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Pediatric Dermatology Vol. 15 No. 3 169-183, 1998

Acute Infectious Purpura Fulminans:

Pathogenesis and Medical Management
Gary L. Darmstadt, M.D.
Department of Pediatrics, Children’s Hospital and Regional Medical Center, University of Washington School of
Medicine, Seattle, Washington

Abstract: Purpura fulminans (PF) is a potentially disabling and life-

threatening disorder characterized by acute onset of progressive cutane-
ous hemorrhage and necrosis, and disseminated intravascular necrosis.
Acute infectious PF occurs most commonly in the setting of meningo-
coccemia due to elaboration of endotoxin. Presence of purpura, particu-
larly when generalized, is an important predictor of a poor outcome fol-
lowing meningococcal infection. Histopathologic hallmarks of acute
infectious PF are dermal vascular thrombosis and secondary hemor-
rhagic necrosis, findings which are identical to those of the Shwartzman
reaction. Acute infectious PF and the Shwartzman reaction have a com-
mon pathogenesis, involving a disturbance in the balance of anticoagu-
lant and procoagulant activities of endothelial cells. This disturbance,
which is triggered by endotoxin, appears to be mediated by cytokines,
particularly interleukin-12, interferon-?, tumor necrosis factor-a, and in-
terleukin-1, leading to the consumption of proteins C and S and anti-
thrombin 111. State-of-the-art therapeutic interventions based on recent
advances in our understanding of the pathogenesis of acute infectious PF
are discussed.

Purpura fulminans (PF) is a potentially disabling and (LPS)-producing gram-negative bacteria (e.g., Neisseria
life-threatening disorder characterized by acute onset of meningitidis) (1). All cases involve dysfunction of he-
progressive cutaneous hemorrhage and necrosis due to mostasis, with a shift from a quiescent state favoring
dermal vascular thrombosis, and disseminated intravas- anticoagulation to a disease state of overwhelming pro-
cular necrosis (DIC). It occurs predominantly in three coagulation.
clinical settings (Table 1): (1) in the neonatal period as a Significant strides have been made in the management
manifestation of inherited, homozygous protein C or, of hereditary neonatal PF because of advances in our
rarely, protein S deficiency; ( 2 ) approximately 7 to 10 understanding of its pathogenesis (e.g., protein C defi-
days after a relatively benign antecedent infection, usu- ciency) and the availability of new therapeutic products
ally involving the skin, such as varicella or scarlet fever (e.g., protein C concentrate) (2,3). Idiopathic PF is an
(i.e., “idiopathic” PF) (Table 2); and ( 3 ) in conjunction uncommon entity that has been reported in less than 100
with an acute infectious illness (i.e., acute infectious PF), children (4,5). It develops while the patient is not acutely
particularly sepsis with endotoxin [lipopolysaccharide] ill, typically during the postinfectious convalescent phase

Address correspondence to Gary L. Darmstadt, M.D., Division of

Infectious Disease, Department of Pediatrics CH-32, Children’s Hos-
pital and Regional Medical Center, 4800 Sand Point Way NE,Seattle,
WA 98105, or e-mail: gdarms@chmc.org.

170 Pediatric Dermatology Vol. 15 No. 3 May/June 1998

TABLE 1. Classification of Purpura Fulminans knowledge, the application of new, potentially more ef-
fective approaches to its medical management will be
I. Hemostasis initiated
A. Protein C anticoagulant system dysfunction discussed.
1. Hereditary
a. Homozygous protein C deficiency EPIDEMIOLOGY
b. Homozygous protein S deficiency
2. Acquired Purpura fulminans develops in 15% to 25% of those with
a. Disseminated intravascular coagulation
B. Disorder of other hemostasis regulatory systems meningococcemia (6-9). It can develop during infection
1. Antithrombin I11 with any of the meningococcal serogroups; endotoxin
11. Idiopathic production, however, appears to be highest among sero-
A. Postinfectious
B. Unknown etiology group C isolates (10). Purpura fulminans occurs only
111. Acute infectious rarely in the course of infection with other organisms,
even in the setting of sepsis with DIC. In one series of
patients with pneumococcal sepsis, however, 6% (101
of varicella, group A streptococcal infection, or a non- 165) developed symmetrical peripheral gangrene (1 1). In
specific viral exanthematous illness. Some cases have the neonate, acute infectious PF may be due to group B
followed conditions that apparently were not infectious, streptococcus.
such as cutaneous hypersensitivity reaction or stomatitis. Although several factors have been identified as pre-
Idiopathic PF differs from the acute infectious form in dictive of a poor outcome from meningococcemia, size
that microthrombi and clinically significant thrombo- of skin hemorrhage increases with disease severity (12),
hemorrhagic manifestations in organs other than the skin and the presence of purpura, particularly when general-
generally are lacking; distal vascular beds (i.e., extremi- ized, is associated with high morbidity and mortality, as
ties) typically are spared; and circulatory collapse is not it reflects a profound disturbance in hemostatic mecha-
present initially, although hypovolemic shock and tissue nisms (8,13-21). While the overall fatality rate in chil-
hypoperfusion may develop due to extravasation of dren with meningococcemia in the United States is less
blood into the skin. These differences are reflected in the than 15%, development of PF heralds mortality in 20%
lower mortality rate associated with idiopathic PF (ap- to 60% of cases. Of those who survive, the majority have
proximately 15%) compared to acute infectious PF. cutaneous and skeletal deformities due to gangrene
The majority of cases of PF develop in childhood (22,23). The presence of petechiae signals septicemia,
during an acute infection, particularly meningococcal and onset within 12 hours of initial medical evaluation
sepsis. This review describes our current knowledge of has been associated with poor outcome in some studies
the pathogenesis of acute infectious PF. Based on this (24,25) but not in others (6,8,17). Thus PF, distinct from
petechiae or other cutaneous manifestations of meningo-
TABLE 2. Infectious Causes of Purpura Fulminans coccemia such as a maculopapular eruption, is an impor-
tant marker of a poor outcome.
I. Idiopathic (postinfectious) purpura fulminans
Streptococcal tonsillopharyngitis
Viral exanthem Lesions of PF are similar regardless of the precipitating
Rubella condition. Cutaneous discomfort develops first, followed
Measles by development of erythema with or without edema and
Upper respiratory tract infection
Gastroenteritis petechiae. Sites of involvement appear transiently like
11. Acute infectious purpura fulminans ecchymoses, and up to this point the pathologic process
Neisseria meningitidis in the skin is reversible without progression to necrosis.
Streptococcus pneumoniae
Streptococcus agalactaeae (group B streptococcus) Lesions evolve rapidly into painful, indurated, well-
Haemophilus influenzae type b demarcated, irregularly bordered purpuric papules and
Rickettsia rickettsii plaques which are surrounded by a thin, advancing ery-
Streptococcus pyogenes (group A streptococcus)
Staphylococcus aureus thematous border (Figs. 1 and 2). Late findings in ne-
Klebsiella pneumoniae crotic areas are the formation of vesicles and bullae (Fig.
Escherichia coli 3), which mark the development of hemorrhagic necro-
Proteus mirabilis
Enterobacter spp. sis, and finally firm eschar which ultimately sloughs.
Neisseria catarrhalis Gangrenous necrosis often extends into subcutaneous tis-
Haemophilus aegypticus sue, and occasionally involves muscle and/or bone (Fig.
Capnocytophaga canimorsus
4); epiphyseal growth plate necrosis in the growing child
Darmstadt: Acute Infectious Purpura Fulminans 171

