SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 16, NO. 4, 1990

Acquired Purpura Fulminans

The rare syndrome of progressive hemorrhagic necrosis of skin known as "purpura fulminans" has long fascinated and challenged physicians. Its dramatic and seemingly inexplicable clinical manifestations have given rise to much speculation regarding pathogenesis, and to many different therapeutic approaches. Within the past decade, a number of important conceptual advances have brought us much closer to understanding this hitherto mysterious disorder. Chief among these is the discovery that purpura fulminans-like skin lesions occur in subjects with inherited and acquired deficiencies of the protein C anticoagulant pathway. It is the purpose of this review to discuss the pathogenesis, clinical features, and treatment of acquired purpura fulminans, within the context of recent advances in our understanding of the regulation of coagulation, the physiology of vascular endothelial cells, and the host response to immunologic challenge. This topic has not been reviewed in depth since 1964,1 so that an updated review seems timely and appropriate. It is my intention not only to provide guidelines for diagnosis and therapy of acquired purpura fulminans, but also to suggest new investigative approaches that might help answer the many unresolved questions regarding the pathogenesis and treatment of this disorder. The term "purpura fulminans" has been applied to dermal vascular thrombosis and hemorrhagic necrosis arising in three different clinical settings: (1) in individuals with preexistent inherited or acquired disorders of the protein C anticoagulant pathway; (2) in individuals with acute, severe infections, usually caused by gramnegative bacteria; and (3) in individuals without known abnormalities of the protein C pathway or acute infec-

From the Division of Hematology, Department of Medicine, University of Southern California School of Medicine, Los Angeles, California. Reprint requests: Dr. Francis Jr., USC School of Medicine, Raulston 322, 2025 Zonal Avenue, Los Angeles, CA 90033. 310

tions. To avoid confusion, the third category will be referred to throughout this review as "idiopathic purpura fulminans," to emphasize its lack of a clearly defined etiology, in contrast to the first two categories. It is recognized, however, that as newer techniques are applied to the study of this syndrome, the term "idiopathic" will become increasingly inappropriate. Skin necrosis in subjects with inherited abnormalities of the protein C pathway is discussed in detail elsewhere in this issue of Seminars, and will be reviewed here only briefly. Skin necrosis in subjects with acute infections will be discussed separately from idiopathic purpura fulminans, because these two disorders differ significantly in pathogenesis, clinical manifestations, and treatment.

IDIOPATHIC PURPURA FULMINANS Clinical Features Idiopathic purpura fulminans is a rare, often devastating disorder in which unexplained, progressive dermal vascular thrombosis and hemorrhagic necrosis occur in a subject who is not acutely infected and who does not have a previous personal or family history of thrombosis. Although it was described as early as 1887,1 Hjort et al2 were the first to delineate its characteristic features clearly: (1) the usual occurrence in young children; (2) the frequent history of an antecedent "preparatory disease," most commonly a bacterial or viral infection involving the skin; (3) the sudden development during an otherwise unremarkable convalescence of progressively enlarging, purplish-black areas of hemorrhagic skin necrosis, sharply demarcated from surrounding normal skin by a narrow red border; (4) the histopathologic findings in involved skin of widespread dermal vascular thrombosis with secondary hemorrhagic infarction; (5) the usual absence of clinically significant thrombohemorrhagic manifestations in organs other than the skin; and (6) the association with marked hypofibrinogenemia and

Copyright © 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.

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ROBERT B. FRANCIS, Jr., M.D.

thrombocytopenia. Hjort et al2 convincingly argued that the disorder is primarily thrombotic in character, with skin bleeding occurring as a secondary consequence of dermal infarction, complicated by the hemostatic defects of severe, acute intravascular coagulation. Using these criteria, they identified 50 cases of purpura fulminans published prior to 1964. With the benefit of hindsight, we now recognize that a few of these probably represent skin necrosis in infants with homozygous protein C deficiency. Also, it is now clear that the syndrome does occur in adults, although less commonly than in children. In all other respects, the clinical description provided by Hjort et al2 remains as valid today as when first published. Most of the well-documented reports of idiopathic purpura fulminans published since 1964 are summarized in Tables 1 and 2 for children3-24 and Tables 3 and 4 for adults. 14,25-32 (Some of these reports also describe subjects with sepsis-associated purpura fulminans, which are not included in Tables 1 through 4.) It is apparent that this syndrome continues to be reported far more frequently in children (29 cases) than in adults (9 cases). The reason for this is not clear, but may be related to three factors: (1) the more frequent occurrence of "preparatory" exanthematous illnesses in this age group; (2) the more active immune response of children; and (3) the immaturity of the protein C anticoagulant pathway in very young children (see later). Twenty-eight of the 29 children had a history of a recent acute infection; in 18 the infection directly involved the skin, most commonly varicella (11 subjects); in five subjects the antecedent infection was pharyngitis. One child developed skin necrosis 1 day after an urticarial reaction to strawberries. In contrast, only three of the nine adults had an antecedent infection, including one 18-year-old with varicella; three subjects had a documented or suspected antecedent dermal hypersensitivity reaction; one subject was pregnant; and two subjects had no history of an antecedent illness. The interval between the onset of the preparatory illness and the development of skin necrosis is typically short. In the cases summarized in Tables 1 and 3, the interval was less than 10 days in the majority of subjects, and 1 month or less in all. The development of skin lesions is rapid, with evolution from initial erythema or cyanosis to frank necrosis in 24 to 48 hours. Most lesions are located on the lower half of the body, with thighs, legs, buttocks, lower abdomen, and (in males) the scrotum and penis most commonly involved. Involvement of the arms, hands, feet, face, or ears is less common; involvement of the upper trunk, neck, and head is distinctly uncommon. The tendency of skin necrosis in idiopathic purpura fulminans to involve certain areas while sparing others is not understood, but the distribution of lesions is similar to that seen in protein C- or

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S-deficient heterozygotes with warfarin-induced skin necrosis33-37 and in individuals with homozygous protein C deficiency,38 suggesting an innate susceptibility of certain areas of the dermis to thrombosis in conditions associated with impaired activity of the protein C pathway. The lesions of idiopathic purpura fulminans have a very characteristic appearance, which clearly differentiates them from other purpuric lesions, such as the palpable purpura of dermal vasculitis or the non-necrotic hematomas of thrombocytopenic purpura and other primary bleeding disorders. Irregular central areas of blueblack hemorrhagic necrosis are surrounded by a thin (10 mm) advancing red border, which fades into uninvolved skin. The lesions are indurated and painful, due to heavy bleeding into the necrotic dermis. Vesicles, bullae, and large blebs often form over necrotic areas and eventually rupture. The contents of the blebs are sterile. Necrosis may extend deep into the subcutaneous tissue. The necrotic tissue gradually forms a thick eschar and sloughs. The resulting tissue defects heal slowly by secondary intention, often with severe scarring or contractures. Autoamputation of necrotic extremities and of the male genitalia may occur. The long-term physical and psychologic consequences of such devastating tissue destruction can be severe and may challenge the skills of the orthopedist, plastic surgeon, and physical therapist. The tendency of idiopathic purpura fulminans to spare the distal extremities contrasts with the pattern of ascending peripheral gangrene often seen in sepsisassociated purpura fulminans (see later). This difference probably reflects the far greater importance of hemodynamic compromise and tissue hypoperfusion in acute sepsis than in idiopathic purpura fulminans. Most subjects with the latter do not present with the profound circulatory collapse characteristic of septic shock, although hypovolemic shock may develop due to severe bleeding into the skin. The majority are normotensive on presentation, with intact peripheral pulses and good distal perfusion. Anemia may or may not be present initially, but marked decreases in the hemoglobin level often occur during the active phase of the illness. In some subjects, a significant component of microangiopathic hemolysis may be seen,19,27 potentially causing confusion with thrombotic thrombocytopenic purpura. Fever and leukocytosis with a left shift are common despite the absence of acute infection. Idiopathic purpura fulminans is primarily a disease of the dermal vasculature. Clinically significant thrombosis or hemorrhage of other organs is surprisingly uncommon, in striking contrast to the severe, sometimes fulminating skin thrombosis. Thrombosis of large arteries and veins or of the pulmonary vasculature may occur, but usually represent relatively late manifestations of

