CLINICAL REVIEW

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

169
170 Pediatric Dermatology Vol. 15 No. 3 May/June 1998
TABLE 1. Classification of Purpura Fulminans
I. Hemostasis initiated
A. Protein C anticoagulant system dysfunction
1. Hereditary
a. Homozygous protein C deficiency
b. Homozygous protein S deficiency
2. Acquired
a. Disseminated intravascular coagulation
B. Disorder of other hemostasis regulatory systems
1. Antithrombin I11
11. Idiopathic
A. Postinfectious
B. Unknown etiology
111. Acute infectious
of varicella, group A streptococcal infection, or a non-
specific viral exanthematous illness. Some cases have
followed conditions that apparently were not infectious,
such as cutaneous hypersensitivity reaction or stomatitis.
Idiopathic PF differs from the acute infectious form in
that microthrombi and clinically significant thrombo-
hemorrhagic manifestations in organs other than the skin
generally are lacking; distal vascular beds (i.e., extremi-
ties) typically are spared; and circulatory collapse is not
present initially, although hypovolemic shock and tissue
hypoperfusion may develop due to extravasation of
blood into the skin. These differences are reflected in the
lower mortality rate associated with idiopathic PF (ap-
proximately 15%) compared to acute infectious PF.
The majority of cases of PF develop in childhood
during an acute infection, particularly meningococcal
sepsis. This review describes our current knowledge of
the pathogenesis of acute infectious PF. Based on this
TABLE 2. Infectious Causes of Purpura Fulminans
I. Idiopathic (postinfectious) purpura fulminans
Varicella
Scarlet fever
Streptococcal tonsillopharyngitis
Viral exanthem
Rubella
Measles
Upper respiratory tract infection
Gastroenteritis
11. Acute infectious purpura fulminans
Neisseria meningitidis
Streptococcus pneumoniae
Streptococcus agalactaeae (group B streptococcus)
Haemophilus influenzae type b
Rickettsia rickettsii
Streptococcus pyogenes (group A streptococcus)
Staphylococcus aureus
Klebsiella pneumoniae
Escherichia coli
Proteus mirabilis
Enterobacter spp.
Neisseria catarrhalis
Haemophilus aegypticus
Capnocytophaga canimorsus
knowledge, the application of new, potentially more ef-
fective approaches to its medical management will be
discussed.
EPIDEMIOLOGY
Purpura fulminans develops in 15% to 25% of those with
meningococcemia (6-9). It can develop during infection
with any of the meningococcal serogroups; endotoxin
production, however, appears to be highest among sero-
group C isolates (10). Purpura fulminans occurs only
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
165) developed symmetrical peripheral gangrene (1 1). In
the neonate, acute infectious PF may be due to group B
streptococcus.
Although several factors have been identified as pre-
dictive of a poor outcome from meningococcemia, size
of skin hemorrhage increases with disease severity (12),
and the presence of purpura, particularly when general-
ized, is associated with high morbidity and mortality, as
it reflects a profound disturbance in hemostatic mecha-
nisms (8,13-21). While the overall fatality rate in chil-
dren with meningococcemia in the United States is less
than 15%, development of PF heralds mortality in 20%
to 60% of cases. Of those who survive, the majority have
cutaneous and skeletal deformities due to gangrene
(22,23). The presence of petechiae signals septicemia,
and onset within 12 hours of initial medical evaluation
has been associated with poor outcome in some studies
(24,25) but not in others (6,8,17). Thus PF, distinct from
petechiae or other cutaneous manifestations of meningo-
coccemia such as a maculopapular eruption, is an impor-
tant marker of a poor outcome.
CLINICAL CHARACTERISTICS
Lesions of PF are similar regardless of the precipitating
condition. Cutaneous discomfort develops first, followed
by development of erythema with or without edema and
petechiae. Sites of involvement appear transiently like
ecchymoses, and up to this point the pathologic process
in the skin is reversible without progression to necrosis.
Lesions evolve rapidly into painful, indurated, well-
demarcated, irregularly bordered purpuric papules and
plaques which are surrounded by a thin, advancing ery-
thematous border (Figs. 1 and 2). Late findings in ne-
crotic areas are the formation of vesicles and bullae (Fig.
3), which mark the development of hemorrhagic necro-
sis, and finally firm eschar which ultimately sloughs.
Gangrenous necrosis often extends into subcutaneous tis-
sue, and occasionally involves muscle and/or bone (Fig.
4); epiphyseal growth plate necrosis in the growing child

Figure 1. Well-defined, irregularly bordered purpuric
plaques on the arm of a child with early acute infectious
purpura fulminans 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
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,
buttocks, and lower trunk. Acute infectious PF fre-
quently progresses proximally and ultimately may form
purpuric plaques of various sizes and shapes in a diffuse,
patchy distribution.
