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

Yun Wang; Jianhua Mao; Li Li; Bing Xiao; Zheng Ruan; Yichen Liu; Guowei Zhang; Dawei Wang; Jian-Qing Mi; Chao Fang; Xiaodong Xi; Xiaofeng Shi; Jin Wang

doi:10.1055/s-0041-1735531

Thrombosis and Haemostasis, Table of Contents

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

Authors

Yun Wang‡^*

¹State 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‡^*

¹State 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‡^*

²Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Bing Xiao

¹State 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

³Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Zheng Ruan

¹State 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

⁴Department of Hematology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
Guowei Zhang

⁵Key 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

¹State 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

¹State 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

²Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Xiaodong Xi

¹State 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

⁴Department of Hematology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China

⁶Department of Hematology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Jin Wang

¹State 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

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 2bF8^trans mice restrictively expressing human B-domain–deleted FVIII (hBDD FVIII) in platelets on a hemophilic (FVIII^null) mice background. The results showed no statistical difference in clot strength and stability between wild-type (WT) and 2bF8^trans 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 2bF8^trans mice were more stable than those in FVIII^null mice, while at high pathological shear rates (2,500 s⁻¹), mimicking atherosclerosis, thrombus size and fibrin deposition in 2bF8^trans 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 2bF8^trans mice. Moreover, a higher ratio of fibrin to platelets was found in thrombus from 2bF8^trans mice following laser-induced injury in cremaster arterioles, which might be the underlying mechanism of thrombus stability in 2bF8^trans 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

Full Text

References

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