What is protein S deficiency?

What is Protein S Deficiency

Protein S deficiency is an inherited thrombophilia (hypercoagulable state) caused by reduced levels or function of protein S, a vitamin K-dependent anticoagulant protein that serves as a cofactor for activated protein C and tissue factor pathway inhibitor, resulting in inadequate regulatory control of the clotting cascade and significantly increased risk of venous thromboembolism. 1, 2

Pathophysiology and Molecular Basis

Protein S functions as a critical endogenous anticoagulant through multiple mechanisms 2:

• Acts as a cofactor for activated protein C (APC), which inhibits blood clotting at the levels of factors V and VIII in the coagulation cascade 3
• Serves as a cofactor for tissue factor pathway inhibitor (TFPI), regulating coagulation during the initiation phase 2
• Possesses direct anticoagulant properties by impeding the intrinsic tenase and prothrombinase complexes 2

The molecular basis involves mutations in the PROS1 gene, with almost 200 mutations characterized to date, approximately 30% of which have been studied in vitro to clarify mechanisms leading to deficiency 4. Large deletions in PROS1 have also been identified as causes of protein S deficiency 4.

Clinical Forms and Circulation

Protein S circulates in two forms 5:

• Free (active) form: Approximately 40% of total protein S, functionally active
• Bound (inactive) form: Approximately 60% complexed with C4b-binding protein, functionally inactive

This distribution is clinically important because only free protein S has anticoagulant activity 5.

Thrombotic Risk

Protein S deficiency is a strong independent risk factor for venous thrombosis 6:

• Present in 20% of idiopathic first venous thrombosis cases 1
• Present in 60% of venous thrombosis cases in pregnant women 1
• Probability of remaining thrombosis-free at age 30 is only 50% for mutation carriers compared to 97% for normal family members (hazard ratio 11.5) 6
• Prevalence among renal transplant recipients is 1.5%, with association to allograft thrombosis 1

Women with protein S deficiency and a positive family history have a postpartum thrombotic risk of 1.76% 7.

Inheritance Pattern

Heterozygous protein S deficiency is well-established as an autosomal dominant trait associated with increased thrombosis risk from both familial and population studies 4. This means a single mutated gene copy from one parent is sufficient to cause the condition 1.

Diagnostic Considerations

Testing should be deferred until at least 6 weeks postpartum when protein S levels return to baseline 8. Several acquired conditions can cause transient protein S deficiency and complicate diagnosis 5:

• Warfarin anticoagulation: Reduces free protein S antigen and creates abnormal electrophoretic forms (apparent half-life 42.5 hours after initiation) 5
• Liver disease: Moderately reduces free protein S with significantly reduced specific activity 5
• Disseminated intravascular coagulation: Causes redistribution to the inactive bound form 5
• Acute thrombosis: Transient deficiency occurs due to redistribution to complexed form 5

Caution should be exercised in diagnosing protein S deficiency during these states using functional assays 5.

Associated Conditions

Beyond venous thromboembolism, protein S deficiency has been associated with 1:

• Recurrent pregnancy loss
• Placental infarction

The condition is classified among heritable thrombophilias alongside factor V Leiden, prothrombin 20210A mutation, antithrombin III deficiency, and protein C deficiency 1.