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Neonatal Purpura Fulminans Due to Homozygous Protein C or Protein S Deficiencies

Neonatal purpura fulminans, usually with onset during the first few days after birth, is a fatal disorder. Evidence to date shows it to be due to a complete deficiency of either protein C or protein S. 1,2 The newborn with homozygous protein C or protein S deficiency first develops disseminated intravascular coagulation (DIC) and fibrin or platelet thrombi in the small vessels of the skin, followed by necrosis and hemorrhage into the dermis and subcutaneous tissues. 1,3-6 If untreated, the coagulopathy and the skin lesions worsen and finally result in death.1 Purpura fulminans is a rapidly spreading lesion of the skin, characterized by thrombosis of the small vessels in the dermis and subdermis, bleeding into the skin, bullae formation in the hemorrhagic areas, absence of bleeding at other sites and no large vessel thrombosis, and rapid death.7 The term "purpura fulminans" was first described in 1887 and was associated with an acquired condition manifesting after a benign infection.7-9 These hemorrhagic skin lesions appear after a mild or benign infection (varicella or streptococcus), which "prepares" the skin for the generation of the purpuric lesion.7-9 Coagulation abnormalities are compatible with DIC, and extensive thrombosis within the venules and capillaries of the skin are consistent pathologic findings.7-9 These fulminating lesions become necrotic, necessitating major debridement or amputation. The mechanism of purpura fulminans initiation and propagation is not fully understood.10 It was not until 1962 that purpura fulminans was reported in a newborn infant.11 It was assumed in this report that purpura fulminans in the newborn was a genetic disease, since three siblings developed the pur-

puric lesions. However, no diagnosis was assigned, since protein C and protein S had not been discovered.11-13 In 1983, the first child with presumed homozygous protein C deficiency was described; this child had died of hemorrhagic complications due to the oral anticoagulant therapy.14 A short while later, the first living, viable child with confirmed homozygous protein C deficiency was described and successfully treated with protein C replacement.4,15 Since then numerous other homozygous protein C-deficient children have been identified, and a report1 on the diagnosis and recommended treatment of homozygous protein C deficiency has been published. 3,5,6,16-18 Recently, the first homozygous protein S-deficient child with purpura fulminans has been reported.2 It appears that these children have basically the same types of lesions and need similar treatment modalities.2 One unique aspect is that the lag period for the onset of the first lesions may be somewhat longer than for the majority of homozygous protein C-deficient infants.2 Although several reports on homozygous protein C deficiency have centered on the diagnosis and treatment of this genetic disease, there is not a comparative study of the initiation and propagation of the skin lesions.1,19 In this report, we will discuss in detail the development of the coagulopathy and the histologic and pathologic progression of the lesions associated with purpura fulminans in patients with homozygous protein C or protein S deficiency. The mechanism of this disease is essentially unknown but will be hypothesized based on current evidence and comparison with similar disorders. Also, we will briefly review the diagnosis and treatment of homozygous protein C deficiency.

OVERVIEW OF THE PROTEIN C SYSTEM From Laboratory Services, Denver VA Medical Center, and Departments of Pathology, Pediatrics and Biochemistry, University of Colorado Health Sciences Center, Denver, Colorado. Reprint requests: Dr. Marlar, Laboratory Services (#113), Denver VA Medical Center, 1055 Clermont St., Denver, CO 80220.

Protein C is one of the major antithrombotic regulatory systems of hemostasis, involving multiple plasma proteins and their interaction with platelets, endothelial

