Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a common, often catastrophic, syndrome that produces the most hypercoagulable of states. Emerging therapeutic strategies use alternative anticoagulants; warfarin's place is being reexamined. Early in the course of warfarin therapy, there may be net procoagulant effects because of the inhibition of protein C. With HIT, it has been suggested that unopposed warfarin can precipitate venous limb gangrene. There are also reports of warfarin-induced skin necrosis. We seek to confirm and increase awareness of the risks of warfarin with HIT. METHODS: We describe 6 patients with HIT seen at 3 medical centers in whom frank or impending venous limb gangrene, central skin necrosis, or both were temporally related to warfarin initiation. RESULTS: At warfarin initiation, 5 patients had recognized HIT and 1 had it recognized later. Complications emerged after 2 to 7 days, and consisted of warfarin-induced skin necrosis (n = 5) and venous limb gangrene (n = 2); 1 patient had both. This emerged with unopposed warfarin in 4 patients and as a direct thrombin inhibitor was being withdrawn in 2. All had supratherapeutic international normalized ratios. One patient required leg and breast amputations, and another one died. CONCLUSIONS: Because of the early effects on protein C, warfarin can precipitate venous limb gangrene and/or skin necrosis in the extreme hypercoagulable milieu of HIT. With HIT, unopposed warfarin should be avoided and caution is needed during transition from a direct thrombin inhibitor. Warfarin should be initiated at modest doses in patients with HIT after platelet recovery. Implications extend to warfarin initiation with other thrombotic diatheses.     

Familial type II protein C deficiency associated with warfarin-induced skin necrosis and bilateral adrenal hemorrhage

A family is described in which venous thromboembolic disease is associated with reduced plasma protein C activity and normal levels of protein C antigen. Immunoelectrophoretic analysis of protein C antigen gave an abnormal pattern in all affected members, suggesting that the disorder is related to the presence of a structurally and functionally abnormal form of protein C. The propositus developed simultaneous warfarin-induced skin necrosis and bilateral adrenal hemorrhage. This is the first reported instance of warfarin-induced skin necrosis associated with a dysfunctional protein C molecule and the first reported instance of simultaneous warfarin-induced skin necrosis and bilateral adrenal hemorrhage.     

Anticoagulant-induced skin necrosis in a patient with hereditary deficiency of protein S

Skin necrosis is a rare but debilitating complication of treatment with vitamin K antagonist anticoagulants such as warfarin. A clinically similar syndrome has been reported less frequently with heparin therapy. We recently managed a thirty-year-old female patient who developed skin necrosis on her left lower extremity while on warfarin for postpartum DVT. The lesions started to develop 48 hr after stopping heparin therapy. Discontinuation of warfarin and reinstitution of heparin was complicated by a rapid decrease in platelet count consistent with heparin-induced thrombocytopenia (HIT) and its associated risk of platelet activation and thrombosis. The diagnosis was supported by the identification of antibodies against heparin/platelet factor 4 complexes in the patient's serum. The platelet count recovered and the patient improved after switching to therapy with the heparinoid danaparoid. Evaluation for a hypercoagulable state revealed a partial deficiency of protein S, a condition that previously was identified in two of her family members. It is not clear if this patient suffered from warfarin-induced skin necrosis, a manifestation of heparin-mediated platelet activation, or a complex condition in which both drugs contributed. HIT may affect 1-3% of patients who receive unfractionated heparin, and this case raises the possibility that heparin may contribute to, or cause, some episodes of skin necrosis attributed to warfarin. Because many patients who develop warfarin-induced skin necrosis have been treated initially with heparin, it would seem prudent to consider HIT in these situations.     

Warfarin-induced skin necrosis after open heart surgery due to protein S and C deficiency

Warfarin-induced skin necrosis is the rare but potentially devastating complication of anticoagulant therapy and commonly occurs in previously undetected C- and S-protein deficient patients. Because routine preoperative examination does not include protein C and S level measurement, detection of these patients preoperatively is generally not possible, which increases the risk of occurrence of this important complication. In this report we present and discuss such a patient, who died from warfarin-induced skin necrosis after coronary artery bypass surgery.     

