What is the management of protein C deficiency?

Management of Protein C Deficiency

The management of protein C deficiency should be tailored based on the severity of deficiency, with homozygous deficiency requiring protein C replacement therapy while heterozygous deficiency typically requires anticoagulation therapy for symptomatic cases or those with thrombotic events. 1, 2

Classification and Clinical Presentation

Protein C deficiency can be classified as:

1. Homozygous deficiency:

   • Presents with purpura fulminans in the newborn period
   • Life-threatening condition with microvascular thrombosis and skin necrosis
   • Requires immediate intervention

2. Heterozygous deficiency:

   • More common presentation
   • Associated with increased risk of venous thromboembolism (VTE)
   • Clinical manifestations typically occur between ages 15-40 years
   • May present with deep vein thrombosis or pulmonary embolism

Management of Homozygous Protein C Deficiency

Acute Management

• First-line therapy: Protein C replacement 2
  • Options include:
    • Protein C concentrate: 20-60 units/kg until clinical lesions resolve
    • Fresh frozen plasma (FFP): 10-20 mL/kg every 12 hours

Long-term Management

1. Protein C replacement therapy 1, 2

   • Continuous IV or subcutaneous administration
   • Dose increases based on age and size of child

2. Vitamin K antagonists (VKA) 1

   • Long-term treatment with warfarin

3. Low molecular weight heparin (LMWH) 1

   • Alternative to VKA

4. Liver transplantation 1

   • Curative option for severe cases with recurrent episodes
   • Recommended only for those who experience complications or failure of medical management

Management of Heterozygous Protein C Deficiency

Asymptomatic Patients

• Without family history of VTE: Clinical surveillance 1
• With family history of VTE: Consider prophylactic anticoagulation in high-risk situations

Symptomatic Patients (with thrombotic events)

1. Acute thrombotic event:

   • Initial treatment with unfractionated heparin (UFH) or LMWH for at least 5 days 1
   • Begin oral vitamin K antagonist therapy as early as day 1
   • Continue UFH/LMWH until INR exceeds 2.0 1

2. Long-term management:

   • First VTE episode:

     • Secondary to transient risk factor: 3 months of anticoagulation
     • Idiopathic: 6-12 months of anticoagulation 3

   • Recurrent VTE: Indefinite anticoagulation 1

   • Target INR: 2.0-3.0 3

Special Considerations

Pregnancy Management

• Antepartum: Clinical surveillance regardless of family history of VTE 1
• Postpartum:
  • Without family history of VTE: Clinical surveillance
  • With family history of VTE: Prophylactic or intermediate-dose LMWH for 6 weeks 1

Warfarin Precautions

• Risk of warfarin-induced skin necrosis in protein C deficient patients 3
• To prevent this complication:
  • Begin with very low dose of warfarin
  • Overlap with therapeutic heparin
  • Gradually increase warfarin over several weeks 2

Laboratory Diagnosis

• Initial testing should measure protein C activity using clot-based or chromogenic methods 4
• Chromogenic assay may miss some cases (particularly Type IIb deficiency) 5
• Consider genetic testing for confirmation, especially with borderline activity levels

Monitoring

• Regular monitoring of anticoagulation therapy with INR testing for patients on warfarin
• Periodic assessment of thrombotic risk factors
• Evaluation for recurrent thrombotic events

Pitfalls to Avoid

1. Failure to recognize neonatal purpura fulminans as a medical emergency requiring immediate protein C replacement
2. Starting warfarin without heparin overlap in protein C deficient patients
3. Using high initial doses of warfarin, which may precipitate skin necrosis
4. Relying solely on chromogenic assays for diagnosis, which may miss some cases
5. Discontinuing anticoagulation prematurely in patients with recurrent thrombotic events