WISN affects 0.01–0.1 % of treated patients. It occurs more frequently in obese middle-aged women, with a female-to-male ratio of 4:1. The majority of patients are ill and hospitalized; DVT, pulmonary embolism, and thrombophlebitis are the most common indications for anticoagulation in these patients.

The pathophysiology of WISN involves the balance of anticoagulation and coagulation forces, perturbed by the initiation of warfarin. Factors inhibited by warfarin, due to their vitamin K-dependence, include factors II, VII, IX, and X as well as anticoagulation proteins C and S. Protein C and factor VII have short half-lives (5–8 h) relative to factors II, IX, and X (2–3 days), leading to a more rapid decrease in the former relative to the latter. This causes a transient hypercoagulable state during the initiation of therapy. This also explains why protein C deficiency (acquired or inherited) is a significant risk factor for development of WISN. Less frequently, protein S deficiency, antithrombin III deficiency, factor V Leiden mutation, and antiphospholipid antibody syndrome have been associated with WISN. Other proposed mechanisms of WISN include the direct toxic effect of warfarin on vessel walls and immunologic hypersensitivity to warfarin.

Early symptoms are localized paresthesia and edema with progression to livedo macules, petechiae, and ecchymosis; hemorrhagic bullae form within 24 h (Fig. 27.1). After days, lesions are characterized by full-thickness necrosis and painful subcutaneous ulcerations. 90 % of cases occur between days 3 and 6 after treatment initiation; almost all occur by day 10. There have been reports of WISN occurring up to 15 years after treatment initiation as well as several days after cessation of therapy. Areas with more subcutaneous fat are more susceptible, such as the abdomen, buttocks, thighs, and breast tissue. One-third of patients have multiple sites of involvement. Of note, the cutaneous appearance of warfarin necrosis is difficult to distinguish from that of heparin necrosis.

Diagnosis is made based on clinical suspicion, biopsy, and ruling out other diagnoses. First steps in management include cessation of warfarin, administration of fresh frozen plasma and vitamin K, and initiation of an alternative anticoagulant such as heparin. Local treatment includes topical bactericidal agents. Surgical debridement, skin grafting, or amputation is required in more than 50 % of cases. Treatment with recombinant protein C has been shown to be beneficial in patients with documented protein C deficiency, but cost is prohibitive. An important distinction between warfarin-induced and heparin-induced skin necrosis is that warfarin can be reintroduced after an episode while heparin cannot, in most circumstances. It is important to start warfarin at a low dose, with slow increase to therapeutic level; loading doses should be avoided, and heparin bridging considered. The lesions are self-limited and generally resolve over several weeks.