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Resistance to activated protein C as a basis for venous thrombosis
1Department for Coagulation Disorders, University of Lund, Malmö General Hospital, Sweden.
Background:
In three families with various forms of venous thrombosis, we observed an apparently inherited poor response to the anticoagulant activated protein C (APC). The condition was due to a deficiency in a previously unrecognized anticoagulant factor that functioned as a cofactor to activated protein C.
Methods:
We conducted the present study to determine the prevalence of resistance to APC in patients with venous thrombosis. We compared 104 consecutive patients with venous thrombosis confirmed by objective tests with 130 controls. In addition, 211 members of 34 families of persons with resistance to APC were studied. The anticoagulant response to APC was measured with a modified version of the activated partial-thromboplastin time test; the results were expressed as APC ratios.
Results:
Forty-five percent of patients had a family history of thrombosis. A significant (P < 0.001) difference in APC ratios was observed between the controls and the patients with thrombosis. For 33 percent of patients, the APC ratio was below the 5th percentile of the control values, although the results of the family studies suggested that the prevalence of APC resistance may be even higher (approximately 40 percent) in the patients with thrombosis. The inherited nature of the defect was confirmed in a majority of cases, and the family studies suggested the mode of inheritance to be autosomal dominant. The thrombosis-free survival of APC-resistant family members was significantly less than that of non-APC-resistant family members.
Conclusions:
There was a high prevalence of APC resistance among young persons with a history of venous thrombosis, and this resistance appeared to be inherited as an autosomal dominant trait.
Insights
Activated protein C (APC) resistance is common in young individuals with venous thrombosis and appears to be inherited. This inherited APC resistance is linked to a higher risk of developing thrombosis.
Area of Science:
- Hematology
- Genetics
- Thrombosis Research
Background:
- Identified an inherited poor response to activated protein C (APC) in families with venous thrombosis.
- This poor response was attributed to a deficiency in a novel APC cofactor.
Purpose of the Study:
- To determine the prevalence of APC resistance in patients experiencing venous thrombosis.
- To investigate the inheritance pattern and clinical significance of APC resistance.
Main Methods:
- Compared APC ratios in 104 venous thrombosis patients versus 130 controls.
- Analyzed APC resistance in 211 members across 34 families with known APC resistance.
- Measured APC response using a modified activated partial-thromboplastin time test.
Main Results:
- A significant difference in APC ratios was found between controls and thrombosis patients (P < 0.001).
- APC resistance was present in 33% of patients, potentially as high as 40% based on family studies.
- The defect showed an autosomal dominant inheritance pattern, with APC-resistant members having reduced thrombosis-free survival.
Conclusions:
- APC resistance is highly prevalent in young individuals with a history of venous thrombosis.
- This resistance is an inherited autosomal dominant trait, increasing thrombosis risk.