2006; 20:602.
Scheinfeld N: Degos disease is probably a distinct entity: a review of
clinical and laboratory evidence. J Am Acad Dermatol 2005; 52:375.
Scheinfeld N: Malignant atrophic papulosis. Clin Exp Dermatol 2007;
32:483.
Shahshahani MM, et al: A case of Degos disease with pleuropericardial
fibrosis, jejunal perforation, hemiparesis, and widespread cutaneous
lesions. Int J Dermatol 2008; 47:493.
Tan WP, et al: Generalized red papules with gastrointestinal
complications. Clin Exp Dermatol 2007; 32:615.
Thomson KF, Highet AS: Penile ulceration in fatal malignant atrophic
papulosis (Degos disease). Br J Dermatol 2000; 143:1320.
Torrelo A, et al: Malignant atrophic papulosis in an infant. Br J Dermatol
2002; 146:916.
Zhao WH, et al: A fatal case of malignant atrophic papulosis. Eur J
Dermatol 2009; 19:193.
Zhu KJ, et al: The use of intravenous immunoglobulin in cutaneous and
recurrent perforating intestinal Degos disease (malignant atrophic
papulosis). Br J Dermatol 2007; 157:206.

Thromboangiitis obliterans

mucosa. Palms, soles, and face are spared, but the penis may
be involved. Over days to weeks, the lesions become umbilicated, with a central depression, which enlarges. The center
becomes distinctively porcelain-white, while the periphery
becomes livid red and telangiectatic. Central atrophy occurs
eventually. The eruption proceeds by crops in which only a
few new lesions appear at any one time. One patient was
reported to develop panniculitis. Lesions characteristic of
Degos disease may be seen in patients with lupus erythematosus, dermatomyositis, scleroderma, and Wegener
granulomatosis.
Systemically, ischemic infarcts involve the intestines, producing acute abdominal symptoms, which include epigastric
pain, fever, and hematemesis. Death is usually due to fulminating peritonitis caused by multiple perforations of the intestine. Less commonly, death occurs from cerebral infarctions.
Wedge-shaped necroses brought on by the occlusion of arterioles and small arteries account for the clinical lesions.
Proliferation of the intima and thrombosis constitute the
typical histologic picture. The thrombosing process is usually
pauci-inflammatory, although neutrophils or lymphocytes
may be found associated with the thrombosis. The overlying
dermis, which is infarcted, contains abundant mucin, especially early in the lesions evolution. Adnexae are typically
necrotic and the depressed central portion may be noted
histologically.
The etiology of this disease is unknown, but based on the
infarctive nature of the lesions and the universal presence of
arteriolar thrombosis, a hyperthrombotic state or endothelial
abnormality is suggested. While most patients have not had
abnormalities identified, abnormal platelet aggregation and
abnormal coagulation have been identified in some cases.
Antiphospholipid antibodies and anticardiolipin antibodies
have been present in some patients, and a Leiden factor V
mutation in one patient. Parvovirus B19 infection was associated with a fatal case in an adult.
Administration of immunosuppressives has not been beneficial. IVIG has been of therapeutic benefit in one case, but failed
in another. Ingestion of low-dose acetylsalicylic acid alone or
in combination with dipyridamole (Persantine) has been effective in some patients. Heparin, as described by Degos, has
been helpful, and should be considered if antiplatelet therapy
is ineffective. Nicotine patches, 5mg/day, were effective in
one case. In severe crises, fibrinolytic therapy should be considered. The prognosis is guarded in patients with systemic
involvement.

Thromboangiitis obliterans (Buergers disease)


Thromboangiitis obliterans (TAO) is a nonatherosclerotic segmental occlusive disease affecting the arteries of multiple
extremities. It is most often seen in men between the ages of
20 and 40 who smoke heavily. Smoking and, rarely, the use of
smokeless tobacco are intimately tied to Buergers disease.
Various diagnostic criteria have been proposed. They usually
include: age younger than 45 (or 50); history of tobacco use;
distal extremity involvement (infrapopliteal segmental arterial
occlusion with sparing of the proximal vasculature); frequent
distal upper extremity involvement (Raynaud or digital
ulcers); consistent angiographic findings; superficial thrombo
phlebitis; exclusion of autoimmune disease, diabetes mellitus,
and hypercoagulable or embolic states.
The vasomotor changes in early cases may be transitory or
persistent; they produce blanching, cyanosis, burning, and tingling. Superficial thrombophlebitis in the leg and foot occurs
in 38% of cases and 44% of patients may have Raynaud phenomenon. The color of the part may change when it is elevated
or lowered below heart level, being red when dependent and
white when elevated. Pain is a constant symptom, coming at
first only after exercise and subsiding on resting. Instep and
foot claudication is the classic complaint. Ultimately, the dorsalis pedis and posterior tibial pulses disappear, followed by
others. In TAO, skin supplied by affected arterioles tends
to break down, with central necrosis and ulceration, and
eventual gangrene (Fig. 35-27). Gastrointestinal involvement
has been reported. Exposure to cold may cause exacerbations,
and more cases are identified in the winter than any other
season.
Arteriography should be carried out to investigate for
central atherosclerotic disease, which may be operable, rather
than the inoperable distal damage of Buergers disease.
A characteristic tapering and occlusion of the major arteries
with corkscrew collateral arteries is found in Buergers
disease on angiography. A vasculo-occlusive syndrome similar
to Buergers disease has been reported in cannabis smokers,
but venous thrombophlebitis does not occur. The pathogenic
mechanism of the vascular occlusion in Buergers disease is
unknown. In one report G20210A prothrombin mutations, the
majority homozygotic, were found, but these findings have
not been reproduced.

835

Arteriosclerosis obliterans

Cutaneous Vascular Diseases

35

Fig. 35-27 Buergers disease.

The most important therapeutic aspect is the cessation of


smoking. Even one or two cigarettes/day, smokeless tobacco,
or nicotine replacement may keep the disease active.
Intravenous iloprost (a prostaglandin analog) may help the
patient with critical limb ischemia get through an acute
episode. Oral iloprost is ineffective. Sympathectomy can
provide temporary relief. Autologous transplantation of bone
marrow mononuclear cells into the calf muscle has benefited
patients with TAO and other forms of limb ischemia. G-CSFmobilized peripheral blood mononuclear cells have had
similar efficacy. In patients who stop smoking and do not have
gangrene, major amputations are rare. In continued smokers,
at least 43% will require amputations. Implantation of a spinal
cord stimulator may be tried.
Boda Z, et al: Stem cell therapy: a promising and prospective approach
in the treatment of patients with severe Buergers disease. Clin Appl
Thromb Hemos 2009; 15:552.
Cazalets C, et al: Cannabis arteritis: four new cases. Rev Med Interne
2003; 24:127.
De Vriese AS, et al: Autologous transplantation of bone marrow
mononuclear cells for limb ischemia in a Caucasian population with
atherosclerosis obliterans. J Intern Med 2008; 263:395.
Espinoza LR: Buergers disease: thromboangiitis obliterans 100 years
after the initial description. Am J Med Sci 2009; 337:285.
Faizer R, Forbes TL: Buergers disease. J Vasc Surg 2007; 46:812.
Kakihana A, et al: Improvement of cardiac function after granulocytecolony stimulating factor-mobilized peripheral blood mononuclear cell
implantation in a patient with non-ischemic dilated cardiomyopathy
associated with thromboangiitis obliterans. Intern Med 2009; 48:1003.
Kobayashi M, et al: Ischemic intestinal involvement in a patient with
Buergers disease: case report and literature review. J Vasc Surg
2003; 38:170.
Laohapensang K, et al: Seasonal variation of Buergers disease in
northern part of Thailand. Eur J Vasc Endovasc Surg 2004; 28:418.
Malecki R, et al: Thromboangiitis obliterans in the 21st centurya new
face of disease. Atherosclerosis 2009; 206:328.
Manfredini R, et al: Thromboangiitis obliterans (Buergers disease) in a
female mild smoker treated with spinal cord stimulation. Am J Med Sci
2004; 327:365.
Matsushita M, et al: Buergers disease in a 19-year-old woman. J Vasc
Surg 2003; 38:175.
Olin JW: Thromboangiitis obliterans (Buergers disease). N Engl J Med
2000; 343:864.

