What is the cause of warfarin (Coumadin)-induced skin necrosis?

Cause of Coumadin-Induced Skin Necrosis

Protein C deficiency is the primary cause of warfarin (Coumadin)-induced skin necrosis. 1

Pathophysiology

Warfarin-induced skin necrosis is an uncommon but serious complication that typically occurs during the first week of therapy (usually between days 3-8). The pathogenesis involves:

1. Initial procoagulant state: When warfarin therapy begins, it causes:

   • Rapid decrease in vitamin K-dependent anticoagulant proteins (especially protein C)
   • Protein C has a shorter half-life (6 hours) than clotting factors II, IX, and X
   • This creates a temporary hypercoagulable state 1, 2

2. Thrombotic mechanism:

   • Extensive thrombosis develops in venules and capillaries within subcutaneous fat
   • This leads to interruption of blood supply to the skin
   • Results in painful necrotic lesions 1

Associated Conditions

While protein C deficiency is most strongly associated with this condition, other factors may contribute:

• Protein S deficiency: Less commonly associated but has been reported 1, 3
• Normal protein C/S levels: Some patients develop necrosis without identifiable deficiencies 1

The pathogenic role of protein C deficiency is supported by the similarity of warfarin-induced necrotic lesions to those seen in neonatal purpura fulminans, which occurs in homozygous protein C deficiency 1.

Clinical Presentation

The condition presents with:

• Pain and erythema initially
• Progression to petechial lesions
• Development of hemorrhagic bullae
• Eventual necrosis and eschar formation 4

Management Considerations

For patients who develop warfarin-induced skin necrosis but require ongoing anticoagulation:

• Immediately discontinue warfarin
• Administer vitamin K and fresh frozen plasma if needed
• Switch to therapeutic heparin or LMWH
• If warfarin must be restarted:
  • Begin with a very low dose (1-2 mg daily)
  • Maintain therapeutic heparin coverage
  • Gradually increase warfarin over several weeks
  • This approach prevents abrupt drops in protein C levels 1, 3

Important Caveat

Despite bridging therapy with heparin or LMWH, warfarin-induced skin necrosis can still occur in susceptible individuals, particularly those with underlying protein C or S deficiencies 4, 5.