Development of systemic consumptive coagulopathy
(i.e., DIC) is a defining feature of PF, which distin-
guishes it from other forms of skin necrosis due to der-
mal vascular occlusion such as warfarin- or heparin-
induced skin necrosis, thrombotic thrombocytopenic
purpura, cryoglobulinemia, antiphospholipid syndrome,
or paroxysmal noctural hemoglobinuria. Shock may oc-
cur in all forms of PF, but is most characteristic of acute
infectious PF. Thrombohemorrhagic manifestations may
be found in multiple vascular beds and organ systems,
Darmstadt: Acute Infectious Purpura Fulminans 171
Figure 3. Purpuric plaques and hemorrhagic bullae on the
leg of a child with severe, advanced purpura fulminans
due to Neisseria meningitidis.
Figure 4. Gangrenous fifth fingertip due to Neisseria men-
ingitidis.
and multiple organ dysfunction syndrome is common.
Fibrinogen, coagulation factors (e.g., factor V and factor
VIII), and platelets are consumed in ongoing thrombosis
and fibrinolysis. Prothrombin time (PT) and partial
thromboplastin time (PTT) are prolonged; fibrin degra-
dation products (e.g., D-dimers) are elevated; and protein
C, protein S, and antithrombin I11 levels are reduced.
The histopathologic hallmarks of PF are dermal vas-
cular thrombosis and secondary hemorrhagic necrosis
(Fig. 5a) (26). Vascular changes are widespread, involv-
ing multiple organ systems, particularly the adrenal
glands (Waterhouse-Friderichsen syndrome), lungs, and
kidneys. The cutaneous vessels most affected are the
postcapillary venules in the subpapillary plexus of the
papillary dermis, where blood flow velocity is slowest.
172 Pediatric Dermatology Vol. I5 No. 3 May/June 1998
A
a elicits a transient perivascular neutrophilic and mono-
Figure 5. Skin biopsy specimens from children with me-
ningococcemia showing (A) dermal vascular thrombosis
and (B) vasculitis. Specimens were stained with hemo-
toxylin and eosin.
Histopathologic changes begin at the junction of terminal
precapillary arterioles with capillaries and generally
spare arteries and arterioles. Microthrombi are mixed,
composed of fibrin, platelets, and leukocytes, particu-
larly neutrophils; Gram-negative diplococci of N. men-
ingitidis occasionally are visible as well. Endothelial cell
swelling is prominent and leads initially to capillary di-
latation, manifest clinically as erythema. Acute vascular
injury progresses to endothelial cell separation and ves-
sel rupture, allowing for extravasation of formed blood
elements into the dermal stroma and development of
clinically visible purpura. Extensive hemorrhage is fol-
lowed by coagulative necrosis. Vasculitis, including a
perivascular neutrophilic infiltrate, is a characteristic fea-
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).
PATH0GENESIS
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
cytic inflammatory reaction with increased vascular per-
meability that is maximal approximately 4 hours after
injection. Vessel damage, however, is not seen at this
stage. Intravenous challenge with the same endotoxin 18
to 24 hours later results in thrombosis with mixed mi-
crothrombi, endothelial cell swelling, dilatation of blood
vessels, and necrotizing neutrophilic vasculitis, leading
to extravasation of formed blood elements and purpura
localized to the prepared dermal site. The degree of hem-
orrhage elicited by the challenge correlates directly with
the accumulation of leukocytes after the priming reaction
(32). Development of microthrombi only at skin sites
prepared previously with endotoxin suggests that af-
fected endothelial cells were made more thrombogenic
during the intervening period between the local and the
systemic injections. Of note, a generalized Shwartzman
reaction can be produced by two intravenous injections
of endotoxin spaced 18 to 24 hours apart, producing a

syndrome which models DIC (30). Tissue damage is
similar in the local and generalized Shwartzman reac-
tions, suggesting that they share a common pathogenesis.
The local Shwartzman reaction is thought to be more like
idiopathic/postinfectious PF, with cutaneous lesions lim-
ited to sites prepared in the skin by an antecedent infec-
tion, whereas the generalized Shwartzman reaction
resembles acute infectious PF with formation of micro-
thrombi in multiple organ systems.
Hemostatic Balance
Central to the pathogenesis of the Shwartzman reaction
is a disturbance in the balance of anticoagulant and pro-
coagulant activities of endothelial cells. Normally, in the
absence of disease, the balance of hemostatic activity on
the surface of endothelial cells favors anticoagulation.
