Varicella Purpura Fulminans Associated With Heterozygosity for Factor V Leiden and Transient Protein S Deficiency

Purpura fulminans is an acute, rapidly progressive hemorrhagic necrosis of the skin attributable to dermal vascular necrosis that is associated with disseminated intravascular coagulation. It is a rare and occasionally life-threatening disorder that occurs most commonly in the setting of acute, severe bacterial or viral infection, or as a postinfectious syndrome after infections such as primary varicella or scarlet fever.1–4Postinfectious purpura fulminans usually occurs 7 to 10 days after onset of symptoms of the acute infection.5 The ecchymotic lesions are most commonly distributed symmetrically on the lower extremities and buttocks, although the trunk and upper extremities can be involved. Visceral involvement is less frequent but can lead to hematuria or gastrointestinal hemorrhage.6Transient or congenital deficiencies of protein C or protein S have been documented in many cases of purpura fulminans in recent years.1,4,7,8 Protein C is the best known among the identified anticoagulant factors in the delicate molecular balance of hemostasis. Activated protein C degrades activated coagulation factors VIIIa and Va, attenuating their procoagulant activation of factors X and prothrombin. Protein S is a cofactor to activated protein C, which accounts for the increased risk of thrombosis associated with protein S deficiency states.9Factor V Leiden, a factor V variant resulting from a single point mutation at nucleotide 1691 (guanine to adenine, resulting in arginine 506 to glutamine), has been recognized recently as a risk factor for thrombotic events in adults.10 Reported thromboses in children with factor V Leiden have included catheter-related thrombosis11 and renal vein and venous sinus thrombosis in a neonate.12 The presence of factor V Leiden also heightens the risk for thrombotic events among adolescents and young women who use oral contraceptives (odds ratio, 4.9; 95% confidence interval, 2.0–11.7).13The factor V Leiden mutation confers resistance to protein C activation and the subsequent degradation of factors Va and VIIIa. It therefore interferes with the natural inhibition of coagulation by activated protein C, predisposing to hypercoagulable states. Factor V Leiden appears to be the most common genetic cause of thrombophilia.14 At least one factor V Leiden allele is present in 5.3% of white Americans, 2.2% of Hispanic Americans, 1.2% of African-Americans, and 0.4% of Asian Americans.15 The heterozygous state is a risk factor for thrombophilia.We report a child with varicella-associated purpura fulminans who had a transient deficiency of protein S and heterozygosity for factor V Leiden.A 5-year-old white boy developed pain in his lower legs on the sixth day after eruption of varicella exanthem. The pain was associated with bruise-like lesions anterior to both ankles. The next day these areas enlarged and became darker in color. He complained of abdominal pain and dysuria and developed swelling in his penis and scrotum. His urine was described as reddish in color. He had no fever, vomiting, or diarrhea.He had been treated with amoxicillin and ibuprofen from the second to the seventh day of his exanthem. He had no previous history of excessive bleeding, easy bruisability, or thromboses and no previous hospitalizations or serious illnesses. He previously had not had varicella or varicella vaccine. There was no family history of bleeding disorders, stroke, or thrombophlebitis.On the tenth day of illness, he was admitted to the Brenner Children's Hospital for further evaluation. He was alert and oriented. Temperature was 98.5°F, pulse 84 beats/minute, respiratory rate 24 breaths/minute, blood pressure 105/67 mm Hg, and weight 19.1 kg. Scattered, crusted varicella lesions were present. Both ankles and the right foot were mildly swollen with mild pain on movement. A necrotic, dark purple lesion, ∼10 × 5 cm in size, with irregular but well demarcated borders and a surrounding rim of erythema was present over the anterolateral aspect of each ankle, with extension onto the lower leg. A similar 2 × 3-cm lesion was present on the anterior right thigh. There was mild right upper quadrant tenderness on abdominal palpation and the liver edge was palpable 3 cm below the costal margin. The scrotum was swollen and dusky and paraphimosis was present.His hemoglobin was 10.9 g/dL and hematocrit 30.8%. Platelet count was 219 000/mm3 and the white blood cell (WBC) count was 20 900/mm3 with differential of 72% segmented neutrophils, 25% lymphocytes, and 3% monocytes. Urinalysis showed a specific gravity of 1.025, pH of 6.5, >50 red blood cells per high-power field [RBC/hpf], and 0–1 WBC/hpf. Serum alanine and aspartate aminotransferases were normal. Serum albumin was 4.0 g/dL.His prothrombin time was >100 second, activated partial thromboplastin time >300 second, and fibrinogen <15 mg%. His prothrombin assay was 30% (normal 50–150%), factor V assay 38% (50–150%), and factor VIII assay 64% (50–200%). Plasma levels of factors VII, IX, and XI were normal. Dimer test was positive at 1:16 000. Protein C activity was 33% (60–140%) and protein S activity and antigen were nondetectable (Table 1).The patient received 10 mL/kg of fresh frozen plasma on the day of admission. Within 48 hours he had full correction of his prothrombin time, partial thromboplastin