Is protein S activity the same as protein S deficiency?

Protein S Activity vs. Protein S Deficiency

Protein S activity is not the same as protein S deficiency, but rather protein S activity testing is one method used to diagnose protein S deficiency. Protein S deficiency can be present even when protein S activity appears normal.

Understanding Protein S and Its Function

Protein S functions as a crucial cofactor for activated protein C (APC) in the natural anticoagulant system, which regulates blood coagulation by inactivating procoagulant factors Va and VIIIa 1. This system provides important control of blood coagulation, with deficiencies associated with increased thrombosis risk.

Protein S exists in two forms in plasma:

• Free protein S (approximately 40%) - functionally active
• Bound protein S (approximately 60%) - complexed with C4b-binding protein and functionally inactive 2

Relationship Between Protein S Activity and Deficiency

Protein S deficiency is classified into three types:

1. Type I: Low total protein S antigen, low free protein S antigen, and low protein S activity
2. Type II: Normal total and free protein S antigen, but low protein S activity (qualitative defect)
3. Type III: Normal total protein S antigen, but low free protein S antigen and low protein S activity

The key distinction is that protein S activity measures the functional capacity of protein S, while protein S deficiency is a broader clinical condition that can be caused by:

• Decreased total protein S levels
• Normal total levels but decreased free protein S
• Normal levels but dysfunctional protein S

Diagnostic Considerations

A critical finding from research shows that a normal functional protein S activity result does not exclude protein S deficiency. The sensitivity of functional protein S activity testing for detecting protein S deficiency is only 45.5%, though specificity is high at 95.3% 3. This means many cases of protein S deficiency would be missed if only activity testing were performed.

According to a study by Pathophysiology of Haemostasis and Thrombosis, "Functional PS activity testing should not be used as a screening test to eliminate free antigenic PS testing for the laboratory diagnosis of PS deficiency" 3.

Clinical Implications

Protein S deficiency is associated with:

• Increased risk of venous thromboembolism
• Recurrent thrombotic events
• Potential complications during pregnancy

The European Society of Cardiology notes that protein S deficiency is among the defects in anticoagulant systems associated with venous thromboembolism, though they have not been conclusively linked to outcomes in unstable coronary artery disease 4.

Testing Recommendations

For accurate diagnosis of protein S deficiency, guidelines suggest:

1. Measure both protein S activity and free protein S antigen levels
2. Consider the clinical context (history of thrombosis, family history)
3. Test during stable conditions (not during acute thrombosis, pregnancy, or while on anticoagulants)

Treatment Considerations

For patients with protein S deficiency:

• The American Society of Hematology suggests postpartum antithrombotic prophylaxis for women with protein S deficiency and a family history of VTE 4
• Oral anticoagulant therapy may need to be replaced by heparin treatment during pregnancy 4
• Skin necrosis is a potential complication during the first week of oral anticoagulant therapy in patients with protein S deficiency 4

In conclusion, while protein S activity testing is a component of diagnosing protein S deficiency, it is not equivalent to the condition itself, and normal activity results do not rule out protein S deficiency.