Systems for ensuring this include the protein C-
thrombomodulin system, the antithrombin 111-heparin
system, profibrinolytic mechanisms involving plasmino-
gen activation, and inhibition of platelet aggregation
through release of prostacyclin (33-36). Thrombomodu-
lin is a high-affinity receptor for thrombin. Binding of
thrombin to thrombomodulin activates protein C, which
in turn, in concert with its cofactor protein S, destroys
clotting factors V and VIII of the intrinsic hemostatic
cascade. This prevents factor V-mediated binding of pro-
thrombin to the surface of the platelet, thereby suppress-
ing production of thrombin. Concurrently, interaction of
thrombin with thrombomodulin makes thrombin unavail-
able to stimulate a plethora of pathophysiologic proin-
flammatory and prothrombotic events in sepsis, includ-
ing the expression of platelet activating factor and the
activation, adhesion, and aggregation of platelets; the
transformation of fibrinogen into fibrin with release of
fibrinopeptides; the activation of clotting factors V and
VIII; and induction of expression of granule membrane
protein- 140 on endothelial cells (which promotes adhe-
sion of neutrophils). Thrombin attached to thrombo-
modulin can be inactivated by antithrombin I11 at a faster
rate than can free thrombin. Antithrombin 111 is the major
inhibitor of the coagulation cascade. Heparin or heparin-
like molecules on endothelial cells stimulate formation
of a complex between antithrombin Ill and the active
serine center of the serine protease thrombin, neutraliz-
ing the activity of thrombin. Similarly, heparin also fa-
cilitates inactivation of other serine proteases of the co-
agulation cascade (i.e., factors IXa, Xa, XIa, XIIa) by
antithrombin Ill. Lysis of microthrombi is promoted by
endothelial cells through synthesis and release of plas-
minogen activators such as tissue plasminogen activator
(t-PA), which in turn initiates activation of plasminogen.
Darmstadt: Acute Infectious Purpura Fulminans 173
Plasminogen is bound specifically to fibrin, becoming
intermeshed and concentrated within the fibrin clot as it
forms. There it is sequestered away from protease inhibi-
tors (e.g., a,-antiplasmin) normally present in the blood,
and can be activated by fibrin-bound t-PA to plasmin.
Plasmin remains bound to fibrin where it is protected
from a,-antiplasmin, upregulates its own generation, and
degrades fibrinogen and fibrin to dissolve the clot. Out-
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
plasmin is generated and the capacity of a,-antiplasmin
to neutralize plasmin in the blood is overcome. Levels of
a,-antiplasmin fall due to excessive activation of the
fibrinolytic system. Plasmin is then bound to a secondary
inhibitor, called a,-macroglobulin, but low-level plas-
min activity persists within this complex and systemic
fibrinolysis is able to continue. Measurement of the
cleaved fibrinogen species produced by the action of
plasmin forms the basis for a variety of tests utilized in
detecting the systemic fibrinolysis seen in DIC. Biologi-
cal actions of these cleavage products include potentia-
tion of the hypotensive effects of bradykinin and chemo-
taxis of monocytes and neutrophils. A final endothelial
cell-derived regulator of fibrinolysis is plasminogen ac-
tivator inhibitor-1 (PAI-1). The major physiologic role of
PAI-1 is to suppress the function of t-PA and thus to
modulate fibrinolysis.
Cytokines
When endothelial cells are injured, a shift in the balance
of hemostasis toward a procoagulant state occurs. In
acute infectious PF, this is triggered by endotoxin, which
in turn causes local production and release of proinflam-
matory molecules. Principle proinflammatory molecules
include the cytokines tumor necrosis factor-a (TNF-a),
interferon-? (IFN-y), and interleukin- 1 (IL- 1). During
the first or priming step of the Shwartzman reaction, it
appears that endotoxin first induces the release of IL- 12
from a variety of cell types, including T and B lympho-
cytes, natural killer (NK) cells, and mononuclear phago-
cytes (37). IL-12 in turn induces production of IFN-y,
principally from NK cells (38). For optimum generation
of IFN-y, however, the presence of TNF-a and macro-
phages is required (39,40). IFN-y, which plays a central
role in the priming reaction (37,38), activates macro-
phages to produce monokines, including TNF-a and IL-
1; sensitizes endothelial cells; and primes the endothelial
cells to produce TNF-a and IL-1 during the intravenous
challenge phase of the Shwartzman reaction. A crucial
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
vascular endothelial cells in dermal blood vessels
(41,42). This may be due principally to the action of
endotoxin and TNF-a, and perhaps also IL-1 and IFN-y,
all of which are capable of upregulating ICAM-1 expres-
sion. Injection of IFN-y, TNF-a, or TNF-a and IL-1
acting synergistically can be used in place of endotoxin
to prepare the skin for a local Shwartzman reaction
(37,43,44). The inflammatory infiltrate generated during
the priming phase, as a consequence of upregulated
ICAM-1 expression (41), and the plasma leakage ob-
served during the priming phase depend on local genera-
tion of TNF-a(45). Generation of an acute inflammatory
cell infiltrate is an absolute requirement of the Shwartz-
man reaction; the reaction does not occur in neutropenic
animals (46). The perivascular, interstitial infiltrate gen-
erated during the priming phase, however, does not cause
vascular damage or hemorrhage.
