Livedoid vasculopathy

INTRODUCTION
Livedoid vasculopathy is a chronic, painful, thrombo-occlusive cutaneous vasculopathy that involves the distal
lower extremities and feet. Characteristic clinical features include livedoid skin changes (linear or angular,
erythematous nodules), atrophie blanche (smooth, ivory-white plaques), and ulceration. The diagnosis is
confirmed through a skin biopsy that demonstrates characteristic vascular abnormalities, including intraluminal
thrombosis, endothelial proliferation, and subintimal hyaline degeneration.

PATHOGENESIS is unclear. The disorder can occur either independently or in association with acquired or
inherited thrombophilia or various systemic diseases.

NOMENCLATURE
The literature on livedoid vasculopathy is highly problematic with regard to nomenclature. A variety of other
terms have been used to refer to this condition, most often "atrophie blanche" and "livedoid (or livedo)
vasculitis." However, "atrophie blanche" is most appropriately used as a descriptive term for the smooth, ivory-
white plaques that characteristically occur in livedoid vasculopathy but may also occur in other disorders,
particularly venous insufficiency. The use of "vasculitis" should be avoided because true vasculitis, as
demonstrated by destructive inflammation within the blood vessel wall, is absent.

EPIDEMIOLOGY AND PATHOGENESIS

Livedoid vasculopathy primarily occurs in young to middle-aged adults and is more common in females than
males. The pathogenesis is not well understood but is postulated to involve increased coagulation or impaired
fibrinolysis that results in occlusion of dermal blood vessels with fibrin thrombi.

CLINICAL FEATURES
Livedoid vasculopathy occurs on the lower leg (most common site), ankle, and/or dorsal foot. The presentation
is often bilateral, but unilateral involvement may also occur. The characteristic clinical findings are livedoid
changes and atrophie blanche. Ulceration is an additional common finding.

●Livedoid changes – Livedoid changes are deep, barely palpable, slightly erythematous nodules that have a linear
or angular shape. The appearance resembles patchy livedo reticularis (picture 1).

●Atrophie blanche – Atrophie blanche appears as smooth, ivory-white, atrophic plaques surrounded by
hyperpigmentation and telangiectasias. The plaques often have small amounts of stippled pigment. Atrophie
blanche can develop in sites of prior ulceration or in the absence of preceding ulcers.
●Ulcers – Superficial ulcers are common and typically range from 1 to 5 mm in diameter. Larger and deeper
ulcers may also occur. Removal of eschar will reveal a punched-out, angular, or stellate ulcer.

Livedoid changes are often the initial clinical manifestation of livedoid vasculopathy. Alternatively, ankle edema
or small, slightly raised papules with telangiectasias or purpura and peripheral petechiae may precede livedoid
changes. Ulcers are often persistent; even with treatment, healing may take several months.
Most patients with livedoid vasculopathy experience substantial pain, burning, or itching in involved areas.

PATHOLOGY
The characteristic pathologic changes occur in the blood vessels of the upper, middle, and/or lower dermis. The
blood vessels demonstrate thickening and focal thrombosis, with endothelial proliferation and hyaline
degeneration of the subintimal layer. The hyaline material stains positively by the periodic acid-Schiff technique
but is also visualized well on hematoxylin eosin staining. The elastic laminae of involved vessels are usually
preserved, and the vascular wall is rarely destroyed. Vessel lumina are occluded by proliferating cells embedded
within loose, fibrinoid material. The surrounding inflammatory reaction is relatively mild and consists primarily
of lymphocytes. Extravasation of red blood cells may be present.

The histologic findings in the dermal vasculature that strongly support a diagnosis of livedoid vasculopathy are:
●Intraluminal thrombosis
●Endothelial proliferation
●Subintimal hyaline degeneration

ASSOCIATED DISORDERS
Primary livedoid vasculopathy can occur with or without identifiable predisposing risk factors for thrombosis.
(including antiphospholipid antibodies, paraproteinemias, and genetic disorders).
Secundary livedoid vasculopathy can also occur in the setting of a defined illness, particularly a systemic
rheumatic disease. The diseases most commonly diagnosed in the setting of livedoid vasculopathy are the
primary antiphospholipid syndrome, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis,
mixed connective tissue disease, and undifferentiated connective tissue disease.

