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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/3591

Title: Potential role of activated factor VIII (FVIIIa) in FVIIa/tissue factor-dependent FXa generation in initiation phase of blood coagulation.
Other Titles: 凝固初期相における活性型凝固第Ⅶ因子/組織因子依存性の活性型凝固第Ⅹ因子生成に対する活性型凝固第Ⅷ因子の働き
Authors: Furukawa, Shoko
Nogami, Keiji
Ogiwara, Kenichi
Shima, Midori
Keywords: FVIIa
Tissue factor
FVIII
FXa generation
Initiation phase
Issue Date: Apr-2019
Publisher: Springer Nature
Citation: International journal of hematology Vol.109 No.4 p.390-401 (2019 Apr)
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 (FVIIIaVIIa/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 FVIIIaVIIa/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.
Description: 博士(医学)・乙第1429号・平成31年6月26日
© Japanese Society of Hematology 2019
This is a post-peer-review, pre-copyedit version of an article published in International journal of hematology. The final authenticated version is available online at: http://dx.doi.org/10.1007/s12185-019-02611-3.
発行元が定める登録猶予期間終了の後、本文を登録予定(2020.04)
URI: http://hdl.handle.net/10564/3591
ISSN: 09255710
Academic Degrees and number: 24601B1429
Degree-granting date: 2019-06-26
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2019年度

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