Miszta Adam, Ahmadzia Homa K, Luban Naomi L C, Li Shuhui, Guo Dong, Holle Lori A, Berger Jeffrey S, James Andra H, Gobburu Jogarao V S, van den Anker John, de Laat Bas, Wolberg Alisa S
Department of Pathology and UNC Blood Research Center, University of North Carolina, Chapel Hill, NC, USA.
Synapse Research Institute, Maastricht, The Netherlands.
J Thromb Haemost. 2021 Jan;19(1):221-232. doi: 10.1111/jth.15114. Epub 2020 Dec 26.
Essentials Tranexamic acid (TXA) is an antifibrinolytic drug used to reduce bleeding. Assaying plasmin generation (PG) in plasma detects clinically relevant TXA levels in vitro and ex vivo. 3.1-16.2 µg/mL TXA half-maximally inhibits PG in plasma from women undergoing cesarean delivery. PG velocity shows the strongest dose-relationship at low TXA concentrations (≤10 µg/mL). ABSTRACT: Background Tranexamic acid (TXA) is used to reduce bleeding. TXA inhibits plasmin(ogen) binding to fibrin and reduces fibrinolysis. TXA antifibrinolytic activity is typically measured by clot lysis assays; however, effects on plasmin generation (PG) are unclear due to a lack of tools to measure PG in plasma. Aims Develop an assay to measure PG kinetics in human plasma. Determine effects of TXA on PG and compare with fibrinolysis measured by rotational thromboelastometry (ROTEM). Methods We characterized effects of plasminogen, tissue plasminogen activator, fibrinogen, and α -antiplasmin on PG in vitro. We also studied effects of TXA on PG in plasma from 30 pregnant women administered intravenous TXA (5, 10, or 15 mg/kg) during cesarean delivery. PG was measured by calibrated fluorescence. PG parameters were compared with TXA measured by mass spectrometry and ROTEM of whole blood. Results The PG assay is specific for plasmin and sensitive to tissue plasminogen activator, fibrin(ogen), and α -antiplasmin. Addition of TXA to plasma in vitro dose dependently prolonged the clot lysis time and delayed and reduced PG. For all doses of TXA administered intravenously, the PG assay detected delayed time-to-peak (≤3 hours) and reduced the velocity, peak, and endogenous plasmin potential (≤24 hours) in plasma samples obtained after infusion. The PG time-to-peak, velocity, and peak correlated significantly with TXA concentration and showed less variability than the ROTEM lysis index at 30 minutes or maximum lysis. Conclusions The PG assay detects pharmacologically relevant concentrations of TXA administered in vitro and in vivo, and demonstrates TXA-mediated inhibition of PG in women undergoing cesarean delivery.
氨甲环酸（TXA）是一种用于减少出血的抗纤溶药物。检测血浆中的纤溶酶生成（PG）可在体外和体内检测出临床相关的TXA水平。在接受剖宫产的女性血浆中，3.1 - 16.2µg/mL的TXA可使PG抑制达到半数最大效应。在低TXA浓度（≤10µg/mL）时，PG速度显示出最强的剂量关系。摘要：背景 氨甲环酸（TXA）用于减少出血。TXA抑制纤溶酶（原）与纤维蛋白结合并减少纤维蛋白溶解。TXA的抗纤溶活性通常通过凝块溶解试验来测量；然而，由于缺乏测量血浆中PG的工具，其对纤溶酶生成（PG）的影响尚不清楚。目的 开发一种用于测量人血浆中PG动力学的检测方法。确定TXA对PG的影响，并与旋转血栓弹力图（ROTEM）测量的纤维蛋白溶解进行比较。方法 我们在体外表征了纤溶酶原、组织纤溶酶原激活剂、纤维蛋白原和α-抗纤溶酶对PG的影响。我们还研究了TXA对30名在剖宫产期间静脉注射TXA（5、10或15mg/kg）的孕妇血浆中PG的影响。通过校准荧光测量PG。将PG参数与通过质谱法测量的TXA以及全血的ROTEM进行比较。结果 PG检测对纤溶酶具有特异性，并且对组织纤溶酶原激活剂、纤维蛋白（原）和α-抗纤溶酶敏感。在体外向血浆中添加TXA剂量依赖性地延长凝块溶解时间，并延迟和减少PG。对于所有静脉注射剂量的TXA，PG检测在输注后获得的血浆样本中检测到峰值时间延迟（≤3小时），并降低了速度、峰值和内源性纤溶酶潜力（≤24小时）。PG的峰值时间、速度和峰值与TXA浓度显著相关，并且在30分钟或最大溶解时比ROTEM溶解指数的变异性更小。结论 PG检测可检测体外和体内给药的药理学相关浓度的TXA，并证明TXA在剖宫产女性中对PG的介导抑制作用。