The second or challenge phase of the Shwartzman
reaction, which results in the vasculitis and hemorrhage
that becomes manifest clinically as purpura, requires the
recruitment and aggregation of neutrophils in the dermal
vessels of prepared skin sites (47,48). An early, critical
event of the challenge phase appears to be the upregula-
tion of CD1 1b/CD18 (Mac-1) on leukocytes, which sub-
sequently allows them to adhere to the ICAM-1 mol-
ecules that were expressed on vascular endothelial cells
during the priming phase and to aggregate within af-
fected vessels (41,42). Endothelial cells that are injured
by endotoxin, or by exposure to TNF-a and IL-I , and/or
infiltrating neutrophils synthesize and express tissue fac-
tor (i.e., tissue thromboplastin), the most potent proco-
agulant known, on their surface (49-52). TNF-a also
induces the expression of tissue factor on monocytes
(53). In children with meningococcal sepsis, tissue factor
expression is increased on circulating monocytes (54).
Tissue factor activates the extrinsic pathway, leading ul-
timately to production of fibrin. Deposition of fibrin due
to tissue factor-initiated coagulation within the vessels of
prepared skin sites is required for pathogenesis of the
Shwartzman reaction (47). Exposure of endothelial cells
to endotoxin or to TNF-a and IL-1 also suppresses
thrombomodulin activity (55,56). This leads to decreased
protein C activity and in turn to impaired degradation of
activated factors V and VIII, and to increased thrombin
procoagulant activity through enhanced availability of
thrombin. Secretion of PAI-1 by endothelial cells also is
increased, which further promotes thrombosis (57,58).
Cytokines, particularly TNF-a, which are produced
by injured endothelial cells as well as by injured kera-
tinocytes and infiltrating monocytes and neutrophils, ap-
pear to be the principle mediators of the hemodynamic
and histopathologic events during the second (i.e., pro-
voking) phase of the Shwartzman reaction. The effects of
TNF-a are potentiated by IL-1 and IFN-y (37). Serum
levels of TNF-a were elevated in 91% of children with
acute infectious PF, and the level of TNF-a correlated
negatively with fibrinogen levels and positively with en-
dotoxin levels (59) and with the severity of infection and
mortality (60).
A central concept in the pathogenesis of the Shwartz-
man reaction which has emerged recently is that of cy-
tokine balance. Concurrently with the production of pro-
inflammatory cytokines such as TNF-a, endotoxin also
induces the production of antiinflammatory molecules
such as IL-10. IL-10 is a potent macrophage deactivator
which blocks the synthesis of TNF-a, IL-1, and other
proinflammatory cytokines such as IL-6, IL-8, and
granulocyte-macrophage colony-stimulating factor (GM-
CSF) by monocytes (61) and macrophages (62). Further-
more, IL-10 suppresses synthesis of IFN-y by helper T
cells (63) and NK cells (64). Mice deficient in IL-10
production were extremely vulnerable to generation of a
generalized Shwartzman reaction, requiring 100- to 200-
fold less endotoxin during the priming phase compared
to wild-type mice (65). Production of TNF-a in response
to endotoxin sensitization also was exaggerated. More-
over, IL-10 infusion blocked the sensitization step. Per-
haps endogenous IL- 10 normally inhibits the production
of IL-12 and IFN-y during the preparatory phase of the
Shwartzman reaction (65).
Acquired Protein C and Protein S Deficiency
Protein C naturally attenuates the proinflammatory ac-
tivity stimulated by endotoxin and cytokines. It decreases
endotoxin-induced cytokine production by monocytes
and inhibits the downregulation of CD14 and C D l l b on
leukocytes by endotoxin (66). Acquired deficiency of
protein C has been described in many patients with acute
infectious PF (67-74) and is increasingly implicated in
the pathogenesis of this disorder. The degree of protein C
deficiency can be correlated with size of skin lesions
(73), clinical severity of the illness (9), and mortality
(9,70,73). It has been suggested that decreased protein C
levels indicate that meningococcal endotoxin induces a
relatively greater decrease in natural anticoagulant than
procoagulant proteins, and that the coagulopathic effects
of meningococcal endotoxin are greater than those ob-
served in most other bacterial infections (9).
Most patients with reduced protein C levels have a
concomitant reduction in the level of protein S (67-74).
Protein S is active only in the free, unbound form. Nor-
mally, approximately 60% of total protein S is carried by
the complement component C4b binding protein, which
is an acute-phase reactant. Elevation of C4b binding pro-

tein during acute infection may lead to a reduction in free
protein S activity. Relatively low baseline protein C and
S level in infants and young children may explain their
increased risk of development of PF compared to adults
(67).