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cells, and possibly other blood cells. This system is unique in that it has multiple functions, including anticoagulant and profibrinolytic properties.20,21 Protein C, a vitamin K-dependent zymogen, functions in the vascular system as a potent anticoagulant, due largely to a rapid inactivation (proteolytic degradation) of the coagulation Factors Va and VIIIa, the cofactors of the two rate-limiting steps of the coagulation cascade. 22-24 The antithrombotic property of protein C is also due in part to its ability to enhance fibrinolysis, possibly via the inactivation of (or complex formation with) plasminogen activator inhibitor, type 1 (PAI-1). 25,26 Other mechanisms of protein C enhancement of fibrinolysis appear to be more physiologically significant, but are unknown at this time.27 Protein C, a 62,000 d glycoprotein synthesized in the liver, consists of a heavy chain linked by a disulfide bond to a light chain.28 The molecule contains several functional domains: serine active site, activation peptide, gamma-carboxyglutamic acid residues (calcium ion and surface-binding region), and epidermal growth factor region (possible protein S binding region). 28,29 The concentration of protein C in human plasma is about 4 fjig/ml and the half-life is 6 to 9 hours. 1,13,15,30,31 Protein C must be converted to an active serine protease, activated protein C, to be physiologically functional.22,32,33 Physiologic activation occurs when thrombin is tightly bound to the endothelial cell membrane protein, thrombomodulin.33-36 The rate is 20,000 times faster than that with thrombin alone. 34,36 Activation of protein C occurs through the enzymatic removal of a small peptide from the amino terminal end of the heavy chain of the protein C molecule.28,32 The proteolytic inactivation of Factors Va and Villa by activated protein C is analogous to the activation of prothrombin by Factor Xa. 22-24,37,38 The reaction occurs on a phospholipid surface (activated platelet or endothelial cell luminal surface) in the presence of calcium ions. 22,39,40 Furthermore, the reaction is accelerated significantly by a specific protein cofactor, protein S (another vitamin K-dependent protein), which potentiates the binding of activated protein C to the cell surface via a calcium ion bridge. 41-13 In a fashion analogous to the prothrombinase complex, activated protein C and protein S, the phospholipid surface, and calcium ions form a functional enzyme complex. 29,38,41 Protein S (75,000 d) is a single-chain protein with homology of the amino-terminal sequence to protein C and the other vitamin K-dependent coagulation proteins. 44 ' 45 However, the carboxyl-terminal region has no homology with the other vitamin K-dependent proteins and does not contain a serine protease moiety.44,45 It circulates in plasma at a concentration of 30 µg/ml and approximately 50% is bound to another plasma pro-

tein, C4b-binding protein, one of the complement molecules. 46,47 The functional form of protein S is the free or unbound portion of the plasma protein S.46 Activated protein C is regulated in plasma by at least two serine protease inhibitors. 48-50 The two major inhibitors, alphal-antitrypsin and protein C inhibitor, each contribute about 30 to 50% of the inhibition of activated protein C in the plasma milieu. 48-50 Protein C inhibitor is a heparin-dependent inhibitor, increasing the rate of inhibition by 20- to 60-fold in plasma.51 Both alpha1antitrypsin and protein C inhibitor function to inactivate activated protein C by forming a 1:1 covalent complex with its active site. 48-50

CLINICAL ASPECTS OF HOMOZYGOUS PROTEIN C DEFICIENCY Genetics Based on clinical manifestations of protein C or protein S deficiencies, these genetic abnormalities are autosomal with variable penetrance, resulting in two basic groups: (1) families with symptomatic heterozygous individuals (complete penetrance), and 2) families with asymptomatic heterozygotes but homozygotes developing fatal thrombotic complications (little or no penetrance). 1,13,52-54 In the autosomal condition with complete penetrance, the heterozygotes have recurrent venous thrombosis (usually deep vein thrombosis or pulmonary embolism) starting in early adult life. 13,31,52,53 The prevalence of this disorder in the population has been estimated to be 1 in 15,000 to 25,000. 54 The second phenotype is autosomal with little or no penetrance, in which the heterozygotes are asymptomatic and the homozygotes develop the syndrome of purpura fulminans in the neonatal period. 1,5,30,52 The frequency of these asymptomatic heterozygotes is estimated at 1 in 200 to 300 and an estimate of homozygous protein C deficiency is about 1 in 250,000 to 500,000 births. 1,30,52 Determination of the basis of the variable penetrance will have to await further studies. To complicate the genetics of protein C further, the deficiency may be manifested as type I (concordant reduction in protein C activity and antigen) or type II (discordant reduction in protein C activity and antigen). 1,29-31,52 This is similar to other genetic diseases, such as hemophilia, or Factor X and Factor VII deficiencies. Protein S deficiency is similar to protein C deficiency. The same variable penetrance is found; however, it is more complicated because of protein S binding to the complement protein, C4b-binding protein.43