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ACQUIRED PURPURA FULMINANS—FRANCIS

TABLE 1. Idiopathic Purpura Fulminans in Children: Clinical Features and Coagulation Data Preceding Illness

Interval

Location

PT (sec)

PTT (sec)

Fibrinogen (mg/dl)

3

9 mo

Varicella

7 days

Arm, thighs, buttock, abdomen

203

—

4

20 mo

Stomatitis

21 days

Thighs, legs

229

5

11 yr

None

—

Thighs, legs, buttocks

—

— —

—

—

—

6 7/1

312

Age

6 yr 22 mo

3 days

Thighs, legs

—

"A few days"

Thighs, legs

"Prolonged"

Varicella Fever, urticaria

120

>240

11

34 mo

Varicella

8 days

Thighs, legs, buttocks

40%

—

12

3 yr

Varicella

7 days

Thighs, legs

< 10%

—

85

13/1

7 yr

Urticarial reaction to strawberries

1 day

Legs, arms, trunk

14/1

2 yr

Staphylococcal angina

13 days

Thighs, legs

—

—

0

—

14/2

6 yr

Scarlet fever

—

—

0

—

5 yr

Varicella

21 days ?

Legs

15

Legs, sacrum, penis

"Incoagulable"

0

64,000

16/1

7 yr

Tonsillitis

2 days

Feet, legs, arms, ears

—

—

0

31,000

16/2

12 yr

Streptococcal pharyngitis

6 days

Legs, penis, buttocks

26%

—

< 100

54,000

16/3

6 yr

Febrile exanthem

21 days

Feet, legs, thighs, buttocks

13%

< 100

72,000

16/4

7 yr

Streptococcal pharyngitis

8-10 days

Legs, trunk, arm, penis

22%

80

41,000

16/5

3 yr

Rubella HenochSchonlein

21 days

Legs, thighs, buttocks— initially urticarial

80

70,000

17

5 yr

Varicella

7 days

Legs, buttocks

>240

200

18/4

4 mo

Febrile exanthem

7 days

Elbows, knees, ankles

19

10 mo

Fever, cough

20

7 yr

Pharyngitis

21/4

5 yr

Varicella

22

5 yr

Febrile exanthem

23/1

9 yr

24

6 yr

Scarlet fever

5 days

?

"Low"

114,000

20

35,000

5

31,000

—

—

—

"Normal"

15

117,000 60,000

30,000

—

"adeq"

Thigh, leg

150

360

20

50,000

Foot, legs, neck, bladder

50

110

46

60,000

Legs, sacrum, penis

35

1 mo

Thighs

42

78

80

64,000

Varicella

6 days

20

32

80

>80

150

30

21,000

2 wks

Legs, penis

37

41

90

42,000

10 days

Legs, penis, scrotum

16

45

40

152,000

Age (yr)

Preceding Illness

Interval

25

29

Pregnancy

7th month

26

46

None

—

27

74

? sulfa allergy

13/2

39

Mass urticaria

28

18

Phenytoin rash

29

55

Upper respiratory infection

30

57

None

31

68

Pneumonia

32

18

Varicella

3 days ? 2 wks

Location

progressive, poorly controlled disease. 6,27 ' 30 In adults, underlying atherosclerotic vascular disease may increase the likelihood of large-vessel occlusion.30 Although the skin lesions of idiopathic purpura fulminans are initially sterile, secondary infection of gangrenous tissue may occur, contributing to late morbidity and mortality. 11,19,26,30

57

14,700

86

52,000

—

Severe disturbances of coagulation are almost always present from the outset. Moderate to severe thrombocytopenia, marked hypofibrinogenemia, and significantly prolonged clotting times are characteristic (Tables 1 and 3). Many patients are completely defibrinated at presentation. When measured, Factors V and VIII are usually reduced, and fibrin(ogen) degradation products

TABLE 4. Idiopathic Purpura Fulminans in Adults: Therapy and Outcome Ref/Case No.

Therapy

Response

Outcome

25

Prednisolone

Slow

Survival with scarring

26

Blood, fibrinogen, steroids

Poor

Death from secondary infection

27

Whole blood, heparin, fibrinogen

Poor

Death from pulmonary thrombosis and hemorrhage

13/2

Blood

Slow

Survival with extensive scarring

28

Heparin, steroids

Slow

Survival with minimal scarring

29

Whole blood, platelets, heparin

Rapid

Relapse when heparin stopped after 6 days; survival with minimal scarring

30

Blood, plasma, heparin

Rapid

Relapse when heparin stopped after 5 days; death 2 days after bilateral above-knee amputations from secondary sepsis and myocardial infarction

31

Blood, plasma, platelets

Rapid

Survival with scarring

32

Plasma, heparin

Slow

Survival with scarring

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ACQUIRED PURPURA FULMINANS—FRANCIS

The overall mortality rate of 18% in the cases noted in Tables 2 and 4 (14% in children and 33% in adults) is considerably lower than that reported for cases prior to 1964.2 This may be due to several factors: improved general supportive and rehabilitative care, better treatment of secondary infections, and more widespread use of heparin to interrupt dermal thrombosis (see later). Secondary infection was the major cause of death in this series (four subjects);11,19,26,30 in only two subjects was

death due directly to thrombotic complications.16,27 However, 7 of the 31 survivors, all children, had major lower extremity amputations. The time course of idiopathic purpura fulminans is typically short: arrest of skin necrosis or death occurred within 1 month in all but two subjects listed in Tables 2 and 4. 5,13 One of these refused to seek medical attention initially and subsequently repeatedly refused skin grafting.13 The illness in the other subject was atypical, not only because of its prolonged, remitting and relapsing course, but also because of its lack of an antecedent illness and its association with periorbital and conjunctival edema and hemorrhage.5 In no other subject in this series did delayed relapse of skin necrosis occur after the initial episode had resolved. No additional thrombotic events have occurred in the few subjects in whom long-term follow-up has been reported.13-15

Differential Diagnosis Various features of idiopathic purpura fulminans may cause confusion with simple dermal hemorrhage, postinfectious thrombocytopenic purpura, thrombotic thrombocytopenic purpura, Henoch-Schonlein purpura, and other types of vasculitis. These can be distinguished relatively easily, however. Large soft-tissue hematomas in individuals with trauma or underlying bleeding diatheses can be expansile and produce significant anemia but are almost never associated with extensive tissue necrosis unless they cause a secondary compartmental compression syndrome. Moreover, they do not produce the laboratory picture of intravascular coagulation. Similarly, postinfectious immune thrombocytopenia is not associated with skin necrosis or intravascular clotting. The skin lesions of Henoch-Schonlein purpura are typically small and urticarial and only rarely lead to extensive necrosis.39 Also, significant involvement of joints, kidneys, and other viscera are common in HenochSchonlein purpura but very uncommon in idiopathic purpura fulminans. Thrombotic thrombocytopenic purpura causes fragmentation hemolysis, thrombocytopenia, and hyaline thrombosis of small vessels but does not cause massive skin necrosis. Laboratory evidence for intravascular clotting is present in a minority of cases of thrombotic thrombocytopenic purpura but is virtually never as severe as that seen in idiopathic purpura fulminans. It is important to distinguish idiopathic purpura fulminans from purpura fulminans in subjects with homozygous protein C deficiency38 or acquired inhibitors of the protein C anticoagulant pathway,40 because the natural history and therapy of these two disorders differs significantly from idiopathic purpura fulminans. Whereas idiopathic purpura fulminans usually responds