Some patients with postinfectious PF have had pro-
found depression in levels of protein s, with normal to
only slightly decreased protein C at presentation and/or
relatively rapid recovery of protein C compared to pro-
tein S levels, suggesting that a subtle difference exists in
the pathophysiology of their disease compared to those
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-
tibodies (79,80); many of these patients have also had
lupus anticoagulant and antiphospholipid antibodies
(77,80,81). These autoantibodies appear to bind to and
increase the clearance of protein S. Patients with post-
infectious (i.e., post-varicella) transient protein S de-
ficiency, including those with autoantibody-mediated
disease, manifest a spectrum of thromboembolic compli-
cations, ranging from pulmonary emboli and/or throm-
botic events affecting other internal organs but sparing
the skin, to PF with coexistent major organ thromboem-
bolic disease (78-80,82,83). The presence of autoanti-
bodies directed against protein S has important implica-
tions for therapy, since protein S levels in these patients
may not respond to administration of fresh frozen plasma
(FFP) (79). Furthermore, infusions of FFP may facilitate
the formation of immune complexes and induce a serum-
sickness-like illness (79).
Generation of dermal vascular necrosis and hemor-
rhagic skin necrosis in PF involves a combination of
disordered hemostasis and inflammatory-mediated
pathologic changes. Events that are common in all forms
of PF include increased tissue factor expression and ex-
posure, downregulation of thrombomodulin expression
and protein C activity, and impaired fibrinolysis (1). In
patients with PF due to hereditary protein C or protein S
deficiency, disordered hemostasis predominates, and
little or no inflammatory infiltrate is present. The role of
cytokines in the pathogenesis of these lesions is thought
to be minor (1). In acute infectious PF, however, cyto-
kine-mediated inflammation may play a predominant
role, while disordered hemostasis augments the patho-
logic process.
Reduction of protein C and protein S in acute infec-
tious PF most likely stems from consumption during co-
agulopathy, and their derangement is thought to perpetu-
ate and exacerbate rather than initiate dermal vascular
thrombosis (4). Nevertheless, therapy directed at restor-
ing the functional capacity of the protein C system in
animal models had led to promising results. Giving rab-
Darmstadt: Acute Infectious Purpura Fulminans 175
bits human activated protein C attenuated the local
Shwartzman reaction (84). In a baboon model of Gram-
negative sepsis, blocking protein C activation with
monoclonal antibodies increased mortality, suggesting
that protein C played an important role in attenuating
coagulopathy in sepsis (85). When protein C was admin-
istered prophylactically, it prevented the coagulopathic
and lethal effects of endotoxin-associated sepsis (85),
further suggesting that the protein C system may play a
role in modulating the effects of inflammatory cytokines
(4).
Consumption of Antithrombin I11
A decrease in antithrombin I11 also occurs in patients
with acute infectious PF (68,71-73,86,87). In some pa-
tients with PF, derangement in antithrombin I11 appeared
to more closely parallel the clinical course than did levels
of protein C or protein S (72). Interest in the utility of
antithrombin 111 concentrate as a therapeutic measure in
PF has increased because of studies in animals and hu-
mans which have demonstrated its efficacy as a prophy-
lactic and therapeutic agent in DIC (88-93).
Complement
Complement, along with specific antibodies, plays a piv-
otal role in defense against N. meningitidis. Interestingly,
while those with defects in the terminal complement cas-
cade (C5 to C9) have increased risk of acquiring menin-
gococcemia, the severity of their infections tends to be
relatively mild; rather, they are at increased risk for re-
current episodes. Overall approximately 4% of those
who present with acute, first-episode meningococcemia
have a terminal complement deficiency and low total
hemolytic complement levels (CH,,). More severe epi-
sodes may be associated with a rare, properdin defi-
ciency (94). These patients have normal CH,, but low
alternative hemolytic complement.
In the course of meningococcal infection, significant
complement activation occurs, leading to formation of
the anaphylatoxins C3a, C4a, and C5a (95). Complement
activation appears to play an important role during the
provoking phase of the Shwartzman reaction by upregu-
lating expression of CD 18 on neutrophils, activating
them, and inducing them to adhere to ICAM-1 on endo-
thelium of prepared skin sites (42). In addition, genera-
tion of the membrane attack complex at the bacterial
surface induces release of endotoxin. Increasing severity
of disease and mortality are associated with higher levels
of C3 activation products and terminal complement com-
plex (96).
176 Pediatric Dermatology Vol. 15 No. 3 May/June 1998
Location of Purpura
There is no adequate explanation for why lesions of PF
develop at particular skin sites. Hypotheses include site-
specific differences in cytokine release by endothelial
cells; variability in endothelial cell expression of proco-
agulant and anticoagulant factors, cytokine receptors, or
transduction of signal following binding of cytokine to
its receptor; differences in expression of cell adhesion
molecules and thus in leukocyte trafficking; physical
properties of the skin such as variations in temperature or
blood flow; or cutaneous trauma (1).
