Warfarin-Induced Skin Necrosis

Why warfarin can cause skin necrosis

Warfarin works by blocking vitamin K, which the liver needs to make several clotting factors (II, VII, IX and X) and two natural anticoagulants, protein C and protein S.

Protein C has a much shorter half-life (about 8 hours) than most clotting factors, especially factor II (about 60 hours). In the first days of warfarin, protein C levels fall faster than clotting factors. For a short time the blood is actually more likely to clot. In susceptible people, clots form in the small veins of the skin and fat, cutting off blood flow and causing tissue death.

This is why warfarin is started with an overlapping fast-acting anticoagulant (usually heparin) when treating a clot, and why very high loading doses are avoided.

Risk factors

• protein C deficiency, inherited or acquired, the most important
• protein S deficiency, factor V Leiden and other clotting disorders
• large initial (loading) doses of warfarin
• starting warfarin without heparin overlap in someone with an active clot
• female sex, obesity and middle age
• heparin-induced thrombocytopenia if warfarin is started while platelets are still low, which can also cause venous limb gangrene

Symptoms

The changes usually develop over hours to a day:

1. pain and a sense of pressure in an area of skin, often before any visible change
2. red, swollen or bruise-like patches with poorly defined edges
3. purple or dark discoloration (purpura), sometimes with a net-like pattern
4. blood-filled blisters
5. black, hardened, dead skin (necrosis) with a sharp edge
6. deeper tissue loss in severe cases

Common sites are areas rich in fat: breasts, thighs, buttocks, belly and, in men, sometimes the penis. It can affect a single area or several.

Similar conditions

• simple bruising from warfarin over-anticoagulation
• calciphylaxis, a form of calcinosis in kidney failure
• cellulitis and necrotizing infections
• vasculitis
• heparin-induced skin necrosis at injection sites
• purpura fulminans from severe infection

Diagnosis

The diagnosis is clinical, based on the timing and appearance. Doctors will:

• examine the skin and check for infection
• check the INR and blood count
• test protein C, protein S and antithrombin levels, ideally after recovery and off warfarin, because warfarin itself lowers them
• check for HIT if heparin was used
• sometimes take a skin biopsy, which shows clots in small vessels without inflammation of the vessel walls

Treatment

• stop warfarin immediately
• give vitamin K to reverse warfarin's effect and restore protein C
• start heparin (unfractionated or low molecular weight) to treat any clot and prevent new ones, unless HIT is present
• protein C concentrate or fresh frozen plasma to rapidly replace protein C, particularly in known deficiency
• wound care, with specialist input
• surgery: removing dead tissue (debridement), skin grafts, and in severe cases removal of a breast or limb

Future anticoagulation

Many people can later use a direct oral anticoagulant (such as apixaban or rivaroxaban), which does not affect protein C. If warfarin is needed again, it is restarted only under full heparin cover, at a low dose, increased gradually, without a loading dose.

Prevention

• start warfarin at standard low doses, not large loading doses
• overlap warfarin with heparin for at least 5 days and until the INR is in range when treating a clot
• consider testing for protein C deficiency in people with a personal or family history of clotting disorders before warfarin
• report new skin pain or discoloration immediately in the first week of warfarin

Frequently asked questions

What is warfarin-induced skin necrosis?

It is a rare complication in which small blood vessels in the skin and fat clot in the first days of warfarin treatment, causing painful patches that turn purple, blister and become black, dead tissue. It needs emergency treatment.

Why does warfarin cause skin necrosis?

Warfarin lowers protein C, a natural anticoagulant, faster than it lowers clotting factors. For a few days, the blood is temporarily more prone to clot, especially in people with protein C deficiency, leading to clots in small skin vessels.

When does warfarin necrosis occur?

It usually appears 3 to 5 days after starting warfarin, and almost always within the first 10 days. It is very unusual after someone has been taking warfarin steadily for a long time.

How is warfarin skin necrosis treated?

Warfarin is stopped, vitamin K is given, and heparin is used for anticoagulation. Protein C concentrate or plasma may be given. The damaged skin needs wound care, and some people need surgery or skin grafts.

Can I take blood thinners again after warfarin necrosis?

Usually yes. Direct oral anticoagulants are often a good option because they do not affect protein C. If warfarin is necessary, it is restarted slowly at low doses with full heparin cover, under close supervision.