Management of Protein S Deficiency
Anticoagulation for Symptomatic Patients
Patients with protein S deficiency who have experienced a venous thromboembolic event require indefinite anticoagulation with vitamin K antagonists (warfarin), targeting an INR of 2.0-3.0. 1 This recommendation is based on the high absolute recurrence risk of approximately 8% per year in this population 1, and the 5-fold increased thrombotic risk compared to those without the deficiency 2.
Key Management Points:
Long-term warfarin therapy is the cornerstone of treatment for symptomatic protein S deficiency, with strict INR monitoring initially 2-3 times weekly until therapeutic range is achieved, then weekly, and eventually every 4 weeks once stable 1.
Avoid high-intensity anticoagulation (INR >3.0), as this significantly increases bleeding risk without providing additional protection against thrombosis 1.
Never abruptly discontinue anticoagulation, as this may result in a temporary hypercoagulable state 1.
Nearly half of thrombotic events in protein S deficiency occur spontaneously without identifiable precipitating factors, though pregnancy/puerperium and immobility/trauma are important triggers 2.
Management of Asymptomatic Carriers
For asymptomatic individuals with protein S deficiency identified through family screening, clinical surveillance without routine prophylactic anticoagulation is appropriate. 1 The evidence shows no benefit of prophylaxis in asymptomatic carriers, and bleeding risk outweighs any potential advantage 1.
High-Risk Situations Requiring Prophylaxis:
Surgery and prolonged immobilization: Prophylactic anticoagulation with low molecular weight heparin (LMWH) should be provided during these high-risk periods 1.
Avoid oral contraceptives and hormone replacement therapy in women with protein S deficiency, as these significantly increase thrombotic risk 3.
Pregnancy Management
Antepartum Period:
Women with protein S deficiency but NO family history of VTE should NOT receive antepartum prophylaxis (conditional recommendation, very low certainty evidence) 3, 1.
Women with protein S deficiency AND a positive family history of VTE may be offered antepartum LMWH prophylaxis, though this remains a conditional recommendation based on very low certainty evidence 1.
Postpartum Period:
The postpartum period carries substantially higher thrombotic risk than the antepartum period, with a risk of 1.76% (95% CI 0-5.99%) in women with protein S deficiency and a family history of VTE. 1
For women with protein S deficiency and a family history of VTE, provide LMWH prophylaxis for 6 weeks postpartum 1.
Women without a family history of VTE do not require routine postpartum prophylaxis 1.
The absolute risk falls below 1 in 10,000 after 6 weeks postpartum, making extended prophylaxis unnecessary 1.
LMWH is the preferred anticoagulant agent during pregnancy and the immediate postpartum period 1.
Diagnostic Considerations
When to Test:
Order a comprehensive thrombophilia panel in young adults with unprovoked VTE and a family history of thrombosis, including functional (free) protein S, total protein S, protein C, antithrombin, factor V Leiden, prothrombin G20210A, lupus anticoagulant, anticardiolipin antibodies, anti-β2-glycoprotein-1 antibodies, and factor VIII levels 1.
Free protein S level is the most reliable predictor of protein S deficiency, with 97.7% sensitivity and 100% specificity 2.
Critical Testing Pitfalls to Avoid:
Never test during acute thrombosis, as protein S levels will be artificially low and non-diagnostic 4.
Never test during pregnancy, as pregnancy significantly lowers protein S levels; defer testing until at least 6 weeks postpartum 4.
Never test patients on warfarin, as vitamin K antagonists reduce protein S levels 4.
Test for compound heterozygosity (co-presence of factor V Leiden and prothrombin G20210A mutations), as this genotype confers a markedly increased recurrence risk (odds ratio ≈6.7) and substantially changes management decisions 1.
Family Screening
Screen first-degree relatives with functional protein S assays, as protein S deficiency is inherited in an autosomal-dominant pattern 1.
Relatives with PROS1 gene defects have a 5.0-fold higher risk of thrombosis (95% CI 1.5-16.8) compared to those without the defect 2.
Asymptomatic carriers should receive clinical surveillance only, without routine prophylactic anticoagulation 1.
Special Clinical Scenarios
Neonatal Homozygous Protein S Deficiency:
Administer 10-20 mL/kg of fresh frozen plasma every 12 hours or protein concentrate (when available) until clinical lesions resolve 1.
After initial stabilization, long-term treatment options include vitamin K antagonists, LMWH, protein replacement, or liver transplantation 1.
Perioperative Management:
For patients on chronic warfarin requiring procedures, protein S deficiency is classified as severe thrombophilia requiring heparin bridging during warfarin interruption for high-risk procedures 1.
Withhold warfarin 5 days before a procedure, bridge with therapeutic-dose LMWH or unfractionated heparin, and resume warfarin after adequate hemostasis 1.
However, recent guidelines suggest that most thrombophilias, including protein S deficiency, do not require bridging for temporary anticoagulation interruption, and the decision should be individualized with hematology consultation 1.
Impact on Acute VTE Management
Routine thrombophilia testing does not alter initial acute VTE treatment, which remains identical regardless of test results 1. However, identifying protein S deficiency is essential for informing decisions on anticoagulation duration, family counseling, and pregnancy-related planning 1.