What is warfarin-induced skin necrosis?
Warfarin is an anticoagulant medicine (blood thinner). Warfarin-induced skin necrosis refers to a rare condition in which there is paradoxical blood clotting. Blood clots block the blood vessels and cause necrosis, where an area of skin is destroyed. Warfarin-induced skin necrosis affects one in every 10,000 patients prescribed warfarin.
The onset is usually within the first 2 to 5 days of warfarin therapy when the blood tends to clot more than is normal. Skin necrosis affects areas of the body with a high fat content.
Warfarin can also give rise to calciphylaxis, a form of cutaneous necrosis due to occlusion of blood vessels with calcium.
Who gets warfarin-induced skin necrosis?
Warfarin-induced skin necrosis is more common in women than men. It usually occurs between the age of 50 and 70 years. It is more common in obese patients and perimenopausal women.
Warfarin-induced skin necrosis is more likely if warfarin is given without heparin or if a higher loading dose of warfarin is given in the first day or two of treatment.
Very rarely, warfarin-induced skin necrosis occurs weeks or months after starting warfarin therapy. This may occur in the following circumstances:
- the dose of warfarin has been increased
- prescribed doses have not been taken
- liver disease
- drug interactions.
Calciphylaxis is more often seen in the setting of chronic renal failure but may be rarely caused by warfarin when kidney function is normal.
What causes warfarin-induced necrosis?
Warfarin is a widely used anticoagulant or blood-thinner. It works by inactivating vitamin K-dependent clotting factors II, VII, IX and X. At the same time, Vitamin K dependent proteins C and S are inactivated – these are natural anticoagulants.
Half the activated Protein C disappears within 6 hours (its half-life). So, Protein C runs out during the first few days of warfarin therapy, before Factor X and II disappear, which have half-lives of 2-5 days. In some circumstances, this leads to excessive clotting.
Why the skin necrosis happens in the areas of fat abundance is unclear; possibly these areas are more susceptible because of reduced blood supply.
Warfarin-induced calciphylaxis may be due to inhibition of the matrix protein Gla, which normally prevents calcium deposition in the blood vessels.
What are the risk factors for warfarin-induced skin necrosis?
Risk factors for warfarin-induced skin necrosis include:
- Inherited deficiency of Protein C, Protein S or Factor V Leiden
- Mutations in methylene tetrahydrofolate reductase gene causing hyperhomocysteinaemia
- Antithrombin III deficiency
- Antiphospholipid antibodies.
What are the clinical features of warfarin-induced skin necrosis?
The first sign is usually pain and purpura (a purplish bruise-like rash), which over a few days becomes bluish-black with a red rim. Blood blisters and full thickness skin necrosis (skin death) follows. There may be a red netlike rash around the necrotic area (retiform purpura). Affected areas are most often the breasts, thighs, buttocks, hips and abdomen, but early warfarin-induced skin necrosis can also cause blue toe syndrome.
Investigations
The diagnosis of warfarin-induced skin necrosis is made clinically.
A skin biopsy can aid in diagnosis. Histopathology of warfarin necrosis usually reveals clotting within blood vessels in the skin without any inflammation. Warfarin can also precipitate calciphylaxis, recognised on biopsy by calcium deposition in the affected skin.
Blood tests for protein C and protein S levels are important to assess the likely predisposing causes.
What is the treatment for warfarin-induced skin necrosis?
The mainstay of treatment of warfarin-induced skin necrosis is to stop warfarin. If anticoagulation is required, heparin can be used. Sometimes Vitamin K is used to hasten the reversal of warfarin effects. If there is life-threatening coagulation then protein C concentrates can be used.
Once warfarin is stopped small areas of skin necrosis can be left to heal, but larger areas of skin necrosis may require surgery and skin grafting.
Warfarin has been cautiously restarted in lower doses in some patients when needed for long-term anticoagulation. This is best done with advice from a haematologist.