Purpura fulminans from reduced protein S following cytomegalovirus and varicella infection
Authors: Lionel Kankeu Fonkoua, Simin Zhang, Ethan Canty, Aubree Fairfull, Sarah Benich, Andrea Knab, Hyma Polimera, Natthapol Songdej
Journal: American Journal of Hematology (2018)

A 42-year-old woman with past medical history significant for chronic inflammatory demyelinating polyneuropathy (CIDP), treated with azathioprine and monthly intravenous immunoglobulin, presented to an outside hospital with 1 wk history of fever, headache, arthralgias, nausea, and diarrhea. She was also noted to have a pink left-sided facial rash. She denied any known sick contacts, but reported a history of dental infections with extraction of multiple teeth in the weeks prior to presentation. Family history was notable for a mother with rheumatoid arthritis and an aunt with lupus. This patient's initial presentation could be consistent with a viral illness, with upper respiratory infection and gastroenteritis. Given her recent dental extractions, constitutional symptoms, and rash, cellulitis is also a possibility. At the outside hospital, she was started on intravenous ampicillin-sulbactam upon admission. Within 2 d of outside hospital admission, her left facial rash quickly became purpuric and painful, rapidly progressed to her bilateral face, ears, and upper arms (Figure 1 ), and eventually evolved into ecchymotic lesions with necrotic eschar and well-demarcated bullae. Labs were notable for platelet count 116 K/μL (150-400 K/μL), fibrinogen 98 mg/dL (170-440 mg/dL), haptoglobin 37.2 mg/dL (34-225 mg/dL), LDH 407 U/L (140-271 U/L), and CRP 3.5 mg/dL (0-0.8 mg/dL). Given rash, thrombocytopenia, and family history of rheumatoid arthritis and lupus, a possible immune etiology was considered for her clinical presentation, including antiphospholipid antibody syndrome, thrombotic thrombocytopenic purpura (TTP), cryoglobulinemia type I, medium-vessel vasculitis, and serum sickness. She was started on methylprednisolone for possible TTP at the outside hospital. Due to unclear etiology for the patient's rash and lab abnormalities, she was transferred to our institution for further evaluation and management. At our institution, presenting vitals showed temperature of 35.6°C, blood pressure 132/92, heart rate 85, and oxygen saturation of 97%. Initial labs were significant for WBC 1.83 K/μL (4-10.4 K/μL), Hb 10.1 g/dL (11.7-15 g/dL), platelet count 107 K/μL (150-400 K/μL), PT 14.3 seconds (9.4-12.3 seconds), INR 1.4 (1-1.2), PTT 50 seconds (23-35 seconds), D-Dimer 13.19 mg/L (0-0.52 mg/L), reticulocytes 3.32% (0.4%-2.05%), LDH 1131 U/L (313-618 U/L), and fibrinogen 111 mg/dL (208-435 mg/dL). ESR was 4 mm/hr (0-30 mm/hr) and CRP was 4 mg/dL (<1.00 mg/dL). Testing for lupus anticoagulant, and anti-cardiolipin and beta-2 glycoprotein antibodies were negative. Peripheral blood smear showed morphologically normal red blood cells with rare schistocytes, normal WBC morphology without blasts, and an adequate number and normal appearance of platelets, occasionally with areas of platelet clumping, which may account for some degree of thrombocytopenia. Skin punch biopsy of the left arm revealed a slight increased number of telangiectatic blood vessels within the dermis with focal thrombus formation and sparse inflammatory infiltrate (Figure 2 ), consistent with a diagnosis of vasculopathy. Her labs were notable for coagulopathy with elevated PT, INR, and PTT. She also had an elevated D-dimer and low fibrinogen, consistent with disseminated intravascular coagulation (DIC). DIC, along with the purpuric appearance of her rash, and the skin biopsy findings, were consistent with a clinical diagnosis of purpura fulminans (PF). On account of her otherwise relatively well appearance, hemodynamic stability and negative blood cultures for bacterial growth, neither bacteremia and/or sepsis was felt to be responsible for her development of PF. Given normal haptoglobin, rare schistocytes, exam evidence of PF, and lab evidence of DIC, TTP was felt to be unlikely. Plasma exchange was not initiated; however, methylprednisolone was continued given concern for vasculitis. At our institution, steroids were continued for 11 d given that vasculitis was at that time also on the differential diagnosis, after which steroids were eventually tapered off (total steroid exposure including taper was approximately 1 month). We further considered other potential etiologies of PF, such as acute leukemia, occult malignancy, and also paroxysmal nocturnal hemoglobinuria (PNH), which has been rarely associated with PF.1-3 Bone marrow aspiration and biopsy revealed mildly hypocellular bone marrow with mild hypoplasia of myelopoiesis and erythropoiesis, hyperplasia of megakaryocytes, and no increase in blasts. Flow cytometry revealed no PNH clones. Ferritin and triglyceride levels were normal at 53.8 ng/mL (6.2-137 ng/mL) and 168 mg/dL (<200 mg/dL) respectively. Imaging of chest, abdomen and pelvis showed no concern for occult malignancy. Overall, there was no evidence of acute leukemia, occult malignancy, or PNH. She continued to have fevers as high as 39°C, and the infectious disease service was consulted. Infectious workup was negative for bacterial and fungal infections. There was an elevated cytomegalovirus (CMV) viral load by PCR at 292 467 copies/mL (<500 copies/mL), for which she was started on ganciclovir therapy. She was also found to have positive varicella zoster virus (VZV) IgM at 1.37 ISR (≤0.9 ISR) and IgG antibody titers. VZV PCR in plasma was negative. On further questioning, the patient reported previous chickenpox infection at age 9. There was no known