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Chaza Alaji: Diagnosing Protein C and Protein S Deficiency

Chaza Alaji/LinkedIn

Oct 20, 2026, 03:24

Chaza Alaji: Diagnosing Protein C and Protein S Deficiency

Chaza Alaji, Medical Laboratory Specialist and Supervisor at Privat university-private laboratory-general hospital, shared a post on LinkedIn:

”Protein C and Protein S: Laboratory Assessment and Genetic Diagnosis of Inherited Deficiency:

The balance between coagulation and anticoagulation is essential for preventing pathological thrombosis. Protein C and Protein S are central to this balance, and understanding their biology is critical for accurate thrombophilia assessment.

How Do They Work?

Thrombin bound to endothelial thrombomodulin activates Protein C, with support from the endothelial protein C receptor (EPCR). Activated Protein C (APC), assisted by Protein S, inactivates factors Va and VIIIa, reducing thrombin generation and fibrin formation.

Inherited Deficiency: PROC and PROS1

Pathogenic variants in PROC may cause Protein C deficiency, while variants in PROS1 may cause Protein S deficiency.
Both conditions increase susceptibility to venous thromboembolism, including deep vein thrombosis (DVT) and pulmonary embolism (PE). Severe Protein C deficiency can cause neonatal purpura fulminans.

Protein C deficiency is classified as:

Type I: Reduced antigen concentration and activity.
Type II: Reduced functional activity despite a potentially normal antigen concentration.

Protein S deficiency requires careful interpretation of free antigen, total antigen when indicated, and functional activity.

Laboratory Diagnosis: Function First

Assessment may include:

Protein C activity and antigen.
Free Protein S antigen, with total antigen and activity when appropriate.

Acquired conditions can mimic inherited deficiency. Liver disease, vitamin K deficiency, pregnancy, estrogen exposure, and anticoagulant therapy may alter results. Testing must therefore be timed and interpreted according to the clinical context.

Molecular Diagnostics: Beyond Conventional Testing

Modern genetic approaches can clarify selected cases:

Sanger sequencing: Analysis of specific gene regions.
Next-generation sequencing (NGS): Assessment of PROC, PROS1, or broader thrombophilia panels.
MLPA: Detection of certain deletions and duplications that sequencing alone may miss.

Variant interpretation using ACMG/AMP criteria must be integrated with the patient’s clinical and laboratory findings.

An Important Diagnostic Principle

A genetic variant does not automatically establish disease. A variant of uncertain significance (VUS) is not diagnostic on its own.
Genetic testing complements, rather than replaces, functional and antigenic assays. It is most useful when the clinical presentation, laboratory phenotype, or family history justifies further investigation and when the result may influence management or family assessment.

The Laboratory Take-Home Message

Accurate diagnosis of Protein C and Protein S deficiency requires integration of functional assays, antigen measurements, genetic findings, and clinical context.

The goal is not merely to identify an abnormal result, but to establish whether it represents a genuine inherited deficiency with clinical significance.”

Chaza Alaji: Diagnosing Protein C and Protein S Deficiency