Low‐molecular‐weight heparin‐induced skin necrosis: a potential association with pre‐existent hypercoagulable states

Abstract

A 76-year-old patient was admitted to our hospital with dyspnea. His past medical history disclosed a 17-year duration of polycythemia vera with thrombocytosis; arterial hypertension; diabetes mellitus; hyperuricemia; auricular fibrillation; and chronic bronchitis. He had been treated with hydroxyurea, digoxin, allopurinol, and enalapril. Although pulmonary embolism was not demonstrated, at admission, as a result of the presence of thrombocytosis and arrhythmia, prophylactic treatment with subcutaneous enoxaparin, 60 mg twice daily, was prescribed. Five days after the first injection, two symmetric erythematous patches, 5 cm in diameter, were noted at the abdominal wall area coincident to the points of subcutaneous enoxaparin injection. During the following 24 h, the lesions enlarged and evolved to form purplish-blue necrotic plaques, 15 cm × 5 cm in diameter (1, 2). The development of this localized side-effect led to the discontinuation of treatment with enoxaparin. Figure 1Open in figure viewerPowerPoint Symmetric plaques of abdominal skin necrosis Figure 2Open in figure viewerPowerPoint Purplish-blue necrotic plaque, 15 cm × 5 cm in diameter A skin biopsy taken from the margin of the lesion showed multiple fibrin thrombi in the dermal microvasculature with ischemic necrosis of the overlying epidermis (Fig. 3). Routine laboratory testing showed: hemoglobin, 74 g/L; white blood cell count, 28.5 × 109/L; platelets, 1025 × 109/L; creatinine, 1.5 mg/dL; and uric acid, 11.8 mg/dL. Coagulation studies showed: prothrombin time ratio, 1.17; thromboplastin time ratio, 1.36; fibrinogen, 3.6 g/L; normal protein C; and negative lupic anticoagulant factor. In contrast, protein S function was reduced: 56% (normal, 71–142%) with low free protein S (63%; normal, 72–139%) and normal total protein S (protein S deficiency type III). Immunoglobulin G (IgG) antiphospholipid antibody was normal, but IgM was increased to 4.25 (normal, < 3.1). Heparin–platelet factor 4 (PF4) antibodies were also demonstrated. There was no significant change in the platelet count throughout the patient's admission. Figure 3Open in figure viewerPowerPoint Superficial dermal vascular occlusion and ischemic necrosis of the epidermis (hematoxylin and eosin; original magnification, ×60) The lesions were treated locally, and complete healing was observed after approximately 1 month. Skin necrosis is a rare complication of subcutaneous low-molecular-weight heparin injections. Heparin-induced skin necrosis is now thought to be caused by an antibody-mediated local prothrombotic condition associated with platelet activation and increased thrombin production. The association of heparin-induced skin necrosis with antibodies directed against PF4 is a well-established phenomenon. The concomitant participation of other procoagulant factors, however, has received little attention in the literature. The observation of heparin-induced skin necrosis should motivate a systematic search for the presence of anti-PF4 antibodies, but also for additional genetic or acquired procoagulant factors. As heparin-induced skin necrosis may be a marker for increased risk of systemic arterial or venous thromboembolism, an increased awareness regarding the significance of this potential side-effect is important in order to avoid further potentially severe associated complications.