This results from the fact that these proteins have different half-lives: 1.5 to six hours for factor VII and eight hours for protein C, versus one day for factor IX, two days for factor X and two to five days for factor II. The larger the initial dose of vitamin K-antagonist, the more pronounced these differences are. This coagulation factor imbalance leads to paradoxical activation of coagulation, resulting in a hypercoagulable state and thrombosis. The blood clots interrupt the blood supply to the skin, causing necrosis. Protein C is an innate anticoagulant, and as warfarin further decreases protein C levels, it can lead to massive thrombosis with necrosis and gangrene of limbs. Notably, the prothrombin time (or international normalized ratio, INR) used to test the effect of warfarin is highly dependent on factor VII, which explains why patients can have a therapeutic INR (indicating good anticoagulant effect) but still be in a hypercoagulable state.In one third of cases, warfarin necrosis occurs in patients with an underlying, innate and previously unknown deficiency of protein C. The condition is related to purpura fulminans, a complication in infants with sepsis which also involves skin necrosis. These infants often have protein C deficiency as well. There have also been cases in patients with other deficiency, including protein S deficiency, activated protein C resistance (Factor V Leiden) and antithrombin III deficiency.Although the above hypothesis is the most commonly accepted, others believe that it is a hypersensitivity reaction or a direct toxic effect.
These include gradual increase starting from low doses and supplemental administration of protein C (pure or from fresh frozen plasma).The necrotic skin areas are treated as in other conditions, sometimes healing spontaneously with or without scarring, sometimes going on to require surgical debridement or skin grafting. History
While skin necrosis in patients had been previously described, Verhagen was the first to publish a paper on this relationship in the medical literature, in 1954. See also
List of cutaneous conditions


== References ==