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Dual effect of histone H4 on prothrombin activation
1Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA.
Journal of Thrombosis and Haemostasis : JTH
|July 1, 2016
Summary
Histone H4 exhibits a dual role in prothrombin activation. It enhances thrombin generation by factor Xa alone but inhibits it when cofactor Va is present, impacting blood coagulation.
Area of Science:
- Biochemistry
- Molecular Biology
- Hematology
Background:
- Recent studies show histone H4 converts prothrombin to thrombin.
- This conversion is dependent on the catalytic Ser and Gla domain.
Purpose of the Study:
- To investigate histone H4's effect on prothrombin activation by factor Xa.
- To examine histone H4's influence on prothrombinase complex activity.
Main Methods:
- Kinetic assays were used to study prothrombin activation.
- Electrostatic calculations explored histone H4 binding sites on prothrombin.
Main Results:
- Histone H4 enhances prothrombin activation by factor Xa over 10-fold without cofactor Va.
- Histone H4 completely inhibits prothrombin activation by factor Xa in the presence of cofactor Va.
- Histone H4 promotes slow autoactivation and FXa-mediated thrombin generation without phospholipids.
Conclusions:
- Histone H4 binding to prothrombin has a significant dual effect on its activation by FXa.
- Histone H4 drastically inhibits prothrombin activation by the prothrombinase complex, suggesting a key role in pathophysiology.
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