Skin necrosis associated with acquired protein C deficiency in patients with renal failure and calciphylaxis

PURPOSE: To determine if the natural anticoagulant protein C plays a role in the pathogenesis of systemic calciphylaxis, a syndrome characterized by extensive vascular and soft tissue calcification and skin necrosis, which is similar to that seen in warfarin-induced skin necrosis. PATIENTS AND METHODS: The study population included five patients with end-stage renal disease and systemic calciphylaxis undergoing hemodialysis, 12 patients without evidence of calciphylaxis undergoing dialysis, eight patients with nephrotic syndrome, and eight normal healthy volunteers. Protein C antigen levels were measured by rocket immunoelectrophoresis, and functional activity was quantitated by a chromogenic assay and an anticoagulant assay utilizing the venom of Agkistrodon contortrix. RESULTS: Skin biopsy specimens of involved areas in three patients showed thrombotic occlusion of venules identical to that seen in warfarin-induced skin necrosis. Protein C antigen levels were normal in all groups. However, protein C activity was significantly reduced as measured by chromogenic (p less than 0.01) or anticoagulant assays (p less than 0.01) in patients with calciphylaxis compared with the other three groups. CONCLUSION: These findings suggest that hypercoagulability due to functional protein C deficiency may contribute to thrombosis, resulting in skin necrosis and digital gangrene in systemic calciphylaxis.     

Warfarin-induced skin necrosis in 2 patients with protein S deficiency: successful reinstatement of warfarin therapy.

Warfarin-induced skin necrosis is a rare but serious complication of oral anticoagulant therapy. This condition has been associated with protein C deficiency but only rarely reported in patients with a deficiency of protein S. We have managed 2 patients with a history of warfarin-induced skin necrosis who were diagnosed as being protein-S-deficient. Since both patients were candidates for long-term anticoagulant therapy we elected to reintroduce warfarin using a regimen designed to minimize the risk of recurrent skin necrosis. While they were therapeutically anticoagulated with heparin, warfarin was started at 1 mg/day and the dose was increased gradually. Heparin was not discontinued until the prothrombin times were in the therapeutic range for at least 72 h. Both patients tolerated the reinstitution of warfarin without difficulty and they have now been followed for over 2 years on oral anticoagulants without complication.     

Deep-vein thrombosis and coumarin skin necrosis associated with a factor V inhibitor with lupus-like features

We report a 71-year-old man who developed deep-vein thrombosis after major surgery. Coumarin skin necrosis developed after starting oral anticoagulant therapy. An inhibitor to factor V (61 Bethesda units) with lupus-like features was found as well as a low protein C level. The occurrence of these very rare findings indicates that despite profound procoagulant inhibition (factor V inhibition and anticoagulant therapy), hypercoagulation can occur. Am. J. Hematol. 57:176–178, 1998. © 1998 Wiley-Liss, Inc.     

Neonatal purpura fulminans due to homozygous protein C or protein S deficiencies

Homozygous protein C deficiency or homozygous protein S deficiency are rare genetic diseases with catastrophic and fatal purpura fulminans-like or thrombotic 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 the 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.     

Skin necrosis and protein C deficiency associated with vitamin K depletion in a patient with renal failure.

Skin necrosis similar to that induced by warfarin was seen in a patient who had never received the drug but who was vitamin K-deficient due to malnutrition and prolonged treatment with broad-spectrum antibiotics. He also had end-stage renal failure and was receiving prophylactic subcutaneous heparin therapy because of immobilization. His plasma protein C antigen level and, disproportionately, his plasma protein C functional activity were decreased. Both protein C values improved after vitamin K therapy, discontinuation of heparin, and initiation of hemodialysis. We surmise that skin necrosis occurred as a result of protein C deficiency caused by vitamin K depletion. Production of abnormal (descarboxy) protein C/protein S due to vitamin K deficiency and increased protein C inhibitory activity associated with renal failure and/or heparin administration may have contributed to the clinical picture. This rare but serious complication of a relatively common disorder, viz., vitamin K deficiency, reinforces the importance of vitamin K supplementation in malnourished patients who receive long-term antibiotic maintenance therapy.     

