Department of Pediatrics and.
Department of Medicine, Weill Cornell Medicine, New York, NY.
Blood. 2021 Apr 22;137(16):2221-2230. doi: 10.1182/blood.2020008123.
Reduced plasma fibrinolysis has been identified as a potential risk factor for venous thromboembolism (VTE), but the role of cell surface fibrinolysis in VTE is unknown. The annexin A2/S100A10 complex serves as a coreceptor for plasminogen and tissue plasminogen activator (tPA), augmenting plasmin generation by 60-fold on the endothelial cell surface. Several studies in both mice and humans support the concept that A2 regulates fibrin homeostasis and intravascular thrombosis in vivo. Here, we examined A2 protein expression and function in 115 adult subjects with VTE and 87 healthy controls. Using peripheral blood mononuclear cells as a surrogate for endothelial cells, we found a 41% mean decrease in cell surface tPA-dependent fibrinolytic activity in subjects who had a positive personal and family history of VTE but tested negative for known inherited thrombophilias (ITs). A2 protein was reduced on average by 70% and messenger RNA levels by 30%, but neither decrease correlated with anticoagulant therapy. Neither cell A2 protein nor cell surface plasmin generation correlated with plasma-based clot lysis times, suggesting that the plasma and cell surface fibrinolytic systems operate independently of one another. These data suggest that reduced expression of annexin A2 protein is associated with cell surface hypofibrinolysis and may represent a novel risk factor for IT.
血浆纤维蛋白溶解减少已被确定为静脉血栓栓塞症（VTE）的潜在风险因素，但细胞表面纤维蛋白溶解在 VTE 中的作用尚不清楚。膜联蛋白 A2/S100A10 复合物作为纤溶酶原和组织型纤溶酶原激活物（tPA）的核心受体，使内皮细胞表面纤溶酶的生成增加 60 倍。在小鼠和人类的多项研究中都支持 A2 调节纤维蛋白溶解平衡和体内血管内血栓形成的概念。在这里，我们检查了 115 例 VTE 成年患者和 87 例健康对照者的 A2 蛋白表达和功能。使用外周血单核细胞作为内皮细胞的替代物，我们发现具有阳性个人和家族 VTE 史但对已知遗传性血栓形成倾向（ITs）检测为阴性的患者的细胞表面 tPA 依赖性纤维蛋白溶解活性平均降低了 41%。A2 蛋白平均减少 70%，信使 RNA 水平减少 30%，但两者均与抗凝治疗无关。细胞 A2 蛋白和细胞表面纤溶酶生成均与基于血浆的血栓溶解时间无关，表明血浆和细胞表面纤维蛋白溶解系统彼此独立运行。这些数据表明，膜联蛋白 A2 蛋白表达减少与细胞表面纤维蛋白溶解减少有关，可能是 IT 的一个新的危险因素。