time, fibrinogen, factor VIII, and protein C but not his protein S activity. The patient was found to be heterozygous for factor V Leiden (by polymerase chain reaction amplification of the DNA fragment containing the mutation site and subsequent restriction endonuclease digestion as previously described10).Abdominal ultrasound showed a markedly thickened, echogenic, irregular bladder wall that was suggestive of intramural hemorrhage. Punch skin biopsy of the margin of the left lower extremity lesion showed numerous fibrin thrombi, without accompanying vasculitis, both immediately adjacent to the epidermal necrosis and deeper within the dermis, consistent with purpura fulminans. He remained afebrile and the skin lesions did not increase in size. His platelet count remained normal and the hematuria and dysuria resolved. He was discharged after 3 days with silver sulfadiazine 1% cream to be applied topically to the lower-extremity lesions.Two weeks later he received split-thickness skin grafts to both lower-extremity lesions, which subsequently healed well. Factors II, V, VII, VIIIc, IX, X, and XI all were normal at that time. The urinary bladder appeared normal by ultrasonography after 4 weeks. His factor V Leiden heterozygosity was confirmed and his mother and 6-year-old brother also were found to be heterozygous for factor V Leiden. Protein S levels slowly returned toward normal over the next 4 months (Table 1).Transient deficiency of protein S activity recently has been described as a potential causal factor in the development of varicella-associated purpura fulminans.516–18 An Arabian child with double heterozygosity for factor V Leiden and protein S deficiency who developed varicella-associated purpura fulminans has been reported.19 That case and this report of varicella-associated purpura fulminans with transient protein S deficiency and factor V Leiden heterozygosity suggest that deficiency of protein S activity alone may not be sufficient to cause the postinfectious purpura fulminans associated with varicella. The relative frequency of the factor V Leiden mutation in the population, coupled with the rarity of varicella-associated purpura fulminans, suggests that the presence of factor V Leiden alone also is not sufficient to induce varicella-associated purpura fulminans. Cases such as ours support the hypothesis that at least two and perhaps more concurrent abnormalities in the naturally occurring anticoagulant pathway are necessary to trigger the development of purpura fulminans during varicella infection.The mechanism of transient protein S activity associated with varicella infection appears to be the induction of anti-protein S immunoglobulin M and immunoglobulin G autoantibodies. These antibodies persist for only a few months,5 after which time the protein S activity returns to normal. Such was the case with the child in this report (Table 1). The frequency with which antibodies to protein S are induced in children during varicella infection is unknown.Ischemic stroke attributable to cerebral artery stenosis or occlusion also has been described in children after varicella infection. In a recent case series, 3 of 6 children with cerebrovascular events occurring within 4 months of varicella infection had evidence of transient protein S deficiency, but 3 had no evidence of protein C, protein S, or antithrombin III deficiencies.20 Vasculitic injury also has been suggested as a mechanism of cerebral artery occlusion after chickenpox.21 Although the role of factor V Leiden was not evaluated in these reports, the possibility remains that varicella-related vasculitis or risk factors other than protein S deficiency and factor V Leiden may play a role in the causation of some of the thrombotic events associated with varicella infection.The initial deficiency of protein C activity in this child apparently was attributable to a consumption coagulapathy that corrected rapidly with treatment. It seems likely that varicella infection in this child somehow activated the coagulation cascade, perhaps through vasculitic injury. Once activated in the presence of two defects in the natural anticoagulant pathway (one congenital and one acquired), a consumptive hypercoagulable process ensued.Based on the available case series of varicella-associated purpura fulminans in children, it appears reasonable to evaluate children with any varicella-associated thrombotic event for the presence of protein S and protein C deficiencies and the factor V Leiden mutation. Screening for antithrombin III deficiency and anti-cardiolipin antibodies also might be considered. Thrombophilia screening should be considered for purpura fulminans associated with other infections, as it is for unexplained thrombotic events in children. Of note, the consumption coagulopathy and purpura associated with severe meningococcal infection were not associated with the factor V Leiden mutation in a recently reported study.22The rare but potentially serious occurrences of thrombotic events associated with varicella infection further support recommendations for universal vaccination of children for varicella. The association of factor V Leiden with varicella-associated purpura fulminans suggested by this case also supports a strong consideration for varicella vaccination of individuals identified as having the factor V Leiden mutation, if they have not yet had primary varicella infection.