The Defective Down Regulation of Fibrinolysis in Haemophilia A Can Be Restored by Increasing the TAFI Plasma Concentration

Laurent O. Mosnier; Ton Lisman; Marijke van den H. Berg; Karel H. Nieuwenhuis; Joost C.M. Meijers; Bonno N. Bouma

doi:10.1055/s-0037-1616530

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2001; 86(04): 1035-1039
DOI: 10.1055/s-0037-1616530

Special Article

Schattauer GmbH

The Defective Down Regulation of Fibrinolysis in Haemophilia A Can Be Restored by Increasing the TAFI Plasma Concentration

Laurent O. Mosnier

¹Thrombosis and Haemostasis Laboratory, Dept. of Haematology, University Medical Center, Utrecht, the Netherlands

²Institute of Biomembranes, Utrecht University, Utrecht, the Netherlands

,

Ton Lisman

¹Thrombosis and Haemostasis Laboratory, Dept. of Haematology, University Medical Center, Utrecht, the Netherlands

²Institute of Biomembranes, Utrecht University, Utrecht, the Netherlands

,

Marijke van den H. Berg

³Van Creveld Kliniek, University Medical Center, Utrecht, the Netherlands

,

Karel H. Nieuwenhuis

⁴Dept. of Haematology, University Medical Center, Utrecht, the Netherlands

,

Joost C.M. Meijers

¹Thrombosis and Haemostasis Laboratory, Dept. of Haematology, University Medical Center, Utrecht, the Netherlands

⁵Dept. of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands

,

Bonno N. Bouma

¹Thrombosis and Haemostasis Laboratory, Dept. of Haematology, University Medical Center, Utrecht, the Netherlands

²Institute of Biomembranes, Utrecht University, Utrecht, the Netherlands

› Author Affiliations

Abstract

Summary

TAFI (thrombin activatable fibrinolysis inhibitor) down regulates fibrinolysis after activation by relatively high concentrations of thrombin generated during coagulation via thrombin mediated factor XI activation and subsequent activation of the intrinsic pathway. It is this secondary burst of thrombin that is severely diminished in haemophilia A, a deficiency of coagulation factor VIII. We therefore investigated the role of TAFI in haemophilia A by measuring the clot lysis times of tissue factor induced fibrin formation and tPA mediated fibrinolysis. In haemophilia A plasma clot lysis times were normal at relatively high tissue factor concentrations but severely decreased at moderate to low tissue factor concentrations, indicating that the thrombin generation via the extrinsic pathway was insufficient to activate TAFI. Addition of factor VIII, TAFI or thrombomodulin restored the clot lysis times at low tissue factor concentrations. This confirms the hypothesis that the bleeding disorder in haemophilia A is not merely a defect in the initial clot formation but is in fact a triple defect: reduced thrombin formation via the extrinsic pathway at low tissue factor concentrations, a reduced secondary burst of thrombin generation via the intrinsic pathway and a defective down regulation of the fibrinolytic system by the intrinsic pathway.

Keywords

Haemophilia A - coagulation - fibrinolysis - factor VIII - Thrombin activatable fibrinolysis inhibitor (TAFI) - carboxypeptidase U

Full Text

References

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