Warfarin: reports of calciphylaxis

Calciphylaxis is a very rare but serious condition causing vascular calcification and skin necrosis.

Advice for healthcare professionals:

  • calciphylaxis is a very rare but serious condition that is most commonly observed in patients with known risk factors such as end-stage renal disease
  • cases have been reported in patients taking warfarin, including those with normal renal function, and evidence suggests that on rare occasions warfarin use might lead to calciphylaxis
  • if calciphylaxis is diagnosed, appropriate treatment should be started and consideration should be given to stopping treatment with warfarin

Warfarin is an oral anticoagulant. It is a vitamin K antagonist that acts by inhibiting the formation of active clotting factors II, VII, IX, and X.

Risk of calciphylaxis

Calciphylaxis is a very rare but serious condition that causes vascular calcification and cutaneous necrosis. The mortality rate is high. It is also known as calcific uremic arteriolopathy.

The condition is most commonly observed in patients with end-stage renal disease on dialysis, or in those with known risk factors such as: protein C or S deficiency; hyperphosphataemia; hypercalcaemia; or hypoalbuminaemia.

Cases of calciphylaxis have been reported in patients taking warfarin. Pre-existing renal disease was commonly reported in cases, but some reports noted normal renal function.

An EU-wide review of relevant evidence recently concluded that there is a reasonable possibility that on rare occasions warfarin use might lead to calciphylaxis. The product information for warfarin will be updated with the above advice. The patient information leaflet will also be updated to warn patients of the risk of calciphylaxis, with advice to consult their doctor if they develop a painful skin rash.

Potential mechanisms

Calciphylaxis is poorly understood and the exact pathogenesis is unknown. Calciphylaxis and warfarin-induced skin necrosis can present with similar clinical findings, but can be differentiated by histopathology.1 The mechanism could be mediated through the matrix Gla protein, which is a vitamin-K-dependent protein involved in the inhibition of calcification. Warfarin inhibits Gla protein and may therefore promote vascular calcification in susceptible individuals.2

Article citation: Drug Safety Update Volume 9 Issue 12 July 2016: 1.

  1. Nazarian RM et al. Warfarin-induced skin necrosis. Journal of the American Academy of Dermatology 2009; 61: 325–32.

  2. Saifan C et al. Warfarin-induced calciphylaxis: a case report and review of literature. International Journal of General Medicine 2013; 6: 665–69.

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