MEDICAL MANAGEMENT
Greater understanding of the pathophysiology of PF has
allowed the design of new approaches to the medical
management of this disorder during the past decade
(Table 3). Before considering these therapies, however, it
must first be emphasized that initial management of the
patient with acute infectious PF must be focused on pre-
serving life through respiratory and hemodynamic sup-
port and prompt intravenous antibiotic coverage (e.g.,
third-generation cephalosporin such as ceftriaxone). Cir-
culatory collapse with tissue hypoperfusion and ischemia
directly damages endothelial cells and predisposes to
thrombosis; the propensity to develop microthrombi is
exacerbated in the presence of flow stasis. Furthermore,
the high levels of catecholamines produced during shock
shunt blood away from the liver, decreasing hepatic syn-
thesis of the proteins involved in preserving hemostatic
balance and decreasing hepatic clearance of activated
clotting factors. The relative contribution of inflamma-
tory cytokines and components of hemostasis in the
pathogenesis of acute infectious PF may vary from pa-
TABLE 3. Therapeutic Modalities in the Medical
Management of Acute Infectious Purpura Fulminans
Fresh frozen plasma
Cryoprecipitate
Vitamin K
Protein C concentrate
Antithrombin I11 concentrate
Heparin
Tissue plasminogen activator
Prostacyclin
Epidural sympathetic blockade
Topical nitroglycerin
Plasmapheresis
Double-volume exchange transfusion
Hyperbaric oxygen
Hirudin (leeches)
Antiendotoxin antibodies
Anti-TNF-a antibody
IL-1 receptor antagonist
Platelet activating factor receptor antagonist
Pentoxify lline
tient to patient. Consequently, therapy must be individu-
alized, and often will involve a combination of modali-
ties. Acute infectious PF typically is a fulminant disorder
with rapid progression to irreversible tissue necrosis, em-
phasizing the importance of prompt therapeutic interven-
tion. Surgical consultation should be sought early in the
course to monitor compartment pressures and intervene
in compartment syndrome. Nutritional support is also
important, and should be continued during the rehabili-
tative phase.
Initial laboratory determinations that will help to
guide therapeutic decisions in the management of pa-
tients with PF include a complete blood count, platelet
count, PT, PTT, fibrinogen, fibrin degradation products,
protein C, free protein S, and antithrombin 111. Blood
components that may be necessary in individual cases,
depending on the results of these tests, include packed
red blood cells for anemia due to massive hemorrhage
into the skin, platelets to correct thrombocytopenia due
to platelet consumption, and/or cryoprecipitate to replace
fibrinogen in patients with DIC.
Therapeutic interventions that should be initiated for
all patients with PF and DIC include vitamin K and FFP
(8-12 mgkg every 12 hours), which are given to correct
possible deficiencies of vitamin K-dependent coagula-
tion factors (97,98), antithrombin 111, protein C, and pro-
tein s. Fresh frozen plasma does not aggravate consump-
tive coagulopathy, is not associated with bleeding or
thrombocytopenia, and thus is preferable to heparin (99).
Continued use of FFP should be guided by regular mea-
surements of protein C, protein S, and antithrombin 111
levels. It is recommended that antithrombin I11 be main-
tained above 50% of normal and protein C and S at at
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,
since test results may be unavailable to influence man-
agement decisions. Although FFP is effective in many
patients, the fluid volume that must be administered dur-
ing repeated infusions may limit its utility. In such in-
stances, particularly when PF continues to advance in a
given patient in whom the levels of specific factors such
as protein C or antithrombin 111 remain low despite maxi-
mal therapy with FFP, one may consider the use of pro-
tein C and/or antithrombin I11 concentrates (see below).
An additional, albeit low risk of use of FFP is the trans-
mission of blood-borne disease.
Heparin may be effective in reversing the develop-
ment of skin necrosis in some patients with PF, particu-
larly those with thrombotic or prethrombotic states, in-
cluding those with autoantibodies against protein s.
Heparin acts through a combination of inhibition of clot-
ting, interruption of consumption of anticoagulant fac-

tors, and/or inhibition of the procoagulant and antifibri-
nolytic effects of thrombin. It is capable of preventing
the Shwartzman reaction (77,79,100-102). Two prospec-
tive, controlled trials of heparin use in acute meningo-
coccemia, however, demonstrated no effect on survival
(103,104). While benefit is often not seen in PF, heparin
may limit skin, digit, and extremity necrosis in some
patients (7,105,106). Concurrent administration of FFP
(which contains antithrombin 111) or antithrombin 111
concentrate may be necessary for an effect to be realized,
given that heparin acts by facilitating the activity of an-
tithrombin 111. Heparin may exacerbate bleeding or in-
duce thrombocytopenia. consequently, many experts are
reluctant to administer this unproven therapy and cor-
rectly assert that control of the underlying pathologic
process that triggered DIC is the most important step in
controlling it.
