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01-04-2019 | Original Article

Potential role of activated factor VIII (FVIIIa) in FVIIa/tissue factor-dependent FXa generation in initiation phase of blood coagulation

Authors: Shoko Furukawa, Keiji Nogami, Kenichi Ogiwara, Midori Shima

Published in: International Journal of Hematology | Issue 4/2019

Abstract

Factor VIIa/tissue factor (FVIIa/TF) initiates blood coagulation by promoting FXa generation (extrinsic-Xa). Subsequent generation of intrinsic FXa (intrinsic-Xa) amplifies thrombin formation. Previous studies suggested that FVIIa/TF activates FVIII rapidly in immediate coagulation reactions, and FVIIa/TF/FXa activates FVIII prior to thrombin-dependent feedback. We investigated FVIII/FVIIa/TF/FXa relationships in early coagulation mechanisms. Total FXa generated by FVIIa/TF and FVIIa/TF-activated FVIII (FVIIIa_VIIa/TF) was 22.6 ± 1.7 nM (1 min); total FXa with FVIIa-inhibitor was 3.4 ± 0.7 nM, whereas FXa generated by FVIIa/TF or FVIII/TF was 10.4 ± 1.1 or 0.74 ± 0.14 nM, respectively. Little Xa was generated by FVIII alone, suggesting that intrinsic-Xa mechanisms were mediated by FVIIIa_VIIa/TF and FVIII/TF in the initiation phase. Intrinsic-Xa was delayed somewhat by von Willebrand factor (VWF). FVIII activation by FXa with FVIIa/TF was comparable to activation with Glu-Gly-Arg-inactivated-FVIIa/TF. TF counteracted the inhibitory effects of VWF on FXa-induced FVIII activation mediated by Arg³⁷² cleavage. The FVIII-C2 domain bound to cytoplasmic domain-deleted TF (TF¹⁻²⁴³), and VWF blocked this binding by > 80%, indicating an overlap between VWF- and TF¹⁻²⁴³-binding site(s) on C2. Overall, these data suggest that FVIII-associated intrinsic-Xa, governed by both FVIIa/TF-induced and FXa-induced FVIII activation mediated by FVIII-TF interactions, together with FVIIa-dependent extrinsic-Xa mechanisms, may be central to the initiation phase of coagulation.

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Title: Potential role of activated factor VIII (FVIIIa) in FVIIa/tissue factor-dependent FXa generation in initiation phase of blood coagulation
Authors: Shoko Furukawa
Keiji Nogami
Kenichi Ogiwara
Midori Shima
Publication date: 01-04-2019
Publisher: Springer Japan
Published in: International Journal of Hematology / Issue 4/2019
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI: https://doi.org/10.1007/s12185-019-02611-3

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