Concurrent protein C deficiency and lupus anticoagulants.

An inherited deficiency of protein C, a recognized hypercoagulable state, may cause a clinically significant deep venous thrombosis. Only some persons with a deficiency of protein C experience thrombosis, and almost always the thrombotic event occurs in the venous circulation. Warfarin-induced skin necrosis, a rare event observed in some patients soon after treatment with warfarin is begun, is believed to be another manifestation of this deficiency. We describe a young woman whose basal functional and antigenic levels of protein C were about 45% and who experienced both deep venous thrombosis and warfarin-induced skin necrosis in a clinically severe course. Evidence for lupus anticoagulants was present, with prolonged activated partial thromboplastin time that was corrected when lysed platelets were added, prolonged Russell's viper venom time, anticardiolipin antibodies, and other laboratory evidence. Lupus anticoagulants are associated also with a significant incidence of thrombosis, including arterial thrombosis, and this patient developed concurrently arterial thrombosis. The combined effects of protein C deficiency and lupus anticoagulants, exacerbated by other potentially thrombogenic conditions, are believed responsible for the severe thrombotic events experienced by this patient.     

Inhibition of activated protein C anticoagulant activity by prothrombin

In this study, we test the hypothesis that prothrombin levels may modulate activated protein C (APC) anticoagulant activity. Prothrombin in purified systems or plasma dramatically inhibited the ability of APC to inactivate factor Va and to anticoagulate plasma. This was not due solely to competition for binding to the membrane surface, as prothrombin also inhibited factor Va inactivation by APC in the absence of a membrane surface. Compared with normal factor Va, inactivation of factor Va Leiden by APC was much less sensitive to prothrombin inhibition. This may account for the observation that the Leiden mutation has less of an effect on plasma-based clotting assays than would be predicted from the purified system. Reduction of protein C levels to 20% of normal constitutes a significant risk of thrombosis, yet these levels are observed in neonates and patients on oral anticoagulant therapy. In both situations, the correspondingly low prothrombin levels would result in an increased effectiveness of the remaining functional APC of approximately 5-fold. Thus, while the protein C activation system is impaired by the reduction in protein C levels, the APC that is formed is a more effective anticoagulant, allowing protein C levels to be reduced without significant thrombotic risk. In situations where prothrombin is high and protein C levels are low, as in early stages of oral anticoagulant therapy, the reduction in protein C would result only in impaired function of the anticoagulant system, possibly explaining the tendency for warfarin-induced skin necrosis.     

Hereditary protein C deficiency

Hereditary protein C deficiency, which is inherited as an autosomal-dominant trait, predisposes to venous thrombotic disease. Heterozygotes are at risk for superficial thrombophlebitis, deep venous thrombosis and/or pulmonary embolism, which may occur without apparent cause at a young age. Other manifestations are cerebral venous thrombosis and mesenteric vein thrombosis. In severe, often homozygous, protein C deficiency, a purpura fulminans syndrome may occur shortly after birth, resulting in death due to extensive thrombosis, if it is not adequately treated. The thrombotic manifestations in heterozygotes are effectively prevented by coumarin therapy. However, in the initial phase of oral anticoagulant therapy, the patients have an increased risk for the development of coumarin-induced haemorrhagic skin necrosis. The purpura fulminans syndrome can be treated with either replacement therapy or with coumarin therapy. Heparin appears to be ineffective in the prevention of both the purpura fulminans syndrome and the coumarin-induced skin necrosis.     