836

Arteriosclerosis obliterans is an occlusive arterial disease most


prominently affecting the abdominal aorta, and the small and
medium-sized arteries of the lower extremities. The symptoms
are due to ischemia of the tissues. There is intermittent claudication manifested by pain, cramping, numbness, and fatigue
in the muscles on exercise; these are relieved by rest. There
may be rest pain at night when in bed. Also, sensitivity to
cold, muscular weakness, stiffness of the joints, and paresthesia may be present. Sexual impotence is common and there is
an increased frequency of coronary artery disease.
Impaired to absent pulses (dorsalis pedis, posterior tibial, or
popliteal arteries) may be found on physical examination, confirming the diagnosis. The feet, especially the toes, may be red
and cold. Striking pallor of the feet on elevation and redness
when dependent are compatible findings. Decreased to absent
hair growth may be observed on the legs. Ulceration and gangrene may supervene. If present, they usually begin in the toes
and are quite painful. Arteriography may be indicated as a
preliminary to corrective surgery (arterial grafts). Occasionally,
subclavian atherosclerosis may give rise to these signs in the
distal upper extremity, producing painful nails and loss of
digital skin. Diabetes mellitus, smoking, and hyperlipidemia
are risk factors for the development of atherosclerosis.
Claudication and diminished blood pressure in the affected
extremity are findings that may lead to earlier diagnosis and
thus to curative surgical intervention. Usually, bypass of the
affected artery or sympathectomy, or both, are the preferred
treatment. Balloon angioplasty or stent placement may also be
effective. When critical limb ischemia is present, injection of
stem cells into the calf muscle may be beneficial.
Kerdel FA, et al: Subclavian occlusive disease presenting as a painful
nail. J Am Acad Dermatol 1984; 10:523.
Matsumoto K, et al: Insulin resistance and arteriosclerosis obliterans in
patients with NIDDM. Diabetes Care 1997; 20:1738.

Diffuse dermal angiomatosis


Diffuse dermal angiomatosis (DDA) is a not uncommon disorder that preferentially affects women. The most common
location is the breast, especially the dependent portion.
Affected women tend to have large, pendulous breasts, and
are usually older than 45 years of age. Patients may have had
a reduction mammoplasty (often decades before), and the
disease tends to localize adjacent to the scar from that procedure. The clinical lesions may be reticulated groups of telangiectasias, ischemic (retiform) purpura, or ulceration, or
some combination. The erythematous/telangiectatic plaques
are slightly palpable but not usually indurated. The nipple and
areola are spared. The affected patients often have multiple
risk factors for a hypercoagulable state or premature atherosclerosis. These include a personal history of atherosclerotic
cardiovascular disease, obesity, smoking, hypertension, mutations in the thrombolytic pathway (analogous to those seen in
livedoid vasculopathy), and a strong family history for premature atherosclerotic disease-related cardiovascular events. The
areas involved are very similar to those affected by other prothrombotic disorders such as warfarin necrosis and heparin
necrosisskin with overly abundant adipose tissue. The breast
is most commonly affected, but the abdomen and medial
thighs are also sites of predilection. Usually, only one site is
affected, but if the breast is involved, the process can be bilateral. Surgical procedures on the affected area may lead to
ulceration that is very painful and slow to heal. Because a
surgical procedure triggered the ulceration, a mistaken diagnosis of pyoderma gangrenosum may be entertained.

McLaughlin ER, et al: Diffuse dermal angiomatosis of the breast:


response to isotretinoin. J Am Acad Dermatol 2001; 45:462.
Pichardo RO, et al: What is your diagnosis? Diffuse dermal
angiomatosis secondary to anticardiolipin antibodies. Am J
Dermatopathol 2002; 24:502.
Quatresooz P, et al: Diffuse dermal angiomatosis: a previously
undescribed pattern of immunoglobulin and complement deposits in
two cases. Am J Dermatopathol 2006; 28:150.
Villa MT, et al: The treatment of diffuse dermal angiomatosis of the
breast with reduction mammaplasty. Arch Dermatol 2008; 144:693.
Yang H, et al: Diffuse dermal angiomatosis of the breast. Arch Dermatol
2006; 142:343.

Mucocutaneous lymph node syndrome


(Kawasakis disease)
The typical presentation is an irritable, ill-appearing, febrile
infant or child younger than 5 years old. Clinical findings (four
of which, plus fever for 5 days, are diagnostic of Kawasaki
syndrome) include a skin eruption; stomatitis (injected
pharynx, strawberry tongue) and fissuring cheilitis; edema of
the hands and feet; conjunctival injection; and cervical lymph
adenitis. The skin eruption is polymorphous and may be
macular, morbilliform, urticarial, scarlatiniform, erythema
multiforme-like, pustular, or erythema marginatum-like. An
early finding (within the first week) is the appearance of an
erythematous, desquamating perianal eruption in about twothirds of patients. Periorbital edema has been reported. Fifteen
to 20% of children with Kawasakis disease (KD) and fever will
not have one or more of the other cardinal features. These
cases are termed incomplete KD. These patients are still at
risk for cardiac disease.
Numerous cutaneous and systemic complications have been
reported as accompanying or following KD. Pincer nail
deformities may appear and resolve spontaneously. Intestinal
pseudo-obstruction may occur. Facial nerve paralysis has been
described, and a severe peripheral vasculitis with vasospasm,
digital ischemia, and gangrene can occur. Numerous children
have developed guttate or plaque psoriasis 1020 days after
the KD had begun. The presumed mechanism is the triggering
of psoriasis by the superantigens associated with the acute
illness.
The acute illness evolves over 1020 days. A week or two
following the acute illness, the fingers and toes desquamate,
starting around the nails (Fig. 35-28). Coronary artery aneu-

Fig. 35-28 Desquamation in Kawasakis disease.

Mucocutaneous lymph node syndrome

Histologically, a diffuse dermal proliferation of endothelial


cells and bland blood vessels occupies much of the dermis.
Atypical cells and atypical vascular shapes (as seen in angio
sarcoma and Kaposi sarcoma) are not seen. The dermal cells
stain for markers of endothelial cells The pathogenesis is felt
to be local chronic ischemia, which may either lead to vascular
proliferation (angiomatosis), or if acute and severe, may lead
to retiform purpura or ulceration. The fatty areas are poorly
oxygenated (worse in the obese patient), and the pendulous
nature of the breasts may stretch or tether the vessels, further
compromising the circulation. Inherited and acquired hypercoagulable risk factors (smoking, atherosclerosis, and so on)
contribute to the pathogenesis.
The treatment involves reversing the contributing factors.
This includes stopping smoking, weight reduction, and antithrombotic medications such as low-dose aspirin, 81mg per
day, and pentoxifylline, 400mg BID. Reduction mammoplasty
may lead to resolution. Atherosclerosis of the arteries serving
the affected area may be found, and vascular surgery to
enhance circulation may lead to improvement. One patient has
been successfully treated with isotretinoin. Isotretinoin has a
fibrinolytic effect, which may be the mechanism by which it
improved DDA in this one patient.

rysms occur in 2025% of untreated children and 35% of


treated children. This is the most common cause of acquired
cardiac disease in young children. The cardiac involvement,
which, in addition to aneurysms, can include decreased left
ventricular function, arrhythmias, mitral regurgitation, and
pericardial effusion, may lead to immediate cardiac complications, the major cause of morbidity and mortality. In addition,
over time, those with aneurysms can develop coronary artery
stenosis, and as a result acute cardiac events can occur in
young adulthood.

Pathogenesis
A viral or infectious pathogenesis is attractive for the following reasons:
1. Cases were rare before 1950.
2. KD affects children older than 3 months but younger
than 8 years.
3. Seasonal peaks occur in the winter and spring.
4. Focal epidemics have been reported.
5. Oligoclonal IgA immune responses are found, suggesting
a respiratory portal of entry of an infectious agent.
There are increased superantigens in the stool of children
with KD. A KD-like illness has been described with group
A meningococcal septicemia. An infectious pathogenesis,
therefore, remains the most plausible etiologic hypothesis.
It has long been suspected that there is a genetic basis for
KD. The disease is 1020 times more common in persons from
Northeast Asia (Japan and Korea), where rates of up to 1 per
150 children are reported. When these Asians move to the US,
they still have this high rate of increased susceptibility. The
risk of a sibling developing KD is increased tenfold. Children
of parents who had KD in childhood have a twofold increased
risk of developing KD. A recent genome-wide search of almost
1000KD cases and family members found strong linkage to
five genes, three of which form a single functional network.
The central gene of this network is CAMK2D, which encodes
a serine/threonine kinase expressed in cardiomyocytes and
vascular endothelial cells. These genes are already known to
be involved in cardiac and inflammatory pathways. The transcripts of these genes were also markedly suppressed during
KD. The previously reported genetic associations for KD were
not found in this study, including the ITPKC gene mutation.
Coronary arterial disease occurs after day 10 of the illness
(subacute phase), in combination with thrombocythemia (up
to 1 million). This combination of an altered endovascular
surface and too many platelets, plus abnormal blood flow in
837

Cutaneous Vascular Diseases

35

the coronary aneurysms, leads to thrombosis and occlusion of


the vessels and the subsequent cardiac events.

