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A new hereditary abnormal protein C (protein C Yonago) with a dysfunctional Gla-domain
K Iijima1, C Fukuda, K Nakamura
1Department of Clinical Laboratory, Tottori University Hospital, Yonago, Japan.
Insights
A hereditary dysfunctional protein C, termed protein C Yonago, was identified in a family with recurrent thrombosis. This protein C abnormality likely stems from a defect in the Gla domain, impacting anticoagulant function.
Area of Science:
- Biochemistry
- Hematology
- Genetics
Background:
- Protein C is a crucial anticoagulant vitamin K-dependent protein.
- Dysfunctional protein C can lead to thrombotic disorders.
Observation:
- A 60-year-old male presented with recurrent thrombosis and reduced protein C anticoagulant activity and calcium-dependent antigen levels.
- Amidolytic activity and total antigen levels were normal, suggesting a specific functional defect.
- Electrophoresis and adsorption studies indicated abnormalities related to the Gla domain.
Findings:
- A familial abnormal protein C, designated protein C Yonago, was identified.
- The abnormality was present in 5 family members, though only one was symptomatic.
- The defect is likely located in the Gla domain or associated structures, affecting calcium binding and anticoagulant function.
Implications:
- This discovery highlights the role of Gla domain defects in hereditary thrombophilia.
- Protein C Yonago represents a novel molecular basis for thrombotic risk.
- Understanding such specific protein C defects is vital for accurate diagnosis and management of coagulation disorders.
Abstract:
A familial abnormal protein C most probably with the dysfunctional Gla domain was found in a 60-year-old man with recurrent thrombosis. Namely, the anticoagulant activity as measured by the APTT method and the antigen level by an ELISA utilizing a calcium-dependent antibody were reduced to nearly half of normal, 43.5% and 2.1 micrograms/ml (normal range: 2.8-5.0 micrograms/ml), respectively. On the other hand, the amidolytic activity determined on a synthetic chromogenic substrate, S-2366, and the total antigen measured by an ELISA utilizing a polyclonal antibody were both in the normal range, 74.1% and 83% of normal, respectively. Crossed immunoelectrophoresis showed more anodal migration than the normal control in the presence of calcium ions, and adsorption of protein C to barium citrate was insufficient. These data altogether indicated that a half population of protein C in the patient's plasma was dysfunctional in the Gla domain or its related structures. Four other members of his immediate family were found to have the same abnormality of protein C, although they had been all asymptomatic. We thus conclude that the dysfunctional protein C is hereditary, and that the abnormalities noted in several tests are most likely due to a structural defect residing in the Gla or its related regions. We hereby designate this abnormal protein C as protein C Yonago.