Massive Skin Necrosis Associated to the Prothrombin Gene G20210A Mutation

Skin necrosis is an infrequent feature related with multiple causes, including an evolving spectrum of prothrombotic abnormalities of the hemostasis system (deficiences of antithrombin, proteins C or S, antiphospholipid antibodies, or mutations in the factor V gene) (1). A 43-year-old white woman presented with a one year history of painful, progressive cutaneous lesions. She had a depressive syndrome treated with levopromazine, lorazepam and perphenazine associated with amitriptiline. Moreover, she referred compulsive intake up to 20 tables by day of pyrithyldione associated with diphenhydramine (Soñodor®), a hypnotic medication available over the counter in Spain. Symmetrical erythemato-purpuric plaques with serohematic bullae and necrotic eschars were observed on the tip of the nose, cheeks, ears, breast and anterolateral aspects of the limbs, covering 30% of total body surface (Fig. 1). Biopsy specimens disclosed massive thrombosis in small and middle-size dermal and subcutaneous vessels, without signs of vasculitis. Direct immunofluorescence and microbiological studies were negative. Laboratory tests revealed raised titers of antinuclear antibodies (1/2560) and a positive rheumatoid factor. Tests for cryoglobulins, complement, rapid plasma reagin and other autoantibodies were negative. A complete study of thrombosis risk factors, including fibrinogen, fibrin split products, lupus anticoagulant, antithrombin, protein C, protein S (total, free and functional), activated protein C resistance, anticardiolipin antibodies, homocystein, plasminogen, heparin cofactor II, t-PA, PAI-1, HRG, TFPI and factor V Leiden, was normal. IgM antiphosphatidil coline and IgM antiphosphatidil serine were slightly positive. Raised plasma levels of factor VIII and factor II were observed (226% and 145%, respectively). Analysis of the 3’-untranslated region of the prothrombin (PT) gene 20210 variant, performed as described previously (2), showed that the patient, her mother and her sister were heterozygous carriers of this mutation. Hypnotic medication was discontinued and cutaneous lesions healed after treatment with plasmapheresis, low-weight molecular heparin and surgical desbridement of eschars. She has suffered two relapses of similar cutaneous lesions triggered by self-taking the drug. The last one improved rapidly with early treatment using subcutaneous enoxaparin (80 mg daily). This unique case meets the criteria of thrombophilia: recurrent events of thrombosis in atypical sites (skin) in a young woman (3). Inherited and environmental factors may contribute to this disorder. The PT G20210A mutation has been recently described as a clear risk factor for venous thrombosis in the legs and cerebral-vein thrombosis (2, 4). Only one case of skin necrosis related to this abnormality and induced by warfarin has been reported (5). Our patient had both acquired (antiphospholipid antibodies) and inherited (PT G20210A mutation) causes of thrombosis, which could be acting sinergycally. Some times, exogenous factors such as the use of oral contraceptives, warfarin, surgery, trauma, and prolonged immobilization, are needed as triggers for thrombosis in predisposed persons (4, 5). In this case, abusive intake of pyrithyldione (a hypnotic pyridone) plus diphenhydramine (a sedative antihistamine) could contribute to the development of thrombosis. Relapses of cutaneous lesions after reexposure to the drug suggest a causal relation, although the pathogenic mechanism remains unknown. Side effects related to pyrithyldione include agranulocytosis, arthalgia, fever, vasculitis, cutaneous necrosis, livedo reticularis, trombotic purpura and, in combination with heroin, fatal intoxication (6-8). However, underlying abnormalities of the hemostasis system have not been previously demonstrated in such cases.