Characteristics of the Thrombus Formation in Transgenic Mice with Platelet-Targeted Factor VIII Expression
Characteristics of the Thrombus Formation in Transgenic Mice with Platelet-Targeted Factor VIII Expression
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DOI：
10.1055/s-0041-1735531
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发表时间：
2021-09
影响因子：
6.7
通讯作者：
Yun Wang;J. Mao;Li Li-Li;Bing Xiao;Z. Ruan;Yichen Liu;Guowei Zhang;Dawei Wang;J. Mi;C. Fang;X. Xi;Xiaofeng Shi;Jin Wang
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文献类型：
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作者：
Yun Wang;J. Mao;Li Li-Li;Bing Xiao;Z. Ruan;Yichen Liu;Guowei Zhang;Dawei Wang;J. Mi;C. Fang;X. Xi;Xiaofeng Shi;Jin Wang
血小板靶向FVIII基因治疗可以有效地恢复血友病A （HA）的出血表型，但血小板中因子VIII （FVIII）异位表达的血栓形成特征尚不清楚。在这里，我们在血友病（FVIII）小鼠背景下，在血小板中限制性表达人b结构域缺失的FVIII （hBDD FVIII）的2bF8trans小鼠。结果显示野生型（WT）和2bF8trans小鼠的凝块强度和稳定性无统计学差异，但反应时间（R-time）较长。流体动力学分析表明，在剪切速率为500 ~ 1,500 s−1时，通常会发生生理性止血，2bF8trans小鼠形成的血栓比fviii inull小鼠更稳定，而在高病理剪切速率（2,500 s−1）时，模拟动脉粥样硬化，2bF8trans小鼠的血栓大小和纤维蛋白沉积比WT小鼠小。血栓形态分析显示，2bF8trans小鼠损伤部位的血栓中存在纤维蛋白的局部集中沉积，纤维蛋白与活化的血小板共定位。此外，在激光诱导的动脉小动脉损伤后，2bF8trans小鼠的血栓中发现了更高的纤维蛋白与血小板的比例，这可能是生理动脉环境下2bF8trans小鼠血栓稳定性的潜在机制。这些观察结果表明，血栓的特定形态特征可能有助于血小板靶向FVIII基因治疗HA的有效性和安全性。
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.