Risk of Thrombosis in Protein S Deficiency
Patients with protein S deficiency face a substantially elevated risk of venous thromboembolism, with asymptomatic carriers experiencing thrombotic events at a rate of 3.5% per patient-year, representing a 5-fold increased risk compared to non-deficient relatives. 1, 2
Quantified Thrombotic Risk
Asymptomatic Carriers
- Annual incidence of thromboembolism: 3.5% per patient-year in prospective follow-up of asymptomatic protein S deficient individuals 1
- 5-fold increased risk of venous thrombosis compared to relatives without the PROS1 gene defect 2
- Nearly half of thrombotic events occur spontaneously without identifiable precipitating factors 2
High-Risk Clinical Scenarios
- Pregnancy/postpartum period: Represents a major precipitating factor for thrombosis in protein S deficient women 1, 2
- Immobility and trauma: Significant triggers for thrombotic events 2
- Surgical procedures: Carry elevated thrombotic risk without prophylaxis 1
Risk Stratification by Genotype
- Splice-site or major structural PROS1 mutations: Associated with higher thrombotic risk and lower protein S levels compared to missense mutations 2
- Family history of VTE: Postpartum thrombotic risk of 1.76% (95% CI, 0%-5.99%) in women with protein S deficiency and positive family history 3
Management Approach
For Patients with Prior Thrombosis
Long-term anticoagulation with vitamin K antagonists (warfarin) targeting INR 2.0-3.0 is recommended for patients with documented thrombotic events. 4, 5
- Duration of anticoagulation: 6-12 months minimum for first episode; indefinite therapy suggested for idiopathic thrombosis 5
- Target INR: 2.5 (range 2.0-3.0) for all treatment durations 5
- Risk-benefit reassessment should occur periodically for patients on indefinite anticoagulation 5
For Asymptomatic Carriers
Clinical surveillance without routine prophylactic anticoagulation is appropriate for asymptomatic protein S deficient individuals. 4
- Prophylactic anticoagulation should be provided during high-risk situations: surgery, prolonged immobilization, or pregnancy 4
- Heparin prophylaxis is highly effective in preventing thrombosis during high-risk procedures 1
Pregnancy Management
Antepartum Period
- For women without family history of VTE: Antepartum prophylaxis is NOT recommended (conditional recommendation) 3, 4
- Low molecular weight heparin (LMWH) is the preferred agent when prophylaxis is indicated during pregnancy 4
Postpartum Period
- For women WITH family history of VTE: Postpartum antithrombotic prophylaxis is suggested for 6 weeks 3, 4
- For women WITHOUT family history of VTE: Postpartum prophylaxis is NOT recommended 3
Special Considerations
Neonatal Homozygous Deficiency
- Immediate treatment with fresh-frozen plasma (10-20 mL/kg every 12 hours) or protein concentrate until clinical lesions resolve 4
- Long-term options: VKA, LMWH, protein replacement, or liver transplantation 4
Bridging Therapy
Bridging with heparin is NOT required for most patients with protein S deficiency during temporary anticoagulation interruption, as it is classified as a higher-risk thrombophilia but does not mandate bridging in most clinical scenarios 3
Critical Pitfalls to Avoid
- Abrupt discontinuation of anticoagulation: Creates a temporary hypercoagulable state 4
- High-intensity anticoagulation (INR >3.0): Significantly increases bleeding risk without additional thrombotic protection 4
- Failure to provide prophylaxis during high-risk situations: Surgery, immobilization, and pregnancy/postpartum period require prophylactic anticoagulation even in asymptomatic carriers 4, 1
- Assuming DOACs are equivalent: Limited evidence exists for DOAC efficacy in protein S deficiency, with at least one case report of recurrent thrombosis during DOAC therapy 6