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In the confirmed cases of homozygous protein C deficiency, essentially all of the patients have developed four general complications: cerebral thrombosis, ophthalmic thrombosis, DIC, and purpura fulminans. 1,19,30,52 The usual presenting complication is purpura fulminans.1,52 To date, there have been over 20 confirmed cases of severe homozygous protein C deficiency and two cases of homozygous protein S deficiency, with all but a few resulting in purpura fulminans.1,2,52 The skin lesions are preceded by DIC. 1,3-6 DIC in homozygous protein C or protein S deficiency is severe, resulting in significant fibrinogen and platelet consumption.2,3,5 The nonpurpura fulminans cases have presented with significant large vessel thrombosis (inferior vena cava, renal veins, and iliac veins).56 In all cases, protein C activity (if determined) was undetectable, but protein C antigen has varied from undetectable to 30% of normal. 1,30,52 Usually, infants were born to asymptomatic heterozygous protein Cdeficient parents or with other family members with the condition. The pregnancies were uncomplicated and went to full term.1 The cerebral and ophthalmic thrombotic complications occur in utero, manifesting as hydrocephalus, mental retardation, delayed neurologic development, seizures, and retinal thrombosis leading to partial or complete blindness, respectively.1'30'52

Diagnosis The following are brief recommendations for the diagnosis of new patients with either homozygous protein C or homozygous protein S deficiencies.1,19 More detailed protocols for the diagnosis of these disorders have been reviewed recently. 119 On recognition of purpuric lesions in a newborn infant without a known cause, blood samples from the neonate and both parents should be obtained and assayed immediately for protein C activity and total and free protein S antigen.1'2'19 There may be delays in arranging these tests; therefore the initial treatment of fresh frozen plasma (FFP) infusion (see later and Marlar et al 1,2,19 ) must be started as soon as the sample has been drawn, before the results are obtained. A definitive diagnosis of homozygous protein C deficiency or homozygous protein S deficiency is difficult in the neonate, since levels of vitamin K-dependent coagulation factors are low in the newborn,57 and premature or sick newborns with respiratory distress syndrome may have undetectable levels of protein C or protein S.58 To diagnose the homozygous condition after treatment has been initiated, both protein C and protein

S should be measured when the child is clinically stable, 8 to 12 hours after plasma infusions, and the protein C and protein S levels should be determined in both parents.1'2'19 These components also should be determined in all siblings and other family members.1'2'19

Treatment The infant should receive FFP (10 to 15 cc/kg every 12 hours) and the other complications such as (hydrocephalus, seizures, and blindness) are treated symptomatically.1 Uniquely, if the lesions have started to develop within the last 1 to 2 hours, FFP administration may allow the lesions to recede and disappear with no lingering effects; however, if the lesions are older or fully developed, then they are permanent and will remain (discussed in more detail later). 1,4,30 The FFP doses should be administered via a central line until all lesions (central nervous system [CNS], skin, ocular, and others) are healed, usually 4 to 8 weeks. 1,19 Regular monitoring for DIC and protein C levels during FFP therapy is necessary to evaluate for consumption and treatment.1 For long-term treatment of homozygous protein C deficiency, two methods can be used: administration of protein C (using either FFP or prothrombin complex concentrate) or vitamin K antagonists (warfarin).1,19 The current recommended long-term treatment protocol is to use a vitamin K antagonist.1 This method involves the reduction of the procoagulant factors to help regulate hemostasis.1,19,30,59 The treatment protocol for oral anticoagulant therapy is detailed elsewhere.1,19 Warfarin should be administered daily until a minimum maintenance dose is established to keep the child symptom free. In case of recurrence of purpura fulminans while on oral anticoagulant therapy, FFP therapy should be reinstituted.1 Fresh skin lesions may improve dramatically after the administration of FFP. 1,3,19 The parents and medical staff should observe for bleeding complications and the recurrence of purpura fulminans, so that immediate care can be given. Protein C replacement with prothrombin complex concentrate has been used successfully, but its routine use must await the development of a specific protein C concentrate and/or recombinant protein c. 1,15,30,31,52,60 Complications of this mode of treatment include loss of venous access, blood-transmitted diseases, and catheter-tip thrombosis.1