DIAGNOSIS
The diagnosis of livedoid vasculopathy is confirmed through the detection of consistent histologic findings in a
patient with suggestive physical findings (eg, livedoid changes, atrophie blanche, ulcers) on the lower extremities.
The cutaneous manifestations alone are insufficient to confirm the diagnosis, as similar findings may occur in
other disorders. Thus, a skin biopsy is mandatory.

For patients with ulcers, a careful history and physical examination can be helpful for determining whether other
diagnoses should be included in the differential diagnosis.
The ideal biopsy type is a fusiform incisional biopsy that includes subcutaneous fat. Alternatively, a 4 to 6 mm
punch biopsy can be performed. The optimal site for a biopsy is the edge of a new ulcer or a new purpuric
papule.

After the diagnosis has been confirmed histopathologically, an underlying disorder must be excluded.

DIFFERENTIAL DIAGNOSIS
The differential diagnosis of livedoid vasculopathy includes a broad array of conditions that may cause skin
discoloration, cutaneous ulcers, or nodules of the lower extremities. The most common disorders in the
differential diagnosis are lower extremity chronic venous disease, peripheral vascular disease, and vasculitis.

●Chronic venous disease – Venous insufficiency involving the lower extremities often presents with cutaneous
hyperpigmentation, edema, and varicosities on the lower extremities. Ulceration can occur and is most often
found near the medial malleolus. Ulcers are typically shallow with irregular borders and yellow, fibrinous
exudate. Atrophie blanche may also occur. The diagnosis often can be made clinically; venous ultrasonography
can be helpful when the diagnosis is uncertain.

●Peripheral vascular disease – Peripheral vascular disease of the lower extremities can result in ischemic ulcers,
which are often located on the toes, heel, malleoli, or shin. The painful ulcers are well demarcated, with a
"punched-out" appearance.

●Vasculitis – Vasculitis involving medium-sized cutaneous blood vessels (eg, cutaneous polyarteritis nodosa,
antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, mixed cryoglobulinemia, thromboangiitis
obliterans, lymphocytic thrombophilic arteritis) may present with subcutaneous nodules, ulcers, livedo
reticularis, or livedo racemosa. A skin biopsy can differentiate livedoid vasculopathy from vasculitis.

ADDITIONAL EVALUATION
After the diagnosis of livedoid vasculopathy has been confirmed histologically, patients should be evaluated for
underlying disorders. The evaluation should begin with a complete history, review of systems, and physical
examination to assess for findings suggestive of thrombophilia or a systemic rheumatic disease. Although we
typically perform laboratory testing for thrombophilia in all patients, we limit laboratory investigation for
systemic rheumatic diseases to patients who exhibit other findings suggestive of such diseases.

Examples of studies often included in our laboratory assessment include:

●Tests for acquired and inherited thrombophilia
●Complete blood count
●Comprehensive metabolic panel
●Urinalysis
●Erythrocyte sedimentation rate and C-reactive protein
●Rheumatoid factor and antibodies to cyclic citrullinated peptides
●Serum complement levels (eg, CH50, C3, and C4)
●Antinuclear antibody titer
●Antineutrophil cytoplasmic antibodies (ANCA)
●Serum cryoglobulins
●Serum protein electrophoresis and immunofixation

The primary value in evaluating patients for a systemic rheumatic disease is the identification of patients at risk
for other complications of the identified condition. Treatment of the underlying systemic rheumatic disease does
not seem to have a consistent effect on livedoid vasculopathy, and the presence of a systemic rheumatic disease
does not usually alter the approach to treatment. In contrast, the presence of thrombophilia influences our
approach to treatment.

TREATMENT
Treatment of livedoid vasculopathy usually involves a combination of interventions. No single therapeutic
approach is effective for all patients.

General measures — Pain management and wound care are important components of management. Smoking
cessation and compression also may be beneficial.

●Pain management – Pain secondary to livedoid vasculopathy can be severe. Our first-line approach to pain
management usually consists of acetaminophen or nonsteroidal anti-inflammatory drugs. Treatments typically
used for neuropathic pain, such as tricyclic drugs, gabapentin, pregabalin, or carbamazepine, may be useful for
patients with recalcitrant ulcerations.
●Wound care – Wound care should involve maintenance of a moist wound environment and control of
superinfection.
●Smoking cessation – Although the effects of smoking cessation on livedoid vasculopathy have not been studied,
we encourage patients to stop smoking because of the negative effects of smoking on wound healing. In addition,
there is a proposed relationship between livedoid vasculopathy and smoking.
●Compression – Clinical experience suggests that compression therapy is beneficial in patients with associated
venous insufficiency provided ankle-brachial index results do not suggest concomitant arterial insufficiency.

