ACMT Visual Pearl: Necrosis in the Name of Anticoagulation

4. Warfarin

The image shows skin changes associated with warfarin-induced skin necrosis, a rare side effect of warfarin use, especially in high doses or when used without concomitant “bridging” with heparin. Skin changes typically begin as localized pain and erythema, which progress to petechial hemorrhages, ecchymoses, and eventually to necrosis with hemorrhagic blisters [1].

Background

Warfarin-induced skin necrosis (WISN) was first identified in 1943, but its association with anticoagulant use was not recognized until 1952 [2,3]. Anticoagulant therapy is one of the most prescribed drug classes, with warfarin remaining the treatment of choice in certain situations, such as in patients with mechanical heart valves (e.g., valvular atrial fibrillation) and those with antiphospholipid syndrome with high-risk features. Skin-related complications, specifically necrosis, are extremely rare, with a reported incidence ranging from 0.01% to 0.4% [4].

What causes warfarin-induced skin necrosis? [5-7]

• Warfarin inhibits the activation of Vitamin K-dependent clotting factors (II, VII, IX, and X).
• Warfarin also inhibits the activation of Protein C and S, vitamin K–dependent glycoproteins with anticoagulant effects.
• Due to differences in half-lives (Protein C levels being shortest), there is an imbalance between procoagulant and anticoagulant effects, leading to a brief period of hypercoagulability during warfarin initiation.
• This hypercoagulable state may result in the development of microthrombi in small cutaneous vessels, ultimately resulting in skin necrosis.
• Risk factors for warfarin-induced skin necrosis:
  • Female sex (4:1 predominance); perimenopausal age
  • Obesity
  • Protein C or S deficiency
  • Factor V Leiden
  • Antithrombin III
  • Antiphospholipid antibodies

What is the presentation of warfarin-induced skin necrosis? [4-8]

• Skin changes typically appear 3-5 days after initiating warfarin therapy, and the risk is higher when warfarin is started without the concomitant use of other anticoagulants (e.g., heparin).
• The most common sites affected are the buttocks, abdomen, thighs, calves, and breasts, which are adipose-rich and have poor perfusion.
• Skin changes begin with localized pain and erythema, which can progress to petechial hemorrhage, ecchymosis, and necrosis with hemorrhagic blisters.
• The differential diagnosis of warfarin-induced skin necrosis includes:
  • Cellulitis
  • Calciphylaxis
  • DIC
  • Necrotizing fasciitis
  • Phlegmasia cerulea dolens
  • Purpura fulminans
  • Venous gangrene
  • Vasculitis

How do I make this diagnosis?

• This is a clinical diagnosis.
• Suspicion should be higher in patients started on warfarin without a heparin bridge, those with protein C or S deficiency, or those with necrotic skin lesions in areas of high adiposity.
• Laboratory findings may include prolonged PT, elevated INR, low protein C levels, low protein S levels, elevated D-dimer, and a normal platelet count. However, these findings are neither sensitive nor specific [9].
• Histological findings include cutaneous infarcts, hemorrhages, breakdown of precapillary arterioles, and fibrin deposits, with no evidence of vascular or perivascular inflammation [5].

What is the treatment of warfarin-induced skin necrosis? [5,6]

• The first step in management is the cessation of warfarin.
• If anticoagulation is necessary, IV heparin should be used until signs of improvement of the necrosis (i.e., lack of progression of skin necrosis or signs of wound healing) are observed.
• Once skin changes begin to improve, warfarin can be reintroduced in combination with heparin, with titration to a therapeutic INR.
• Case reports also describe both surgical and medical management options for debridement and wound care of necrotic skin.

Bedside Pearls

• Warfarin-induced skin necrosis typically occurs 3-5 days after initiation, particularly if no bridging anticoagulant was administered.
• Treatment includes cessation of warfarin and wound care of necrotic skin
• Warfarin can be reintroduced with heparin once skin changes are improved.