PATHOLOGY OF THE PURPURA FULMINANS SKIN LESIONS The most striking feature of homozygous protein C and protein S deficiencies is the development of skin

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lesions, termed "purpura fulminans." 1-6,30,52 In the majority of reported cases, these skin lesions are the first sign that the patient has a major coagulation defect. 119 The first appearance of the initial skin lesions usually ranges from 1 to 2 hours to 5 days after birth; however, in several cases the lesions have not occurred until several months after birth. 1-6-30,52-61,62 The skin lesions have appeared essentially on all parts of the body, with the majority occurring on the extremities, buttocks, abdomen, and scalp (Table 1 and Figs 1-11). 130 Many of the lesions tend to be symmetrically distributed.3 The lesions are likely to develop at sites of previous punctures (needle and heel sticks, intravenous sites), old injuries, and pressure points.1,4 Based on the observations of one of the authors (R. A.M.) and those of the physicians who have cared for these children, the development of purpura fulminanslike skin necrosis can be separated into two distinct phases. The first phase is the time period in which the initial lesions develop and grow, but interestingly are reversible (Figs 1, 2). 1,30 This reversible lesion growth can be halted and reversed with the administration of protein C in the form of FFP or prothrombin complex concentrate.1,3,4,30 The second phase is an irreversible lesion that will continue to develop whether treated with protein C replacement or not (Figs 3, 4, 5). 1 , 4 - 6 , 3 0 , 5 2 , 6 0 This irreversible lesion will ultimately develop into a large full-thickness necrotic region of the skin (Fig. 6). It is very similar to the lesion seen in acute infectious purpura fulminans (Fig. 7). 63 The very small outer margin of the irreversible lesion appears to be in the reversible phase and can be resolved, if properly treated.3

FIG. 1. Formation of a reversible lesion at the site of an old healing lesion on the thigh. Note the darker (red) discoloration around and to the lower left of the old healing lesion. This lesion completely disappeared on administration of fresh frozen plasma. (From DiScipio and Davie.44 Reprinted with permission.)

tend to be circular or oval shaped (Figs 1 and 2). 3,5 The lesion turns reddish-purple within 20 minutes to 1 hour after their initial appearance.1,3,5 This lesion appears to grow radially outward at a rate of about 1 cm per 20 to 30 minutes. 1,3,5,30,60 The reversible phase apparently lasts only 1 to 3 hours, at which time the lesion becomes

Reversible Lesion The initial lesions develop with a 4 to 8 cm diameter, patchy erythemic cool, indurated areas that TABLE 1. Location of Purpuric Skin Lesions in Homozygous Protein C Deficiency Body Region

Episodes (%)

Head: Scalp Face and mouth

24

Trunk: Back Chest Abdomen Buttock

46

Upper extremities: Arms Hands and fingers

13

Lower extremities: Legs Feet and toes

17

16 8 14 11 13 8 8 5 11 6

FIG. 2. A reversible lesion that formed on the inner surface of the elbow. The lesion was unique in that it was not symmetrical but had the same coloration and appearance as the lesion shown in Figure 1. Both this lesion and the lesion in Figure 1 appeared during the same episode and were accompanied by DIC.

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FIG. 3. A partially developed irreversible lesion on the wrist of a newborn infant with homozygous protein C deficiency. The dark central region was purplish-black surrounded by wide margin of erythema. On treatment with protein C replacement, the erythemic margin would probably disappear (reversible region), whereas the central region (irreversible lesion) would remain. (This infant was described by Hartman et al.59 This figure was kindly supplied by Dr. Kip Hartman.)