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are increased, consistent with intravascular coagulation. A few subjects have also been reported to have marked reductions in one or more vitamin K-dependent procoagulant factors,3,10 suggesting the possibility of associated vitamin K deficiency. To date, plasma protein C and S levels have been measured during the acute phase of skin necrosis in only one subject,32 and have been found to be markedly reduced, suggesting a pathogenetic role for impaired activity of the protein C anticoagulant pathway (see later). Protein C levels have been measured after recovery in several subjects, 22,24,31,32 and total and free protein S in one subject,32 and have been found to be normal. Histopathologically, the involved skin is characterized by widespread thrombosis of small vessels. 1,5,11,16, 19,27,29,32 The thrombi are composed predominantly of fibrin, in contrast to the hyaline thrombi of thrombotic thrombocytopenic purpura. A less prominent but also characteristic finding is a mild inflammatory reaction, with perivascular cuffing by leukocytes. Focal necrosis of dermal vessels may also occur. However, deposition of immunoglobulins and complement has not been found in the skin of the few subjects so far studied,29,31 suggesting that the lesions are not the result of an antigen-antibody reaction. The lack of a prominent inflammatory component is one of the features that differentiates idiopathic purpura fulminans from other disorders of the dermal vasculature, such as drug-induced vasculitis and Henoch-Schonlein purpura. However, it should be noted that both allergic skin reactions and Henoch-Schonlein purpura have been reported on rare occasions to serve as the preparatory illness for subsequent "classic" purpura fulminans.13,16,28 In such cases a more prominent vasculitic component may be observed on skin biopsy.28 The histopathologic changes of idiopathic purpura fulminans are essentially identical to those of the local Shwartzman reaction (see later) and are also very similar to those of skin necrosis in individuals with inherited deficiencies of the protein C anticoagulant pathway,33-38 with the possible exception of less marked or absent perivascular leukocyte cuffing in the latter. This may be an important difference, since perivascular leukocyte infiltration may be a marker for the pathogenic involvement of endogenous inflammatory cytokines (see later).

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well to heparin (see later) and, once resolved, does not recur, skin necrosis in protein C-deficient homozyotes,38 and in the one individual with an acquired inhibitor of the protein C pathway so far reported,40 recurs whenever anticoagulant therapy or protein C replacement therapy is interrupted, and it may not be responsive to heparin. Skin necrosis in an infant under 1 month of age should be presumed to be due to homozygous protein C deficiency and managed accordingly.38 A high index of suspicion must be maintained in older children as well, since some homozygotes have been reported to remain asymptomatic for as long as 10 months after birth.41 For these reasons, it is particularly important to measure plasma protein C and S in young children with idiopathic purpura fulminans and in their parents, and to test for an inhibitor of the protein pathway in older subjects with purpura fulminans who have a previous history of thrombosis or skin necrosis.40 Early in the course of apparently idiopathic purpura fulminans, it may not be clear whether an underlying severe, acute infection is present, especially as fever and leukocytosis are typically present in both disorders. If any doubt exists, and particularly if signs of shock are present, blood cultures should be obtained and empiric broad-spectrum antibiotics given. Antibiotic coverage should include the meningococcus, gram-negative bacilli, and gram-positive cocci, since these are the organisms most commonly associated with skin necrosis (see later).

Pathogenesis The pathogenesis of idiopathic purpura fulminans is poorly understood. However, the fact that a similar syndrome of skin necrosis can be produced in laboratory animals (the local Shwartzman reaction), and also occurs in human subjects with severe impairment of the protein C anticoagulant pathway, strongly suggests that inflammatory cytokines (interleukin-1 and tumor necrosis factor) and acquired abnormalities of the protein C anticoagulant pathway are involved in the pathogenesis of idiopathic purpura fulminans.

The Local Shwartzman Reaction as a Model of Idiopathic Purpura Fulminans In this model, the skin of a rabbit (the most susceptible animal) is injected with an agent (classically endotoxin) that causes granulocytes to accumulate or with isolated leukocyte granules (the "preparing agent"). Twenty four hours later, an agent that induces intravascular coagulation, such as endotoxin, kaolin, or starch (the "provoking agent"), is injected intravenously, and the prepared skin site undergoes vascular thrombosis and

secondary hemorrhagic necrosis.42 This reaction can be viewed as a localized thrombotic manifestation in a susceptible regional vascular bed of a systemic hypercoagulable state. The local Shwartzman reaction is a better model for idiopathic purpura fulminans than is the Arthus reaction, because the latter involves a specific antigenantibody reaction in the prepared skin.42 There are many similarities between the local Shwartzman reaction and idiopathic purpura fulminans, including an essentially identical dermal histopathologic picture, an association with intravascular coagulation, and the ability of heparin to prevent skin necrosis.42 Also, an analogy has often been drawn between the preparatory skin injection in the local Shwartzman reaction and the antecedent illness in idiopathic purpura fulminans. Early investigators ascribed the peculiar susceptibility to thrombosis of the "prepared" dermal vasculature in the local Shwartzman reaction to endothelial damage caused by release of leukocyte granule enzymes.42 More recently, it has been shown that the skin can also be prepared by interleukin-1 and tumor necrosis factor,43 suggesting that these cytokines may play a key role in the pathogenesis of the local Shwartzman reaction, and of idiopathic purpura fulminans as well.

Role of Inflammatory Cytokines It has recently been recognized that the skin is an important immunologic organ and that keratinocytes can secrete interleukin-1.44 Among their many effects, cytokines cause profound changes in the function of vascular endothelial cells, including enhanced expression of cell surface leukocyte adhesion molecules and procoagulant activity (tissue factor), down-regulation of the cell surface cofactor for thrombin activation of protein C (thrombomodulin), inhibition of secretion of tissue-type plasminogen activator (t-PA), and enhanced secretion of type 1 plasminogen activator inhibitor.45-47 These changes favor in-migration of granulocytes and formation of fibrin thrombi, the two characteristic histopathologic features of both the local Shwartzman reaction and idiopathic purpura fulminans. It is therefore very likely that endotoxin prepares the skin in the local Shwartzman reaction by inducing the local elaboration of interleukin-1 and tumor necrosis factor by keratinocytes,44 dermal endothelial cells, 48 and possibly other skin cells. One can speculate that the antecedent illness usually associated with idiopathic purpura fulminans similarly prepares the skin for thrombosis by inducing local elaboration of interleukin-1 and tumor necrosis factor. A key difference between the local Shwartzman reaction and idiopathic purpura fulminans, however, may be that a systemic hypercoagulable state must be created separately by the provoking agent to precipitate dermal vascular thrombo-

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sis in the local Shwartzman reaction, whereas in idiopathic purpura fulminans, dermal thrombosis is initiated by primary procoagulant changes in the dermal endothelium itself. This mechanism provides a possible explanation for one of the most striking and hitherto puzzling features of idiopathic purpura fulminans: the tendency of clinically significant thrombosis to involve only the dermal vasculature.

