Elevated plasma factor VIII enhances venous thrombus formation in rabbits: Contribution of factor XI, von Willebrand factor and tissue factor

Chihiro Sugita; Atsushi Yamashita; Yunosuke Matsuura; Takashi Iwakiri; Nozomi Okuyama; Shuntaro Matsuda; Tomoko Matsumoto; Osamu Inoue; Aya Harada; Takehisa Kitazawa; Kunihiro Hattori; Midori Shima; Yujiro Asada

doi:10.1160/TH13-01-0069

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 110(01): 62-75
DOI: 10.1160/TH13-01-0069

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Elevated plasma factor VIII enhances venous thrombus formation in rabbits: Contribution of factor XI, von Willebrand factor and tissue factor

Authors

Chihiro Sugita

¹Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
Atsushi Yamashita

¹Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
Yunosuke Matsuura

¹Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

²Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
Takashi Iwakiri

¹Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

²Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
Nozomi Okuyama

¹Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
Shuntaro Matsuda

³Divisions of Community and Family Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
Tomoko Matsumoto

⁴Department of Pediatrics, Nara Medical University, Nara, Japan
Osamu Inoue

⁵Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
Aya Harada

⁶Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan
Takehisa Kitazawa

⁶Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan
Kunihiro Hattori

⁶Research Division, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan
Midori Shima

⁴Department of Pediatrics, Nara Medical University, Nara, Japan
Yujiro Asada

¹Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

Abstract

Summary

Elevated plasma levels of factor VIII (FVIII) are associated with increased risk of deep venous thrombosis. The aim of this study is to elucidate how elevated FVIII levels affect venous thrombus formation and propagation in vivo. We examined rabbit plasma FVIII activity, plasma thrombin generation, whole blood coagulation, platelet aggregation and venous wall thrombogenicity before and one hour after an intravenous infusion of recombinant human FVIII (rFVIII). Venous thrombus induced by the endothelial denudation of rabbit jugular veins was histologically assessed. Thrombus propagation was evaluated as indocyanine green fluorescence intensity. Argatroban, a thrombin inhibitor, and neutralised antibodies for tissue factor (TF), factor XI (FXI), and von Willebrand factor (VWF) were infused before or after thrombus induction to investigate their effects on venous thrombus formation or propagation. Recombinant FVIII (100 IU/kg) increased rabbit plasma FVIII activity two-fold and significantly enhanced whole blood coagulation and total plasma thrombin generation, but did not affect initial thrombin generation time, platelet aggregation and venous wall thrombogenicity. The rFVIII infusion also increased the size of venous thrombus 1 hour after thrombus induction. Argatroban and the antibodies for TF, FXI or VWF inhibited such enhanced thrombus formation and all except TF suppressed thrombus propagation. In conclusion, elevated plasma FVIII levels enhance venous thrombus formation and propagation. Excess thrombin generation by FXI and VWF-mediated FVIII recruitment appear to contribute to the growth of FVIII-driven venous thrombus.

Keywords

Deep venous thrombosis - factor VIII - factor XI - von Willebrand factor

Full Text

References

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