FIG. 5. Bullae formation in an irreversible lesion on the ankle. Note that the bullae formation is in the center of the lesion. (From Hartman et al.59 Reprinted with permission.)

irreversible and the necrotic process starts. 1,3,5 On the administration of protein C to the homozygous protein C-deficient patient, these lesions decrease in size in reverse fashion from the outside toward the middle until 4 to 5 cm in size. The residual lesion gradually changes from the purplish color to red and finally fades until it totally disappears, leaving no evidence of the lesion. The coagulation parameters during this phase are indicative of DIC: elevated prothrombin time (PT), activated partial thromboplastin time (APPT), and de-

creased platelets, fibrinogen, Factors VIII and V, and antithrombin III. 1,3,5,30 Interestingly in several of these patients, fibrin(ogen) split products were undetectable during this period of reversible lesions and DIC. The histologic picture of the reversible lesion shows fibrin thrombi completely filling all of the capillaries, arterioles, and venules of the epidermis and dermis.3'62 During this period, there is no evidence of perivascular hemorrhage, leukocyte infiltration of the perivascular space, or inflammation. Serial biopsies of the lesions during their growth and subsequent resolution have not been studied in the homozygous protein C-deficient infant. The mechanism of the reversible formation of thrombi within the skin in the homozygous protein C- or protein S-deficient patients is not known or understood.

FIG. 4. Symmetrical irreversible lesions that had stopped growing and were completely developed on the soles of the feet of a neonate. Note that there is very minimal marginal erythema surrounding the purple-black lesions. (From Sills et al.4 Reprinted with permission.)

FIG. 6. Healing process after the formation of a severe lesion on the ankle and foot. The lesion is a full-thickness injury with healing from the outer margin toward the center. The dark skin areas in the center of the region are nonviable dermal tissue. (This infant was described by Sills et al.4)

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FIG. 7. An example of acquired purpura fulminans showing the similarity of the gross lesions to those observed in homozygous protein C or protein S deficiencies. Note the small border of erythema surrounding the darker central portion of the lesions. Although these lesions are usually larger than those developed in the homozygous patients, there are similarities in both the gross and microscopic appearance. (This is a picture of a child described by Marlar et al.63)

The reversible lesion may also have a counterpart in the lesions seen in other purpuric complications, although the reversible phase may be very short in those lesions. 1,8,10,63

Irreversible Lesion The irreversible lesion develops from the reversible lesion or apparently as an initial lesion (a short reversible lesion?) that develops directly. The 6 to 10 cm patchy red-purplish lesion will continue to grow but more slowly

FIG. 8. Severe scar formation on complete healing of a major lesion in a child with homozygous protein C deficiency. (From DiScipio and Davie.44 Reprinted with permission.)

FIG. 9. An example of autoamputation of the thumb in a child with homozygous protein C deficiency.

(Figs 3, 4, and 5). 1 , 3 - 5 , 3 0 The maximum size is usually reached within 8 to 16 hours. The lesion turns a deeper purple and is edematous, finally developing a black necrotic appearance with bullae formation (Fig. 5). 1-6. 30,52,61,62 The central necrotic area and bullae bleed as the eschar retracts from the surrounding skin tissue. 1,3,5 During this period, the administration of protein C does not have any visible effect on the lessening or reversal of the purpuric necrotic lesion. 3,5,30 Finally, the area becomes gangrenous, sometimes resulting in extremity loss of necessity for debridement with extensive scar formation, which may require skin grafting (Figs. 8, 9). 1,3,5,30 The irreversible lesions require 4 to 8 weeks to heal (Fig. 6). 1,19 These large lesions are full-thickness and

FIG. 10. A low-power micrograph showing the histologic appearance of an irreversible skin lesion in a patient with purpura fulminans. There is minimal infiltration of leukocytes and little evidence of inflammation. The vessels are completely filled with fibrin thrombi. The necrotic process is just starting to take place in this section of the biopsy. Note the formation of a bullae in the upper left corner.

