From the Guidelines
Coumadin (warfarin) induced skin necrosis is primarily caused by a temporary hypercoagulable state due to the rapid decrease in protein C levels, which has a shorter half-life than other vitamin K-dependent clotting factors, leading to localized blood clot formation and tissue necrosis. This condition typically occurs 3-10 days after starting warfarin therapy, with symptoms including rash and necrosis over fatty areas, most commonly the breasts and thighs/buttocks 1. The pathophysiology may also involve large loading doses of warfarin, thrombosis of superficial dermal capillaries, and inherited protein C and S deficiencies 1. Key factors that contribute to this condition include:
- Protein C deficiency, which is supported by the similarity of the necrotic lesions to those of neonatal purpura fulminans, complicating homozygous protein C deficiency 1
- Protein S deficiency, although less common 1
- Baseline-depleted protein C and S activity caused by consumption by the thrombotic process in patients with deep venous thrombosis or pulmonary embolism 1 To prevent this complication, patients starting warfarin should receive overlapping heparin therapy for at least 5 days and until the INR is therapeutic, allowing for balanced reduction of all vitamin K-dependent factors. Discontinuation of warfarin and administration of vitamin K and protein C concentrate may be necessary if skin necrosis develops, and heparin should be used for long-term treatment of thromboembolic disease 1.
From the FDA Drug Label
Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Necrosis appears to be associated with local thrombosis and usually appears within a few days of the start of anticoagulant therapy The cause of Coumadin (warfarin) induced skin necrosis is associated with:
- Local thrombosis
- Hereditary or acquired deficiencies of protein C or its cofactor, protein S 2 It is also noted that not all patients with these conditions develop necrosis, and tissue necrosis occurs in patients without these deficiencies 2
From the Research
Cause of Coumadin-Induced Skin Necrosis
- The exact cause of coumadin-induced skin necrosis is still unknown, but it is believed to be related to the mechanisms involved in the protein C, protein S, and antithrombin III anticoagulant pathways 3.
- The syndrome typically occurs during the first few days of warfarin therapy, often in association with the administration of a large initial loading dose of the drug 3.
- Warfarin-induced skin necrosis is a rare but potentially devastating complication of oral anticoagulation, and it is considered a hypercoagulable event 4.
- The use of warfarin can lead to a range of adverse skin manifestations, including ecchymoses, purpura, hemorrhagic necrosis, and maculopapular vesicular urticarial eruptions 3.
Pathophysiology
- The pathophysiology of warfarin-induced skin necrosis is not fully understood, but it is thought to be related to the inhibition of vitamin K-dependent clotting factors, including protein C and protein S 3.
- The inhibition of these factors can lead to a hypercoagulable state, which can cause thrombosis and necrosis of the skin 4.
- The role of antithrombin III in the pathogenesis of warfarin-induced skin necrosis is also not fully understood, but it is thought to play a role in the regulation of clotting factors 3.
Risk Factors
- The risk of warfarin-induced skin necrosis is increased in patients who receive a large initial loading dose of warfarin 3.
- The risk is also increased in patients who have a history of thrombosis or who have a family history of thrombosis 4.
- Other risk factors for warfarin-induced skin necrosis include the use of other medications that interact with warfarin, such as antibiotics and anti-inflammatory medications 5.