Clinical Presentation

Warfarin skin necrosis is the onset of a major necrotic lesion on the skin within 24 to 72 hours after ingestion of oral vitamin K antagonists (warfarin). It can also be seen with other vitamin K antagonists (4-hydroxycoumarin derivatives, e.g., brodifacoum, difenacoum). It can affect soft tissues in the abdomen, limbs, breasts, and buttocks. It can occur as an apparent isolated event in a patient being treated for venous thromboembolism (VTE) or in other conditions associated with an activated blood coagulation state, such as HITTS, disseminated intravascular coagulation (DIC) from any etiology, or antiphospholipid syndrome.

The skin lesions are retiform purpura that consists of branching purpuric lesions caused by a complete blockage of blood flow in the dermal and subcutaneous vasculature. In addition to an activated blood coagulation state, these lesions can be seen in less common conditions such as snake bite, frostbite, cholesterol embolization, cryoglobulinemia, Neisseria sepsis, and calciphylaxis in the kidney failure patient. These patients are at high risk for VTE, and they can present with additional symptoms and signs of venous thrombosis.

Laboratory Presentation

Clinical coagulation laboratory findings often manifest evidence of DIC. The prothrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged, and the D-dimer (the product of plasmin-cleaved insoluble cross-linked fibrin) is elevated. The patient may be thrombocytopenic from the activated blood coagulation state. A clinical history usually excludes diagnoses of DIC, like those accompanying sepsis from any cause, obstetric catastrophes, trauma, cancer, and major tissue injury such as aortic dissection and necrotizing enterocolitis, among others. In patients with cholesterol embolization and cryoglobulinemia, the laboratory findings are normal, unless there is an associated large volume of dead tissue. Surveillance venous ultrasonography can reveal an occult thrombosis if not otherwise clinically manifest.

Pathophysiology

The basic pathophysiology of warfarin-induced skin necrosis is that warfarin or any other vitamin K antagonist produces a temporary hypercoagulable state upon initial administration. This occurs as a result of the rate by which vitamin K–dependent proteins are reduced and altered by warfarin.

Protein C is an enzyme that functions as an anticoagulant. When protein C is activated on endothelial cell thrombomodulin by thrombin, it degrades activated forms of factors VIII and V that serve as pro-cofactors for factor X and prothrombin activation, respectively (Figure 1). Protein S is a cofactor for activated protein C on cells to inactivate factors VIIIa and Va. Protein C has a half-life of 3 to 4 hours. Factor VII has a half-life of 3 to 6 hours. However, reduction of factor VII alone is not sufficient to anticoagulate a patient in the presence of protein C reduction.

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