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phases, the organizing fibrin thrombi may shrink and gradually disappear as fibrinolysis occurs.3 Once the necrotic process starts in an area, secondary fibrinoid necrosis of vessel walls in the dermis can be seen. Finally, as the area becomes gangrenous, full dermal thickness tissue death is observed that results in extremity loss or significant scar formation.1,3,5

FIG. 11. A higher power micrograph of the pathologic changes of a purpuric skin lesion. The prominent feature is the complete blockage of the vessels with fibrin thrombi. Little or no inflammation is present in the early stages of these lesions.

must heal from the outer viable skin margins inward, in a similar fashion to a burn (Fig. 6), leaving large visible scars (Fig. 8). 1,3-6 At the start of the irreversible lesion period, the patient has laboratory values consistent with DIC: very prolonged APTT and PT, low or undetectable fibrinogen, and low platelets.1,4,5 Other coagulation components (such as Factors Va and Villa and antithrombin III) are also being consumed. At this point, fibrin(ogen) split products are present in the natient 1-6,16-19,30,61,64-66 Histologically, organizing fibrin thrombi and some mixed platelet-fibrin thrombi are found in all superficial and deep dermal arterioles, capillaries, and veins (Figs. 10,11).1,3,5 There is significant evidence of focal perivascular hemorrhage. The extravasation of red blood cells occurs apparently after the start of necrosis of the vessel wall. Evidence of ischemia and sparse leukocyte accumulation in the perivascular space has been found, further suggesting the start of an irreversible necrotic process. Initially, there is usually only moderate evidence of vasculitis of the vessel wall.3 The bullae are formed in the subepidermal layers (Fig. 10). In the later

Homozygous protein C or protein S deficiencies belong to the group of noninflammatory purpuras that include coumarin-induced necrosis and idiopathic purpura fulminans.67 The causes of the noninflammatory purpura group, all of which show intradermal hemorrhage, can be subdivided into deficiencies of collagen formation around capillaries without fibrin thrombi (senile purpura and purpura due to scurvy),68'69 some form of sensitivity without vascular occlusion (idiopathic thrombocytopenic purpura and autoerythrocyte sensitization syndrome),67'70 and sensitization with vascular occlusion (thrombotic thrombocytopenia purpura and paroxysmal nocturnal hemoglobinuria, which may show endothelial cell proliferation;67,71 cryoglobulinemia, which show "thrombi" consisting of immunoglobulin rather than fibrin,67 homozygous protein C or protein S deficiency; warfarin-induced skin necrosis; and idiopathic purpura fulminans). The last two disorders have almost identical histologic and developmental progression as the irreversible phase in homozygous protein C deficiency and may have mechanistic similarity; they do have some differences in both clinical presentation and pathogenesis. 1 ' 3,5 ' 8,52,62,72 " 77 One inflammatory purpura has similar types of lesions and some mechanisms parallel to homozygous protein C deficiency: acute infectious purpura fulminans usually due to meningococcemia.8,63 The histopathologic findings and pathogenesis of the irreversible skin lesions of idiopathic purpura fulminans are comparable with that reported for homozygous protein C or protein S deficiency.3,8,63,72,73 (see other articles in this issue). The thrombotic-hemorrhagic skin lesions appear after a benign infection (varicella, or Streptococcus, for example, scarlatina), which is thought to somehow "prepare" the skin for the purpuric lesions that follow.8,9,77,78 Idiopathic purpura fulminans is a rapidly spreading cutaneous manifestation of an unique DIC process that not only affects the skin and subdermal tissues, but also the deeper soft tissues and larger vessels (often necessitating amputation).8,63,78 The mechanism of this unique form of purpura fulminans still remains a mystery but may involve the protein C system in some fashion, such as a selective decrease in the thrombomod-

