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Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families
B P Koeleman1, P H Reitsma, C F Allaart
1Department of Hematology, University Hospital Leiden, The Netherlands.
Insights
Individuals with both protein C deficiency and Factor V Leiden mutation face a significantly higher risk of thrombosis. This combined genetic risk is more pronounced than having either defect alone, highlighting a critical interaction in thrombophilia.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Heterozygous protein C deficiency increases thrombosis risk, but this is family-specific (clinically dominant vs. recessive).
- A second hereditary risk factor may explain varying thrombotic risk among protein C-deficient families.
- Activated protein C (APC) resistance, linked to the FV Leiden mutation, is a known strong risk factor for thrombosis.
Purpose of the Study:
- To investigate the prevalence of the FV Leiden mutation in protein C-deficient families.
- To determine if the co-inheritance of protein C deficiency and FV Leiden mutation increases thrombotic risk.
- To analyze the genetic linkage between the protein C gene and the FV gene in thrombophilia.
Main Methods:
- Prevalence study of FV Leiden mutation in symptomatic protein C-deficient individuals.
- Segregation analysis of FV Leiden and protein C gene mutations in dominant protein C-deficient families.
- Two-locus linkage analysis to assess the relationship between FV and protein C genes in thrombophilia.
Main Results:
- The FV Leiden mutation was found in 19% of symptomatic protein C-deficient probands.
- Family members with both protein C deficiency and FV Leiden mutation experienced thrombosis at a 73% rate.
- Individuals with only protein C deficiency or only FV Leiden mutation had lower thrombosis rates (31% and 13%, respectively).
Conclusions:
- The co-occurrence of protein C deficiency and FV Leiden mutation significantly elevates thrombosis risk.
- Genetic linkage analysis supports the FV and protein C genes as key loci for thrombophilia.
- Identifying carriers of both genetic defects is crucial for managing thrombotic risk.
Abstract:
Heterozygous protein C deficiency is associated with an increased risk for thrombosis. This association is restricted to a minority of protein C-deficient families, which have been defined as clinically dominant protein C-deficient. In contrast, in the clinically recessive protein C-deficient families, only the homozygous family members are (severely) affected. One possible explanation for this difference in thrombotic risk between families may be the presence of a second hereditary risk factor. A good candidate for this second risk factor is the recently identified resistance to activated protein C (APC). APC resistance, which is associated with a mutation in the FV gene (FV Leiden), is a common and strong risk factor for thrombosis. We show here that the prevalence of the FV Leiden mutation is high among symptomatic protein C-deficient probands (19%). In 6 clinically dominant protein C-deficient families, the segregation of the FV Leiden mutation and the protein C gene mutation was studied. A thrombotic episode had been experienced by 73% of the family members having both the protein C gene mutation and the FV Leiden mutation. In contrast, respectively, 31% and 13% of the family members having either the protein C gene mutation or the FV Leiden mutation had experienced a thrombotic episode. Moreover, the result of a two locus linkage analysis support the assumption that the FV gene and the protein C gene are the two trait loci responsible for the thrombophilia. These results indicate that carriers of both gene defects have an increased risk for thrombosis compared with related carriers of the single defect.