Treatment
IVIG is the cornerstone of therapy, given in a single dose of
2g/kg infused over 1012h. Response to treatment is best if
given during the first 56 days of the illness; however, children
with persistent fever beyond this period may benefit from later
treatment. Aspirin is used to reduce inflammation and platelet
aggregation. The dose is 80100mg/kg/day in four divided
doses. Once the child has been afebrile for 37 days, the aspirin
dose is decreased to a single daily dose of 35mg/kg. If the
child remains febrile, a second 2g/kg dose of IVIG should be
given. A single dose of infliximab, 5mg/kg, has been reported
to be effective in refractory cases, but response, as with other
treatments, is not universal. If there is no response to the
second IVIG dose, systemic steroid therapy is commonly
given. Angioplasty, thrombolytic therapy, or coronary artery
bypass surgery may be required for patients with coronary
disease.
Ahn SY, et al: Treatment of intravenous immunoglobulin-resistant
Kawasaki disease with methotrexate. Scand J Rheumatol 2005;
34:136.
Ayusawa M, et al: Revision of diagnostic guidelines from Kawasaki
disease (the 5th revised edition). Pediatr Int 2005; 47:232.
Burgner D, et al: A genome-wide association study identifies novel and
functionally related susceptibility loci for Kawasaki disease. PLoS
Genet 2009; 5:e1000319.
Burns JC, Glod MP: Kawasaki syndrome. Lancet 2004; 364:533.
Burns JC, et al: Infliximab treatment for refractory Kawasaki syndrome. J
Pediatr 2005; 146:662.
Fretzayas A, et al: Meningococcal group A sepsis associated with rare
manifestations and complicated by Kawasaki-like disease. Pediatr
Emerg Care 2009; 25:190.
Garty B, et al: Guttate psoriasis following Kawasaki disease. Pediatr
Dermatol 2001; 18:507.
Harnden A, et al: Kawasaki disease. BMJ 2009; 338:1133.
Larralde M, et al: Kawasaki disease with facial nerve paralysis. Pediatr
Dermatol 2003; 20:511.
Miura M, et al: Coronary risk factors in Kawasaki disease treated with
additional gammaglobulin. Arch Dis Child 2004; 89:776.
Muta H, et al: Early intravenous gamma-globulin treatment for Kawasaki
disease: the nationwide surveys in Japan. J Pediatr 2004; 144:496.
Pannaraj PS, et al: Failure to diagnose Kawasaki disease at the
extremes of the pediatric age range. Pediatr Infect Dis J 2004; 23:789.
Thapa R, et al: Neonatal Kawasaki disease with multiple coronary
aneurysms and thrombocytopenia. Pediatr Dermatol 2007; 24:662.
Yamauchi H, et al: Optimal time of surgical treatment for Kawasaki
coronary artery disease. J Nippon Med Sch 2004; 71:279.
Yoon SY, et al: Plaque type psoriasiform eruption following Kawasaki
disease. Pediatr Dermatol 2007; 24:336.

Telangiectasia
Telangiectasia are fine linear vessels coursing on the surface
of the skin; the name given to them collectively is telangiectasia. Telangiectasia may occur in normal skin at any age, in both
sexes, and anywhere on the skin and mucous membranes. Fine
telangiectases may be seen on the alae nasi of most adults.
They are prominent in areas of chronic actinic damage. In
addition, persons long exposed to wind, cold, or heat are
subject to telangiectasia. Calcium channel-blockers may lead
to telangiectatic lesions in a generalized or photodistribution
and contribute to the appearance of photoaging. Telangiectasias
may also be found on the legs as a result of heredity, varicosities, pregnancy, and birth control pill use.
Telangiectases can be found in conditions such as radio
dermatitis, xeroderma pigmentosum, lupus erythematosus,
scleroderma and the CREST syndrome, rosacea, pregnancy,
838

cirrhosis of the liver, AIDS, poikiloderma, basal cell carcinoma, necrobiosis lipoidica diabeticorum, lichen sclerosus et
atrophicus, sarcoid, lupus vulgaris, keloid, adenoma sebaceum,
Kaposiform hemangioendothelioma, angioma serpiginosum,
angiokeratoma corporis diffusum, hereditary benign telangiectasia, Cockayne syndrome, ataxia-telangiectasia, and
Bloom syndrome.
Altered capillary patterns on the finger nailfolds (cuticular
telangiectases) are indicative of collagen vascular disease, such
as lupus erythematosus, scleroderma, or dermatomyositis.
They may infrequently be present in rheumatoid arthritis.
These disorders are reviewed in Chapter 8.
Beaubien ER, et al: Kaposiform hemangioendothelioma. J Am Acad
Dermatol 1998; 38:799.
Cooper SM, Wojnaraowska F: Photo-damage in Northern European renal
transplant recipients is associated with the use of calcium channel
blockers. Clin Exp Dermatol 2003; 28:588.
Grabczynska SA, Cowley N: Amlodipine-induced photosensitivity
presenting as telangiectasia. Br J Dermatol 2000; 142:1255.
Huh J, et al: Localized facial telangiectasias following frostbite injury.
Cutis 1996; 57:97.
Ioulios P, et al: The spectrum of cutaneous reactions associated with
calcium antagonists: a review of the literature and the possible
etiopathogenic mechanisms. Dermatol Online J 2003; 9:6.
Kanekura T, et al: Lichen sclerosus et atrophicus with prominent
telangiectasia. J Dermatol 1994; 21:447.
Silvestre JF, et al: Photodistributed felodipine-induced facial
telangiectasia. J Am Acad Dermatol 2001; 45:323.

Generalized essential telangiectasia


Generalized essential telangiectasia (GET) is characterized by
the appearance of telangiectasia over a large segment of the
body without preceding or coexisting skin lesions. Lesions
tend to appear first on the legs and progress caudad. Women
are more commonly affected, with the condition starting
between age 20 and 50. Characteristic features include:
1. widespread cutaneous distribution
2. progression or permanence of the lesions
3. accentuation in dependent areas and by dependent
positioning
4. absence of coexisting epidermal or dermal changes, such
as atrophy, purpura, depigmentation, or follicular
involvement.
The telangiectases may be distributed over the entire body or
localized to some large area, such as the legs, arms, and trunk.
They may be discrete or confluent. Distribution along the
course of the cutaneous nerves may occur. Systemic symptoms
are absent, although conjunctival telangiectasias can also be
seen. GET is usually not believed to be associated with an
increased risk of epistaxis, but gastrointestinal bleeding has
been reported. Families with this disorder, inherited as an
autosomal-dominant trait, have been reported. The cause of
essential telangiectasia is unknown. Treatment is with vascular lasers, if required.
Collagenous vasculopathy, a condition favoring middleaged males, is clinically similar to GET but histologically distinct. Histologically, markedly dilated subepidermal vessels
are present. These blood vessels have thickened vascular walls
and perivascular hyaline. Type IV collagen staining accentuates the superficial vessels.
Ali MM, et al: Generalized essential telangiectasia with conjunctival
involvement. Clin Exp Dermatol 2006; 31:781.
Davis TL, et al: Collagenous vasculopathy: a report of three cases. J
Cutan Pathol 2008; 35:967.
Gambichler T, et al: Generalized essential telangiectasia successfully
treated with high-energy, long-pulse, frequency-doubled Nd:YAG laser.
Dermatol Surg 2001; 27:355.