Pharmacologic therapy — Limited data suggest that therapies that minimize risk for thrombosis, including
antiplatelet, anticoagulant, and fibrinolytic agents, can improve livedoid vasculopathy. Benefit from
immunomodulatory, vasodilatory, and other interventions has also been reported. Combination therapy is often
necessary.
For patients without an identified thrombophilia aspirin is our preferred first-line therapy. Pentoxifylline is our
favored initial treatment for patients who cannot tolerate aspirin. Pentoxifylline 3x400 improves hyperviscosity
of the blood and has inhibitory effects on platelet and erythrocyte aggregation. The drug has appeared helpful
for livedoid vasculopathy in case series. Gastrointestinal distress is a potential side effect. For patients who can
tolerate aspirin but fail to improve on aspirin alone, we typically add pentoxifylline. When patients have
insufficient responses to aspirin and pentoxifylline, we often proceed to anticoagulation.

For patients with an identified thrombophilia anticoagulants are often used as first-line therapy;

Improvement in signs and symptoms of livedoid vasculopathy are expected within the first few months of
treatment There is no fixed endpoint for therapy in patients who respond to treatment. Discontinuation of
treatment may be attempted after ulcer healing; however, continuous treatment may be necessary to maintain
improvement.

Other therapies — Other therapies that may be useful based upon case reports or small case series include tissue
plasminogen activator (10 mg intravenously given for 14 days), doxycycline (100 mg twice daily), danazol (200
mg per day), hyperbaric oxygen (1.5 to 2 hours for up to 15 treatment sessions), intravenous immune globulin
(monthly infusions of 0.5 g/kg given over two or three consecutive days), nifedipine (10 to 20 mg three times per
day), psoralen plus ultraviolet A (PUVA, 0.5 to 1 mJ/cm2 per treatment session), and sulfasalazine (3x1 g ).

PROGNOSIS
Livedoid vasculopathy often recurs upon discontinuation of treatment. Long-term treatment with an effective
regimen is usually necessary.
SUMMARY AND RECOMMENDATIONS

●Livedoid vasculopathy is a chronic, recurrent, thrombo-occlusive vasculopathy of the distal lower extremities
and feet that can lead to ulcer formation. Livedoid vasculopathy can occur independently or in the setting of a
variety of thrombophilic states and underlying systemic disorders.

●Characteristic clinical features of livedoid vasculopathy include livedoid changes, atrophie blanche (ivory-white
plaques with peripheral hyperpigmentation and telangiectasias), painful ulcers, and edema.

●A skin biopsy is necessary to confirm the diagnosis. The biopsy should include the full thickness of the dermis
as well as subcutaneous fat. The optimal sites for biopsy are at the edge of a new ulceration or over a new
purpuric papule. The histologic findings that strongly support a diagnosis of livedoid vasculopathy include
intraluminal thrombosis, endothelial proliferation, and subintimal hyaline degeneration in dermal blood vessels.

●Livedoid vasculopathy may occur in association with thrombophilia and systemic rheumatic diseases. Patients
diagnosed with livedoid vasculopathy should be assessed for these conditions.

●Data on treatment options for livedoid vasculopathy are limited, and the best approach to treatment is unclear.
Pain control and wound care are important components of management. Smoking cessation and compression
may also be beneficial.

●Therapies reported as beneficial for livedoid vasculopathy have included antiplatelet, anticoagulant,
fibrinolytic, immunomodulatory, and vasodilatory agents. For patients without an identified thrombophilia, we
suggest aspirin as initial treatment based upon case reports and case series that suggest benefit as well as the
tolerability, wide availability, and low cost of this therapy. Pentoxifylline is an alternative first-line treatment
option that may be particularly useful for patients who cannot tolerate aspirin. Patients who do not respond to
first-line treatments may benefit from other anticoagulants or other interventions.

●Selection of treatment for patients diagnosed with thrombophilia is based upon knowledge of the therapies
known to reduce thrombosis in the specific thrombophilia.