Purple digit syndrome and warfarin-induced skin necrosis

Warfarin is used extensively in clinical practice for numerous indications. It is generally safe. Bleeding is the major risk of warfarin; several uncommon adverse skin manifestations may also be associated with its use. These range from ecchymoses and purpura, haemorrhagic necrosis and maculopapular vesicular urticarial eruptions to cutaneous necrosis, purple digit syndrome and warfarin-induced skin necrosis. Early recognition and diagnosis of these adverse reactions are important to avoid morbidity and possible mortality. All health professionals should be aware of these complications.     

Warfarin-associated multiple digital necrosis complicating heparin-induced thrombocytopenia and Raynaud's phenomenon after aortic valve replacement for adenocarcinoma-associated thrombotic endocarditis

Necrosis of the digits is a rare complication of warfarin therapy of obscure pathogenesis. We report a 61-year-old woman with a 12-month history of Raynaud's phenomenon who developed multiple digital necrosis following aortic valve replacement with mechanical prosthesis for aortic insufficiency caused by nonbacterial thrombotic endocarditis. Exacerbation of Raynaud's phenomenon occurred during the postoperative period, with daily episodes of ischemia of the fingers and toes that improved with local warming. However, coincident with the occurrence of immune heparin-induced thrombocytopenia, and while undergoing routine warfarin anticoagulation because of the mechanical valve prosthesis, the patient abruptly developed progression of digital ischemia to multiple digital necrosis on postoperative day 8, at the time the international normalized ratio reached its peak value of 4.3. All limb pulses were readily palpable, and vascular imaging studies showed thrombosis only in the superficial femoral and popliteal veins of the right leg. Coagulation studies showed greatly elevated levels of thrombin-antithrombin complexes and prothrombin fragment F1.2 levels, consistent with uncontrolled thrombin generation. After vitamin K administration, no abnormalities of the protein C anticoagulant pathway were identified, consistent with previous studies of other patients with warfarin-induced necrosis complicating heparin-induced thrombocytopenia. Subsequently, the patient was shown to have metastatic breast adenocarcinoma, which explained the patient's initial presentation with nonbacterial thrombotic endocarditis. This patient case suggests that multiple digital gangrene can result from the interaction of various localizing and systemic factors, including compromised microvascular blood flow (Raynaud's phenomenon), increased thrombin generation (heparin-induced thrombocytopenia, adenocarcinoma), and warfarin-induced failure of the protein C natural anticoagulant pathway.     

Multicentric warfarin-induced skin necrosis complicating heparin-induced thrombocytopenia.

Two patients developed catastrophic multicentric skin necrosis while receiving warfarin to treat venous thromboembolism complicated by immune-mediated heparin-induced thrombocytopenia (HIT). Patient 1 developed skin necrosis involving the breasts, thighs, and face, as well as venous limb gangrene and bilateral hemorrhagic necrosis of the adrenal glands, resulting in death. The second patient developed bilateral mammary necrosis necessitating mastectomies, as well as skin necrosis involving the thigh. Neither patient had an identifiable hypercoagulable syndrome, other than HIT. HIT may represent a risk factor for the development of multicentric warfarin-induced skin necrosis (WISN).     

Low molecular weight heparin-induced skin necrosis occurring distant from injection sites and without thrombocytopenia

Tietge UJF, Schmidt HH-J, Jäckel E, Trautwein C, Manns MP (Medizinische Hochschule Hannover, Hannover, Germany). Low molecular weight heparin-induced skin necrosis occurring distant from injection sites and without thrombocytopenia (Case Report). J Intern Med 1998; 243 : 313–15. In this paper we report a case of 76-year-old white male patient with skin necrosis induced by subcutaneous prophylactic administration of low-molecular-weight heparin (LMWH). Skin necrosis occured distant from heparin injection sites and without concomitant thrombocytopenia. This is the first reported case presenting these clinical findings.     

Nécroses cutanées aux anti-vitamines K : un déséquilibre entre facteurs pro- et anticoagulants

Introduction

Skin necrosis with vitamin k antagonists are rare. They affect more frequently middle-aged and obese women, often within 10 days after initiating of treatment. They occur most often in a context of thrombophilia.

