Hereditary dysfunctional protein C molecules (type II): assay characterization and proposed classification

Area of Science:

• Hematology
• Molecular Biology
• Genetics

Background:

• Hereditary thrombotic disease is often caused by Protein C (PC) deficiency.
• Two types of PC deficiency exist: Type I (decreased activity and antigen) and Type II (dysfunctional molecule with low activity vs. antigen).
• Few Type II patients have been described, necessitating further investigation into the molecular basis of this condition.

Purpose of the Study:

• To evaluate dysfunctional Protein C (PC) molecules in Type II deficiency.
• To compare PC clotting activity, amidolytic activity, and antigen levels.
• To develop a nomenclature algorithm for Type II PC deficiency based on molecular defects.

Main Methods:

• Development of an automated PTT-based clotting PC assay.
• Comparison of PC antigen, amidolytic activity, and clotting activity in ten affected families.
• Analysis of the correlation between clotting activity and antigen levels in normal individuals and Type I patients.

Main Results:

• The developed PC assay was sensitive, specific, accurate, and reproducible.
• A strong correlation (r=0.918) was observed between clotting activity and antigen in normal and Type I PC deficiency.
• In Type II patients, clotting activity was reduced while antigen levels remained normal; amidolytic activity was normal in 4/10 families, suggesting defects outside amidolytic regions.

Conclusions:

• The molecular basis of Type II PC deficiency is diverse and complex.
• Defects in Type II PC deficiency can involve various functional domains of the PC molecule.
• A nomenclature algorithm is proposed to classify Type II PC deficiency based on defect location within PC domains.