Figure 1. Well-defined, irregularly bordered purpuric Figure 3. Purpuric plaques and hemorrhagic bullae on the
plaques on the arm of a child with early acute infectious leg of a child with severe, advanced purpura fulminans
purpura fulminans due to Neisseria meningitidis. due to Neisseria meningitidis.

Figure 2. Well-defined, purpuric plaques on the arm of a

child, late in the course of meningococcemia.

may lead to limb foreshortening. The distal extremities

are often most severely involved, usually in a symmetric
manner, probably due to the presence of fewer collateral
channels for tissue perfusion, and the relatively greater Figure 4. Gangrenous fifth fingertip due to Neisseria men-
impact of circulatory collapse on perfusion of distal vas-
cular beds. This differs from idiopathic or postinfectious
PF, which typically begins in the skin of the thighs, legs, and multiple organ dysfunction syndrome is common.
buttocks, and lower trunk. Acute infectious PF fre- Fibrinogen, coagulation factors (e.g., factor V and factor
quently progresses proximally and ultimately may form VIII), and platelets are consumed in ongoing thrombosis
purpuric plaques of various sizes and shapes in a diffuse, and fibrinolysis. Prothrombin time (PT) and partial
patchy distribution. thromboplastin time (PTT) are prolonged; fibrin degra-
Development of systemic consumptive coagulopathy dation products (e.g., D-dimers) are elevated; and protein
(i.e., DIC) is a defining feature of PF, which distin- C, protein S, and antithrombin I11 levels are reduced.
guishes it from other forms of skin necrosis due to der- The histopathologic hallmarks of PF are dermal vas-
mal vascular occlusion such as warfarin- or heparin- cular thrombosis and secondary hemorrhagic necrosis
induced skin necrosis, thrombotic thrombocytopenic (Fig. 5a) (26). Vascular changes are widespread, involv-
purpura, cryoglobulinemia, antiphospholipid syndrome, ing multiple organ systems, particularly the adrenal
or paroxysmal noctural hemoglobinuria. Shock may oc- glands (Waterhouse-Friderichsen syndrome), lungs, and
cur in all forms of PF, but is most characteristic of acute kidneys. The cutaneous vessels most affected are the
infectious PF. Thrombohemorrhagic manifestations may postcapillary venules in the subpapillary plexus of the
be found in multiple vascular beds and organ systems, papillary dermis, where blood flow velocity is slowest.
172 Pediatric Dermatology Vol. I5 No. 3 May/June 1998

ture of acute infectious PF that distinguishes it from

other forms of PF (Fig. 5b).
Preliminary identification of N. meningitidis as the
cause of PF can sometimes be made by finding the
Gram-negative diplococci on Gram’s stain of material
obtained by needle aspiration of a petechial skin lesion
(27j, or by scraping the lesion with a needle and making
a smear of blood (28).

The histopathologic changes in acute infectious PF are
essentially identical to those of the Shwartzman reaction.
Comparison of these entities has provided valuable in-
sight into possible pathogenetic mechanisms of PF. Out
of this increased understanding of the pathophysiology
of PF has come the design of more directed and poten-
tially more effective therapy for PF.