Role of the Protein C Anticoagulant Pathway The reports of dermal vascular thrombosis and hemorrhagic necrosis in infants with homozygous protein C deficiency,38 in adults with heterozygous protein C or S deficiency during warfarin therapy,33-37 and in one subject with an acquired inhibitor of protein C activity,40 strongly suggest that abnormalities of the protein C pathway may also contribute to the development of idiopathic purpura fulminans. Both syndromes are usually associated with intravascular coagulation, and the histopathology of the affected skin is almost identical, with one possible exception: the apparent lack of dermal vascular leukocyte infiltration in many subjects with preexistent abnormalities of the protein C pathway, which might indicate a lack of involvement of inflammatory cytokines in the pathogenesis of these lesions (see before). The unusual susceptibility of the dermal vasculature to thrombosis in subjects with preexistent abnormalities of the protein C pathway is not understood but provides another possible explanation for the selective involvement of the skin in idiopathic purpura fulminans. In view of these similarities, it is significant that plasma protein C has been reported to be markedly reduced (39% of normal) and plasma free protein S to be completely absent in the one subject with idiopathic purpura fulminans so far studied during the active phase of skin necrosis.32 Although the assay methods used were not reported, it is possible that plasma protein C activity was in fact considerably lower than 39% initially, if this value was obtained using an immunologic assay, since immunologic assays may measure inactive (uncarboxylated) protein C and the protein C-protein C inhibitor complex as well as free, active protein C. Also, plasma levels of C4b-binding protein were not measured, so that we do not know to what extent the absence of free protein S during the acute phase was due to increased binding to C4b-binding protein, which is often elevated during acute inflammation and infection.49 Although these findings require confirmation in additional subjects, they suggest that severe acquired deficiencies of both proteins C and S may contribute to dermal thrombosis during the active phase of idiopathic purpura fulminans. The most likely cause of reduced protein C and S in idiopathic purpura fulminans is consumption during

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intravascular coagulation.50,51 If so, reduced protein C and S levels, along with cytokine-induced down-regulation of endothelial thrombomodulin,46 probably play a permissive rather than initiating role in the development of dermal vascular thrombosis. Vitamin K deficiency could also contribute to reduced proteins C and S in subjects whose oral intake is poor and who are taking antibiotics because of an antecedent infection. This possibility is further suggested by the finding of markedly reduced levels of vitamin K-dependent procoagulant factors in some subjects during the active phase of idiopathic purpura fulminans.3,10 Protein C and S levels are normally lower in very young children than in older children and adults,52 which may explain the tendency of idiopathic purpura fulminans to affect young children. Free protein S is reduced during pregnancy,53 which may help explain the rare occurrence of idiopathic purpura fulminans in pregnancy.25 Another possible although less likely cause of reduced protein C pathway activity in idiopathic purpura fulminans is a transient antibody inhibitor. For example, antiphospholipid antibodies, which have been reported to inhibit thrombomodulindependent activation of protein C, 54,55 can arise transiently after acute infections.56 A longer-lasting inhibitor, such as that reported by Mitchell et al, 40 is unlikely to be present in most subjects in view of the rarity of late relapses, but such an inhibitor is a consideration in subjects who have a prolonged, remitting or relapsing course5 or who have a previous history of thrombosis or skin necrosis. It is also possible that some subjects with idiopathic purpura fulminans may have inherited deficiencies of protein C, protein S, or thrombomodulin, which could contribute to the development of dermal thrombosis after an acute infection or dermal allergic reaction. Although normal postrecovery plasma levels of protein C have been reported in a few subjects, 22,24,31,32 and normal postrecovery plasma levels of total and free protein S have been reported in one subject,32 most of these measurements were performed using immunoassays, so that functional deficiencies of proteins C and S were not excluded. Moreover, the investigations of Miletich et al57 indicate that asymptomatic heterozygous protein C deficiency may be fairly common, so that the lack of other thrombotic problems in subjects with idiopathic purpura fulminans or in their relatives does not necessarily exclude the possibility of inherited protein C deficiency. However, it is clear that this could only represent a minor contributing factor, given the rarity of idiopathic purpura fulminans and its absence in the subjects studied by Miletich et al. 57 Clearly, more extensive investigations of plasma protein C and S levels and dermal vascular thrombomodulin expression need to be performed in future subjects with idiopathic purpura

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SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 16, NO. 4, 1990 protein S could also have important consequences for therapy (see later).

fulminans and in their families, using both immunoassays and activity assays to clarify the role of inherited and acquired abnormalities of the protein C pathway in the development of this disorder. Finally, Taylor et al58 have shown that pretreatment of laboratory animals with activated protein C protects them from shock, intravascular coagulation, and death after injection of gram-negative bacilli.58 Since endotoxin produces many of its physiologic effects by stimulating endogenous release of interleukin-1 and tumor necrosis factor (see later), these observations suggest that activated protein C plays an important role in modulating the effects of the inflammatory cytokines, either directly or via its anticoagulant or antifibrinolytic actions. Thus, one can speculate that inherited or acquired abnormalities of the protein C pathway might enhance the procoagulant effects of inflammatory cytokines on the dermal vasculature and contribute to the development of dermal thrombosis in idiopathic purpura fulminans.

Although no studies of plasma antithrombin III during the active phase of skin necrosis have been reported using modern assay methods, the severe intravascular clotting in idiopathic purpura fulminans is likely to cause significant reductions in this important anticoagulant factor.60,62 (One subject was reported to have a normal antithrombin III level after normalization of the coagulopathy.24) In other conditions associated with markedly reduced plasma antithrombin III, replacement therapy with plasma or antithrombin III concentrate has sometimes been necessary to interrupt ongoing intravascular clotting,60,62 suggesting a possible role for antithrombin III replacement therapy in idiopathic purpura fulminans also.

Role of Intravascular Coagulation

Summary of Possible Pathogenesis

It is not known whether the marked consumption of fibrinogen, Factors V and VIII, and platelets during the active phase of idiopathic purpura fulminans occurs primarily in the dermal vasculature or in the circulation at large. Although many authors have assumed that true disseminated intravascular coagulation occurs, it is clear that a similar coagulopathy can be produced by massive clotting in large local vascular beds, such as giant cavernous hemangiomas and abdominal aortic aneurysms.59 Thus, the coagulation abnormalities accompanying idiopathic purpura fulminans could well be due entirely to extensive clotting in the vessels of the skin, consistent with the hypothesis that this disorder is caused by primary procoagulant alterations in the dermal vascular endothelium. Regardless of the cause or location, massive intravascular clotting generates secondary changes in the coagulation system that favor continuation of the thrombotic process, especially consumption of antithrombin III, protein C, and protein S. 50,51,60 In addition, thrombin itself can induce procoagulant changes in endothelial function.61 It is therefore possible that the pathogenesis of idiopathic purpura fulminans involves a vicious cycle, in which initial cytokine-induced procoagulant changes in the dermal vascular endothelium and widespread activation of coagulation in the skin lead to secondary consumption of anticoagulant factors, to thrombin-induced procoagulant alterations in endothelial function, and to further activation of coagulation. Such a vicious cycle could explain why the skin lesions in idiopathic purpura fulminans classically expand centrifugally. Secondary consumption of antithrombin III, protein C, and

Although admittedly speculative, the following model of the pathogenesis of idiopathic purpura fulminans is offered in the hope that it will stimulate further investigation. 1. Immunologic stimulation of the skin by an antecedent infection or allergic reaction leads to local elaboration of interleukin-1 and tumor necrosis factor by keratinocytes, dermal endothelial cells, or other skin cells. 2. These cytokines induce procoagulant and antifibrinolytic changes in the dermal vascular endothelium and in-migration of leukocytes. 3. Induction of dermal endothelial tissue factor expression by cytokines leads to initiation of clotting in the dermal vasculature. Secondary consumption of protein C, protein S, and antithrombin III occurs, which together with cytokine-induced inhibition of dermal endothelial thrombomodulin expression and endothelial fibrinolytic activity predisposes to further clotting and thrombus formation. Additional procoagulant and antifibrinolytic changes in dermal endothelial function are produced by thrombin. A vicious cycle is established that eventuates in massive dermal vascular thrombosis and in profound consumption of circulating procoagulant and anticoagulant factors and platelets. 4. This process is particularly likely to occur when other causes of reduced protein C pathway activity are present: in very young subjects with an immature protein C pathway, in subjects with vitamin K deficiency due to poor oral intake and antibiotic therapy, and in subjects with transient postinfectious antibody inhibitors of the protein C pathway.

