What is the management of Protein S deficiency?

Management of Protein S Deficiency

Anticoagulation therapy is the cornerstone of management for Protein S deficiency, particularly in patients with a history of thrombosis or those at high risk for thrombotic events. 1

Understanding Protein S Deficiency

• Protein S is an essential natural anticoagulant that functions as a cofactor for activated protein C (APC) and tissue factor pathway inhibitor (TFPI), playing a crucial role in regulating coagulation 2
• Deficiency in Protein S is associated with increased risk of venous thromboembolism (VTE) and may contribute to arterial thrombosis 2
• Protein S deficiency can be hereditary or acquired, with acquired causes including pregnancy, oral contraceptive use, liver disease, and inflammation 3, 4

Diagnostic Approach

• Diagnosis requires measuring both total and free Protein S levels, as only free Protein S is functionally active 5
• Testing should be performed when patients are not on anticoagulation therapy, as warfarin can reduce Protein S levels 5
• Caution should be exercised when diagnosing Protein S deficiency in patients with acute thrombosis, as transient deficiency can occur due to redistribution to the complexed form 5
• Confirm diagnosis with repeat testing after resolution of acute thrombotic events 4

Treatment Recommendations

For Patients with History of Thrombosis

• Long-term anticoagulation with vitamin K antagonists (VKAs) is recommended with a target INR of 2.0-3.0 1
• Higher intensity anticoagulation (INR 3.0-5.0) is not recommended as it increases bleeding risk without providing additional protection against thrombosis 1
• For patients with severe thrombophilia (including Protein S deficiency) who have experienced thromboembolic events, anticoagulation should be considered indefinitely 1

For Asymptomatic Carriers

• Prophylactic anticoagulation is generally not recommended for asymptomatic individuals with Protein S deficiency unless additional risk factors are present 1
• Consider prophylactic anticoagulation during high-risk situations such as surgery, prolonged immobilization, or pregnancy 1

Special Considerations

• In pregnant women with Protein S deficiency and prior thrombosis, prophylactic anticoagulation with low molecular weight heparin is recommended throughout pregnancy and postpartum period 1
• Oral contraceptives should be avoided in women with Protein S deficiency as they can further decrease Protein S levels 3
• In patients with Protein S deficiency undergoing renal transplantation, anticoagulation should be considered due to increased risk of graft thrombosis 1

Management Algorithm

1. Confirm diagnosis of Protein S deficiency with appropriate laboratory testing

   • Measure both total and free Protein S levels 5
   • Repeat testing if done during acute thrombosis or while on anticoagulation 5

2. Risk stratification:

   • History of thrombosis? (Yes/No)
   • Additional risk factors? (Family history, other thrombophilias, etc.) 1
   • Specific clinical scenario (pregnancy, surgery, etc.) 3, 4

3. Treatment decision:

   • For patients with history of thrombosis: Long-term anticoagulation with VKAs (target INR 2.0-3.0) 1
   • For asymptomatic carriers: Observe and educate about signs/symptoms of thrombosis; consider prophylaxis only during high-risk situations 1
   • For pregnant women: LMWH throughout pregnancy and postpartum period if history of thrombosis 1
   • For patients undergoing surgery: Perioperative prophylactic anticoagulation 1

Monitoring and Follow-up

• For patients on long-term VKA therapy, monitor INR initially twice or three times weekly until therapeutic range is achieved, then weekly, and eventually every 4 weeks once stable 1
• Educate patients about potential drug interactions that may affect anticoagulation status 1
• Monitor for complications of anticoagulation, particularly bleeding 1
• Be aware that skin necrosis can occur during the first week of VKA treatment in patients with Protein S deficiency 1

Pitfalls to Avoid

• Do not diagnose Protein S deficiency based on a single test during acute thrombosis or while on anticoagulation 5
• Avoid abrupt discontinuation of anticoagulation therapy, which may result in a temporary hypercoagulable state 1
• Do not prescribe oral contraceptives to women with known Protein S deficiency 3
• Be cautious with high-intensity anticoagulation (INR > 3.0) as it significantly increases bleeding risk without providing additional protection 1