From the Koch Institute for Integrative Cancer Research, Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts (C.D.B, Y-W.K, G.S., D.L., M.B.Y.); Division of Acute Care Surgery and Critical Care, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (C.D.B., M.B.Y.); Department of Surgery, University of Colorado Denver, Denver, Colorado (H.B.M., E.E.M.); Department of Radiology, University of Colorado Denver, Denver, Colorado (M.P.C.); and Department of Surgery, Denver Health Medical Center, Denver, Colorado (E.E.M.).
J Trauma Acute Care Surg. 2019 Jan;86(1):101-107. doi: 10.1097/TA.0000000000002092.
Both tissue plasminogen activator (tPA) in the circulation and urokinase (uPA) in tissues cleave plasminogen (PLG) to plasmin to promote clot lysis. Tranexamic acid (TXA) blocks both the tPA-dependent generation of plasmin on blood clots as well as active plasmin binding to polymerized fibrin, and is commonly administered for bleeding in trauma to limit fibrinolysis. In addition to lysing clots, however, active plasmin also cleaves complement proteins, potentially enhancing inflammation. Because TXA does not block uPA-dependent plasmin generation from PLG and instead augments it, we hypothesized that administration of TXA could enhance or inhibit proinflammatory C5a formation in a PLG activator-dependent manner.
Citrate platelet-poor plasma (PPP) and PPP depleted of complement protein C3 or PLG were obtained from healthy donors and commercial sources. Platelet-poor plasma was treated ex vivo with or without TXA and either with or without tPA or with or without uPA. Clotting was then induced by calcium and thrombin in clotted PPP experiments, while unclotted PPP experiments were treated with vehicle controls. C5a levels were measured via enzyme-linked immunosorbent assay. Data were expressed as mean ± SEM.
Plasmin-mediated fibrinolysis by tPA in clotted PPP led to an approximately threefold increase in C5a production (p < 0.0001), which was significantly inhibited by TXA (p < 0.001). Paradoxically, when fibrinolysis was induced by uPA, TXA treatment led to further increases in C5a production beyond uPA alone (p < 0.0001). Furthermore, clotting was not required for C5a generation from uPA + TXA. C3 depletion had no effect on C5a production, while depletion of PLG eliminated it.
Tranexamic acid administration can have proinflammatory or anti-inflammatory effects through regulating C5a generation by plasmin, depending on the predominating PLG activator. Tranexamic acid may cause significant inflammatory C5a elevations in injured tissues by augmenting uPA-mediated plasmin generation in a fibrin-independent manner. In contrast, TXA reduces C5a generation during tPA-mediated fibrinolysis that may reduce inflammatory responses. In vivo validation of these novel ex vivo findings is warranted and may have important clinical consequences.
组织型纤溶酶原激活物（tPA）在循环系统中，尿激酶（uPA）在组织中均可将纤溶酶原（PLG）裂解为纤溶酶，以促进血栓溶解。氨甲环酸（TXA）可阻断 tPA 依赖性纤维蛋白凝块上纤溶酶的生成以及已激活的纤溶酶与聚合纤维蛋白的结合，并常用于创伤性出血以限制纤维蛋白溶解。然而，除了溶解血栓外，激活的纤溶酶还可裂解补体蛋白，从而潜在增强炎症反应。由于 TXA 不能阻断 uPA 依赖性 PLG 生成的纤溶酶，反而增强了其作用，我们假设 TXA 的给药方式可通过 PLG 激活物依赖性方式增强或抑制促炎 C5a 的形成。
从健康供体和商业来源获得柠檬酸盐血小板贫乏血浆（PPP）和缺乏补体蛋白 C3 或 PLG 的 PPP。PPP 血小板贫乏血浆在体外经 TXA 处理，与 tPA 联合或不联合，或与 uPA 联合或不联合。在血栓 PPP 实验中通过钙和凝血酶诱导血栓形成，在未凝结的 PPP 实验中用载体对照处理。通过酶联免疫吸附试验测量 C5a 水平。数据表示为平均值±SEM。
tPA 在血栓 PPP 中的纤溶作用导致 C5a 生成增加约三倍（p < 0.0001），TXA 显著抑制了 C5a 的生成（p < 0.001）。矛盾的是，当 uPA 诱导纤溶时，TXA 治疗导致 C5a 的生成进一步增加，超过 uPA 单独作用（p < 0.0001）。此外，uPA + TXA 产生 C5a 不需要凝血。C3 耗竭对 C5a 的生成没有影响，而 PLG 耗竭则消除了 C5a 的生成。
根据 PLG 激活物的主导作用，氨甲环酸的给药方式可以通过调节纤溶酶的 C5a 生成来发挥促炎或抗炎作用。TXA 可能通过以纤维蛋白非依赖性方式增强 uPA 介导的纤溶酶生成，在受伤组织中引起显著的炎症性 C5a 升高。相反，TXA 减少 tPA 介导的纤溶过程中的 C5a 生成，这可能减轻炎症反应。需要对这些新的体外发现进行体内验证，这可能具有重要的临床意义。