Role of Antithrombin III

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5. Additional, poorly understood genetic or acquired abnormalities in endothelial function, cytokine secretion, the response to cytokines, and the hemostatic system may also be involved.

Treatment As shown in Tables 2 and 4, many different therapies have been employed to arrest the progression of dermal necrosis in idiopathic purpura fulminans, including glucocorticoids, whole blood, plasma, fibrinogen, dextran, heparin, warfarin, vitamin K, epsilon-aminocaproic acid (EACA), hyperbaric oxygen, and combinations of these. In evaluating these therapies, three points must be kept in mind. First, the pathogenesis of idiopathic purpura fulminans may vary among different subjects, so that there may be no single optimal therapy. For example, a treatment that is effective in replenishing simple deficiencies of protein C and S may not be useful in reversing the effects of an inhibitor of the protein C pathway. Second, to be truly effective, a therapy must induce rapid, complete arrest of ongoing dermal thrombosis and skin necrosis, so that massive tissue loss is prevented and long-term physical and psychologic sequelae are minimized. Third, no therapy, regardless of its effectiveness in arresting dermal thrombosis, can prevent extensive tissue loss if it is instituted after widespread skin infarction has already occurred. In this section, each potential therapeutic agent is discussed individually, after which a combined modality approach is recommended, based on the best results of previous experience and on current concepts regarding the pathogenesis of the disease.

Whole Blood and Plasma Rapid improvement in skin necrosis has been reported after administration of fresh whole blood or plasma, usually in combination with other agents (Tables 2 and 4). The amounts administered have varied considerably; in some cases very large amounts of blood and plasma have been given to compensate for massive blood loss into infarcted skin.7 There is only one well-documented report of a clear-cut response to plasma alone;22 in this case, 10 ml/kg of fresh frozen plasma every 8 hours induced a rapid improvement in both skin lesions and intravascular clotting, but when after 4 days the dose was decreased to 10 ml/kg every 12 hours, intravascular clotting increased and heparin was added to obtain a remission. In another case, immediate improvement in the skin lesions was noted after administration of 250 ml of fresh whole blood and 2 gm of fibrinogen to a 9-month-old subject.3 Whole blood and plasma supply

319 not only procoagulant factors, but also protein C, protein S, and antithrombin III, which may be of value in inhibiting dermal thrombosis if plasma levels of these factors are reduced. Replenishment of antithrombin III may also improve the effectiveness of heparin.60 Fresh frozen plasma (8 to 12 ml/kg every 12 hours) is the recommended treatment for purpura fulminans in infants with homozygous protein C deficiency;38 with this dose, peak plasma protein C levels of 15 to 30% of normal and trough levels of 4 to 10% are achieved. One of the problems in evaluating the response of idiopathic purpura fulminans to plasma is that plasma levels of antithrombin III, protein S, and protein C have not been monitored; it is possible that poor responses to plasma have been due to inadequate replenishment of anticoagulant factors. It is highly desirable that plasma therapy in future cases be monitored with serial determinations of plasma antithrombin III, protein C, and protein S.

Heparin Rapid improvement in skin necrosis has been reported after administration of heparin, both alone and in combination with other agents (Tables 2 and 4). Relapse is common when heparin is decreased, interrupted for surgical procedures, or discontinued within 7 days after an initial response is obtained, 10,15-17,24,29,30 suggesting that the underlying hypercoagulable state persists for at least a week after the initial appearance of skin lesions. Heparin catalyzes the inhibition of thrombin, Factor IXa, and Factor Xa by antithrombin III. 60 Its effectiveness in idiopathic purpura fulminans may be due to inhibition of clotting, interruption of consumption of anticoagulant factors, or inhibition of the procoagulant and antifibrinolytic effects of thrombin on dermal endothelial function.61 Heparin used alone has not been effective in arresting skin necrosis in subjects with homozygous protein C deficiency, however,38 and heparin may also be ineffective when plasma antithrombin III levels are reduced.60 Therefore concomitant administration of plasma might improve the effectiveness of heparin in idiopathic purpura fulminans by replenishing protein C and antithrombin III if these factors are reduced.

Vitamin K Vitamin K has been used in combination with other therapeutic agents in a number of cases, without clear evidence of benefit. The main theoretical rationale for its use is to normalize plasma protein C and S levels in subjects with underlying vitamin K deficiency, a possible but as yet unproven contributing factor to dermal thrombosis in idiopathic purpura fulminans.

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Warfarin Warfarin has not proven effective in stopping skin necrosis during the acute phase of idiopathic purpura fulminans and may even exacerbate thrombosis in these subjects,5,15,16 perhaps because it reduces plasma levels of the active forms of protein C and S. This may be analogous to warfarin-induced skin necrosis in subjects with preexistent heterozygous deficiencies of proteins C and S. 33-37 One of the two primary thrombotic deaths in the series summarized in Tables 2 and 4 occurred 4 days after stopping heparin and starting warfarin.16 Warfarin does not appear to induce relapses of idiopathic purpura fulminans if given after the skin lesions have healed, 15,20 but there is no evidence that long-term prophylactic therapy with warfarin is indicated in most subjects after recovery, since the risk of late relapse appears to be very low.

EACA There is one report of rapid arrest of skin necrosis in idiopathic purpura fulminans after administration of EACA alone. EACA inhibits fibrinolysis by preventing t-PA and plasminogen from binding to fibrin and may have other, less well-defined effects on inflammation and the immune response.63 It is not clear how EACA might induce a remission in idiopathic purpura fulminans, and it could conceivably exacerbate dermal vascular thrombosis by impairing the fibrinolytic response to clotting.

Glucocorticoids Although glucocorticoids have frequently been used in idiopathic acquired purpura fulminans, there is no clear evidence that they are effective. Reported responses to glucocorticoids alone have generally been slow (Tables 2 and 4), in contrast to the rapid responses often achieved with heparin or plasma. Some authors consider glucocorticoids to be contraindicated because of their ability to enhance the local Shwartzman reaction.1,42 However, they could be useful in three special situations: as anti-inflammatory agents when the preparatory illness is an allergic reaction, such as mass urticaria or a drug eruption;13,28 as immunosuppressive therapy if an antibody inhibitor of the protein C pathway is present;40 or for treatment of adrenal insufficiency if adrenal thrombosis and hemorrhage is suspected.64

Dextran Most of the reported responses to dextran have occurred in subjects who also received blood, plasma, or heparin.5,9,16 In only one subject, who had an atypical,

prolonged, remitting or relapsing course, did dextran appear to provide definite independent benefit.5 Another subject, treated only with dextran and vitamin K, had a slow response.18 Dextran is a high molecular weight polymer that inhibits coagulation and cell aggregation. The value of dextran in idiopathic purpura fulminans remains unclear, but its use might be considered in subjects who fail to respond to optimized plasma and heparin therapy (see later).

