Protein S Deficiency: Evaluation and Management
Immediate Diagnostic Workup
For a young adult with unprovoked VTE and family history of thrombosis, order a comprehensive thrombophilia panel including functional protein S assay (free and total), protein C, antithrombin, factor V Leiden, prothrombin G20210A, lupus anticoagulant, anticardiolipin antibodies, anti-β2-glycoprotein-1 antibodies, and factor VIII levels. 1, 2, 3
Critical Testing Details:
- Measure free protein S specifically, not just total protein S, as total levels can be normal while free (functional) protein S is severely reduced 4
- Test for compound heterozygosity (factor V Leiden + prothrombin mutation), which carries substantially elevated recurrence risk (OR 6.69) and dramatically alters management 1, 3
- Timing matters: ideally test at least 2-4 weeks after completing acute anticoagulation to avoid false-positive results from acute thrombosis or warfarin effect 2
Anticoagulation Strategy
Initiate long-term anticoagulation with vitamin K antagonists targeting INR 2.0-3.0, as protein S deficiency confers a high absolute recurrence risk of 7.7-8.4% annually. 2, 5
Duration of Treatment:
- For unprovoked VTE with protein S deficiency: indefinite anticoagulation is recommended 2
- The annual recurrence rate without anticoagulation is 8.4% (95% CI: 5.8-11.7%) for protein S deficiency specifically 5
- Cumulative recurrence rates reach 15% at 1 year, 38% at 5 years, and 53% at 10 years 5
- This high recurrence risk justifies lifelong therapy, particularly given the low major bleeding rate of 0.5% annually on oral anticoagulation 5
Alternative Agents:
- Low molecular weight heparin (LMWH) is preferred during pregnancy and the immediate postpartum period 2
- Direct oral anticoagulants (DOACs) may be considered, though vitamin K antagonists remain the guideline-recommended standard 2
Monitoring Protocol
INR monitoring should occur 2-3 times weekly until therapeutic range is achieved, then weekly, and eventually every 4 weeks once stable. 2, 6
Key Monitoring Points:
- Educate patients about drug interactions that affect anticoagulation status 2
- Monitor for bleeding complications, particularly with INR >3.0, which significantly increases bleeding risk without additional protection 2
- Never abruptly discontinue anticoagulation, as this creates a temporary hypercoagulable state 2
Family Screening Considerations
Screen first-degree relatives with functional protein S assays, as this is an inherited condition with autosomal dominant transmission. 1, 4, 7
Management of Asymptomatic Family Members:
- For asymptomatic relatives with protein S deficiency: clinical surveillance without prophylactic anticoagulation is appropriate 2
- The evidence shows no benefit from routine prophylaxis in asymptomatic carriers, and the bleeding risk outweighs potential benefits 1
- Provide prophylactic anticoagulation only during high-risk situations: surgery, prolonged immobilization, or pregnancy 2
Pregnancy-Specific Management
Antepartum Period:
- For women with protein S deficiency WITHOUT family history of VTE: do not use antepartum prophylaxis 1, 2
- For women with protein S deficiency WITH family history of VTE: consider antepartum prophylaxis with LMWH (conditional recommendation given very low certainty evidence) 1, 2
Postpartum Period:
- For women with protein S deficiency AND family history of VTE: provide postpartum prophylaxis with LMWH for 6 weeks 1, 2, 6
- The postpartum thrombotic risk is 1.76% (95% CI: 0-5.99%) in those with family history, justifying prophylaxis 1, 2
- For women WITHOUT family history of VTE: postpartum prophylaxis is not recommended 1
Rationale:
The postpartum period carries higher thrombotic risk than antepartum, with risk particularly concentrated in the first 3-6 weeks after delivery 1. The absolute risk after 6 weeks drops below 1 in 10,000, making extended prophylaxis beyond 6 weeks unnecessary 1.
Critical Contraindications
Avoid all estrogen-containing contraceptives and hormone replacement therapy, which synergistically increase thrombotic risk 6
Specific Restrictions:
- Combined oral contraceptives are absolutely contraindicated 3
- Even vaginal estradiol requires careful consideration and is contraindicated if: homozygous protein S deficiency, compound heterozygosity with other thrombophilias, active cancer, or less than 3 months post-VTE 3
- Pregnancy itself increases VTE risk sixfold, further amplified by protein S deficiency 8
Special Clinical Scenarios
Neonatal Homozygous Protein S Deficiency (Purpura Fulminans):
- Administer 10-20 mL/kg fresh frozen plasma every 12 hours OR protein concentrate until clinical lesions resolve 2, 9
- Long-term options include vitamin K antagonists, LMWH, protein replacement, or liver transplantation 2
Perioperative Management:
- For patients on chronic warfarin requiring procedures: withhold warfarin 5 days before, bridge with therapeutic-dose LMWH or unfractionated heparin, resume warfarin after adequate hemostasis 2
- However, recent evidence suggests individualized decision-making with hematology consultation, as not all protein S deficiency cases require bridging 2
Evidence Quality and Nuances
The recommendation for indefinite anticoagulation after unprovoked VTE is based on convincing evidence that longer-term secondary prophylaxis yields comparable benefits regardless of thrombophilia status 1. The key distinction is that protein S deficiency confers a substantially higher absolute recurrence risk (8.4% annually) compared to VTE patients without thrombophilia 5, making the risk-benefit calculation favor indefinite therapy.
The evidence does NOT support routine thrombophilia testing changing acute VTE management, as initial treatment is identical 1. However, identifying protein S deficiency is crucial for duration decisions, family counseling, and pregnancy planning 1, 2.
For asymptomatic family members, the absolute risk of first VTE remains relatively low despite the thrombophilia, while anticoagulation carries definite bleeding risk, explaining why prophylaxis is not recommended outside high-risk situations 1.