Experimental Modalities
Because of the limitations of treatment with FFP and/or
heparin, additional modalities have been attempted in the
treatment of PF. None of these, however, have been
evaluated in a controlled prospective trial. Their use,
therefore, remains experimental, and, in many cases,
controversial. Consequently, while we await further data
from controlled clinical trials on efficacy and safety of
these experimental products, FFP remains central in the
treatment of PF.
Protein C Concentrate
Five children with acute infectious PF and DIC have
been treated successfully with protein C concentrate, 70
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).
Rising protein C levels were associated with an increase
in fibrinogen, a decrease in D-dimers, and arrest of DIC.
Although protein C concentrate appears to hold promise
as an adjunctive treatment in PF, its availability may be
limited. It is anticipated that protein S concentrates might
be efficacious, particularly in patients with anti-protein S
autoantibodies (79), but these products are not yet avail-
able.
Antithrombin III Concentrate
Administration of antithrombin I11 concentrate, 60 IU/kg
loading dose, then 60 IU/kg/24 hr for 2 days, to two
adults with acute infectious PF resulted in normalization
of antithrombin I11 levels within 24 hours, concomitant
with improved skin perfusion, reversal of DIC, and im-
provement in skin lesions (68,72). This occurred despite
a more marked and prolonged depression of protein C
than antithrombin I11 levels.
Darmstadt: Acute Infectious Purpura Fulminans 177
Tissue Plasminogen Activator
By the time PF is apparent clinically, significant intra-
vascular microthromboses and impairment of fibrinoly-
sis have developed. Use of recombinant tissue plasmin-
ogen activator @-PA) is predicated upon the notion that
dissolution of microthromboses could restore organ per-
fusion and reduce mortality, since levels of PAI-1 cor-
relate with mortality in acute infectious PF (107). While
protein C concentrate has little fibrinolytic effect, rt-PA
given as an adjunctive therapy appears to have improved
the microcirculation and restored peripheral pulses in
three patients with acute infectious PF due to N. menin-
gitidis (108-1 10). It may be particularly useful in lysing
clots, such as intracardiac or renal vein thromboses.
Given that levels of PAI-1 are highest in patients with
meningococcemia during the first few hours after hospi-
tal admission (107), this therapy theoretically is of great-
est benefit when given as soon as possible. It does not
affect blood pressure, and its short half-life (5 minutes)
allows for precise use and minimization of side effects.
Deleterious bleeding is of concern. Approximately 0.5%
to 1.0% of adults given rt-PA following myocardial in-
farction have developed hemorrhagic stroke (1 11). Simi-
larly, in a review of 154 children given fibrinolytic
therapy for femoral artery thrombosis after cardiac cath-
eterization, one child (0.6%) suffered significant intrace-
rebral hemorrhage (1 12). It is likely that the incidence of
hemorrhagic complications would be higher in those
with severe coagulopathy. Until further data on its use
are available, rt-PA should be reserved for those patients
with fulminant, life-threatening PF with shock and with
major vessel thrombosis who have failed conventional
management (108).
Prostacyclin
Prostacyclin is a vasodilator which also prevents
thromboxane-induced platelet aggregation. It has been
used successfully in patients with pneumococcal and
group B streptococcal PF (1 13-1 15). An added benefit of
prostacyclin in the treatment of neonates is its action to
relieve pulmonary hypertension (1 13). On the other
hand, prostacyclin may cause hypotension, and its use is
contraindicated in patients with shock.
Vasodilatation
Epidural sympathetic blockade with bupivicaine has
been utilized successfully in a limited number of patients
to restore tissue perfusion, alleviate ischemia, and re-
verse the development of PF (1 16-1 18). Theoretically
this technique works primarily by dilating vessels in mi-
crovascular beds which have constricted in response to
systemic release of vasoactive mediators or afferent no-
ciceptive signals, and presumably it has its greatest effect
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-
vantageous when utilized early in the course (1 1) in pa-
tients with limited PF who require vasopressors for
hemodynamic instability and in whom systemic vasodi-
lators are contraindicated. Epidural sympathetic block-
ade should not be employed in those with meningitis or
uncontrolled coagulopathy.
Topical application of nitroglycerin (e.g., Nitropaste
2%) was used successfully to restore perfusion and arrest
or reverse development of cutaneous necrosis on various
areas of the body (e.g., forearms, legs, buttocks, penis)
after sympathetic caudal blockade had failed (1 19).
