Rate-limiting roles of the tenase complex of factors VIII and IX in platelet procoagulant activity and formation of platelet-fibrin thrombi under flow

Haematologica
Frauke SwieringaJohan W M Heemskerk

Abstract

The importance of factor Xa generation in thrombus formation has not been studied extensively so far. Here, we used mice deficient in either factor VIII or factor IX to determine the role of platelet-stimulated tenase activity in the formation of platelet-fibrin thrombi on collagen. With tissue factor present, deficiency in factor VIII or IX markedly suppressed thrombus growth, fibrin formation and platelet procoagulant activity (phosphatidylserine exposure). In either case, residual fibrin formation was eliminated in the absence of tissue factor. Effects of factor deficiencies were antagonized by supplementation of the missing coagulation factor. In wild-type thrombi generated under flow, phosphatidylserine-exposing platelets bound (activated) factor IX and factor X, whereas factor VIII preferentially co-localized at sites of von Willebrand factor binding. Furthermore, proteolytic activity of the generated activated factor X and thrombin was confined to the sites of phosphatidylserine exposure. With blood from a hemophilia A or B patient, the formation of platelet-fibrin thrombi was greatly delayed and reduced, even in the presence of high concentrations of tissue factor. A direct activated factor X inhibitor, rivaroxaban, add...Continue Reading

Citations

Feb 6, 2016·Journal of Thrombosis and Haemostasis : JTH·Lawrence F Brass, Scott L Diamond
May 22, 2016·Thrombosis Research·Johanna P van GeffenJohan W M Heemskerk
Mar 31, 2017·Platelets·Magdolna NagyFrauke Swieringa
Feb 6, 2016·Arteriosclerosis, Thrombosis, and Vascular Biology·Frauke SwieringaPaola E J van der Meijden
Aug 26, 2017·Current Opinion in Oncology·Maria Ilaria Del PrincipeAdriano Venditti
Dec 22, 2019·Journal of Thrombosis and Haemostasis : JTH·Sanne L N BrounsJohan W M Heemskerk
Jun 7, 2019·Scientific Reports·Sanjeev Kiran GotruAttila Braun
Nov 16, 2018·Nature Reviews. Cardiology·Paola E J van der Meijden, Johan W M Heemskerk
Jan 29, 2020·Research and Practice in Thrombosis and Haemostasis·Xinren YuScott L Diamond
Jul 27, 2018·Research and Practice in Thrombosis and Haemostasis·Frauke SwieringaPaola E J van der Meijden
Sep 7, 2018·Blood Advances·Smita JoshiSidney W Whiteheart
Jun 17, 2020·International Journal of Laboratory Hematology·Ibrahim Tohidi-EsfahaniVivien M Y Chen
Dec 4, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·Gina PerrellaJohan W M Heemskerk
Jan 26, 2021·Frontiers in Cardiovascular Medicine·Jiayu WuConstance C F M J Baaten
Jun 3, 2021·International Journal of Molecular Sciences·Rahim KanjiDiana A Gorog

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