Hyperbaric Oxygen Hyperbaric oxygen has been used in two subjects in combination with heparin,16 without definite evidence of independent therapeutic benefit. There are two case reports of its successful use as the sole therapeutic agent in an unusual syndrome of postinfectious peripheral edema and cyanosis labeled "purpura fulminans,"65,66 but it is doubtful that these cases represent true idiopathic purpura fulminans.

Recommended Approach to the Investigation and Treatment of Idiopathic Purpura Fulminans 1. As soon as the diagnosis is suspected, obtain punch biopsies of both involved skin (including the advancing border of the lesions) and adjacent normalappearing skin; freeze portions in fixative and save for later immunofluorescence studies of dermal endothelial tissue factor and thrombomodulin expression, using commercially available antibodies, as well as dermal immunoglobulin and complement deposition. 2. Obtain a complete blood cell count, platelet count, routine coagulation tests, and a fibrinogen level. If possible, also measure plasma protein C, protein S, and antithrombin III levels, in both the patient and in family members, using functional as well as immunologic assays. Freeze aliquots of citrated plasma for later measurement of these factors (if assays are not immediately available), as well as C4b-binding protein, interleukin-1, tumor necrosis factor, and antiphospholipid antibodies, using commercially available assays. 3. Immediately begin therapy with fresh frozen plasma, 8 to 12 ml/kg every 8 hours22 (to replenish possible deficiencies of procoagulant factors, antithrombin III, protein C, and protein S), vitamin K either orally or intravenously (to correct possible vitamin K deficiency), and full-dose heparin by constant intravenous infusion (to inhibit intravascular clotting and reduce consumption of anticoagulant factors). Monitor response to therapy with frequent serial measurements of platelets, routine clotting tests, fibrinogen, and, if possible, plasma antithrombin III activity, protein C activity, and free

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life-threatening bleeding complications directly related to heparin supervene. Avoid interrupting heparin during this period for surgical procedures unless absolutely necessary. 7. After recovery, obtain additional punch biopsies of skin for immunofluorescence studies of dermal endothelial tissue factor and thrombomodulin expression, and additional citrated plasma for determination of plasma protein C antigen and activity, total and free protein S, antithrombin III, C4b-binding protein, interleukin-1, tumor necrosis factor, and antiphospholipid antibodies.

Follow-up Care and Rehabilitation The long-term consequences of massive skin necrosis can be severe. Patients with substantial gangrene and tissue loss may require care from plastic surgeons, orthopedists, rehabilitation specialists, and psychologists. It is hoped that as the promptness and effectiveness of initial therapy increases, the severe long-term consequences of idiopathic purpura fulminans will be reduced.

Future Prospects for Therapy Both recombinant activated protein C and recombinant soluble thrombomodulin are under development. The use of recombinant activated protein C or plasma in conjunction with recombinant soluble thrombomodulin could avoid one theoretical problem of plasma alone: inhibition of activation of infused protein C by cytokine or thrombin-induced down-regulation of endothelial thrombomodulin expression.46,61

PURPURA FULMINANS ASSOCIATED WITH SEVERE INFECTIONS Clinical Features Skin necrosis is an unusual but important complication of many severe acute infections. The organism most often involved has been the meningococcus (Neisseria meningitidis).12,21,67-70 Other reported organisms include Neisseria catarrhalis, Staphylococcus albus, group A and B streptococci, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus aegyptius, Klebsiella, Escherichia coli, Enterobacter, Proteus mirabilis, and Rickettsia rickettsii.12,21,69-78 Like idiopathic purpura fulminans, sepsis-associated purpura fulminans occurs much more frequently in children, especially young children, than in adults. 67-78 Also, the dermal histopathology73,78,79 and the association with intravascular clotting are similar. However, sepsis-associated purpura fulminans typically differs in three impor-

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protein S antigen. Freeze aliquots of citrated plasma from each serial determination for later measurement of C4bbinding protein, interleukin-1, and tumor necrosis factor. If possible, give sufficient fresh frozen plasma to keep antithrombin III above 50% of normal, and protein C and free protein S at least 15 to 30% of normal. (These recommendations represent extrapolations from previous experiences with homozygous protein C deficiency38 and with inherited and acquired deficiencies of antithrombin III.60,62) 4. If difficulty is encountered in achieving these levels of anticoagulant factors with fresh frozen plasma and heparin alone, and skin necrosis does not begin to respond within 72 hours, consider the addition of antithrombin III concentrate and prothrombin complex concentrate. The use of antithrombin III and prothrombin complex concentrate in idiopathic purpura fulminans is untested, and this recommendation is contingent on the as yet undocumented possibility that consumption of anticoagulant factors might be so rapid in some subjects with idiopathic purpura fulminans that even vigorous plasma replacement therapy in combination with heparin might be insufficient to replenish plasma levels of antithrombin III and proteins C and S. Since prothrombin complex concentrate contains variable amounts of activated procoagulant factors, it can potentially exacerbate thrombosis and should be given with heparin. It should not be used if the subject is responding well to other measures or if plasma levels of proteins C and S can be maintained above 15 to 30% of normal with other measures. If possible, protein C in the concentrate should be measured prior to use, since some lots contain relatively small amounts.38 Also, subjects who respond poorly to plasma and heparin should be tested for an antibody inhibitor of the protein C pathway.40 If an inhibitor is present, immunosuppressive therapy, intravenous gamma globulin, and plasmapheresis should be considered. 5. Administer whole blood, packed red cells, and crystalloids as needed to compensate for blood loss into the skin. If there is any suspicion of infection, obtain cultures and begin broad-spectrum antibiotics to protect against meningococci, gram-negative bacilli, and grampositive cocci. Watch for signs of upper or lower extremity compartment syndrome secondary to massive dermal hemorrhage; fasciotomy may be indicated. Subjects with extensive skin lesions should be cared for in the same way as for burn patients. 6. Continue fresh frozen plasma at least until routine coagulation tests and (if assays are available) plasma proteins C and S and antithrombin III levels become normal. Continue full-dose intravenous heparin for at least 2 weeks after active skin necrosis has ceased, to avoid a relapse of skin necrosis, 10,15-17,24,29,30 unless

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tant ways from idiopathic purpura fulminans. First, the initial presentation in sepsis-associated purpura fulminans is often that of overwhelming acute infection, with profound hypotension and peripheral hypoperfusion, in contrast to idiopathic purpura fulminans, in which the blood pressure and peripheral pulses are usually wellpreserved initially. Second, the skin necrosis in sepsisassociated purpura fulminans often begins in the distal extremities, with subsequent proximal progression, or diffusely involves the entire body in a patchy distribution. These patterns of skin involvement contrast with idiopathic purpura fulminans, in which the necrosis usually begins in the skin of the thighs, legs, buttocks, and lower trunk, and much less commonly involve the feet, toes, hands, and fingertips. Third, clinically significant thrombohemorrhagic manifestations in other organs, especially the lungs, kidneys, and adrenal glands, are much more common in sepsis-associated purpura fulminans,21,78 probably because endotoxemia produces more severe systemic hemodynamic disturbances and alterations in endothelial function than are present in idiopathic purpura fulminans (see later). However, in some subjects with sepsis-associated purpura fulminans, the location of skin necrosis is similar to idiopathic purpura fulminans, and shock is not present, 71,72 suggesting that the infection might be serving as the preparatory illness for the development of "classic" purpura fulminans.