Unilateral nevoid telangiectasia


In unilateral nevoid telangiectasia (UNT), fine, thread-like telangiectases develop in a unilateral, sometimes dermatomal (or
following the lines of Blaschko) distribution. Spider angiomas
may also be present. The most common distribution is unilateral or bilateral involvement of the third and fourth cervical
dermatomes. The condition is rare in men; in affected women,
it starts in adulthood. The familial form (very rare) favors
males, is autosomal-dominant, and appears postnatally. UNT
is associated with conditions that have increased levels of
estrogen: puberty, pregnancy, oral contraceptive use, HCV
infection, and cirrhosis. Treatment with pulse dye laser can be
effective.
Dadlani C, et al: Unilateral nevoid telangiectasia. Dermatol Online J
2008; 14:3.
Derrow AE, et al: Acquired unilateral nevoid telangiectasia in a
51-year-old female. Int J Dermatol 2008; 47:1331.
Hynes LR, et al: Unilateral nevoid telangiectasia: occurrence in two
patients with hepatitis C. J Am Acad Dermatol 1997; 36:819.
Karakas M, et al: Unilateral nevoid telangiectasia. J Dermatol 2004;
31:109.
Kreft B, et al: Unilateral nevoid telangiectasia syndrome. Dermatology
2004; 209:215.
Sardana K, et al: Unilateral nevoid telangiectasia syndrome. J Dermatol
2001; 28:453.
Sharma VK, Khandpur S: Unilateral nevoid telangiectasiaresponse to
pulsed dye laser. Int J Dermatol 2006; 45:960.
Taskapan O: Acquired unilateral nevoid telangiectasia syndrome (letter).
J Am Acad Dermatol 1998; 39:138.
Woollons A, et al: Unilateral naevoid telangiectasia syndrome in
pregnancy. Clin Exp Dermatol 1996; 21:459.

Hereditary hemorrhagic telangiectasia


(Oslers disease)
Also known as OslerWeberRendu disease, hereditary hemorrhagic telangiectasia (HHT) is characterized by small tufts
of dilated capillaries scattered over the mucous membranes
and the skin. These slightly elevated lesions develop mostly
on the lips, tongue, palate, nasal mucosa, ears, palms, fingertips, nailbeds, and soles. They may closely simulate the telangiectases of the CREST variant of scleroderma, which may
be distinguished by the lack of other features of CREST syndrome and by anticentromere antibodies, which are not found
in HHT. Diagnostic criteria have been proposed and include:
1. epistaxisspontaneous, recurrent nosebleeds
2. telangiectasesmultiple at characteristic sites (lips, oral
cavity, fingers, nose) (Fig. 35-29)
3. visceral lesionsgastrointestinal bleeding, pulmonary,
hepatic, cerebral, or spinal arteriovenous malformation
(AVM)
4. family historyone affected first-degree relative.
The presence of three of the four criteria indicates a definite
diagnosis, while two of four indicate a possible diagnosis.
There are at least three variants, HHT1 and HHT2, and a third
associated with juvenile polyposis.
Frequent nosebleeds and melena are experienced because of
the telangiectasia in the nose and gastrointestinal tract.
Epistaxis is the most frequent and persistent sign. Worsening
epistaxis may herald high-output cardiac failure from AVMs.
Pregnancy can also exacerbate HHT. Gastrointestinal bleeding
is the presenting sign in up to 25% of cases; however, 4050%
develop gastrointestinal bleeding some time during the course
of their disease. Chronic persistent anemia requiring iron and

Fig. 35-29 Hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia

Long D, Marshman G: Generalized essential telangiectasia. Australas J


Dermatol 2004; 45:67.

blood transfusions is characteristic of severe cases. The spleen


may be enlarged. Pulmonary and CNS AVMs may appear
later in life. Liver failure can result from diffuse intrahepatic
shuntinghepatic artery to vein, bypassing the liver parenchyma. Retinal arteriovenous aneurysms occur only rarely.
Other sites of bleeding may be the kidney, spleen, bladder,
liver, meninges, and brain. The risk of cerebral hemorrhage
from cerebral AVMs, cerebral abscesses, and pulmonary hemorrhage from pulmonary AVMs is probably high enough that
asymptomatic patients should be screened for the presence of
cerebral and pulmonary AVMs. Because of the risk of cerebral
abscess, some have advocated antibiotic prophylaxis for dental
and contaminated skin procedures.
The telangiectases tend to increase in number in middle age;
however, the first appearance on the undersurface of the
tongue and floor of the mouth is at puberty. Pulmonary or
intracranial arteriovenous fistulas and bleeding in these areas
may be a cause of death.
HHT is inherited as an autosomal-dominant trait. The vascular abnormalities found in HHT consist of direct arterio
venous connections without an intervening capillary bed.
Affected patients have mutations in one of three genes, most
commonly in two, endoglin (ENG) or ALK-1 (ACVRL1). They
encode a homodimeric integral membrane glycoprotein,
which is a transforming growth factor (TGF)- receptor. HHT1
is associated with ENG mutations, and HHT2 with ACVRL1
mutations. HHT1 patients have a higher prevalence of pulmonary AVMs, while HHT2 patients tend to have a milder phenotype and later age of onset, but increased liver manifestations.
Patients with HHT and juvenile polyposis have mutations in
the MADH4 gene, a downstream effector of TGF- signaling.
TGF- is a potent stimulator of vascular endothelial growth
factor (VEGF) production. VEGF leads to disorganized and
tortuous vessels, as seen in HHT. VEGF levels are increased
in patients with HHT.
Treatment is directed at controlling the specific complication, and identifying and treating AVMs before they become
symptomatic. The tendency to epistaxis has been reduced by
estrogen therapy and some recommend oral contraceptives for
affected postpubertal females. Dermoplasty of the bleeding
nasal septum may be performed by replacing the mucous
membrane with skin from the thigh or buttock. Repeated laser
treatments of the nasal and gastrointestinal mucosa are often
required. Topical tranexamic acid has been used to control
epistaxis. Bleeding episodes are treated supportively with iron
and red blood cell transfusions. Interventional radiology with
selective embolization can treat pulmonary and CNS AVMs
and episodes of bleeding, avoiding invasive surgeries. In
patients with liver failure or high-output heart failure due to
liver AVMs, liver transplantation may be required. Blocking
839

Cutaneous Vascular Diseases

35

VEGF with thalidomide (or more effectively with lenalidomide) can reduce gastrointestinal bleeding and transfusion
dependence. Bevacizumab, a monoclonal inhibitor of VEGF,
has dramatically improved some severely ill HHT patients,
reducing the size and flow of their hepatic AVMs, reversing
heart and liver failure, and reducing transfusion
requirement.
Abdalla SA, et al: Visceral manifestations in hereditary haemorrhagic
telangiectasia type 2. J Med Genet 2003; 40:494.
Al-Saleh S, et al: Screening for pulmonary and cerebral arteriovenous
malformations in children with hereditary haemorrhagic telangiectasia.
Eur Respir J 2009; 34:875.
Bose P, et al: Bevacizumab in hereditary hemorrhagic telangiectasia. N
Engl J Med 2009; 360:2143.
Bowcock SJ, Patrick HE: Lenalidomide to control gastrointestinal
bleeding in hereditary haemorrhagic telangiectasia: potential
implications for angiodysplasias? Br J Haematol 2009; 146:220.
Faughnan ME, et al: International Guidelines for the Diagnosis and
Management of Hereditary Hemorrhagic Telangiectasia. J Med Genet
2009 Jun 29 (Epub ahead of print).
Fernandez-Fernandez FJ: Hereditary haemorrhagic telangiectasia: from
symptomatic management to pathogenesis based treatment. Eur J
Hum Genet 2009 Nov 4 (Epub ahead of print).
Flieger D, et al: Dramatic improvement in hereditary hemorrhagic
telangiectasia after treatment with the vascular endothelial growth
factor (VEGF) antagonist bevacizumab. Ann Hematol 2006; 85:631.
Fuchizaki U, et al: Hereditary haemorrhagic telangiectasia (Rendu
OslerWeber disease). Lancet 2003; 362:1490.
Gallione CJ, et al: A combined syndrome of juvenile polyposis and
hereditary haemorrhagic telangiectasia associated with mutations in
MADH4 (SMAD4). Lancet 2004; 363:852.
Garcia-Tsao G, et al: Liver disease in patients with hereditary
hemorrhagic telangiectasia. N Engl J Med 2000; 343:931.
Goussous T, et al: Hereditary hemorrhagic telangiectasia presenting as
high output cardiac failure during pregnancy. Cardiol Res Pract 2009;
2009:437237.
Haneen S, et al: Mutation analysis of Endoglin and Activin receptorlike kinase genes in German patients with hereditary hemorrhagic
telangiectasia and the value of rapid genotyping using an allelespecific PCR-technique. BMC Med Genet 2009; 10:53.
Kanna B, Das B: Hemorrhagic pericardial effusion causing pericardial
tamponade in hereditary hemorrhagic telangiectasia. Am J Med Sci
2004; 327:149.
Khalid SK, et al: Worsening of nose bleeding heralds high cardiac
output state in hereditary hemorrhagic telangiectasia. Am J Med 2009;
122:779.e1.
Klepfish A, et al: Intranasal tranexamic acid treatment for severe
epistaxis in hereditary hemorrhagic telangiectasia. Arch Intern Med
2001; 161:767.
Lee JB, et al: The diagnostic quandary of hereditary haemorrhagic
telangiectasia vs. CREST syndrome. Br J Dermatol 2001; 145:646.
Mager JJ, Westermann CJJ: Value of capillary microscopy in the
diagnosis of hereditary hemorrhagic telangiectasia. Arch Dermatol
2000; 136:732.
Mei-Zahav M, et al: Symptomatic children with hereditary hemorrhagic
telangiectasia: a pediatric center experience. Arch Pediatr Adolesc
Med 2006; 160:596.
Mitchell A, et al: Bevacizumab reverses need for liver transplantation in
hereditary hemorrhagic telangiectasia. Liver Transpl 2008; 14:210.

