What conditions make a patient high risk for purpura fulminans when starting warfarin (International Normalized Ratio (INR) anticoagulant)?

High-Risk Conditions for Purpura Fulminans When Starting Warfarin

Protein C deficiency is the primary risk factor for developing purpura fulminans when initiating warfarin therapy, with protein S deficiency being a less common but significant risk factor. 1, 2

Pathophysiology and Risk Factors

Warfarin-induced skin necrosis, which can progress to purpura fulminans, occurs due to a temporary hypercoagulable state created during warfarin initiation. This happens because:

• Protein C has a shorter half-life (4-6 hours) compared to procoagulant factors II, IX, and X (24-72 hours)
• When warfarin is started, especially at high loading doses, protein C levels drop rapidly before reduction in procoagulant factors occurs 1, 3
• This creates a temporary prothrombotic state leading to extensive thrombosis of venules and capillaries within subcutaneous fat

Specific High-Risk Conditions:

1. Protein C deficiency (present in approximately 75% of cases) 3
2. Protein S deficiency (less common but well-documented) 1
3. High loading doses of warfarin (rapid initiation protocols) 3
4. Sepsis (can cause acquired protein C and protein S deficiency) 4
5. Female gender (middle-aged perimenopausal women are at higher risk) 3
6. Previous history of thrombotic events 5
7. Absence of concurrent heparin therapy during warfarin initiation 1

Clinical Presentation and Timing

Warfarin-induced skin necrosis typically occurs:

• Between the 3rd and 8th day of therapy 1, 3
• Affects areas with substantial subcutaneous fat (breasts, thighs, buttocks)
• Begins as painful, erythematous lesions that progress to hemorrhagic bullae and full-thickness necrosis

Prevention in High-Risk Patients

For patients with known risk factors (especially protein C or S deficiency):

1. Start warfarin at low doses (e.g., 2 mg daily) 1
2. Provide concurrent therapeutic anticoagulation with heparin or LMWH during warfarin initiation 1, 3
3. Continue heparin/LMWH until INR is therapeutic for at least 3-5 days 6, 5
4. Gradually increase warfarin dose over several weeks rather than using loading doses 1
5. Monitor INR frequently during initiation phase

Management if Purpura Fulminans Develops

If warfarin-induced purpura fulminans occurs:

1. Immediately discontinue warfarin 3, 2
2. Administer vitamin K to reverse warfarin effects 3
3. Start therapeutic heparin or LMWH for continued anticoagulation 3
4. Obtain surgical consultation for potential debridement of necrotic tissue 3
5. Consider alternative long-term anticoagulation options:
   • Direct oral anticoagulants (DOACs) like edoxaban 7
   • Carefully reintroduce warfarin at very low doses with concurrent heparin if DOACs not an option 6, 5

Important Caveats

• The risk of warfarin-induced skin necrosis is approximately 0.01-0.1% of patients starting warfarin 3
• Patients may develop this complication even without identifiable protein C or S deficiency 1
• Warfarin-induced skin necrosis resembles neonatal purpura fulminans seen in homozygous protein C deficiency 1
• Testing for protein C and S deficiency should be done before starting warfarin in patients with personal or family history of thrombophilia

By identifying high-risk patients and using appropriate initiation protocols, the risk of this rare but serious complication can be significantly reduced.