Pathogenesis Role of Endotoxin Circulating endotoxin undoubtedly plays a central role in the pathogenesis of sepsis-associated purpura fulminans. High levels of circulating endotoxin have been reported in subjects with sepsis-associated purpura fulminans.78 Endotoxin directly activates coagulation via the intrinsic pathway, leading to generation of the potent vasodilator bradykinin.80 Endotoxin also induces procoagulant changes in endothelial function.81 These effects contribute to the hypotension and intravascular clotting characteristic of septic shock. Meningococcal endotoxin has been shown to be more toxic and more capable of eliciting the local Shwartzman reaction than endotoxin from other gram-negative organisms,82 which may at least partially explain the propensity of the meningococcus to cause purpura fulminans. Endotoxin can serve as both the preparing and provoking agent for the local Schwartzman reaction, as noted before.42

Role of Cytokines Endotoxin stimulates endogenous release of tumor necrosis factor,83 which in turn induces interleukin-1

release.84 Both cytokines are important mediators of septic shock.85,86 Also, as noted previously, these cytokines induce procoagulant and antifibrinolytic changes in endothelial function, leading to activation of coagulation and to inhibition of the protein C and fibrinolytic pathways. 44-47 Elevated plasma levels of tumor necrosis factor, interleukin-1, and gamma interferon have been reported in children with meningococcemic purpura,87 and tumor necrosis factor levels have been shown to correlate inversely with fibrinogen levels in these subjects,87 suggesting a direct relationship between endogenous cytokine release and the development of purpura and intravascular clotting in meningococcemia. Many of the characteristic clinical differences between idiopathic and sepsis-associated purpura fulminans can be explained by the hypothesis that the secretion and effects of cytokines are restricted primarily to the skin in the former, but are systemic in the latter.

Role of Shock In contrast to idiopathic purpura fulminans, circulatory collapse with resultant tissue hypoperfusion and ischemia is probably an important factor in the development of tissue necrosis in severe acute infections. Tissue hyperperfusion not only directly damages and kills cells but also predisposes to thrombosis via endothelial injury and flow stasis. Since hypoperfusion in septic shock is usually most marked in the distal extremities, it is not surprising that tissue necrosis is often most marked at these sites.

Role of Intravascular Clotting Although the coagulopathy associated with severe acute infections appears to be similar to that of idiopathic purpura fulminans, there may be an important difference: in idiopathic purpura fulminans, activation of coagulation and consumption of procoagulant and anticoagulant factors may take place primarily or exclusively in the dermal vasculature, whereas in acute severe sepsis, systemic disturbances of endothelial function induced by circulating endotoxin and cytokines are more likely to be present, leading to activation of coagulation in many different vascular beds. Thus, the coagulopathy in acute severe sepsis may more properly be termed disseminated intravascular coagulation. This may be one reason why clinically significant thrombohemorrhagic manifestations in organs other than the skin are much more common in sepsis-associated purpura fulminans than in idiopathic purpura fulminans.21 As discussed previously, intravascular clotting leads to secondary consumption of antithrombin III, protein C, and protein S, 50,51,60 which may predispose to further intravascular clotting. The

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Role of the Protein C Pathway Plasma protein C and free protein S have been reported to be reduced acutely in children with meningococcemic purpura,88 probably due to consumption during intravascular clotting. Endothelial thrombomodulin expression in these subjects may also be downregulated by endotoxin, cytokines, or thrombin,46'61'81 further impairing the protein C pathway. Impaired protein C pathway activity may contribute not only to thrombosis, but also to the systemic toxicity of gramnegative sepsis, for, as previously mentioned, prior administration of activated protein C protects animals from gram-negative septic shock.58

Treatment

ever, there are no published reports to support this approach, and no prospective randomized controlled studies comparing plasma therapy with supportive therapy alone have been conducted. Even if protein C and S levels were normalized by such therapy, down-regulation of thrombomodulin by endotoxin, cytokines, or thrombin 46,61,81 might still severely inhibit the activity of the protein C pathway. If plasma therapy is to be used, it should ideally be monitored with frequent determinations of plasma protein C, protein S, and antithrombin III levels.

Glucocorticoids The usefulness of glucocorticoids in septic shock continues to be a very controversial topic, and is beyond the scope of this review. Glucocorticoids may be useful in sepsis-associated purpura fulminans if adrenal thrombosis with secondary adrenal insufficiency is present, however.68,78

General Considerations Future Prospects for Therapy Therapy of sepsis-associated purpura fulminans is directed primarily at arresting the infection and reversing shock with antibiotics, fluids, and pressors. There is as yet no convincing evidence that other therapeutic agents are useful in treating skin necrosis in acute severe infections.

Heparin The usefulness of heparin in the treatment of sepsis-associated purpura fulminans is difficult to determine from the relatively few published reports of its use 21,68,72,74,75,77 No randomized, prospective, controlled trials of heparin versus supportive therapy alone have been conducted. However, it is interesting that the apparently fortuitous administration of heparin via a femoral arterial catheter in one newborn subject appears to protect that leg from skin necrosis, whereas the other leg and both hands were severely affected.74 Heparin carries the risk of exacerbating bleeding and may not be effective if plasma antithrombin III levels are very low due to consumption.60 Therefore, if heparin is given, it may be useful to measure plasma antithrombin III levels and to give plasma or antithrombin III concentrate if a significant deficiency of this factor is present.

Plasma Since plasma proteins C and S and antithrombin III are likely to be significantly reduced in sepsis-associated purpura fulminans,60,88 replacement therapy with fresh frozen plasma could be useful in inhibiting intravascular clotting and in improving the efficacy of heparin. How-

Recombinant activated protein C or recombinant soluble thrombomodulin in conjunction with plasma are potentially attractive treatments for sepsis-associated purpura fulminans for two reasons: they might directly combat septic shock58 and they do not depend on endogenous activation of protein C to be effective. The major problem with this approach is that human subjects, unlike laboratory animals, cannot be treated prior to the development of infection, and these agents may be much more effective when given prophylactically than when given after shock and skin necrosis have already developed. Similar considerations apply to the use of neutralizing antibodies to tumor necrosis factor.89,90

CONCLUSIONS Idiopathic purpura fulminans and sepsis-associated purpura fulminans remain major therapeutic challenges. Despite important conceptual advances, the pathogenesis of these disorders is still incompletely understood. It is hoped that more detailed investigations of future subjects with purpura fulminans will lead to an improved understanding of the role of the protein C pathway, disturbed endothelial function, and inflammatory cytokines in their pathogenesis, and that this in turn will lead to improved methods of treatment.

REFERENCES 1. Henoch E: Ueber Purpura fulminans. Berl Klin Wochenschr 24:8-10, 1887.

