Introduction:
Coumadin is an oral blood-thinning medication used to manage deep vein thrombosis, pulmonary thromboembolism, cardiac bypass graft prophylaxis, and prosthetic heart valve patients. Skin necrosis from coumadin is a severe but rare condition, occurring in 1:10,000 patients who receive anticoagulant therapy, with a male-female ratio of 4:1. It has a high morbidity rate, and immediate surgical intervention with local debridement is required. Failure of early diagnosis and treatment can lead to death.
What Is Blood Coagulation?
Coagulation is a physiologic process of blood clot formation. The first stage involves primary hemostasis characterized by constriction of the blood vessel and platelet clumping at the injury site. Next, clotting involves the interaction of several blood components known as coagulation factors. Activation of factor X plays a vital role in both pathways resulting in clot formation.
The extrinsic pathway is first activated in response to a protein known as tissue factor. For example, when a blood vessel ruptures, the cells come into contact with blood containing tissue factor activating factor VII, forming factor VIIa. This activation triggers a flow of reactions resulting in the production of factor X.
An injury within a blood vessel activates the intrinsic pathway. This activates factor XII (Hageman factor), which occurs in circulating blood over the injured site. The extrinsic pathway also activates intrinsic pathway components. Cross-activation thus serves to intensify coagulation.
The production of factor X results in the division of prothrombin to thrombin. Thrombin catalyzes the conversion of fibrinogen (a soluble plasma protein) into long, sticky threads of insoluble fibrin. The fibrin threads create a mesh of platelets, blood cells, and plasma. In a few minutes, the fibrin meshwork contracts, squeezing out its fluids. This process of clot retraction is the final step in coagulation. It yields a resilient, insoluble clot that can withstand the friction of blood flow.
Coumadin is an anticoagulant that disrupts this coagulation process and maintains the blood in a fluid state.
What Are the Causes of Coumadin-Induced Skin Necrosis?
Coumadin is a commonly used blood thinner. It works by deactivating vitamin K-dependent blood clotting factors II, VII, IX, and X and Vitamin K-dependent proteins C and S, which are natural anticoagulants.
The half-life of activated protein C is less than 6 hours. So, protein C exhausts during the first few days of warfarin therapy. The half-life of factors X and II is 2-5 days, which disappears between 7 to 10 days. Sometimes, this causes excessive clotting of blood.
Thrombosis, hypersensitivity, hemorrhage, factor VII deficiency, protein C deficiency, and direct toxic effects of warfarin can potentiate skin necrosis.
The reason behind skin necrosis in the fat abundance area is unclear but can be due to decreased blood supply.
Coumadin-induced calciphylaxis may occur due to matrix protein inhibition, which is responsible for preventing calcium deposition in the blood vessels.
What Are the Risk Factors of Coumadin-Induced Skin Necrosis?
Risk factors for coumadin-induced skin necrosis include,
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Perimenopausal age.
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Viral infections, hepatic disease, and drug interactions.
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Deficiency of protein S or Factor V Leiden, protein C, antithrombin III, hyperhomocysteinemia, and antiphospholipid antibodies are common underlying risk factors.
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Large loading doses of warfarin or without an initial parallel dose of heparin.
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Methylenetetrahydrofolate reductase gene mutation causes hyperhomocysteinemia.
What Are the Clinical Features of Coumadin-Induced Skin Necrosis?
It usually starts one to ten days after warfarin intake as sudden, localized pain and well-defined erythematous bullae formation. Next, a purplish bruise-like rash turns into bluish-black with a red rim over time. Blood sores and full-thickness skin necrosis follows. Finally, a red net-like rash may be around the dead skin area known as retiform purpura. It may be associated with paresthesia or a pressure sensation. Commonly affected areas are breasts, hips, abdomen, thighs, and buttocks. The early stage of coumadin-induced skin necrosis can cause blue toe syndrome.
What Are the Investigations for Coumadin-Induced Skin Necrosis?
Coumadin-induced skin necrosis is usually diagnosed with its clinical presentation.
Other investigations include:
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Skin biopsy reveals clotting within blood vessels of the skin. Coumadin also precipitates calciphylaxis – a deposition of calcium in the skin.
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Blood tests detect protein C and protein S levels in the blood.
How Is Coumadin-Induced Skin Necrosis Treated?
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The primary treatment of coumadin-induced skin necrosis is to stop coumadin. Alternatively, heparin can be used.
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When Coumadin therapy is stopped, small areas of skin necrosis heal, while the more significant areas require surgical intervention and skin grafting.
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Local treatment includes topical bactericidal agents.
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Mastectomy or amputation may be required.
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Vitamin K or Fresh frozen plasma is used to reverse the coumadin effects. In life-threatening cases, protein C concentrates are infused.
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Coumadin should be carefully restarted with low doses when required under the guidance of a hematologist.
How Can It Be Prevented?
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Recognize the high-risk individuals for Coumadin therapy.
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Start with a daily minimum dose of Coumadin instead of the loading dose.
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Simultaneous heparin therapy can reduce thrombus progression and skin necrosis.
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Address localized skin discomfort of the patient.
What Is the Lesion Similar to Coumadin-Induced Skin Necrosis?
Clinically, Coumadin-induced skin necrosis can mimic.
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Calciphylaxis.
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Microembolization (septic emboli, cholesterol emboli).
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Thrombocytopenia and thrombosis syndrome.
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Disseminated intravenous coagulation.
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Purpura fulminans.
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Necrotizing fasciitis.
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Cryoglobulinemia (types II and III).
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Decubitus ulcers.
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Snake venoms induced skin necrosis.
Conclusion:
Coumadin-induced skin necrosis is an uncommon complication of anticoagulant therapy with a high morbidity and mortality rate, indicating immediate drug termination and replacement with another anticoagulant drug. When two or more drugs are simultaneously administered, laboratory investigation may help decide the causative agent. A skin biopsy, in combination with the clinical history, helps in proper diagnosis and treatment.
