Nielsen Vance G
Department of Anesthesiology, The University of Alabama, Birmingham, Alabama 35249-6810, USA.
Ann Thorac Surg. 2006 May;81(5):1720-7. doi: 10.1016/j.athoracsur.2005.12.027.
Excessive protamine administration to neutralize heparin after cardiopulmonary bypass has been implicated as a cause of postoperative hemorrhage. Protamine directly inhibits thrombin and tissue factor (TF)-mediated activation of factor VII. However, the half-life of protamine is only 4.5 minutes; thus the purpose of this study was to determine if protamine could enhance fibrinolysis, explaining the delayed, protamine-associated hemorrhage observed in the postoperative period.
Human plasma containing 0, 6.25, 12.5, or 25 microg/mL of protamine (n = 6 per condition) was exposed to 0.01% tissue factor and tissue-type plasminogen activator (tPA, 100 U/mL) for 30 minutes, with clot growth and disintegration measured by Thromboelastograph (Haemoscope Corp, Skokie, IL). The TF was increased to 0.1% in additional experiments with plasma containing protamine (25 microg/mL) and tPA.
Protamine significantly (p < 0.05) delayed the time to clot initiation, decreased the speed of clot propagation, and diminished clot strength in a concentration-dependent fashion. The onset of fibrinolysis was significantly (p < 0.05) increased only in samples with 25 microg/mL of protamine, and the rate of clot lysis was not different among the conditions. The clot duration time (from initiation to disintegration) was significantly (p < 0.05) decreased in a concentration-dependent manner by protamine. Increased TF concentration (0.1%) significantly improved clot growth kinetics and prolonged clot duration in samples with 25 microg/mL of protamine compared with samples activated with 0.01% TF.
Protamine enhanced fibrinolysis by decreasing clot strength by diminishing TF-initiated thrombin generation. Additional, clinical investigation is warranted to mechanistically implicate protamine-mediated enhancement of fibrinolysis to delayed bleeding after cardiopulmonary bypass.
体外循环后过量使用鱼精蛋白中和肝素被认为是术后出血的一个原因。鱼精蛋白直接抑制凝血酶以及组织因子（TF）介导的因子VII激活。然而，鱼精蛋白的半衰期仅为4.5分钟；因此，本研究的目的是确定鱼精蛋白是否能增强纤维蛋白溶解，从而解释术后观察到的与鱼精蛋白相关的延迟性出血。
将含有0、6.25、12.5或25μg/mL鱼精蛋白的人血浆（每种情况n = 6）暴露于0.01%组织因子和组织型纤溶酶原激活剂（tPA，100 U/mL）中30分钟，通过血栓弹力图仪（美国伊利诺伊州斯科基市血液显微镜公司）测量血凝块的形成和溶解。在含有鱼精蛋白（25μg/mL）和tPA的血浆的额外实验中，将组织因子增加到0.1%。
鱼精蛋白以浓度依赖的方式显著（p < 0.05）延迟了血凝块开始形成的时间，降低了血凝块扩展的速度，并减弱了血凝块强度。仅在含有25μg/mL鱼精蛋白的样本中，纤维蛋白溶解的起始显著（p < 0.05）增加，并且在不同条件下血凝块溶解的速率没有差异。鱼精蛋白以浓度依赖的方式显著（p < 0.05）缩短了血凝块持续时间（从开始形成到溶解）。与用0.01%组织因子激活的样本相比，增加组织因子浓度（0.1%）显著改善了含有25μg/mL鱼精蛋白的样本中的血凝块形成动力学并延长了血凝块持续时间。
鱼精蛋白通过减少组织因子启动的凝血酶生成来降低血凝块强度，从而增强纤维蛋白溶解。有必要进行进一步的临床研究，以从机制上阐明鱼精蛋白介导的纤维蛋白溶解增强与体外循环后延迟性出血之间的关系。