The Shwartzman Reaction

The local Shwartzman reaction is a hemorrhagic and
necrotizing inflammatory lesion provoked by the injec-
tion of endotoxin from Gram-negative bacteria (29,30).
Endotoxin from N. meningitidis is 5- to 10-fold more
effective at eliciting the reaction than endotoxin from
other Gram-negative bacteria (31). Furthermore, endo-
toxin levels in plasma of patients with fulminant menin-
gococcemia are among the highest ever recorded ( 12),
perhaps accounting, at least in part, for the increased
incidence of PF in patients with meningococcemia com-
pared to sepsis with other organisms.
The two-step Shwartzman reaction is initiated by a
local, priming intradermal injection of endotoxin. This
a elicits a transient perivascular neutrophilic and mono-
Figure 5. Skin biopsy specimens from children with me- cytic inflammatory reaction with increased vascular per-
ningococcemia showing (A) dermal vascular thrombosis
and (B) vasculitis. Specimens were stained with hemo- meability that is maximal approximately 4 hours after
toxylin and eosin. injection. Vessel damage, however, is not seen at this
stage. Intravenous challenge with the same endotoxin 18
Histopathologic changes begin at the junction of terminal to 24 hours later results in thrombosis with mixed mi-
precapillary arterioles with capillaries and generally crothrombi, endothelial cell swelling, dilatation of blood
spare arteries and arterioles. Microthrombi are mixed, vessels, and necrotizing neutrophilic vasculitis, leading
composed of fibrin, platelets, and leukocytes, particu- to extravasation of formed blood elements and purpura
larly neutrophils; Gram-negative diplococci of N. men- localized to the prepared dermal site. The degree of hem-
ingitidis occasionally are visible as well. Endothelial cell orrhage elicited by the challenge correlates directly with
swelling is prominent and leads initially to capillary di- the accumulation of leukocytes after the priming reaction
latation, manifest clinically as erythema. Acute vascular (32). Development of microthrombi only at skin sites
injury progresses to endothelial cell separation and ves- prepared previously with endotoxin suggests that af-
sel rupture, allowing for extravasation of formed blood fected endothelial cells were made more thrombogenic
elements into the dermal stroma and development of during the intervening period between the local and the
clinically visible purpura. Extensive hemorrhage is fol- systemic injections. Of note, a generalized Shwartzman
lowed by coagulative necrosis. Vasculitis, including a reaction can be produced by two intravenous injections
perivascular neutrophilic infiltrate, is a characteristic fea- of endotoxin spaced 18 to 24 hours apart, producing a
Darmstadt: Acute Infectious Purpura Fulminans 173

syndrome which models DIC (30). Tissue damage is Plasminogen is bound specifically to fibrin, becoming
similar in the local and generalized Shwartzman reac- intermeshed and concentrated within the fibrin clot as it
tions, suggesting that they share a common pathogenesis. forms. There it is sequestered away from protease inhibi-
The local Shwartzman reaction is thought to be more like tors (e.g., a,-antiplasmin) normally present in the blood,
idiopathic/postinfectious PF, with cutaneous lesions lim- and can be activated by fibrin-bound t-PA to plasmin.
ited to sites prepared in the skin by an antecedent infec- Plasmin remains bound to fibrin where it is protected
tion, whereas the generalized Shwartzman reaction from a,-antiplasmin, upregulates its own generation, and
resembles acute infectious PF with formation of micro- degrades fibrinogen and fibrin to dissolve the clot. Out-
thrombi in multiple organ systems. side the milieu of the clot, a,-antiplasmin is able to neu-
tralize plasmin, restricting fibrinolytic activity to the re-
gion of the clot. During DIC, however, excessive
Hemostatic Balance
plasmin is generated and the capacity of a,-antiplasmin
Central to the pathogenesis of the Shwartzman reaction to neutralize plasmin in the blood is overcome. Levels of
is a disturbance in the balance of anticoagulant and pro- a,-antiplasmin fall due to excessive activation of the
coagulant activities of endothelial cells. Normally, in the fibrinolytic system. Plasmin is then bound to a secondary
absence of disease, the balance of hemostatic activity on inhibitor, called a,-macroglobulin, but low-level plas-
the surface of endothelial cells favors anticoagulation. min activity persists within this complex and systemic
Systems for ensuring this include the protein C- fibrinolysis is able to continue. Measurement of the
thrombomodulin system, the antithrombin 111-heparin cleaved fibrinogen species produced by the action of
system, profibrinolytic mechanisms involving plasmino- plasmin forms the basis for a variety of tests utilized in
gen activation, and inhibition of platelet aggregation detecting the systemic fibrinolysis seen in DIC. Biologi-
through release of prostacyclin (33-36). Thrombomodu- cal actions of these cleavage products include potentia-
lin is a high-affinity receptor for thrombin. Binding of tion of the hypotensive effects of bradykinin and chemo-
thrombin to thrombomodulin activates protein C, which taxis of monocytes and neutrophils. A final endothelial
in turn, in concert with its cofactor protein S, destroys cell-derived regulator of fibrinolysis is plasminogen ac-
clotting factors V and VIII of the intrinsic hemostatic tivator inhibitor-1 (PAI-1). The major physiologic role of
cascade. This prevents factor V-mediated binding of pro- PAI-1 is to suppress the function of t-PA and thus to
thrombin to the surface of the platelet, thereby suppress- modulate fibrinolysis.
ing production of thrombin. Concurrently, interaction of
thrombin with thrombomodulin makes thrombin unavail- Cytokines
able to stimulate a plethora of pathophysiologic proin-
flammatory and prothrombotic events in sepsis, includ- When endothelial cells are injured, a shift in the balance
ing the expression of platelet activating factor and the of hemostasis toward a procoagulant state occurs. In
activation, adhesion, and aggregation of platelets; the acute infectious PF, this is triggered by endotoxin, which
transformation of fibrinogen into fibrin with release of in turn causes local production and release of proinflam-
fibrinopeptides; the activation of clotting factors V and matory molecules. Principle proinflammatory molecules
VIII; and induction of expression of granule membrane include the cytokines tumor necrosis factor-a (TNF-a),
protein- 140 on endothelial cells (which promotes adhe- interferon-? (IFN-y), and interleukin- 1 (IL- 1). During
sion of neutrophils). Thrombin attached to thrombo- the first or priming step of the Shwartzman reaction, it
modulin can be inactivated by antithrombin I11 at a faster appears that endotoxin first induces the release of IL- 12
rate than can free thrombin. Antithrombin 111 is the major from a variety of cell types, including T and B lympho-
inhibitor of the coagulation cascade. Heparin or heparin- cytes, natural killer (NK) cells, and mononuclear phago-
like molecules on endothelial cells stimulate formation cytes (37). IL-12 in turn induces production of IFN-y,
of a complex between antithrombin Ill and the active principally from NK cells (38). For optimum generation
serine center of the serine protease thrombin, neutraliz- of IFN-y, however, the presence of TNF-a and macro-
ing the activity of thrombin. Similarly, heparin also fa- phages is required (39,40). IFN-y, which plays a central
cilitates inactivation of other serine proteases of the co- role in the priming reaction (37,38), activates macro-
agulation cascade (i.e., factors IXa, Xa, XIa, XIIa) by phages to produce monokines, including TNF-a and IL-
antithrombin Ill. Lysis of microthrombi is promoted by 1; sensitizes endothelial cells; and primes the endothelial
endothelial cells through synthesis and release of plas- cells to produce TNF-a and IL-1 during the intravenous
minogen activators such as tissue plasminogen activator challenge phase of the Shwartzman reaction. A crucial
(t-PA), which in turn initiates activation of plasminogen. event during the priming process appears to be upregu-
174 Pediatric Dermatology Vol. 15 No. 3 May/June 1998