Leg ulcers
Leg ulcers are a common medical condition, affecting 35% of
the population over the age of 65. The cause of chronic leg
ulceration is venous insufficiency alone in 4560% of cases,
arterial insufficiency in 1020%, diabetes mellitus in 1525%,
or combinations in 1015%. Smoking and obesity increase the
risk for ulcer development and persistence, independent of the
underlying cause. Defining the cause of the leg ulceration is
important in treating the leg ulcer.
The wound healing response is complex, involving intricate
interactions between different cell types, structural proteins,
840

growth factors, and proteinases. Normal wound repair consists of three phasesinflammation, proliferation, and
remodelingthat occur in a predictable sequence.

Venous diseases of the extremities


Stasis dermatitis
Stasis dermatitis presents as erythema and a yellowish or
light-brown pigmentation of the lower third of the lower legs,
especially in the area just superior to the medial malleolus. An
associated eczematous dermatitis may occur. The dermatitis
may be weepy or dry, scaling or lichenified; it is almost invariably hyperpigmented by melanin and hemosiderin. Varicose
veins are usually present, though they need not be numerous
or conspicuous. Stasis dermatitis is a cutaneous marker for
venous insufficiency. The approach to management should be
two-fold: relief of symptoms and treatment of the underlying
venous insufficiency. Patients with pruritus and an eczematous component should be treated with emollients and topical
corticosteroids. The daily use of elevation and support stockings is strongly recommended.

Venous insufficiency and obesity-associated


mucinosis
Localized areas of mucin deposition can be observed directly
over the perforators on the lower extremity. These present as
blushed, redblue, partially compressible, agminated papules.
On biopsy, deposits of dermal mucin against a background of
the changes of venous insufficiency are seen. In the setting of
morbid obesity and lower extremity edema, pretibial translucent papules can appear and merge into plaques. The plaques
are composed of dermal mucin (hyaluronic acid). The diagnosis of pretibial myxedema is usually made, but thyroid functions are normal. With weight loss the lesions improve,
suggesting that they were due to the lower extremity edema/
venous insufficiency of obesity.

Venous insufficiency ulceration


Stasis dermatitis and venous ulceration result from increased
pressure in the venous system of the lower leg. The most
common cause is insufficiency of the valves in the deep venous
system and lower perforating veins of the lower leg. With each
contraction of the calf, blood should be pumped to the heart
via this muscle pump. Intact valves in the lower leg are
required to prevent this pumped blood from refluxing out
through the perforators into the superficial system. Increased
flow through the superficial system results in enlargement of
the superficial venous plexus and the appearance of varicose
veins. Increased pressure on the iliac veins from pregnancy
or obesity, or simple inactivity may also result in the appearance of venous insufficiency, as well. The valvular insufficiency results in disorder in the venous and capillary circulation
in the leg. Valve insufficiency may occur from prior thrombo
phlebitis or congenital weakness. Prolonged standing
without walking or contracting the calf muscles, sitting for
long periods, anemia, zinc deficiency, and a defective fibrinolytic system may accelerate the process. If a history of thrombo
phlebitis is present, an evaluation for a hypercoagulable
state, such as a deficiency of Leiden factor V, should be
considered.
Edema and fibrosis develop in the skin over the medial
aspect of the ankle and lower third of the shin (Fig. 35-30).
Following minor trauma, a macular hemorrhage appears. This
is the premonitory sign of an impending ulceration. Venous

Fig. 35-30 Stasis dermatitis, venous insufficiency.

Fig. 35-31 Venous leg ulcer.

ulcers usually occur on the lower medial aspect of the leg.


They may appear on the background of stasis dermatitis with
lipodermatosclerosis (Fig. 35-31). Venous ulcerations can be
painful, but not as painful as pyoderma gangrenosum or arterial or embolic ulcerations. The ulcer tends to be round or
oblong and has a characteristic yellow, fibrinous base. Multiple
lesions may occur.
In most cases, the diagnosis of a venous ulceration can be
made on clinical grounds. If there is no clear history or physical findings of venous insufficiency, venous rheography can
be performed. An ABI (ankle:brachial index, or ratio of blood
pressure in the leg to the arm) should be performed, especially
in cases where peripheral pulses are diminished and hair on

Venous diseases of the extremities

the lower legs is lost. This will identify coexistent arterial


disease. More extensive vascular studies may be necessary to
identify the presence and extent of arterial disease or focal
venous valvular incompetence or congenital absence. In leg
ulcers of the lower medial leg, even if cutaneous findings of
venous insufficiency are absent, venous insufficiency will still
be the most common cause of the ulcer. Lesions in atypical
locations, those that do not respond appropriately to therapy,
and those in which venous rheography is normal may require
a biopsy to exclude other causes, including a cutaneous neoplasm. Additional workup may also be required to identify
other, less common causes of leg ulcers, such as cholesterol
emboli, atherosclerotic disease, diabetes mellitus, sickle cell
disease, vasculitis, infection, and pyoderma gangrenosum.
Despite extensive research and the marketing of many new
products and devices for the treatment of leg ulcers, very little
has changed in their management over the last decades.
Treatment is primarily to improve venous return and reduce
edema. Compression therapy is the mainstay of treatment.
This involves the use of pressure wraps, such as Unna boots
covered with Coban or elastic wraps. Elevation of the leg
above the heart, for as much of the time as is possible (a
minimum of 2h twice a day), is also beneficial. Elastic support
of the legs must be continued after the ulcer heals. Other
causes of edema, such as cardiac failure, must be addressed.
The avoidance of long, cramped sitting (in airplanes or vehicles) or prolonged standing is advisable. Diuretics are overused and not proven to be of benefit. If there is a central cause
of fluid retention (cirrhosis, heart failure, renal failure), diuretics may be beneficial, but otherwise they are best avoided.
Avoidance of trauma is important. Pentoxifylline, 400800mg
three times a day, in addition to compression, is beneficial in
healing refractory venous ulcerations. A cooperative patient
and a patient physician are necessary in the long-term management of venous disease. Topical anti-infectives are usually
not necessary (except metronidazole gel to prevent anaerobic
overgrowth). There is a high risk of allergic contact dermatitis
from other topical antibiotics. Oral antibiotics should only be
used to treat associated invasive infection. A rim of erythema
commonly surrounds an ulcer. Expanding erythema, an
enlarging ulcer, or increasing pain or tenderness may be signs
of infection. Surface cultures and Gram stains may demonstrate colonizing, but not pathogenic, bacteria. Biopsy for histology and tissue homogenate culture is the most effective way
to demonstrate a true invasive pathogen.
Many treatment options have been developed for chronic
ulcers. Unfortunately, conclusive comparative studies between
the various treatment alternatives are lacking. All are to be
used in combination with compression treatment. Occlusive
and semipermeable biosynthetic wound dressings can be very
effective when combined with compression. They can speed
healing, reduce pain, make dressing changes infrequent, and
help debridement. If a hard eschar is present over the ulcer
when first seen, a dressing will assist in its removal. Early in
the treatment of an ulcer, a highly inflammatory and exudative
phase occurs. This will often wash off the semipermeable
dressing and may require the use of fenestrated dressings and
even the application of absorbent padding over the dressing
for the first few weeks. The patient will interpret this increased
wound exudate, which is normal and indicates the conversion
of a non-healing to a healing wound, as an infection. He/she
should be appropriately educated before such dressings are
applied. Dressings containing dilute acetic acid or silver may
help reduce bacterial overgrowth in the wound, but fail to
decrease the time to healing. However, metronidazole gel
0.75% instilled into the wound will help to reduce the amount
of wound exudate (by eliminating anerobic bacteria) and
remove the smell of the wound exudate. The smell of achronic

