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Thromb Haemost 2022; 122(05): 755-766
DOI: 10.1055/s-0041-1735531
Cellular Haemostasis and Platelets

Characteristics of the Thrombus Formation in Transgenic Mice with Platelet-Targeted Factor VIII Expression

Yun Wang‡   *
1   State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Pôle Sino-Français des Sciences du Vivant et Genomique, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
,
Jianhua Mao‡   *
1   State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Pôle Sino-Français des Sciences du Vivant et Genomique, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
,
Li Li‡   *
2   Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
,
Bing Xiao
1   State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Pôle Sino-Français des Sciences du Vivant et Genomique, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
3   Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
,
Zheng Ruan
1   State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Pôle Sino-Français des Sciences du Vivant et Genomique, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
,
Yichen Liu
4   Department of Hematology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
,
Guowei Zhang
5   Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Department of Basic Medical Sciences, Hangzhou Normal University School of Medicine, Hangzhou, Zhejiang, China
,
Dawei Wang 
1   State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Pôle Sino-Français des Sciences du Vivant et Genomique, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
,
Jian-Qing Mi
1   State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Pôle Sino-Français des Sciences du Vivant et Genomique, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
,
Chao Fang
2   Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
,
Xiaodong Xi
1   State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Pôle Sino-Français des Sciences du Vivant et Genomique, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
,
Xiaofeng Shi
4   Department of Hematology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
6   Department of Hematology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
,
Jin Wang
1   State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Pôle Sino-Français des Sciences du Vivant et Genomique, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
› Author Affiliations Funding This work was supported by grants from the National Natural Science Foundation of China (81970112, 81700130, 81670127, 81570178, 81270594), Shanghai Municipal Health Commission in China (201940342), and Novo Nordisk Haemophilia Research Fund in China.
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Abstract

Platelet-targeted FVIII gene therapy can efficiently recover bleeding phenotype for hemophilia A (HA), yet characteristics of thrombus formation with this ectopic expression of factor VIII (FVIII) in platelets remain unclear. Here, we generated 2bF8trans mice restrictively expressing human B-domain–deleted FVIII (hBDD FVIII) in platelets on a hemophilic (FVIIInull) mice background. The results showed no statistical difference in clot strength and stability between wild-type (WT) and 2bF8trans mice, but with a prolonged reaction time (R-time), by thromboelastography. Fluid dynamics analysis showed that at the shear rates of 500 to 1,500 s−1, where physiological hemostasis often develops, the thrombi formed in 2bF8trans mice were more stable than those in FVIIInull mice, while at high pathological shear rates (2,500 s−1), mimicking atherosclerosis, thrombus size and fibrin deposition in 2bF8trans mice were less than those in WT mice. Thrombus morphology analysis showed that there was a locally concentrated deposition of fibrin in thrombus at the injured site and fibrin co-localized with activated platelets in 2bF8trans mice. Moreover, a higher ratio of fibrin to platelets was found in thrombus from 2bF8trans mice following laser-induced injury in cremaster arterioles, which might be the underlying mechanism of thrombus stability in 2bF8trans mice at physiological arterial circumstance. These observations suggest that specific morphological features of the thrombi might contribute to the efficacy and safety of platelet-targeted FVIII gene therapy for HA.

Keywords

hemophilia A - gene therapy - platelet-targeted - thrombus structure

* These authors contributed equally to this article.


Supplementary Material



Publication History

Received: 26 March 2021

Accepted: 31 July 2021

Article published online:
29 September 2021

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