lation of intracellular adhesion molecule- 1 (ICAM-1) on voking) phase of the Shwartzman reaction. The effects of
vascular endothelial cells in dermal blood vessels TNF-a are potentiated by IL-1 and IFN-y (37). Serum
(41,42). This may be due principally to the action of levels of TNF-a were elevated in 91% of children with
endotoxin and TNF-a, and perhaps also IL-1 and IFN-y, acute infectious PF, and the level of TNF-a correlated
all of which are capable of upregulating ICAM-1 expres- negatively with fibrinogen levels and positively with en-
sion. Injection of IFN-y, TNF-a, or TNF-a and IL-1 dotoxin levels (59) and with the severity of infection and
acting synergistically can be used in place of endotoxin mortality (60).
to prepare the skin for a local Shwartzman reaction A central concept in the pathogenesis of the Shwartz-
(37,43,44). The inflammatory infiltrate generated during man reaction which has emerged recently is that of cy-
the priming phase, as a consequence of upregulated tokine balance. Concurrently with the production of pro-
ICAM-1 expression (41), and the plasma leakage ob- inflammatory cytokines such as TNF-a, endotoxin also
served during the priming phase depend on local genera- induces the production of antiinflammatory molecules
tion of TNF-a(45). Generation of an acute inflammatory such as IL-10. IL-10 is a potent macrophage deactivator
cell infiltrate is an absolute requirement of the Shwartz- which blocks the synthesis of TNF-a, IL-1, and other
man reaction; the reaction does not occur in neutropenic proinflammatory cytokines such as IL-6, IL-8, and
animals (46). The perivascular, interstitial infiltrate gen- granulocyte-macrophage colony-stimulating factor (GM-
erated during the priming phase, however, does not cause CSF) by monocytes (61) and macrophages (62). Further-
vascular damage or hemorrhage. more, IL-10 suppresses synthesis of IFN-y by helper T
The second or challenge phase of the Shwartzman cells (63) and NK cells (64). Mice deficient in IL-10
reaction, which results in the vasculitis and hemorrhage production were extremely vulnerable to generation of a
that becomes manifest clinically as purpura, requires the generalized Shwartzman reaction, requiring 100- to 200-
recruitment and aggregation of neutrophils in the dermal fold less endotoxin during the priming phase compared
vessels of prepared skin sites (47,48). An early, critical to wild-type mice (65). Production of TNF-a in response
event of the challenge phase appears to be the upregula- to endotoxin sensitization also was exaggerated. More-
tion of CD1 1b/CD18 (Mac-1) on leukocytes, which sub- over, IL-10 infusion blocked the sensitization step. Per-
sequently allows them to adhere to the ICAM-1 mol- haps endogenous IL- 10 normally inhibits the production
ecules that were expressed on vascular endothelial cells of IL-12 and IFN-y during the preparatory phase of the
during the priming phase and to aggregate within af- Shwartzman reaction (65).
fected vessels (41,42). Endothelial cells that are injured
by endotoxin, or by exposure to TNF-a and IL-I , and/or
Acquired Protein C and Protein S Deficiency
infiltrating neutrophils synthesize and express tissue fac-
tor (i.e., tissue thromboplastin), the most potent proco- Protein C naturally attenuates the proinflammatory ac-
agulant known, on their surface (49-52). TNF-a also tivity stimulated by endotoxin and cytokines. It decreases
induces the expression of tissue factor on monocytes endotoxin-induced cytokine production by monocytes
(53). In children with meningococcal sepsis, tissue factor and inhibits the downregulation of CD14 and C D l l b on
expression is increased on circulating monocytes (54). leukocytes by endotoxin (66). Acquired deficiency of
Tissue factor activates the extrinsic pathway, leading ul- protein C has been described in many patients with acute
timately to production of fibrin. Deposition of fibrin due infectious PF (67-74) and is increasingly implicated in
to tissue factor-initiated coagulation within the vessels of the pathogenesis of this disorder. The degree of protein C
prepared skin sites is required for pathogenesis of the deficiency can be correlated with size of skin lesions
Shwartzman reaction (47). Exposure of endothelial cells (73), clinical severity of the illness (9), and mortality
to endotoxin or to TNF-a and IL-1 also suppresses (9,70,73). It has been suggested that decreased protein C
thrombomodulin activity (55,56). This leads to decreased levels indicate that meningococcal endotoxin induces a
protein C activity and in turn to impaired degradation of relatively greater decrease in natural anticoagulant than
activated factors V and VIII, and to increased thrombin procoagulant proteins, and that the coagulopathic effects
procoagulant activity through enhanced availability of of meningococcal endotoxin are greater than those ob-
thrombin. Secretion of PAI-1 by endothelial cells also is served in most other bacterial infections (9).
increased, which further promotes thrombosis (57,58). Most patients with reduced protein C levels have a
Cytokines, particularly TNF-a, which are produced concomitant reduction in the level of protein S (67-74).
by injured endothelial cells as well as by injured kera- Protein S is active only in the free, unbound form. Nor-
tinocytes and infiltrating monocytes and neutrophils, ap- mally, approximately 60% of total protein S is carried by
pear to be the principle mediators of the hemodynamic the complement component C4b binding protein, which
and histopathologic events during the second (i.e., pro- is an acute-phase reactant. Elevation of C4b binding pro-
Darmstadt: Acute Infectious Purpura Fulminans 175

