What is the recommended treatment for individuals with protein S deficiency?

Treatment of Protein S Deficiency

For patients with protein S deficiency who have experienced a thrombotic event, long-term anticoagulation with warfarin targeting an INR of 2.0-3.0 is recommended, with indefinite therapy suggested for idiopathic thrombosis. 1

Treatment Based on Clinical Presentation

Symptomatic Patients (History of Thrombosis)

Duration of anticoagulation depends on the nature of the thrombotic event:

• First episode provoked by transient risk factor: 3 months of warfarin therapy 1
• First episode of idiopathic (unprovoked) thrombosis: 6-12 months minimum, with indefinite therapy suggested 1
• Recurrent thrombosis: Indefinite anticoagulation 2, 1

Target INR: 2.5 (range 2.0-3.0) for all treatment durations 1

The FDA label explicitly states that protein S deficiency warrants 6-12 months of treatment initially, with indefinite therapy suggested for idiopathic thrombosis, and the risk-benefit should be reassessed periodically. 1 This recommendation is supported by randomized trials demonstrating that oral anticoagulants reduce recurrent venous thrombosis risk by 90%, and that longer treatment durations (6 months vs 6 weeks, and 2 years vs 3 months) provide superior protection. 2

Asymptomatic Patients (No History of Thrombosis)

Clinical surveillance without routine anticoagulation is appropriate for asymptomatic individuals with protein S deficiency. 3

Prospective cohort data shows that asymptomatic protein S deficient patients have a thrombosis incidence of 3.5% per patient-year compared to 0% in non-deficient relatives, representing a significantly elevated risk. 4 However, the absolute risk does not justify routine prophylactic anticoagulation given bleeding risks of approximately 3% per year with warfarin therapy. 5

Special Clinical Situations

Pregnancy Management

For pregnant women with protein S deficiency:

• Without prior VTE and no family history: Antepartum clinical surveillance only; postpartum clinical surveillance only 3
• Without prior VTE but with family history of VTE: Consider antepartum prophylactic anticoagulation; postpartum prophylaxis with LMWH for 6 weeks is suggested 3
• With prior VTE: Prophylactic LMWH throughout pregnancy and 6 weeks postpartum 3

The postpartum thrombotic risk in women with protein S deficiency and positive family history is 1.76% (95% CI, 0%-5.99%), which justifies prophylaxis during this high-risk period. 3 LMWH is the preferred agent during pregnancy and the immediate postpartum period. 3

High-Risk Situations (Surgery, Immobilization)

Prophylactic anticoagulation with heparin is recommended during high-risk situations such as surgery or prolonged immobilization in both symptomatic and asymptomatic individuals. 3

Prospective data demonstrates that heparin prophylaxis is highly effective in preventing thrombosis during high-risk situations—in one cohort, 5 major and minor surgeries were performed without thromboembolic complications using heparin prophylaxis. 4

Perioperative Anticoagulation Management

Bridging with LMWH is NOT routinely required when temporarily interrupting anticoagulation in most patients with protein S deficiency. 2

While protein S deficiency is classified as a higher-risk thrombophilia, it does not mandate bridging therapy in most clinical scenarios. 2, 3 However, hematological consultation is suggested for individual risk assessment. 2 For cardiac surgery patients with protein S deficiency, perioperative warfarin therapy with target INR of 2.0 and incomplete protamine antagonism has been suggested to minimize perioperative thromboembolic risk. 6

Neonatal Homozygous Protein S Deficiency

For neonates with homozygous protein S deficiency presenting with purpura fulminans or thrombosis:

• Acute management: Fresh frozen plasma 10-20 mL/kg every 12 hours OR protein S concentrate (when available) until clinical lesions resolve 3
• Long-term options: VKA, LMWH, protein replacement, or liver transplantation 3

Alternative Anticoagulant Options

Direct Oral Anticoagulants (DOACs)

While warfarin remains the standard of care, emerging evidence suggests DOACs may be effective alternatives in selected patients. Case series report successful use of rivaroxaban in severe protein S deficiency with warfarin-induced skin necrosis, and apixaban in patients with protein C/S deficiency-induced thrombosis. 7, 8

Rivaroxaban may be particularly valuable in patients developing warfarin-induced skin necrosis, as it directly inhibits factor Xa without reducing protein C levels (which warfarin does, potentially worsening the hypercoagulable state in severe protein S deficiency). 8 However, these are case reports and series—warfarin remains the evidence-based first-line therapy per FDA labeling and guidelines. 1

Monitoring and Follow-Up

For patients on long-term warfarin therapy:

• Initial monitoring: INR 2-3 times weekly until therapeutic range achieved 3
• Maintenance monitoring: Weekly initially, then every 4 weeks once stable 3
• Patient education: Counsel regarding drug interactions and bleeding risk 3

Critical Pitfalls to Avoid

Do not use high-intensity anticoagulation (INR >3.0) as it significantly increases bleeding risk without additional therapeutic benefit. 3, 1 The FDA label explicitly states that INR >4.0 provides no additional benefit and increases bleeding risk. 1

Do not abruptly discontinue anticoagulation, which may result in a temporary hypercoagulable state. 3

Do not initiate warfarin without considering heparin bridging in severe protein S deficiency, as warfarin initially reduces protein C levels before reducing procoagulant factors, potentially worsening hypercoagulability. 2 Concomitant heparin for 5-7 days during warfarin initiation may minimize the incidence of warfarin-induced skin necrosis. 1

Reassess the risk-benefit ratio periodically (e.g., annually) in patients receiving indefinite anticoagulation, as bleeding risk accumulates over time. 1