841

Cutaneous Vascular Diseases

35

leg ulcer may reduce the patients quality of life. Becaplermin


(Regranex) is expensive, but promotes wound healing.
Granulation tissue formation is enhanced. It may be useful in
wounds that are unable to develop a granulation tissue base
despite local care and conservative debridement. Weekly de
bridement of the anesthetic dead fibrinous tissue can be useful
in stimulating granulation tissue at the base of slow-to-heal
venous ulcerations. Injection of granulocytemacrophage
colony-stimulating factor (GM-CSF) into the ulcer base may
also stimulate refractory ulcers to heal. It is very expensive.
Grafts and skin substitutes should be reserved for refractory
ulcers that have failed conservative therapy. In more than 90%
of cases, only simple but persistently applied measures are
required. Enhanced compliance, longer elevation, and removal
of leg edema are the first steps in attempting to heal refractory
leg ulcers. If these are not optimized, expensive dressing and
medications will not lead to healing. The role of vascular
surgery or venous ablation in the healing of leg ulcers is
controversial.
Risk factors that predict failure to heal within 24 weeks of
limb compression therapy include a large wound area, history
of venous ligation or stripping, history of hip or knee replacement, ABI <0.80, fibrin on 50% or more of the wound surface,
and the presence of the ulcer for an extended time. For every
6 months of duration, the ulcer healing time doubles.

Arterial insufficiency (ischemic) ulcer


Ischemic ulcers are mostly located on the lateral surface of the
ankle or the distal digits. The initial red, painful plaque breaks
down into a painful superficial ulcer with a surrounding zone
of purpuric erythema. Granulation tissue is minimal, little or
no infection is present, and a membranous inactive eschar
forms over the ulcer. Patients at risk are those with longstanding hypertension, smokers, diabetics, and those with
hyperlipidemia. The presence of an arterial ulceration identifies patients at increased risk for limb loss.
Signs and symptoms indicating that arterial disease is the
cause of the ulceration include thinning of the skin, absence of
hair, decreased or absent pulses, pallor on elevation, coolness
of the extremity, dependent rubor, claudication on exercise,
and pain on elevation (especially at night) relieved on dependency. In progressive disease, the diagnosis of thromboangiitis
obliterans, or Buergers disease, should be considered. Patients
with arterial insufficiency are also at risk for cholesterol emboli,
another arterial cause of lower leg ulceration. Eosinophilia,
palpable peripheral pulses, sudden onset, and associated renal
insufficiency are clues to the diagnosis of cholesterol emboli.
The diagnosis of arterial insufficiency can usually be confirmed by physical examination and careful palpation of the
pulses in the legs. For more accurate evaluation, take the blood
pressure in the arm and leg. They should be nearly identical.
The ratio of the popliteal to brachial pressure is called the ABI.
If it is less than 0.75, arterial insufficiency exists; if less than
0.5, the insufficiency is substantial.
Surgical intervention may be required to heal the ulceration.
If the blood supply cannot be improved, little can be done,
except to prevent infection by the measures described under
venous ulcers. The area should be protected from injury and
cold, and smoking and tight socks should be avoided.
Hyperbaric oxygen may be of some use, but it is limited by
availability and cost.

Neuropathic ulcers
Foot ulcers in diabetics are usually related to sensory neuropathy. Offloading the ulcer is the primary principle of manage842

ment. Necrotic tissue should be debrided back to bleeding


viable tissue. As the foot is typically insensate, this can be done
in the office without the need for anesthetic. Associated osteomyelitis is best treated by removal of the infected bone.
Consultation with or referral to a podiatrist or orthopedic
surgeon may be indicated. Various shoes and padded boots
can be used to offload different areas of the foot. An orthotics
consultation is usually indicated. Clinical infection should be
treated, but simple colonization typically does not require
treatment. After the ulcer heals, a shoe of appropriate depth
and width will help to prevent recurrence. Frequent foot
inspections for the presence of hot spots, as well as debridement of dystrophic nails, are important facets of prevention of
leg ulcers in diabetics.
Baldursson B, et al: Venous leg ulcers and squamous cell carcinoma.
Br J Dermatol 1995; 133:571.
Choucair M, et al: Compression therapy. Dermatol Surg 1998; 24:141.
Davies C: Use of Doppler ultrasound in leg ulcer assessments. Nurs
Stand 2001; 15:72.
Falanga V, et al: Rapid healing of venous ulcers and lack of clinical
rejection with an allogeneic cultured human skin equivalent. Arch
Dermatol 1998; 134:293.
Fletcher A, et al: A systematic review of compression treatment for
venous leg ulcers. BMJ 1997; 315:576.
Grossman D, et al: Activated protein C resistance and anticardiolipin
antibodies in patients with venous leg ulcers. J Am Acad Dermatol
1997; 37:409.
Groves RW, Schmidt-Lucke JA: Recombinant human GM-CSF in the
treatment of poorly healing wounds. Adv Skin Wound Care 2000;
13:107.
Hafner J, et al: Leg ulcers in peripheral arterial disease (arterial leg
ulcers): impaired wound healing above the threshold of chronic critical
limb ischemia. J Am Acad Dermatol 2000; 43:1001.
Jull A, et al: Pentoxifylline for treatment of venous leg ulcers: a
systematic review. Lancet 2002; 359:1550.
Maessen-Visch MB, et al: The prevalence of factor V Leiden mutation in
patients with leg ulcers and venous insufficiency. Arch Dermatol 1999;
135:41.
Margolis DJ, et al: Risk factors associated with failure of a venous leg
ulcer to heal. Arch Dermatol 1999; 135:920.
Mekkes JR, et al: Causes, investigation and treatment of leg ulceration.
Br J Dermatol 2003; 148:388.
Michaels JA, et al: Randomized controlled trial and cost-effectiveness
analysis of silver-donating antimicrobial dressings for venous leg
ulcers (VULCAN) trial. Br J Surg 2009; 96:1147.
Padberg F, et al: Does severe venous insufficiency have a different
etiology in the morbidly obese? Is it venous? J Vasc Surg 2003;
37:79.
Pennington M, et al: Cholesterol embolization syndrome: cutaneous
histopathological features and the variable onset of symptoms in
patients with different risk factors. Br J Dermatol 2002; 146:511.
Pugashetti R, et al: Dermal mucinosis as a sign of venous insufficiency.
J Cutan Pathol 2009 Jul 10 (Epub ahead of print).
Rico T, et al: Vascular endothelial growth factor delivery via gene
therapy for diabetic wounds: first steps. J Invest Dermatol 2009;
129:2084.
Rongioletti F, et al: Obesity-associated lymphoedematous mucinosis.
J Cutan Pathol 2009; 36:1089.
Samson RH, et al: Stockings and the prevention of recurrent venous
ulcers. Dermatol Surg 1996; 22:373.
Siddiqui FH, et al: Recombinant granulocyte macrophage colony
stimulating factor (rhu-GM-CSF) in the treatment of extensive leg
ulcers: a case report. Surgery 2000; 127:589.
Sultan MJ, McCollum C: Dont waste money when dressing leg ulcers.
Br J Surg 2009; 96:1099.
Teepe RG, et al: Randomized trial comparing cryopreserved cultured
epidermal allografts with hydrocolloid dressings in healing chronic
venous ulcers. J Am Acad Dermatol 1993; 29:982.
Tokuda Y, et al: Chronic obesity lymphoedematous mucinosis: three
cases of pretibial mucinosis in obese patients with pitting oedema. Br
J Dermatol 2006; 154:157.
Valencia IC, et al: Chronic venous insufficiency and venous leg
ulceration. J Am Acad Dermatol 2001; 44:401.