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ulin on the endothelial cells of the dermal vessels or possibly a selective consumption of protein C 8,63,78,79 (also see Francis and Comp et al in this issue of Seminars). The other similar rare noninflammatory, coagulation-related purpuric syndrome is coumarin-induced skin necrosis. It appears to manifest itself mainly in hereditary deficiencies of protein C or possibly other components of the protein C system. 74,75,80-82 The pathologic findings of the skin lesions in these patients are similar to those described for homozygous protein C deficiency.8,9, 63,74,76 Unlike homozygous protein C or protein S deficiency-induced skin lesions, warfarin-induced skin necrosis may have a predilection for fatty tissue (abdomen, breast, thighs).74 This syndrome occurs in individuals undergoing initial high-dose warfarin therapy (without heparin protection), whereupon protein C (already lower than normal) decreases rapidly (short plasma half-life of 6 to 8 hours) to undetectable levels while the other vitamin K-dependent procoagulant proteins remain within normal limits. 52,63,75,80 This situation probably has the same pathogenesis as the irreversible phase of homozygous protein C deficiency.1,52,79 (See also Comp et al in this issue of Seminars.) The one inflammatory purpuric lesion with some similarity to homozygous protein C is acute infectious purpura fulminans due to fulminant septicemia. Although the pathogenesis and mechanism of acute infectious purpura fulminans are only partially understood, the infection and sepsis appear to lead initially to leukocyte aggregation and leukocyte/fibrin thrombi, which cause skin, spleen, and pulmonary microvascular obstruction. Consumption of protein C and protein S occurs selectively during the purpura fulminans and DIC phase. 8,63, 78,79 The acquired state of total protein C deficiency with the other processes, such as inflammation and thrombus formation in the dermal capillaries, results in the development of purpura fulminans-like lesions. 8,10,63,78,79 Coagulation abnormalities in acute infectious purpura fulminans are compatible with DIC, and extensive thromboses within the vessels of the skin are consistent pathologic findings. 8,9,72,73 One possible mechanism is that the infection or sepsis may consume protein C and protein S either selectively or possibly by systemic coagulation consumption.63 It is possible that there is a selective consumption of protein C, since the levels of two other consumable factors, fibrinogen and antithrombin III, are not drastically decreased.63 The time period of undetectable protein C activity and the onset of acute infectious purpura fulminans has not been established, but may be 6 to 48 hours. 8,63 The major difference between acute infectious and neonatal purpura fulminans is that a definite inflammatory component (with neutrophils in and around the thrombi) is present in the infectious form. 8,63,79 This difference may be why the

lesions are usually much larger and spread more rapidly, are more difficult to treat, and have a high morbidity and mortality.8,63,79 (See also Francis in this issue of Seminars.)

MECHANISTIC SPECULATION The following narrative is a speculative model of the induction of purpuric lesions in patients with homozygous protein C or protein S deficiencies. The basic premise of this pathogenic model can undoubtedly be applied to the other two thrombotic noninflammatory purpuric syndromes already discussed and to some extent the thrombotic inflammatory purpuric syndrome, acute infectious purpura fulminans. The reversible phase of the purpuric lesions may be unique to the homozygous infant or the reversible phase may be present in the other cases but usually unrecognized because of its short duration or minimal symptomology. More detailed mechanistic discussion and classification of skin necrosis is presented by Adcock et al in this issue of Seminars. 1. In homozygous protein C (or protein S) deficiency with purpura fulminans, the patient must have a complete and total deficiency of protein C (or protein S). 1,52 Homozygous patients with some detectable protein C or protein S appear not to develop purpura fulminans, but rather may develop significant lethal large vessel thrombosis. 1,52,56 The probable reason for the lack of development of purpura fulminans in utero is that small amounts of maternal protein C or protein S cross the placenta, thereby protecting the fetus from purpuric lesions; however, the concentration is not substantial enough to protect the fetus from the CNS and ophthalmic thrombotic complications in utero. The reason the fetus tends to experience CNS and ophthalmic complications instead of other large vessel thrombosis is unknown. 2. The initial site of lesion development in the skin probably starts at a minor injury (intravenous site, heel stick, or minor trauma). 1,4,19 At the site of injury, initiation of thrombus formation begins. Since one of the major regulatory systems of hemostasis is missing, the clot continues to grow within the dermis, occluding all of the dermal vessels in the vicinity. Without control, the thrombus continues to enlarge throughout the adjacent dermal area, allowing the reversible phase lesion to grow. The thrombus formation and possibly some lack of interaction of protein C or one of its components with various dermal tissue cells (keratinocytes, dermal endothelial cells, or other cells), induces cytokine (interleukin-1 [IL-1] and tissue necrosis factor [TNF]) generation and release. 10,40,83-86 These cytokines and the activated procoagulants induce a moderate systemic DIC. 10,83,86,87 3. If at this time, the protein C system is reactivated (by protein C or protein S replacement), thrombus