An update on clinical and basic aspects of the protein C anticoagulant pathway

The protein C anticoagulant pathway provides a mechanism for regulating the coagulation process through the selective inactivation of factors Va and VIIIa. Recent studies have suggested that factor V may facilitate this process and that a mutation at one of the inactivation sites can contribute to resistance to activated protein C (APC) inactivation of factor Va. This appears to be a common cause of familial thrombophilia. The control mechanisms involved in factor Va inactivation have also begun to become more clear. Membrane surfaces seem to be critical to complete factor Va inactivation, and the membrane composition requirements for optimal anticoagulant activity are distinct from those of procoagulant reactions. Specifically, the APC anticoagulant activity requires phosphatidylethanolamine, whereas the prothrombin activation complex does not. These observations may partially explain thrombotic complications with antiphospholipid antibodies in which the some antibodies have been shown to react preferentially with phosphatidylethanolamine and could, therefore, selectively block APC function. Clinically, more complete studies on partial protein C deficiency indicate that, at least within families, the deficiency is a significant risk factor for thrombosis. The impact of deficiencies on thrombotic risk suggests that protein C or other components of the pathway may be useful therapeutic agents. The limited clinical experience in treating meningococcemia, warfarin-induced skin necrosis, and homozygous protein C deficiency with protein C concentrates suggests that this approach is safe and effective.     

Thrombotic disorders of hemostasis in patients with deep vein thrombosis

For 22 months we investigated the hemostatic status of 93 inpatients (44 male, and 49 female, average age 54.6 years) with a phlebographically objectified deep venous thrombosis of the leg or iliac veins. Corresponding blood samples were taken before, during, and after therapy. In 58 (62.4%) patients we found several kinds of disorders of hemostasis. There were deficiencies of the protein C, protein S, factor XII, antithrombin III, and the thrombocytes function. In most cases there was a single acquired deficiency of one of these factors. Only in one patient (1.07%) could we verify an inherited deficiency of factor XII. The most frequent disorder was a protein C deficiency in 32 (34.4%) patients. In 44 (47%) operatively treated patients we had postoperative complications such as rethrombosis, phlegmasia coerulea dolens, or development of skin necrosis during anticoagulant therapy in 12 (27.3%) cases. In 10 (83%) of these patients with complications we had found preoperatively a disorder of hemostasis. The statistical correlation between a preoperatively measured deficiency of the protein C and the relapse of deep vein thrombosis was significant (p=0.0026).Presented at the 35th World Congress, International College of Angiology, Copenhagen, Denmark, July 1993     

Liposomal Amphotericin B (AmBisome) in the Treatment of Neonatal Candidiasis in Very Low Birth Weight Infants

Summary AmBisone (2.5–7 mg/kg/day as a continuous 1 h infusion) was evaluated prospectively from September 1994 to January 1998 in 24 very low birth weight infants (mean birth weight 847±244 g, mean gestational age 26 weeks) with systemic candidiasis. Mean age at onset of candidemia was 17 days. One patient had two episodes of candidiasis. Thirteen infants failed previous antifungal therapy with amphotericin B (with or without 5-flucytosine). Candida spp. were isolated from the blood in all 25 episodes and from skin abscesses and urine in four infants each, respectively. There were 13 isolates of Candida albicans, ten of Candida parapsilosis, two of Candida tropicalis and one of Candida glabrata. One infant had a mixed infection with C. albicans and C. parapsilosis. The mean duration of therapy was 21 days; the cumulative AmBisome dose was 94 mg/kg. Fungal eradication was achieved in 92% of the episodes; mean duration of AmBisome therapy until achieving eradication was 9 days. Twenty (83%) infants were considered clinically cured at the end of treatment. No major adverse effects were recorded; one infant developed increased bilirubin and hepatic transaminases levels during therapy. Four (17%) infants died; in two of them (8%) the cause of death was directly attributed to systemic candidiasis. Conclusion: AmBisome represents an effective, safe and convenient antifungal agent in the therapy of systemic fungal infections in very low birth weight infants. Received: March 21, 1999 · Revision accepted: March 3, 2000