Lymphedema is the swelling of soft tissues in which an excess


amount of lymph has accumulated. Chronic lymphedema is
characterized by long-standing, nonpitting edema. A working
classification of lymphedema is shown in Box 35-2.
The most prevalent worldwide cause of lymphedema is
filariasis. In the US the most common cause is postsurgical. If
lymphedema is long-standing, a verrucous appearance to the
affected extremity develops (elephantiasis verrucosa nostra).
Lymphedema of the lower extremity must be distinguished
from lipedema. This syndrome is characterized by bilateral,
symmetrical lower extremity enlargement due to subcutaneous fat deposition. The buttocks to the ankles are affected in
women, starting at puberty with gradual progression. The feet
are spared in lipedema but usually involved in lower extremity lymphedema. Lipedema does not respond to compression
therapy. The skin fold at the base of the second toe is too thick
to pinch in lymphedema but normal in lipedema (Stemmers
sign). Verrucous changes do not occur in lipedema but do
occur in lymphedema. Women with lipedema will have tenderness to pressure on the affected area. There is frequently a
family history of lipedema. Magnetic resonance imaging (MRI)

Box 35-2 Classification of lymphedema


Primary lymphedema
Congenital lymphedema (Milroys disease)
Lymphedema praecox
Lymphedema tarda

Syndromes associated with primary lymphedema










Yellow nail syndrome


Turner syndrome
Noonan syndrome
Pes cavus
Phakomatosis pigmentovascularis
Distichiasislymphedema
Emberger syndrome
WILD syndrome
Hypotrichosis-telangiectasia-lymphedema syndrome

will separate the two entities if the diagnosis cannot be confirmed on a clinical basis.

Types
Lymphedema is classified by clinical type (Box 35-2). Primary
types include congenital, and early- and late-onset types.
Other primary types of lymphedema are associated with characteristic features or syndromes. Some cutaneous disorders
are associated with or are a complication of primary lymphedema. Secondary lymphedema can occur from numerous
causes, including neoplasia and its treatment, infections, and
physical factors.

Lymphedema

LYMPHEDEMA

Lymphedema praecox
Lymphedema praecox develops in females between the ages
of 9 and 25. Swelling appears around the ankle and then
extends upward to involve the entire leg. With the passage of
time, the leg becomes painful, with a dull, heavy sensation.
Once this stage has been reached, the swollen limb remains
swollen, as fibrosis has occurred. Primary lymphedema is
caused by a defect in the lymphatic system. Lymphangiography
demonstrates hypoplastic lymphatics in 87%, aplasia in
approximately 5%, and hyperplasia with varicose dilation of
the lymphatic vessels in 8%.

NonneMilroyMeige syndrome (hereditary


lymphedema)
Milroy hereditary edema of the lower legs is characterized by
a unilateral or bilateral lymphedema present at birth and
inherited as an autosomal-dominant trait. The edema is painless, pits on pressure, is not associated with any other disorder,
and persists throughout life (Fig. 35-32). It may involve
the genitalia and produce lymphangiectasias superficially.
Chylous discharge can occur. The face and arm may also be
involved. Most frequently, the lymphedema is unilateral, and
females are predominantly affected.
Treatment of this particular type of edema is extremely difficult, since the disease is an anomaly of the lymph-draining
vessels. Decongestive physiotherapy can be considered. In
some cases, surgical procedures to remove affected tissue can

Cutaneous disorders sometimes associated with


primary lymphedema



Yellow nails
Hemangiomas
Xanthomatosis and chylous lymphedema
Congenital absence of nails

Secondary lymphedema










Postmastectomy lymphedema
Melphalan isolated limb perfusion
Malignant occlusion with obstruction
Extrinsic pressure
Factitial lymphedema
Postradiation therapy
Following recurrent lymphangitis/cellulitis
Lymphedema of upper limb in recurrent eczema
Granulomatous disease
Rosaceous lymphedema
Primary amyloidosis

Complications of lymphedema



Cellulitis of lymphedema
Elephantiasis nostra verrucosa
Ulceration
Lymphangiosarcoma

Fig. 35-32 Milroys disease. (Courtesy of Lawrence Lieblich, MD)

843

Cutaneous Vascular Diseases

35

be performed. This condition may be linked to a mutation in


flt4, the gene for VEGFR3.

Lymphedemadistichiasis syndrome
The association of distichiasis (double row of eyelashes) and
late-onset lymphedema is a form of hereditary lymphedema
called lymphedema-distichiasis syndrome, or Meige syndrome. It is an autosomal-dominant syndrome with the
appearance of bilateral lymphedema, beginning between the
ages of 8 and 10 in affected boys, and 13 and 30 in affected
girls. Lymphatic vessels are increased (not hypoplastic or
absent, as in other forms of congenital lymphedema) in the
affected legs. Associated findings are varicose veins in 50% by
age 64; congenital ptosis (31%); and congenital heart disease
(6.8%), cleft palate (4%), scoliosis, and renal abnormalities.
There may be phenotypic heterogeneity in this syndrome,
as different types of mutation may lead to slightly different
phenotypes, especially with regard to the ancillary features
associated with the syndrome. This syndrome is due to a
mutation in the FOXC2 transcription factor. This factor is
expressed in developing eyelids, lymphatics, lymphatic valves,
and other tissues with abnormalities in this syndrome.

Emberger syndrome
Emberger syndrome is primary lymphedema associated with
myelodysplasia. This genetic syndrome presents with lymphedema of one or both lower limbs and often the genitalia
between infancy and puberty. Myelodysplastic syndrome
and/or acute myeloid leukemia developing in adolescence or
childhood are preceded by pancytopenia with a high incidence of monosomy 7 in the bone marrow. Associated features
include mild skeletal abnormalities, deafness, and multiple
warts.

WILD syndrome (Warts, Immunodeficiency,


Lymphedema, anogenital Dysplasia)
Lymphedema appears in early childhood and may progress to
involve all 4 extremities and the genitalia. Widespread flat
warts appear during childhood resembling the numerous flat
warts seen in epidermodysplasia verruciformis. The anogenital region develops numerous warts and anogenital dysplasia.
Helper T cells are reduced.

Hypotrichosis-telangiectasia-lymphedema syndrome
Lymphedema appears in childhood. Vascular dilations and
telangiectasias appear on the palms and soles. Both autosomal
recessive and autosomal dominant patterns of inheritance
occur, but both forms are due to mutations in the SOX18 gene.

Primary lymphedema associated with yellow nails and


pleural effusion (yellow nail syndrome)
Lymphedema is confined mostly to the ankles and occurs in
about 60% of patients with this syndrome. The nails show a
distinct yellowish discoloration and thickening. Recurrent
pleural effusion or bronchiectasis may be a feature.

Secondary lymphedema
In some malignant diseases, involvement of the axillary or
pelvic lymph nodes will produce blockage and lymphedema.
Malignant disease of the breast, uterus, prostate, skin, bones,
or other tissues may cause such changes. Hodgkin disease and,
especially, Kaposi sarcoma (KS) may be accompanied by significant lymphedema well beyond the amount expected from
the degree of skin involvement by the KS. Such patients
require chemotherapy, as this is the hallmark of lymphatic
involvement by the KS. Chronic lymphedema is frequently
seen after mastectomy and the removal of the axillary nodes;
it may occur after varying lengths of time.
844

Postmastectomy lymphangiosarcoma
(StewartTreves syndrome)
This type of vascular malignancy usually arises in chronic
postmastectomy lymphedema. The lesions are bluish or
reddish nodules arising on the arm. Similarly, primary or secondary lymphedema of the lower extremity may be complicated by angiosarcoma. Angiosarcoma arising in a
lymphedematous extremity often presents with multiple
lesions. Metastasis and death commonly result. Early aggressive surgical treatment with amputation may be life-saving.
The treatment of breast cancer with lumpectomy and local
radiation therapy may be complicated by angiosarcoma of the
breast with minimal or no associated lymphedema. This is
called cutaneous postradiation angiosarcoma of the breast.
This form of angiosarcoma also frequently results in metastasis and death.