previous VZV serologic work-up. The patient had CMV viremia and may have had recent re-infection with VZV with spontaneous clearance. CMV and VZV infections were suspected to explain at least partially the suppression of peripheral blood counts. Additionally, her initial symptoms of fever, fatigue, diarrhea and myalgias may have been secondary to an acute CMV infection. Although her constitutional symptoms could also be attributed to VZV, she did not develop a generalized rash typical of primary VZV infection. Shortly into her hospital course, she also developed painful necrosis in her toes bilaterally (Figure 3 ). In the context of PF and DIC, unfractionated heparin (titrating for goal PTT 60-80 seconds) and intermittent cryoprecipitate (aiming for goal fibrinogen >150 mg/dL) administration were initiated, unfortunately with no initial significant clinical improvement. To further evaluate the etiology of her PF, protein C (PC) and protein S (PS) levels were assessed. PS activity levels were measured in-house using the Stago STA-Staclot Protein S clotting assay. PS free and total antigen levels were measured by microlatex particle-mediated immunoassay (ARUP Laboratories). She had decreased levels of free PS antigen at 21% (55%-123%) and PS functional activity at 15% (50%-120%), with normal levels of total PS antigen 78% (63%-126%). PC activity at 76% (70%-150%) and PC antigen at 74% (70%-140%) were normal. The patient notably does not have a known family history of venous thromboembolism and no family members have ever undergone work-up for PS deficiency. Given suspected PS deficiency as the cause of PF, fresh frozen plasma (FFP) infusions were started and appeared to slow the progression of ischemic necrosis of the toes. She was continued on FFP until free PS antigen levels increased and consistently remained in the 50%-60% range. Her skin lesions continued to clinically improve and necrotic eschars involving bilateral arms were debrided (Figure 4), with plan for later scar revision. Amputation of her necrotic toes was offered, but she declined. Unfractionated heparin was transitioned to apixaban 5 mg twice daily prior to discharge home. Her total hospitalization period was approximately 2 months. She continued to improve remarkably, and within 2 months of discharge, had complete resolution of her bilateral facial purpura and toe necrosis (Figure 4). Interestingly, repeat PS levels approximately 9 months after discharge continued to show lower than normal levels of free PS antigen at 47% and functional activity at 51%, with normal total PS antigen level of 88%. PC activity was normal at 94%. Fibrinogen had returned to normal at 308 mg/dL (208-435 mg/dL) and D-Dimer was negative. Our patient with a history CIDP presented with multiple areas of purpura involving her face, arms, and toes, pancytopenia, and laboratory evidence of DIC, consistent with PF. She also had evidence of CMV viremia and possible recent VZV infection. PF is a rare form of DIC leading to hemorrhagic skin necrosis.4 It is associated with substantial morbidity and mortality, with mortality ranging from 20% to 40%.5 Adults are occasionally affected by PF, though it is predominantly seen in infants and children.6 On skin biopsy, diffuse small blood vessel microthrombi, necrosis, and vasculitis can be present. In our patient, skin biopsy of her left arm showed within the dermis a slight increase in number of telangiectatic blood vessels with focal thrombus formation and sparse inflammatory infiltrate. There are three main documented clinical situations from which PF can develop, including as a result of homozygous PC or PS deficiency in neonates and young children, in acute bacterial or viral infections in patients with acquired deficiency of PC, or as a post infectious syndrome after an illness including with scarlet fever, varicella, or rubella.7, 8 Development of PF has been particularly associated with N. meningitidis, but in patients who have had a splenectomy, has also been associated with infection from S. pneumoniae, H. influenzae and S. aureus.9 Cases of PF occurring generally 7-10 d from an acquired PS deficiency following primarily varicella infection but also after streptococcal infection have been documented in children.10-12 Particularly for cases involving varicella infection, autoantibodies to PS have been documented.10, 11 PF requires early recognition and prompt intervention to prevent progression to limb- or life-threatening tissue thrombosis and hemorrhagic necrosis. Early lesions generally start with erythematous macules that progress to painful purpuric hemorrhagic skin necrosis with occasional vesicle or bulla formation.8 The distribution of early PF lesions differ depending on etiology. PF in the setting of severe infection usually first affects distal extremities with later proximal progression or can occur in a more generalized distribution.8 In homozygous PC or PS deficiency affecting neonates and young children, early PF lesions typically develop in lower limbs and male genitalia and also tend to form at pressure points such as the heels and buttocks. In post infectious PF, early PF lesions have a predilection for the lower body, though typically does not involve the distal extremities, upper body, arms, or head and neck. In males, it may involve the scrotum or penis.8 In general, areas of lesions in PF can also often involve tissue areas with end circulation such as the tip of the nose, ears, and distal extremities, which are often involved symmetrically.13 Our patient did not have a skin distribution pattern as seen in typical post infectious PF, though did have classic PF lesions