Wachtfogel Y T, Kucich U, Hack C E, Gluszko P, Niewiarowski S, Colman R W, Edmunds L H
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pa.
J Thorac Cardiovasc Surg. 1993 Jul;106(1):1-9; discussion 9-10.
Aprotinin reduces blood loss after cardiac operations and decreases the bleeding time. The mechanism of action of aprotinin that produces these effects is not clear. During simulated extracorporeal circulation the contact and complement systems, platelets, and neutrophils are activated. We investigated the effect of aprotinin on kallikrein-C1-inhibitor complex and C1-C1-inhibitor complex formation, neutrophil degranulation, and platelet release and aggregation during simulated extracorporeal circulation. Fresh heparinized human blood was recirculated at 37 degrees C for 2 hours in a spiral coil membrane oxygenator-roller pump perfusion circuit. Changes in platelet count, leukocyte count, platelet response to adenosine diphosphate, and plasma levels of beta-thromboglobulin, kallikrein-C1-inhibitor complexes, C1-C1-inhibitor complexes, and neutrophil elastase were measured before and at 5, 30, 60, and 120 minutes of recirculation at 0, 0.015, 0.03, 0.06, and 0.12 mg/ml doses of aprotinin. Platelet counts decreased to 36% +/- 12% of control values at 5 minutes and increased to 56% +/- 13% at 120 minutes without aprotinin. Aprotinin did not affect platelet counts, but it did prevent the decrease in sensitivity of platelets to adenosine diphosphate and it attenuated beta-thromboglobulin release. In the absence of aprotinin, kallikrein-C1-inhibitor and C1-C1-inhibitor complexes increased progressively to 0.53 +/- 0.14 U/ml and 2.38 +/- 0.33 U/ml, respectively, at 120 minutes. Kallikrein-C1-inhibitor complexes were completely inhibited and C1-C1-inhibitor complexes were partially inhibited at aprotinin concentrations of 0.03 mg/ml or greater. Release of neutrophil elastase was partially but not completely inhibited at the highest dose of aprotinin and was 50% inhibited at a dose of 0.03 mg/ml. Because activation of the fibrinolytic system does not occur in this system, the changes were independent of the inhibition of plasmin. We conclude that aprotinin in high doses completely inhibited kallikrein-induced activation of neutrophils and partially inhibited complement-induced activation. Aprotinin did not directly affect platelet adhesion or aggregation, but it indirectly preserved platelet sensitivity to agonists and also attenuated release of alpha-granule contents. The data indicate that in the presence of aprotinin platelet function was partially preserved, kallikrein production was totally inhibited, complement activation was partially inhibited, and neutrophil release was partially inhibited, thus attenuating the "whole body inflammatory response" associated with cardiopulmonary bypass.
抑肽酶可减少心脏手术后的失血量并缩短出血时间。抑肽酶产生这些作用的作用机制尚不清楚。在模拟体外循环过程中，接触系统和补体系统、血小板及中性粒细胞被激活。我们研究了抑肽酶在模拟体外循环过程中对激肽释放酶-C1抑制物复合物和C1-C1抑制物复合物形成、中性粒细胞脱颗粒以及血小板释放和聚集的影响。新鲜肝素化人血在37℃下于螺旋盘管膜式氧合器-滚压泵灌注回路中再循环2小时。在以0、0.015、0.03、0.06和0.12mg/ml剂量的抑肽酶再循环的0、5、30、60和120分钟时，分别测量血小板计数、白细胞计数、血小板对二磷酸腺苷的反应以及血浆中β-血小板球蛋白、激肽释放酶-C1抑制物复合物、C1-C1抑制物复合物和中性粒细胞弹性蛋白酶的水平。在无抑肽酶时，血小板计数在5分钟时降至对照值的36%±12%，在120分钟时升至56%±13%。抑肽酶不影响血小板计数，但可防止血小板对二磷酸腺苷敏感性的降低，并减弱β-血小板球蛋白的释放。在无抑肽酶时，激肽释放酶-C1抑制物和C1-C1抑制物复合物在120分钟时分别逐渐增加至0.53±0.14U/ml和2.38±0.33U/ml。在抑肽酶浓度为0.03mg/ml或更高时，激肽释放酶-C1抑制物复合物被完全抑制，C1-C1抑制物复合物被部分抑制。在抑肽酶最高剂量时，中性粒细胞弹性蛋白酶的释放被部分但未完全抑制，在0.03mg/ml剂量时被抑制50%。由于该系统中未发生纤溶系统的激活，这些变化与纤溶酶的抑制无关。我们得出结论，高剂量的抑肽酶可完全抑制激肽释放酶诱导的中性粒细胞激活，并部分抑制补体诱导的激活。抑肽酶不直接影响血小板的黏附或聚集，但可间接保持血小板对激动剂的敏感性，并减弱α-颗粒内容物的释放。数据表明，在有抑肽酶存在时，血小板功能部分得以保留，激肽释放酶的产生被完全抑制，补体激活被部分抑制，中性粒细胞释放被部分抑制，从而减弱了与体外循环相关的“全身炎症反应”。