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formation is halted and the platelet-fibrin thrombi present in the dermal lesion are dissolved and removed by an activated fibrinolytic system. 1,3,52,60 Thus, the dermal vessels are opened and the lesions reverse with little or no tissue damage. 4. If protein C (or protein S) replacement is not forthcoming, then these cytokines continue to be produced, leading to perturbation of the dermal (and possibly other organ) endothelial cells, which leads to generation of procoagulant activities and decreased fibrinolytic activity.10,83,86,87 These cytokines start a mild inflammatory response by inducing an influx of leukocytes. 83,86,87 At this time, the lesion becomes irreversible. 4. Within the region of the lesion, a vicious positive feedback cycle is underway. The massive systemic DIC is continuing and the breakdown of the vascular cells within the lesion is also occurring3,63,87 (see also Francis in this issue of Seminars). This leads to perivascular hemorrhage and the start of the necrotic process. 3,8,63 The lesion at this time is irreversible and the necrotic process is underway in the dermal tissue with continued infiltration of leukocytes, cell death, and resultant of bullac formation. 5. Other poorly understood factors, conditions, or causes may play contributing roles in the initiation and enhancement of the lesion or in the rapid progression to the irreversible phase. These may include other cytokine secretion or action, endothelial cell interaction with the protein C system, fibrinolytic system or other factors, and physical or chemical stimuli to change the properties of the dermal tissue. Purpura fulminans due to homozygous protein C deficiency is probably analogous to the local and generalized Shwartzman reaction observed in animals; however, for the first phase and possibly part of the second phase, there is little or no inflammatory reaction in the homozygous protein C-deficient child's lesions, but rather the DIC and cutaneous manifestations are the result of the complete absence of protein C (or protein S) 1,8,52,63,87,89 (see also Brozna in this issue of Seminars). Animal models of these analogous purpuric syndromes (homozygous protein C deficiency, coumadininduced skin necrosis, and idiopathic purpura fulminans) would be an ideal method to study their pathogenesis and their relationship to the protein C system. Protein C and its components may play a significant role in each of these syndromes and must be investigated in detail.

SUMMARY Homozygous protein C deficiency or homozygous protein S deficiency are rare genetic diseases with catastrophic and fatal purpura fulminans-like or throm-

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botic complications occurring during the neonatal period. These diseases can now be successfully treated. Purpura fulminans is at least in part a cutaneous manifestation of the syndrome of systemic DIC. It is characterized by microvascular thrombosis in the dermis followed by perivascular hemorrhage, necrosis, and minimal inflammation. Laboratory findings are consistent with DIC. Although the pathogenesis is not fully understood, the DIC in purpura fulminans appears to involve the skin selectively. The development of purpura fulminans from homozygous protein C or protein S deficiencies can be separated into two distinct phases. The first phase is the time period when the initial reversible lesions develop and grow. This reversible progression can be halted and reversed with the administration of protein C or protein S. The second phase is the irreversible stage in which the lesion continues to develop into a necrotic lesion, whether or not treated with protein C. This irreversible lesion will ultimately develop into a large full-thickness necrotic injury of the skin. It is very similar to the lesions seen in idiopathic purpura fulminans, warfarin-induced skin necrosis, and acute infectious purpura fulminans. Unfortunately, our current understanding of the mechanism or mechanisms of the induction and propagation of the purpura fulminans-like lesions in homozygous protein C or protein S deficiencies is minimal, since it has never been studied. We can only speculate on the mechanism based on laboratory data and comparison with the little that is known about the other similar types of lesions. Acknowledgments. The authors would like to acknowledge the numerous physicians who have shared their experiences during the care of these infants. The authors would like to thank Drs. Dorothy Adcock and John Brozna, and Renee Madden for the numerous discussions on the topic of skin necrosis. Dr. Kip Hartman, Walter Reed Army Institute of Research, is acknowledged for providing the photograph for Figure 3. This work was supported in part by grants to R.A.M. from the National Institutes of Health (HL 29840) and the Veterans Administration.

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