involving distal areas such as nose, ears, and feet, as well as bilateral arms. Her initial involved sites were central, starting on her face, and then progressively involved more peripheral sites such as her ears, arms, and, lastly, toes bilaterally. In affected patients with PF, necrotic skin excision and later grafting are often necessary if they survive the initial stages.6 Amputation may also be required. Our patient did have debridement of her upper arms bilaterally, but declined amputation of affected toes. Her toes eventually fully recovered. We suspect that our patient had a type of post infectious PF from reduced free PS as a result of viral infection with CMV and/or VZV. PS is an essential cofactor for activated PC, one of the major regulators of hemostasis, which when activated by thrombin/thrombomodulin, inactivates factors Va and VIIIa.14 PS and PC therefore both act as potent anticoagulants, and a deficiency in either can lead to hypercoagulability and thrombotic complications. Potential mechanisms of reduced levels of PS free and activity in our patient are elevation of the acute phase reactant C4b-binding protein (C4b-BP) or autoantibodies against PS induced by the viral infection. Normally approximately 60% of total PS is bound to C4b-BP with the remainder of PS circulating in the free form; only free PS possesses anticoagulant activity. In infectious or inflammatory states, elevation of C4b-BP can lead to increased PS binding thereby reducing the amount of PS free and activity. Lastly, there may have also been some contribution from the DIC itself in reducing our patient's PS levels. In children, post infectious PF associated with VZV is well-documented in the literature.10-12, 15-23 In these cases, varicella infection has been shown to induce autoantibody formation that results in lowering of both PS total and free antigen.10, 11, 20 A variety of mechanisms have implicated infectious agents in the induction of autoimmune diseases, with "molecular mimicry" being the prevailing theory. It postulates that inflammation induced by exposure to a foreign antigen can lead to autoimmune phenomena from cross-reactive epitopes.10, 24, 25 In our patient case, we think it is less likely that there was an autoantibody to PS induced from CMV or VZV infection, as cases of PF from varicella with PS autoantibodies in the literature have documented both reduced total and free PS antigen levels.10, 11, 15, 20, 22 Our patient had preserved total PS antigen levels, but reduced PS free and activity levels. More likely, C4b-BP was elevated as an acute phase reactant which would result in lower levels of PS free antigen, but preserved PS total antigen. The likely lack of PS antibodies would also help explain why there was some response in increasing our patient's PS levels with FFP. In cases of autoantibodies against PS, levels did not improve with FFP administration.10 It is also possible that steroid exposure in our patient helped to decrease acute phase reactants and increase PS levels. Notably, in adults there are very limited documented cases of post infectious reduction in PS resulting in PF. One study documented a case of post varicella PF with transient deficiencies in both PC and PS in an 18-year-old.26 There was also a documented case of PF in a 59-year-old woman occurring during sepsis in the setting of strongyloides hyperinfection with concomitant CMV infection, but neither PC or PS levels were reported.27 It is also worth pointing out in our patient there was preserved PC activity despite laboratory evidence of DIC and PF. Indeed, most reported cases of post varicella PF from low PS in the literature document very disproportionately low PS levels in comparison to PC levels.10, 12, 17, 19, 23 Some PC levels have even been documented to be normal.10, 15, 20, 22 The Levin et al10 case series is particularly illustrative, where post infectious PF occurred with essentially undetectable free PS levels and relatively preserved PC activity levels in all 5 patients. This phenomenon was also observed in our patient. Interestingly, months after clinical recovery and resolution of toe necrosis, and while on apixaban, repeat PS levels in our patient showed activity level of 51% and free antigen level of 47%, with normal total PS antigen level of 88% This is particularly notable as apixaban may falsely elevate PS activity levels.28 At the time of repeat testing, fibrinogen, which is also an acute phase reactant, was normal. This suggests that there would be no significant increase in C4b-BP to account for decreased levels of PS free and activity. However, testing for other acute phase reactants including factor VIII and repeat ESR and CRP testing in the future would be useful to rule out low PS free and activity levels due to acute phase reactant. If influence from acute phase reactants is ruled out, the overall PS profile in our patient suggests that she may have heterozygous type III PS deficiency and repeat testing off of apixaban would be potentially further informative. Overall, our patient possibly has an underlying congenital PS deficiency, and development of VZV or CMV infection decreased her PS levels further to precipitate PF. Treatment of PF focuses on treatment of any precipitating underlying condition. Part of the therapeutic armamentarium may also involve prompt anticoagulation with unfractionated heparin, FFP support and/or PC concentrates to replete depleted anticoagulant plasma proteins.10, 29, 30 In antibody-mediated cases of low PS, no standard treatment exist, but some have also used intravenous immunoglobulin, plasmapheresis, or immunosuppression with steroids.12, 18, 22