What is the management for patients with protein S deficiency?

Management of Protein S Deficiency

For patients with protein S deficiency who have experienced a thrombotic event, initiate long-term anticoagulation with warfarin targeting an INR of 2.0-3.0 for 6-12 months minimum, with indefinite therapy strongly suggested for idiopathic thrombosis. 1, 2

Acute Thrombosis Management

For patients presenting with venous thromboembolism (VTE):

• Start therapeutic anticoagulation immediately with low molecular weight heparin (LMWH) or unfractionated heparin while initiating warfarin 2
• Overlap heparin with warfarin for 5-7 days to minimize risk of warfarin-induced skin necrosis, a known complication in protein S deficiency 2
• Target INR of 2.5 (range 2.0-3.0) for all treatment durations 2

Duration of anticoagulation after first thrombotic event:

• Provoked VTE (secondary to transient risk factor): 3 months minimum 2
• Idiopathic VTE with protein S deficiency: 6-12 months recommended, with indefinite therapy strongly suggested 1, 2
• Recurrent VTE (two or more episodes): indefinite anticoagulation 2

The FDA label explicitly recommends 6-12 months for protein S deficiency with first VTE, and indefinite therapy is suggested for idiopathic thrombosis 2. This reflects the higher recurrence risk compared to transient causes.

Asymptomatic Patients

For asymptomatic individuals with protein S deficiency and no prior thrombosis:

• Clinical surveillance without prophylactic anticoagulation is appropriate 1
• Reserve prophylactic anticoagulation for high-risk situations: major surgery, prolonged immobilization, hospitalization, or pregnancy 1

This conservative approach is based on the relatively low absolute thrombotic risk in asymptomatic carriers (1.76% postpartum risk even with positive family history) 1, which does not justify the bleeding risks of chronic anticoagulation.

Pregnancy Management

Antepartum period:

• Without prior VTE: Do NOT use prophylactic anticoagulation during pregnancy, even with positive family history 1
• With prior VTE: Use prophylactic-dose LMWH throughout pregnancy 1

Postpartum period:

• With positive family history of VTE: Administer prophylactic anticoagulation for 6 weeks postpartum 1
• Without family history of VTE: Postpartum prophylaxis is not recommended 1
• LMWH is the preferred agent during pregnancy and immediate postpartum 1

The postpartum period carries higher thrombotic risk than antepartum (1.76% with family history) 3, justifying selective prophylaxis in this window.

Perioperative Anticoagulation 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 3
• Withhold warfarin 5 days before procedure 3
• Bridge with therapeutic-dose LMWH or unfractionated heparin 3
• Resume warfarin after adequate hemostasis 3

Important caveat: Recent guidelines suggest that most thrombophilias, including protein S deficiency, do NOT require bridging for temporary anticoagulation interruption 3, 1. However, the 2018 Asian-Pacific guidelines specifically list protein S deficiency as severe thrombophilia warranting bridging 3. Seek hematology consultation for individualized risk assessment when bridging decisions are needed 3.

Alternative Anticoagulants

Direct oral anticoagulants (DOACs):

• Emerging evidence suggests apixaban may be effective for preventing recurrent thrombosis in protein S deficiency 4
• Three of four patients in a case series tolerated apixaban without bleeding or thrombotic complications 4
• However, one patient developed recurrent thrombosis despite DOAC therapy and required conversion back to warfarin 4

Current recommendation: Warfarin remains the standard of care based on FDA labeling and established guidelines 2. DOACs may be considered as alternatives, but insufficient data exist to recommend them as first-line therapy 4.

Neonatal Homozygous Protein S Deficiency

For neonates with purpura fulminans:

• Administer fresh frozen plasma (FFP) 10-20 mL/kg every 12 hours OR protein S concentrate (when available) until clinical lesions resolve 1
• After stabilization, long-term options include: vitamin K antagonists, LMWH, protein replacement therapy, or liver transplantation 1

Monitoring and Follow-up

INR monitoring on warfarin:

• Initially: 2-3 times weekly until therapeutic range achieved 1
• Then: weekly monitoring 1
• Once stable: every 4 weeks 1

Patient education priorities:

• Drug interactions affecting anticoagulation (antibiotics, NSAIDs, dietary vitamin K) 1
• Signs of bleeding complications 1
• Importance of adherence and regular monitoring 1

Critical Pitfalls to Avoid

Warfarin-induced skin necrosis:

• Occurs in 0.01-0.1% of patients starting warfarin, but protein S deficiency increases this risk 2, 5
• Presents as painful, purplish skin lesions progressing to necrosis, typically 3-10 days after warfarin initiation 2
• Prevention: Always overlap with heparin for 5-7 days when starting warfarin 2
• If necrosis develops: discontinue warfarin immediately, consider heparin for ongoing anticoagulation 2

Abrupt discontinuation:

• Never stop anticoagulation abruptly, as this creates a temporary hypercoagulable state 1
• Taper or bridge appropriately when discontinuation is necessary 1

Excessive anticoagulation:

• INR >3.0 significantly increases bleeding risk without additional thrombotic protection 1
• Target INR 2.0-3.0 is optimal for protein S deficiency 2

Misclassification of thrombotic risk:

• Protein S deficiency WITHOUT prior thrombosis does not warrant chronic anticoagulation 1
• Protein S deficiency WITH prior thrombosis requires long-term (often indefinite) anticoagulation 2
• Family history alone does not mandate chronic anticoagulation in asymptomatic individuals 1