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procoagulant effects of thrombin on endothelial function may also contribute to this process.61

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2. Hjort PF, SI Rapaport, L Jorgensen: Purpura fulminans. Report of a case successfully treated with heparin and hydrocortisone. Review of 50 cases from the literature. Scand J Haematol 1:169-192, 1964. 3. Bouhasin JD: Purpura fulminans. Pediatrics 34:264-270, 1964. 4. van Creveld S, WFJ van der Kolk, IA Mochtar, J Müller: Purpura fulminans: A case with recovery. Clin Pediatr 4:23-27, 1965. 5. Patterson JH, RB Pierce, JR Amerson, WL Watkins: Dextran therapy of purpura fulminans. N Engl J Med 273:734-737, 1965. 6. Recker FT, RP Buckley: Purpura fulminans associated with varicella. Arch Dermatol 94:613-618, 1966. 7. Morse TS, MI Rowe, M Hartigan: Purpura fulminans. Arch Surg 93:268-270, 1966. 8. Allen DM: Heparin therapy of purpura fulminans. Pediatrics 38:211-214, 1966. 9. Smith H: Purpura fulminans complicating varicella: Recovery with low molecular weight dextran and steroids. Med J Aust 2:685687, 1967. 10. Antley RM, CW McMillan: Sequential coagulation studies in purpura fulminans. N Engl J Med 276:1287-1290, 1967. 11. Horder M: Purpura fulminans following varicella. Danish Med Bull 15:221-224, 1968. 12. Fishbein RH: Purpura fulminans: An analysis of the lesion and its treatment. J Pediatr Surg 4:320-329, 1969. 13. Tondra JM: Gangrene of the skin due to allergic reaction. Plast Reconstr Surg 43:392-396, 1969. 14. Frederiks E, AJC Huffstadt: Two cases of purpura fulminans. Br J Plast Surg 23:90-94, 1970. 15. Hattersley PG: Purpura fulminans. Complete recovery with intravenously administered heparin. Am J Dis Child 120:467-471, 1970. 16. Dudgeon DL, DR Kellogg, GS Gilchrist, MM Woolley: Purpura fulminans. Arch Surg 103:351-358, 1971. 17. de Koning J, E Frederiks, P Kerkhoven: Purpura fulminans following varicella. Report of a case with recovery after heparin therapy. Helv Paediatr Acta 27:177-185, 1972. 18. Urbaniak JR, MT O'Neil, LC Meyer: Purpura fulminans. J Bone Joint Surg 55A:69-77, 1973. 19. Nagi NA, ARA Al-Hasso: Purpura fulminans with haemolytic anaemia. Postgrad Med J 50:750-754, 1974. 20. Daeschner CW, U Carpentieri: Purpura fulminans. Tex Med 77:62-64, 1981. 21. Chu DZJ, FW Blaisdell: Purpura fulminans. Am J Surg 143:356362, 1982. 22. Branson HE, J Katz: A structured approach to the management of purpura fulminans. J Natl Med Assoc 75:821-825, 1983. 23. Seagle MB, HG Bingham: Purpura fulminans. Ann Plast Surg 20:576-581, 1988. 24. Dominey A, A Kettler, J Yiannias, JA Tschen: Purpura fulminans and transient protein C and S deficiency. Arch Dermatol 124:1442-1443, 1988. 25. Chenaille PJ, ME Horowitz: Purpura fulminans. A case for heparin therapy. Clin Pediatr 28:95-98, 1989. 26. Badarau L: Nonthrombocytopenic gangrenous purpura fulminans successfully treated during pregnancy. Comments on the etiology and treatment. Am J Obstet Gynecol 96:321-325, 1966. 27. Hollingsworth JH, DN Mohler: Microangiopathic hemolytic anemia caused by purpura fulminans. Ann Intern Med 68:1310-1314, 1968. 28. Case 29-1969, Case Records of the Massachusetts General Hospital. N Engl J Med 281:153-162, 1969. 29. Targan SR, MRG Chassin, LB Guze: Dilantin-induced disseminated intravascular coagulation with purpura fulminans. A case report. Ann Intern Med 83:227-230, 1975.

30. Spicer TE, JM Rau: Purpura fulminans. Am J Med 61:566-571, 1976. 31. Waddell CC, M Franco: Purpura fulminans in an adult. South Med J 74:1533-1534, 1981. 32. Tishler M, AL Abramov, U Seligsohn, Y Kahn: Purpura fulminans in an adult. Israel J Med Sci 22:820-822, 1986. 33. Nalbandian RM, IJ Mader, JL Barrett, JF Pearce, EC Rupp: Petechiae, ecchymoses, and necrosis of skin induced by coumarin congeners. JAMA 192:603-608, 1965. 34. Koch-Weser, J: Coumarin necrosis. Ann Intern Med 68:13651367, 1968. 35. McGehee WG, TA Klotz, DJ Epstein, SI Rapaport: Coumarin necrosis associated with hereditary protein C deficiency. Ann Intern Med 100:59-60, 1984. 36. Teepe RGC, AW Breikmans, BJ Vermeer, AM Nienhuis, EA Loeliger: Recurrent coumarin-induced skin necrosis in a patient with an acquired functional protein C deficiency. Arch Dermatol 122:1408-1412, 1986. 37. Friedman KD, RA Marlar, JG Houston, RR Montgomery: Warfarin-induced skin necrosis in a patient with protein S deficiency. (Abst.) Blood 68(Suppl l):333a, 1986. 38. Marlar RA, RR Montgomery, AW Broekmans, and the Working Party. Diagnosis and treatment of homozygous protein C deficiency. J Pediatr 114:528-534, 1989. 39. Kisker CT, H Glueck, E Kauder: Anaphylactoid purpura progressing to gangrene and its treatment with heparin. J Pediatr 73:748751, 1968. 40. Mitchell CA, JA Rowell, L Hau, JP Young, HH Salem: A fatal thrombotic disorder associated with an acquired inhibitor of protein C. N Engl J Med 317:1638-1642, 1987. 41. Tuddenham EGD, T Takase, AE Thomas, AS Awidi, FF Madanat, MMA Hajir, PBA Kernoff, AV Hoffbrand: Homozygous protein C deficiency with delayed onset of symptoms at 7 to 10 months. Thromb Res 53:475-484, 1989. 42. Hjort PF, SI Rapaport: The Shwartzman reaction: Pathogenetic mechanisms and clinical manifestations. Annu Rev Med 16:135168, 1965. 43. Movat HZ, CE Burrowes, MI Cybulsky, CA Dinarello: Acute inflammation and a Shwartzman-like reaction induced by interleukin-1 and tumor necrosis factor. Synergistic action of the cytokines in the induction of inflammation and microvascular injury. Am J Pathol 129:463-476, 1987. 44. Lisby G, C Avnstorp, GL Wantzin: Interleukin-1, a new mediator in dermatology. Int J Dermatol 26:8-13, 1987. 45. Bevilacqua MP, JS Pober, ME Wheeler, D Mendrick, RS Cotran, MA Gimbrone: Interleukin-1 acts on cultured human vascular endothelial cells to increase the adhesion of polymorphonuclear leukocytes, monocytes and related leukocyte cell lines. J Clin Invest 76:2003-2011, 1985. 46. Nawroth PP, DA Handley, CT Esmon, DM Stern: Interleukin 1 induces endothelial cell procoagulant while suppressing cellsurface anticoagulant activity. Proc Natl Acad Sci USA 83:34603464, 1986. 47. Bevilacqua Mp, RR Schleef, MA Gimbrone, DJ Loskutoff: Regulation of the fibrinolytic system of cultured vascular endothelium by interleukin-1. J Clin Invest 78:587-591, 1986. 48. Stern DM, I Bank, PP Nawroth, J Cassimeris, W Kiesiel, JW Fenton II, C Dinarello, L Chess, EA Jaffe: Self-regulation of procoagulant events on the endothelial cell surface. J Exp Med 162:1223-1235, 1985. 49. Vigano-D'Angelo S, A D'Angelo, CE Kaufman, C Sholer, CT Esmon, PC Comp: Protein S deficiency occurs in nephrotic syndrome. Ann Intern Med 107:42—47, 1987. 50. Griffin JH, DF Mosher, TS Zimmerman,AJ Kleiss: Protein C, an

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