What is the management approach for patients with protein S deficiency who have experienced a cerebrovascular accident (CVA)?

Management of Protein S Deficiency in Cerebrovascular Accident (CVA)

For patients with protein S deficiency who have experienced an arterial ischemic stroke, either anticoagulation or antiplatelet therapy is reasonable, with the choice depending on whether concurrent venous thrombosis is present. 1

Initial Evaluation and Risk Stratification

When a patient with protein S deficiency presents with CVA, the critical first step is determining whether this represents arterial thrombosis alone or if there is concurrent venous thromboembolism:

• Evaluate for deep vein thrombosis (DVT) using lower extremity ultrasonography, as this finding mandates anticoagulation rather than antiplatelet therapy 1
• Perform comprehensive stroke workup to identify alternative mechanisms of stroke beyond the thrombophilia, including cardiac sources (echocardiography), large vessel disease (vascular imaging), and small vessel disease 1
• Consider cerebral venous sinus thrombosis (CVST) if clinical features suggest venous rather than arterial pathology, using CT venography or MR venography for diagnosis 1, 2

Treatment Algorithm Based on Thrombosis Type

Arterial Stroke WITHOUT Venous Thrombosis

Antiplatelet therapy is the reasonable first-line approach for most patients with arterial ischemic stroke and protein S deficiency when no venous thrombosis is identified 1:

• Aspirin 81-325 mg daily should be initiated within 24-48 hours of stroke onset 1
• Continue antiplatelet therapy long-term for secondary stroke prevention 1
• Alternative consideration: Anticoagulation with warfarin (target INR 2.0-3.0) is also reasonable in this scenario, though not superior to antiplatelet therapy based on available evidence 1

Arterial Stroke WITH Concurrent DVT

Anticoagulation is mandatory when venous thrombosis accompanies the arterial stroke 1:

• Initiate therapeutic anticoagulation with either unfractionated heparin or low molecular weight heparin (LMWH) 1, 3
• Transition to warfarin with target INR 2.0-3.0 for long-term management 1, 3
• Duration depends on clinical circumstances: 3-6 months for provoked events, indefinite for unprovoked or recurrent thrombosis 3

Cerebral Venous Sinus Thrombosis

Immediate anticoagulation is indicated even if intracranial hemorrhage is present 1, 2:

• Start IV heparin or subcutaneous LMWH immediately upon diagnosis confirmation 1, 2
• The presence of hemorrhagic transformation is NOT a contraindication to anticoagulation in CVST 2, 4
• Continue anticoagulation for at least 3 months, then transition to antiplatelet therapy 1
• For patients with protein S deficiency and CVST, consider extending anticoagulation to 6-12 months given the underlying thrombophilia 3

Emerging Evidence on Direct Oral Anticoagulants (DOACs)

While warfarin remains the guideline-recommended anticoagulant, emerging case series suggest apixaban may be an effective alternative for patients with protein S deficiency:

• Case reports demonstrate successful prevention of recurrent thrombotic events with apixaban in protein S deficiency 5, 6
• One case series showed 3 of 4 patients with protein S deficiency tolerated apixaban without bleeding or recurrent thrombosis 5
• A specific case of ischemic stroke with protein S deficiency was successfully managed with apixaban 10 mg BID initially, preventing recurrence 6
• However, guideline recommendations still favor warfarin as the evidence base for DOACs in inherited thrombophilias remains limited 1, 3

Special Populations

Pregnancy

For pregnant women with protein S deficiency and prior stroke 3:

• LMWH is the preferred anticoagulant throughout pregnancy and for 6 weeks postpartum
• Warfarin is contraindicated during pregnancy due to teratogenicity
• Postpartum prophylaxis is particularly important as thrombotic risk is highest in this period (1.76% with family history of VTE) 3

Pediatric Patients

For children with protein S deficiency and stroke 1:

• Antiplatelet therapy with aspirin for at least 1 year is reasonable for arterial stroke
• If CVST is present, anticoagulate for minimum 3 months, with consideration for additional 3 months if symptoms persist 2

Critical Pitfalls to Avoid

• Do not diagnose protein S deficiency during acute stroke: Acquired protein S deficiency commonly occurs in acute illness, including stroke itself 7, 8. Confirm the diagnosis 3 months after the acute event when inflammatory markers have normalized 9
• Do not withhold anticoagulation in CVST due to hemorrhage: Hemorrhagic conversion in venous thrombosis results from venous congestion and is not a contraindication to anticoagulation 2, 4
• Do not assume protein S deficiency is the sole stroke mechanism: 83% of young stroke patients with protein S deficiency have alternative or contributing stroke mechanisms that require identification and treatment 1
• Recognize that free protein S deficiency is common in hospitalized patients (20% prevalence) and may not be causally related to the stroke 8

Monitoring and Follow-up

• For patients on warfarin: Target INR 2.0-3.0, with monitoring initially 2-3 times weekly until stable, then monthly 3
• Repeat protein S levels 3 months post-stroke to confirm hereditary deficiency versus acquired deficiency 7, 9
• For CVST patients: Follow-up venography at 3-6 months to assess recanalization 2
• Screen first-degree relatives if hereditary protein S deficiency is confirmed 9