Plasmapheresis
Plasmapheresis and double volume exchange transfusion
are aimed at removing circulating cytokines, endotoxin,
activated monocytes, and granulocytes (120-123). These
forms of therapy appear to be suited for the rare instance
of autoantibody-mediated depletion of an essential he-
mostatic component, as has been reported in children
with PF due to an antibody directed against protein S
(79). Plasmapheresis has the added utility of preventing
fluid overload in patients requiring large volumes of
fluid andlor blood products.
Hyperbaric Oxygen
Hyperbaric oxygen is controversial, but by increasing the
partial pressure of oxygen within patient blood vessels,
the diffusion distance of oxygen into surrounding tissue
may be increased and tissue oxygenation restored. This
modality appears to have prevented or halted the pro-
gression of tissue necrosis in some patients (124-126).
Medicinal Leeches
Medicinal leeches applied to the hands, feet, and legs of
one patient appeared to produce a rapid improvement in
perfusion (127). Hirudin in leech saliva is the most po-
tent inhibitor of thrombin known (128). Furthermore, it
can penetrate thrombi to neutralize thrombin bound to
fibrin, an effect which cannot be achieved with heparin
(129). It is conceivable that inhibition of thrombin, using
recombinant hirudin or hirudin analogs, may be possible
in the future.
Corticosteruids
Although corticosteroids were advocated in the past,
their use in PF is best restricted to patients with adrenal
gland thrombosis and insufficiency (105).
Lessons from Treatment of Sepsis
Based on the notion that massive, uncontrolled inflam-
mation, driven initially by the release of proinflam-
matory cytokines, is the principle cause of sepsis, a host
of novel, targeted immunotherapies for sepsis have been
developed and tested for efficacy in double-blind,
placebo-controlled, randomized trials. Agents tested
have been directed at blocking the activity of endotoxin
[e.g., antiendotoxin antibodies HA- IA and ES generated
against the conserved endotoxin core from the J5 mutant
of Escherichia coli (130-135); neutralizing the effects of
the cytokines whose production is stimulated by endo-
toxin [e.g., recombinant 1L-1 receptor antagonist (136),
dimeric tumor necrosis factor receptor (137), and mono-
clonal antibody to TNF-cr (138); and inhibiting platelet
activation [e.g., platelet activating factor receptor antago-
nist (139,140)]. Pentoxifylline has a variety of actions
including reduction of release of TNF-a (141). Among
these therapies, only antiendotoxin antibodies have been
tested systematically in patients with PF. Rabbits immu-
nized with the JS mutant of E. culi were protected against
development of the Shwartzman reaction when injected
with purified endotoxin from N. nzerzingitidis (142). In
children with acute infectious PF, however, administra-
tion of antiserum raised against E. coli J5 did not alter the
course of disease or mortality (143). A randomized, con-
trolled, multicenter, prospective trial of antiendotoxin anti-
body in patients with meningococcemia is now under way.
Results from trials of immunotherapeutic agents in the
treatment of sepsis have, in general, been disappointing.
Improved survival has been achieved only in subgroups
of patients identified retrospectively, not in the entire
patient population. Substantiation of benefit to those sub-
groups of patients has been difficult to demonstrate pro-
spectively, and these agents largely have been deemed
ineffective in the treatment of patients with sepsis with or
without PF (144-146). This has resulted in a reevaluation
of our hypotheses and assumptions about the pathogen-
esis of sepsis.
It is now generally accepted that the host response to
a severe infectious challenge involves the generation of
both proinflammatory (e.g., TNF-a, IL-1, IL-6) and an-
tiinflammatory molecules (e.g., IL-4, IL-10, IL-11, IL-
13, soluble TNF receptors, IL- 1 receptor antagonists,
transforming growth factor-p) (147,148). The latter mol-
ecules provide a buffer or regulatory check on the action
of the proinflammatory molecules and act to restore ho-
meostasis. It appears that the outcome for the patient may
be dependent on the ability of the immune system to
reestablish a balanced immunologic response. An over-
whelmingly robust proinflammatory response may lead
to shock, while an excessive compensatory antiinflam-
matory reaction may lead to immunosuppression and
increased susceptibility to ongoing, overwhelming, or
secondary infection. Consequently, it has been hypoth-
esized that in order to effectively manage patients with
sepsis, their state of inflammation must be known
(144,146,147). For example, in some patients with a pre-
dominant compensatory antiinflammatory response, it
may be detrimental to administer agents aimed at down-

regulating proinflammatory mediators. Although it
seems counterintuitive, it may, in fact, be necessary in
these instances to administer proinflammatory mediators
in order to restore immunologic balance (149).
It appears unlikely that a single therapeutic agent will
be capable of reversing the complex pathophysiologic
derangements that occur in PF. However, as we gain in
our understanding of the pathophysiologic mechanisms
of PF and in our ability to rapidly diagnose infection and,
perhaps, the inflammatory state of the patient, our ability
to preserve life and prevent disfigurement due to acute
infectious PF is likely to improve.
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