Postinflammatory lymphedema
The lymphedematous extremity may be caused by and worsened by repeated bacterial cellulitis/lymphangitis. It is these
recurrent infectious episodes, when they complicate filariasis,
that cause the elephantiasis. Streptococcal cellulitis following
venectomy in patients who had undergone coronary bypass
surgery is a well-documented cause. However, almost any
chronic or recurrent infection can cause this. Chronic antibiotic
therapy can halt the progression by preventing the attacks of
bacterial cellulitis.

Bullous lymphedema
Commonly misdiagnosed as an immunobullous disease,
bullous lymphedema usually occurs with poorly controlled
edema related to heart failure and fluid overload. Compression
results in healing.

Factitial lymphedema
Also known as hysterical edema, lymphedema can be produced by wrapping an elastic bandage, cord, or shirt around
an extremity, and/or holding the extremity in a dependent
and immobile state. Self-inflicted causes of lymphedema are
usually difficult to prove and may occur in settings of known
causes of lymphedema, such as postphlebitic syndrome or
surgical injury to the brachial plexus. Factitial lymphedema
caused by blunt trauma localized to the dorsum of the hand
or forearm is referred to as Secretan syndrome or loedme
bleu, respectively. It often is unilateral and there may be significant purpura. Effective care of such patients requires psychiatric intervention. Occupational causes must be excluded.

Podoconiosis
Podoconiosis, or mossy foot, is a non-infectious form of lymphedema. It is restricted to tropical regions in Central Africa,
Central America, and North India. It occurs in persons walking
barefoot in soil of volcanic origin. This soil has high concentrations of aluminum, silicon, beryllium, zirconium, magnesium,
and iron. Apparently, colloid-sized particles of the dust penetrate the sole, and migrate to lymph nodes ingested in macro
phages. Lymphatic drainage is impaired by fibrosis of
lymphatic channels, induced by the microscopic deposits of
the substances. Males and females are equally affected, and in
endemic areas up to 5% of the population can develop the
disease. Moving into an endemic area from a non-endemic
area can lead to the condition appearing over the next 5 years.
Podoconiosis begins in childhood or adolescence with mild
swelling of the feet. Burning of the feet occurs at night. The
dorsal surface of the foot itches, and is rubbed and lichenified.
Increased skin markings and finally marked hyperkeratosis
due to repeated infections result. This closely resembles

Other causes
Occupational persistent hand edema in divers, related to the
constrictive action of the divers suits and pricks from sea
urchin spines, can occur.

Evaluation
The diagnosis is usually based on a classic presentation;
however, in the early stages the disease may require further
investigation. Considerations include isotopic lymphoscintigraphy, indirect and direct lymphography, MRI, computed
tomography, and ultrasonography.

Treatment
Most cases are treated conservatively by means of various
forms of compression therapy, complex physical therapy,
pneumatic pumps, and compressive garments. Chronic antibiotic treatment may be beneficial in patients suffering
repeated episodes of erysipelas or cellulitis. In diabetics with
insensate feet, the frequency of infection can be reduced by
wearing properly fitting shoes. Volume-reducing surgery and
lymphatic microsurgery are rarely performed, although a few
centers consistently report favorable results. It is best to refer
these patients to a center versed in the treatment of these
complicated conditions, to optimize patient compliance and
customize therapy to the patients lifestyle.
Allen PJ, et al: Lower extremity lymphedema caused by acquired
immune deficient syndrome-related Kaposis sarcoma. J Vasc Surg
1995; 22:178.
Ameen M, et al: Clinicopathological case 2: lymphoedemadistichiasis
syndrome. Clin Exp Dermatol 2003; 28:463.
Angelini G, et al: Occupational traumatic lymphedema of the hands.
Dermatol Clin 1990; 8:205.
Badger C, et al: Physical therapies for reducing and controlling
lymphoedema of the limbs. Cochrane Database Syst Rev 2004;
4:CD003141.
Bastien MR, et al: Treatment of lymphedema with a multicompartmental
pneumatic compression device. J Am Acad Dermatol 1989; 20:853.
Billings SD, et al: Cutaneous angiosarcoma following breast-conserving
surgery and radiation. Am J Surg Pathol 2004; 28:781.
Campisi C, Boccardo F: Microsurgical techniques for lymphedema
treatment: derivative lymphatic-venous microsurgery. World J Surg
2004; 28:609.
Cerri A, et al: Lymphangiosarcoma of the pubic region: a rare
complication arising in congenital non-hereditary lymphedema. Eur J
Dermatol 1998; 8:511.
Downes M, et al: Vascular defects in a mouse model of hypotrichosislymphedoma-telangiectasia syndrome indicate a role for SOX18 in
blood vessel maturation. Hum Mol Genet 2009; 18:2839.

Durr HR, et al: StewartTreves syndrome as a rare complication of


hereditary lymphedema. Vasa 2004; 33:42.
Fonder MA, et al: Lipedema, a frequently unrecognized problem. J Am
Acad Dermatol 2007; 57:S1
Harel L, et al: Lymphedema praecox seen as isolated unilateral arm
involvement. J Pediatr 1997; 130:492.
Irrthum A, et al: Mutations in the transcription factor gene SOX18
underlie recessive and dominant forms of hypotrichosis-lymphedematelangiectasia. Am J Hum Genet 2003; 72:1470.
Johnson SM, et al: Lymphedemadistichiasis syndrome: report of a
case and review. Arch Dermatol 1999; 135:347.
Joseph A, et al: The efficacies of affected-limb care with penicillin
diethylcarbamazine, the combination of both drugs or antibiotic
ointment, in the prevention of acute adenolymphangitis during
bancroftian filariasis. Ann Trop Med Parasitol 2004; 98:685.
Makrilakis K, et al: Successful octreotide treatment of chylous pleural
effusion and lymphedema in the yellow nail syndrome. Ann Intern Med
2004; 141:246.
Maldonado F, Ryu JH: Yellow nail syndrome. Curr Opin Pulm Med 2009;
15:371.
Miller TA, et al: Staged skin and subcutaneous excision for
lymphedema: a favorable report of long-term results. Plast Reconstr
Surg 1998; 102:1486.
Moorjani N, et al: Pleural effusion in yellow nail syndrome: treatment
with bilateral pleuro-peritoneal shunts. Respiration 2004; 71:298.
Mortimer PS: Managing lymphedema. Clin Dermatol 1995; 13:499.
Nenoff P, et al: Podoconiosis-non-filarial geochemical elephantiasisa
neglected tropical disease. JDDG 2010; 8:7.
Radhakrishnan K, Rockson SG: The clinical spectrum of lymphatic
disease. Ann N Y Acad Sci 2008; 1131:155.
Ruocco V, et al: Lymphedema: an immunologically vulnerable site for
development of neoplasms. J Am Acad Dermatol 2002; 47:124.
Schissel DJ, et al: Elephantiasis nostras verrucosa. Cutis 1998; 62:77.
Tosti A, et al: Systemic itraconazole in the yellow nail syndrome. Br J
Dermatol 2002; 146:1064.
Yalcin E, et al: Yellow nail syndrome in an infant presenting with
lymphedema of the eyelids and pleural effusion. Clin Pediatr 2004;
43:569.

Neuropathic ulcers

elephantiasis verrucosa cutis. The condition is usually asymmetrical. Podoconiosis is prevented by wearing shoes.
Elevation, compression, and local wound care all aid in this
condition. Extensive surgery, as done for filariasis, has had
disappointing results.

Bonus images for this chapter can be found online at


http://www.expertconsult.com
Fig. 35-1 Raynaud disease.
Fig. 35-2 Photo-induced livedo reticularis secondary to quinidine.
Fig. 35-3 Hematoma.
Fig. 35-4 Purpura secondary to vomiting.
Fig. 35-5 Pigmented purpuric dermatosis.
Fig. 35-6 Leukocytoclastic vasculitis, concentration of lesions along
the dividing line between the dorsal foot and sole (Wallace line).
Fig. 35-7 HenochSchnlein purpura.
Fig. 35-8 Hereditary hemorrhagic telangiectasia.
Fig. 35-9 Hereditary hemorrhagic telangiectasia.
Fig. 35-10 Stasis dermatitis, venous insufficiency.
Fig. 35-11 Elephantiasis verrucosa nostra.
Fig. 35-12 Distichiasis. (Courtesy of Curt Samlaska, MD)

845