Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI, USA.
Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.
J Thromb Haemost. 2023 Mar;21(3):639-651. doi: 10.1016/j.jtha.2022.11.034. Epub 2022 Dec 22.
Tissue factor pathway inhibitor (TFPI) is the primary inhibitor of events initiating the blood coagulation pathway. Tfpi mice die during embryonic development. The absence of protease-activated receptor (PAR) 4, the major thrombin receptor on mouse platelets, rescues Tfpimice to adulthood. Among the 3 TFPI isoforms in mice, TFPIα is the only isoform within platelets (pltTFPIα) and the only isoform that inhibits prothrombinase, the enzymatic complex that converts prothrombin to thrombin.
To determine biological functions of pltTFPIα.
Tfpi/Par4 mice were irradiated and transplanted with bone marrow from mice lacking or containing pltTFPIα. Thus, PAR4 expression was restored in the recipient mice, which differed selectively by the presence or absence of pltTFPIα and lacked other forms of TFPI.
Recipient mice lacking pltTFPIα had reduced survival over the 200-day posttransplant period. Necropsy revealed radiation injury associated with large intraventricular platelet-rich thrombi, whereas other organs were not affected. Thrombi were associated with fibrotic presentations, including increased collagen deposition, periostin-positive activated fibroblasts, myofibroblasts, and macrophage infiltrates. Recipient mice containing pltTFPIα showed evidence of radiation injury but lacked heart pathology.
Tfpi/Par4 mice develop severe cardiac fibrosis following irradiation and transplantation with bone marrow lacking pltTFPIα. This pathology is markedly reduced when the mice are transplanted with bone marrow containing pltTFPIα. Thus, in this model system pltTFPIα has an important physiological role in dampening pathological responses mediated by activated platelets within the heart tissue.
组织因子途径抑制剂（TFPI）是启动血液凝血途径的主要抑制剂。Tfpi 小鼠在胚胎发育过程中死亡。缺乏蛋白酶激活受体（PAR）4，即小鼠血小板上主要的凝血酶受体，可使 Tfpimice 存活至成年。在小鼠的 3 种 TFPI 同种型中，TFPIα 是血小板内唯一的同种型（pltTFPIα），也是唯一抑制凝血酶原酶的同种型，凝血酶原酶是将凝血酶原转化为凝血酶的酶复合物。
确定 pltTFPIα 的生物学功能。
用辐照和骨髓移植的方法处理 Tfpi/Par4 小鼠，使其骨髓来源的细胞缺乏或含有 pltTFPIα。因此，受体小鼠中 PAR4 的表达得到了恢复，但存在或缺乏 pltTFPIα，并且缺乏其他形式的 TFPI。
缺乏 pltTFPIα 的受体小鼠在移植后 200 天的存活率降低。尸检显示与大型心室内富含血小板的血栓相关的放射损伤，而其他器官未受影响。血栓与纤维化表现相关，包括胶原沉积增加、骨膜蛋白阳性活化成纤维细胞、肌成纤维细胞和巨噬细胞浸润。含有 pltTFPIα 的受体小鼠显示出放射损伤的证据，但缺乏心脏病变。
Tfpi/Par4 小鼠在接受缺乏 pltTFPIα 的骨髓移植后会发生严重的心脏纤维化。当小鼠接受含有 pltTFPIα 的骨髓移植时，这种病理明显减少。因此，在这个模型系统中，pltTFPIα 在抑制心脏组织中活化血小板介导的病理反应方面具有重要的生理作用。