tein during acute infection may lead to a reduction in free bits human activated protein C attenuated the local
protein S activity. Relatively low baseline protein C and Shwartzman reaction (84). In a baboon model of Gram-
S level in infants and young children may explain their negative sepsis, blocking protein C activation with
increased risk of development of PF compared to adults monoclonal antibodies increased mortality, suggesting
(67). that protein C played an important role in attenuating
Some patients with postinfectious PF have had pro- coagulopathy in sepsis (85). When protein C was admin-
found depression in levels of protein s, with normal to istered prophylactically, it prevented the coagulopathic
only slightly decreased protein C at presentation and/or and lethal effects of endotoxin-associated sepsis (85),
relatively rapid recovery of protein C compared to pro- further suggesting that the protein C system may play a
tein S levels, suggesting that a subtle difference exists in role in modulating the effects of inflammatory cytokines
the pathophysiology of their disease compared to those (4).
with acute infectious PF (75-79). Recently some patients
with postinfectious PF following acute chickenpox have
been shown to have antiprotein S IgM and IgG autoan- Consumption of Antithrombin I11
tibodies (79,80); many of these patients have also had
A decrease in antithrombin I11 also occurs in patients
lupus anticoagulant and antiphospholipid antibodies
with acute infectious PF (68,71-73,86,87). In some pa-
(77,80,81). These autoantibodies appear to bind to and
tients with PF, derangement in antithrombin I11 appeared
increase the clearance of protein S. Patients with post-
to more closely parallel the clinical course than did levels
infectious (i.e., post-varicella) transient protein S de-
of protein C or protein S (72). Interest in the utility of
ficiency, including those with autoantibody-mediated
antithrombin 111 concentrate as a therapeutic measure in
disease, manifest a spectrum of thromboembolic compli-
PF has increased because of studies in animals and hu-
cations, ranging from pulmonary emboli and/or throm-
botic events affecting other internal organs but sparing mans which have demonstrated its efficacy as a prophy-
the skin, to PF with coexistent major organ thromboem- lactic and therapeutic agent in DIC (88-93).
bolic disease (78-80,82,83). The presence of autoanti-
bodies directed against protein S has important implica- Complement
tions for therapy, since protein S levels in these patients
may not respond to administration of fresh frozen plasma Complement, along with specific antibodies, plays a piv-
(FFP) (79). Furthermore, infusions of FFP may facilitate otal role in defense against N. meningitidis. Interestingly,
the formation of immune complexes and induce a serum- while those with defects in the terminal complement cas-
sickness-like illness (79). cade (C5 to C9) have increased risk of acquiring menin-
Generation of dermal vascular necrosis and hemor- gococcemia, the severity of their infections tends to be
rhagic skin necrosis in PF involves a combination of relatively mild; rather, they are at increased risk for re-
disordered hemostasis and inflammatory-mediated current episodes. Overall approximately 4% of those
pathologic changes. Events that are common in all forms who present with acute, first-episode meningococcemia
of PF include increased tissue factor expression and ex- have a terminal complement deficiency and low total
posure, downregulation of thrombomodulin expression hemolytic complement levels (CH,,). More severe epi-
and protein C activity, and impaired fibrinolysis (1). In sodes may be associated with a rare, properdin defi-
patients with PF due to hereditary protein C or protein S ciency (94). These patients have normal CH,, but low
deficiency, disordered hemostasis predominates, and alternative hemolytic complement.
little or no inflammatory infiltrate is present. The role of In the course of meningococcal infection, significant
cytokines in the pathogenesis of these lesions is thought complement activation occurs, leading to formation of
to be minor (1). In acute infectious PF, however, cyto- the anaphylatoxins C3a, C4a, and C5a (95). Complement
kine-mediated inflammation may play a predominant activation appears to play an important role during the
role, while disordered hemostasis augments the patho- provoking phase of the Shwartzman reaction by upregu-
logic process. lating expression of CD 18 on neutrophils, activating
Reduction of protein C and protein S in acute infec- them, and inducing them to adhere to ICAM-1 on endo-
tious PF most likely stems from consumption during co- thelium of prepared skin sites (42). In addition, genera-
agulopathy, and their derangement is thought to perpetu- tion of the membrane attack complex at the bacterial
ate and exacerbate rather than initiate dermal vascular surface induces release of endotoxin. Increasing severity
thrombosis (4). Nevertheless, therapy directed at restor- of disease and mortality are associated with higher levels
ing the functional capacity of the protein C system in of C3 activation products and terminal complement com-
animal models had led to promising results. Giving rab- plex (96).
176 Pediatric Dermatology Vol. 15 No. 3 May/June 1998

