What is the pathophysiology and management of purpura fulminans?

Pathophysiology and Management of Purpura Fulminans

Purpura fulminans is a life-threatening thrombotic disorder characterized by microvascular thrombosis and skin necrosis, primarily caused by severe deficiency of protein C, which requires immediate protein C replacement therapy with or without anticoagulation for optimal management. 1

Pathophysiology

Purpura fulminans (PF) represents a severe form of disseminated intravascular coagulation with three main etiological categories:

1. Congenital Protein C or S Deficiency

   • Homozygous protein C deficiency leads to severe thrombotic complications in neonates
   • Results in unregulated thrombin generation and fibrin deposition
   • Presents with skin necrosis and disseminated intravascular coagulation shortly after birth 1, 2

2. Acquired Protein C/S Deficiency

   • Secondary to severe bacterial infections (especially meningococcal, streptococcal)
   • Sepsis-induced consumption of natural anticoagulants
   • Dysfunction of the protein C-thrombomodulin pathway 3

3. Warfarin-Induced

   • Occurs during initiation of vitamin K antagonist therapy
   • Due to more rapid decline in protein C (short half-life) compared to other vitamin K-dependent factors
   • Typically presents 3-8 days after starting warfarin 1

The central mechanism involves dysregulation of the coagulation system with:

• Severe depletion of protein C and/or protein S
• Uncontrolled thrombin generation
• Microvascular thrombosis in small and medium-sized vessels
• Perivascular hemorrhage and skin necrosis
• Progression to multi-organ failure if untreated 4, 3

Clinical Presentation

• Painful, non-blanching purpuric lesions that rapidly progress to hemorrhagic necrosis
• Symmetrical distribution, often affecting extremities
• Fever, hypotension, and signs of shock in infectious cases
• Laboratory findings: thrombocytopenia, prolonged coagulation times, elevated D-dimer, and low protein C/S levels 5, 6

Management

Congenital Purpura Fulminans (Homozygous Protein C Deficiency)

1. Acute Management

   • Protein C replacement is the first-line therapy rather than anticoagulation alone 1
   • Options for protein C replacement:
     • Protein C concentrate (preferred if available)
     • Fresh frozen plasma (if concentrate unavailable)
   • Dosing should achieve protein C levels of at least 50-80% 1, 2

2. Combined Therapy for Acute Episodes

   • In acute purpura fulminans episodes, anticoagulation plus protein C replacement is superior to anticoagulation alone 1
   • This combination reduces mortality, pulmonary embolism, bleeding, and skin necrosis compared to anticoagulation alone 1

3. Long-term Management Options

   • Continuous Protein C Replacement:

     • Most effective but expensive
     • Administered IV or subcutaneously
     • Dose increases with age/size of child 1

   • Anticoagulation:

     • High-intensity vitamin K antagonists
     • Higher bleeding risk (14% major bleeding rate) 1

   • Combined Approach:

     • Reduced protein C dosing plus lower-intensity anticoagulation
     • Balances cost constraints with reduced bleeding risk 1

   • Liver Transplantation:

     • Curative option as liver is the site of protein C synthesis
     • Consider for severe cases with recurrent episodes
     • Balances long-term benefits against transplant-related risks 1

Acquired Purpura Fulminans

1. Treat Underlying Infection

   • Prompt antimicrobial therapy
   • Source control if applicable

2. Replacement of Anticoagulant Proteins

   • Fresh frozen plasma or protein C concentrate
   • Target normalization of protein C levels 3, 6

3. Anticoagulation

   • Heparin or low molecular weight heparin
   • Monitor closely for bleeding complications

Warfarin-Induced Skin Necrosis/Purpura Fulminans

1. Discontinue Warfarin Immediately

2. Vitamin K Administration

3. Protein C Replacement

   • Fresh frozen plasma or protein C concentrate

4. If Warfarin Must Be Restarted

   • Begin with very low dose (e.g., 2 mg)
   • Overlap with therapeutic heparin
   • Gradually increase warfarin over several weeks
   • This approach prevents abrupt protein C depletion 1

Special Considerations

• Neonates: Require immediate recognition and treatment; mortality approaches 100% if untreated 2
• Surgical Management: Debridement and skin grafting may be necessary for extensive necrosis 5
• Monitoring: Regular assessment of protein C levels, coagulation parameters, and clinical response
• Cost Considerations: Protein C concentrate is expensive; treatment decisions may be influenced by availability and healthcare resources 1

Pitfalls to Avoid

1. Delayed Diagnosis: Early recognition is critical; any neonate with purpuric lesions should be evaluated for protein C deficiency
2. Inadequate Protein C Replacement: Insufficient dosing can lead to treatment failure
3. Overlooking Underlying Causes: Always investigate for sepsis, autoimmune conditions, or malignancy in acquired cases
4. Abrupt Warfarin Initiation: When starting warfarin in high-risk patients, use low initial doses with heparin overlap

The management of purpura fulminans requires rapid intervention with appropriate protein C replacement and consideration of long-term strategies based on the underlying etiology, with the goal of preventing mortality and reducing long-term complications such as limb amputation and scarring.