Location of Purpura tient to patient. Consequently, therapy must be individu-

alized, and often will involve a combination of modali-
There is no adequate explanation for why lesions of PF
ties. Acute infectious PF typically is a fulminant disorder
develop at particular skin sites. Hypotheses include site-
with rapid progression to irreversible tissue necrosis, em-
specific differences in cytokine release by endothelial
phasizing the importance of prompt therapeutic interven-
cells; variability in endothelial cell expression of proco-
tion. Surgical consultation should be sought early in the
agulant and anticoagulant factors, cytokine receptors, or
course to monitor compartment pressures and intervene
transduction of signal following binding of cytokine to
in compartment syndrome. Nutritional support is also
its receptor; differences in expression of cell adhesion
important, and should be continued during the rehabili-
molecules and thus in leukocyte trafficking; physical
tative phase.
properties of the skin such as variations in temperature or
Initial laboratory determinations that will help to
blood flow; or cutaneous trauma (1).
guide therapeutic decisions in the management of pa-
tients with PF include a complete blood count, platelet
MEDICAL MANAGEMENT count, PT, PTT, fibrinogen, fibrin degradation products,
Greater understanding of the pathophysiology of PF has protein C, free protein S, and antithrombin 111. Blood
allowed the design of new approaches to the medical components that may be necessary in individual cases,
management of this disorder during the past decade depending on the results of these tests, include packed
(Table 3). Before considering these therapies, however, it red blood cells for anemia due to massive hemorrhage
must first be emphasized that initial management of the into the skin, platelets to correct thrombocytopenia due
patient with acute infectious PF must be focused on pre- to platelet consumption, and/or cryoprecipitate to replace
serving life through respiratory and hemodynamic sup- fibrinogen in patients with DIC.
port and prompt intravenous antibiotic coverage (e.g., Therapeutic interventions that should be initiated for
third-generation cephalosporin such as ceftriaxone). Cir- all patients with PF and DIC include vitamin K and FFP
culatory collapse with tissue hypoperfusion and ischemia (8-12 mgkg every 12 hours), which are given to correct
directly damages endothelial cells and predisposes to possible deficiencies of vitamin K-dependent coagula-
thrombosis; the propensity to develop microthrombi is tion factors (97,98), antithrombin 111, protein C, and pro-
exacerbated in the presence of flow stasis. Furthermore, tein s. Fresh frozen plasma does not aggravate consump-
the high levels of catecholamines produced during shock tive coagulopathy, is not associated with bleeding or
shunt blood away from the liver, decreasing hepatic syn- thrombocytopenia, and thus is preferable to heparin (99).
thesis of the proteins involved in preserving hemostatic Continued use of FFP should be guided by regular mea-
balance and decreasing hepatic clearance of activated surements of protein C, protein S, and antithrombin 111
clotting factors. The relative contribution of inflamma- levels. It is recommended that antithrombin I11 be main-
tory cytokines and components of hemostasis in the tained above 50% of normal and protein C and S at at
pathogenesis of acute infectious PF may vary from pa- least 25% of normal (4,74), although it is not precisely
known to what level factor activities must be raised to be
effective. Clinical response must be monitored carefully,
TABLE 3. Therapeutic Modalities in the Medical since test results may be unavailable to influence man-
Management of Acute Infectious Purpura Fulminans
agement decisions. Although FFP is effective in many
Fresh frozen plasma patients, the fluid volume that must be administered dur-
Cryoprecipitate ing repeated infusions may limit its utility. In such in-
Vitamin K
Protein C concentrate stances, particularly when PF continues to advance in a
Antithrombin I11 concentrate given patient in whom the levels of specific factors such
Heparin as protein C or antithrombin 111 remain low despite maxi-
Tissue plasminogen activator
Prostacyclin mal therapy with FFP, one may consider the use of pro-
Epidural sympathetic blockade tein C and/or antithrombin I11 concentrates (see below).
Topical nitroglycerin An additional, albeit low risk of use of FFP is the trans-
Double-volume exchange transfusion mission of blood-borne disease.
Hyperbaric oxygen Heparin may be effective in reversing the develop-
Hirudin (leeches) ment of skin necrosis in some patients with PF, particu-
Antiendotoxin antibodies
Anti-TNF-a antibody larly those with thrombotic or prethrombotic states, in-
IL-1 receptor antagonist cluding those with autoantibodies against protein s.
Platelet activating factor receptor antagonist Heparin acts through a combination of inhibition of clot-
Pentoxify lline
ting, interruption of consumption of anticoagulant fac-
Darmstadt: Acute Infectious Purpura Fulminans 177

tors, and/or inhibition of the procoagulant and antifibri- Tissue Plasminogen Activator
nolytic effects of thrombin. It is capable of preventing By the time PF is apparent clinically, significant intra-
the Shwartzman reaction (77,79,100-102). Two prospec- vascular microthromboses and impairment of fibrinoly-
tive, controlled trials of heparin use in acute meningo- sis have developed. Use of recombinant tissue plasmin-
coccemia, however, demonstrated no effect on survival ogen activator @-PA) is predicated upon the notion that
(103,104). While benefit is often not seen in PF, heparin dissolution of microthromboses could restore organ per-
may limit skin, digit, and extremity necrosis in some fusion and reduce mortality, since levels of PAI-1 cor-
patients (7,105,106). Concurrent administration of FFP relate with mortality in acute infectious PF (107). While
(which contains antithrombin 111) or antithrombin 111 protein C concentrate has little fibrinolytic effect, rt-PA
concentrate may be necessary for an effect to be realized, given as an adjunctive therapy appears to have improved
given that heparin acts by facilitating the activity of an- the microcirculation and restored peripheral pulses in
tithrombin 111. Heparin may exacerbate bleeding or in- three patients with acute infectious PF due to N. menin-
duce thrombocytopenia. consequently, many experts are gitidis (108-1 10). It may be particularly useful in lysing
reluctant to administer this unproven therapy and cor- clots, such as intracardiac or renal vein thromboses.
rectly assert that control of the underlying pathologic Given that levels of PAI-1 are highest in patients with
process that triggered DIC is the most important step in meningococcemia during the first few hours after hospi-
controlling it. tal admission (107), this therapy theoretically is of great-
est benefit when given as soon as possible. It does not
Experimental Modalities affect blood pressure, and its short half-life (5 minutes)
allows for precise use and minimization of side effects.
Because of the limitations of treatment with FFP and/or Deleterious bleeding is of concern. Approximately 0.5%
heparin, additional modalities have been attempted in the to 1.0% of adults given rt-PA following myocardial in-
treatment of PF. None of these, however, have been farction have developed hemorrhagic stroke (1 11). Simi-
evaluated in a controlled prospective trial. Their use, larly, in a review of 154 children given fibrinolytic
therefore, remains experimental, and, in many cases, therapy for femoral artery thrombosis after cardiac cath-
controversial. Consequently, while we await further data eterization, one child (0.6%) suffered significant intrace-
from controlled clinical trials on efficacy and safety of rebral hemorrhage (1 12). It is likely that the incidence of
these experimental products, FFP remains central in the hemorrhagic complications would be higher in those
treatment of PF. with severe coagulopathy. Until further data on its use
are available, rt-PA should be reserved for those patients
Protein C Concentrate with fulminant, life-threatening PF with shock and with
Five children with acute infectious PF and DIC have major vessel thrombosis who have failed conventional
been treated successfully with protein C concentrate, 70 management (108).
to 100 U/kg every 6 hours or a continuous infusion of 10
U/kg/hr during the acute phase of the illness (71,74).
Prostacyclin is a vasodilator which also prevents
Rising protein C levels were associated with an increase
thromboxane-induced platelet aggregation. It has been
in fibrinogen, a decrease in D-dimers, and arrest of DIC.
used successfully in patients with pneumococcal and
Although protein C concentrate appears to hold promise
group B streptococcal PF (1 13-1 15). An added benefit of
as an adjunctive treatment in PF, its availability may be
prostacyclin in the treatment of neonates is its action to
limited. It is anticipated that protein S concentrates might
relieve pulmonary hypertension (1 13). On the other
be efficacious, particularly in patients with anti-protein S
hand, prostacyclin may cause hypotension, and its use is
autoantibodies (79), but these products are not yet avail-
contraindicated in patients with shock.
Antithrombin III Concentrate Epidural sympathetic blockade with bupivicaine has
Administration of antithrombin I11 concentrate, 60 IU/kg been utilized successfully in a limited number of patients
loading dose, then 60 IU/kg/24 hr for 2 days, to two to restore tissue perfusion, alleviate ischemia, and re-
adults with acute infectious PF resulted in normalization verse the development of PF (1 16-1 18). Theoretically
of antithrombin I11 levels within 24 hours, concomitant this technique works primarily by dilating vessels in mi-
with improved skin perfusion, reversal of DIC, and im- crovascular beds which have constricted in response to
provement in skin lesions (68,72). This occurred despite systemic release of vasoactive mediators or afferent no-
a more marked and prolonged depression of protein C ciceptive signals, and presumably it has its greatest effect
than antithrombin I11 levels. in those vessels which are only partly occluded by mi-
178 Pediatric Dermatology Vol. 15 No. 3 May/June 1998

crothrombi (1 16). This modality may be particularly ad- placebo-controlled, randomized trials. Agents tested
vantageous when utilized early in the course (1 1) in pa- have been directed at blocking the activity of endotoxin
tients with limited PF who require vasopressors for [e.g., antiendotoxin antibodies HA- IA and ES generated
hemodynamic instability and in whom systemic vasodi- against the conserved endotoxin core from the J5 mutant
lators are contraindicated. Epidural sympathetic block- of Escherichia coli (130-135); neutralizing the effects of
ade should not be employed in those with meningitis or the cytokines whose production is stimulated by endo-
uncontrolled coagulopathy. toxin [e.g., recombinant 1L-1 receptor antagonist (136),
Topical application of nitroglycerin (e.g., Nitropaste dimeric tumor necrosis factor receptor (137), and mono-
2%) was used successfully to restore perfusion and arrest clonal antibody to TNF-cr (138); and inhibiting platelet
or reverse development of cutaneous necrosis on various activation [e.g., platelet activating factor receptor antago-
areas of the body (e.g., forearms, legs, buttocks, penis) nist (139,140)]. Pentoxifylline has a variety of actions
after sympathetic caudal blockade had failed (1 19). including reduction of release of TNF-a (141). Among
these therapies, only antiendotoxin antibodies have been
tested systematically in patients with PF. Rabbits immu-
Plasmapheresis and double volume exchange transfusion
nized with the JS mutant of E. culi were protected against
are aimed at removing circulating cytokines, endotoxin,
development of the Shwartzman reaction when injected
activated monocytes, and granulocytes (120-123). These
with purified endotoxin from N. nzerzingitidis (142). In
forms of therapy appear to be suited for the rare instance
children with acute infectious PF, however, administra-
of autoantibody-mediated depletion of an essential he- tion of antiserum raised against E. coli J5 did not alter the
mostatic component, as has been reported in children
course of disease or mortality (143). A randomized, con-
with PF due to an antibody directed against protein S
trolled, multicenter, prospective trial of antiendotoxin anti-
(79). Plasmapheresis has the added utility of preventing
body in patients with meningococcemia is now under way.
fluid overload in patients requiring large volumes of
Results from trials of immunotherapeutic agents in the
fluid andlor blood products.
treatment of sepsis have, in general, been disappointing.
Hyperbaric Oxygen Improved survival has been achieved only in subgroups
Hyperbaric oxygen is controversial, but by increasing the of patients identified retrospectively, not in the entire
partial pressure of oxygen within patient blood vessels, patient population. Substantiation of benefit to those sub-
the diffusion distance of oxygen into surrounding tissue groups of patients has been difficult to demonstrate pro-
may be increased and tissue oxygenation restored. This spectively, and these agents largely have been deemed
modality appears to have prevented or halted the pro- ineffective in the treatment of patients with sepsis with or
gression of tissue necrosis in some patients (124-126). without PF (144-146). This has resulted in a reevaluation
of our hypotheses and assumptions about the pathogen-
Medicinal Leeches esis of sepsis.
Medicinal leeches applied to the hands, feet, and legs of It is now generally accepted that the host response to
one patient appeared to produce a rapid improvement in a severe infectious challenge involves the generation of
perfusion (127). Hirudin in leech saliva is the most po- both proinflammatory (e.g., TNF-a, IL-1, IL-6) and an-
tent inhibitor of thrombin known (128). Furthermore, it tiinflammatory molecules (e.g., IL-4, IL-10, IL-11, IL-
can penetrate thrombi to neutralize thrombin bound to 13, soluble TNF receptors, IL- 1 receptor antagonists,
fibrin, an effect which cannot be achieved with heparin transforming growth factor-p) (147,148). The latter mol-
(129). It is conceivable that inhibition of thrombin, using ecules provide a buffer or regulatory check on the action
recombinant hirudin or hirudin analogs, may be possible of the proinflammatory molecules and act to restore ho-
in the future. meostasis. It appears that the outcome for the patient may
Corticosteruids be dependent on the ability of the immune system to
Although corticosteroids were advocated in the past, reestablish a balanced immunologic response. An over-
their use in PF is best restricted to patients with adrenal whelmingly robust proinflammatory response may lead
gland thrombosis and insufficiency (105). to shock, while an excessive compensatory antiinflam-
matory reaction may lead to immunosuppression and
increased susceptibility to ongoing, overwhelming, or
Lessons from Treatment of Sepsis
secondary infection. Consequently, it has been hypoth-
Based on the notion that massive, uncontrolled inflam- esized that in order to effectively manage patients with
mation, driven initially by the release of proinflam- sepsis, their state of inflammation must be known
matory cytokines, is the principle cause of sepsis, a host (144,146,147). For example, in some patients with a pre-
of novel, targeted immunotherapies for sepsis have been dominant compensatory antiinflammatory response, it
developed and tested for efficacy in double-blind, may be detrimental to administer agents aimed at down-
Darmstadt: Acute Infectious Purpura Fulminans 179

regulating proinflammatory mediators. Although it Glasgow meningococcal septicemia prognostic score: a

seems counterintuitive, it may, in fact, be necessary in 10-year retrospective survey. Crit Care Med 1991;19:
these instances to administer proinflammatory mediators
16. Tesoro LJ, Selbst SM. Factors affecting outcome in me-
in order to restore immunologic balance (149).
ningococcal infections. Am J Dis Child 1991;145:218-
It appears unlikely that a single therapeutic agent will 220.
be capable of reversing the complex pathophysiologic 17. Toews WH, Bass JW. Skin manifestations of meningo-
derangements that occur in PF. However, as we gain in coccal infections. Am J Dis Child 1974;127:173-176.
our understanding of the pathophysiologic mechanisms 18. Sinclair JF, Skeoch CH, Hallworth D. Prognosis of me-
of PF and in our ability to rapidly diagnose infection and, ningococcal septicemia. Lancet 1987;ii:38.
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to preserve life and prevent disfigurement due to acute 61:S66-57 1.
infectious PF is likely to improve. 20. Chu DZJ, Blaisdell F W . Purpura fulminans. Am J Surg
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