Effect of anti-fibrinolytic therapy on experimental melanoma metastasis

Anti-fibrinolytic agents such as aprotinin and ε-aminocaproic acid (EACA) are used clinically to decrease peri-operative bleeding. Use of these treatments during cancer-related surgeries has led to investigation of the effect of fibrinolysis inhibition on cancer cell spread. The ability of aprotinin to reduce proteolytic activity of proteases required for metastasis suggests that it could have an anti-metastatic effect in patients undergoing tumor resection. However, many metastatic cells in the vasculature of a secondary tissue are associated with a micro-thrombus. The association of tumor cells with thrombi has been shown to increase their survival; therefore inhibition of plasmin-mediated fibrinolysis might instead increase metastatic cell survival by enhancing the association between thrombi and tumor cells. The goal of this work was to determine the effect of anti-fibrinolytic treatment on experimental metastasis and to establish the role of coagulation factors in this effect. The metastatic ability of B16F10 melanoma cells was evaluated in vivo following cell or animal pre-treatment with aprotinin or EACA. Additionally, a novel in vivo technique was developed, to permit analysis of tumor cell association with thrombi in the lung microvasculature using confocal microscopy. Aprotinin and EACA treatment of mice resulted in a significant increase in lung metastasis. Aprotinin treatment increased the size of thrombi in association with cells arrested in lung capillaries. This study suggests that clinical use of anti-fibrinolytic agents for cancer-related surgeries could result in increased metastatic ability of those cells shed immediately prior to and during surgery, and that this approach thus requires further study.     

抑肽酶、乌司他丁加氨甲苯酸与氨甲苯酸对血液纤溶系统的保护作用

目的观察抑肽酶、乌司他丁加氨甲苯酸与氨甲苯酸对体外循环（CPB）心脏手术的血液纤溶系统的保护作用。方法选择36例行风湿性心脏病瓣膜置换术的患者,随机分成三组。抑肽酶组（A组,12例）：在预充液中一次性加入抑肽酶200万U;乌司他丁加氨甲苯酸组（UP组,12例）：在预充液中加入乌司他丁12000U／kg、氨甲苯酸10mg／kg;氨甲苯酸组（P组,12例）：在预充液中加入氨甲苯酸10mg／kg。结果三组CPB时间、输血量比较差异无统计学意义;术后24h胸腔引流量UP组（443．3±150．8）ml、P组（430．0±178．3）ml,与A组的（290．0±98．0）ml比较差异有统计学意义（P〈0．05）。A组有1例发生严重过敏反应。结论抑肽酶、乌司他丁加氨甲苯酸和氨甲苯酸均有维持血液纤溶系统稳定、保护血小板功能的作用,从而减少术中及术后出血。     

Aprotinin in pediatric neuromuscular scoliosis surgery

Reduction of blood transfusions in patients with neuromuscular scoliosis can decrease potential complications such as immune suppression, infection, hemolytic reaction and viral transmission. Aprotinin (Trasylol^®, Bayer), an antifibrinolytic, has proven to be effective in reducing blood loss in cardiac and liver surgery, but little data exists in patients undergoing spinal fusion for neuromuscular scoliosis. The purpose of this study was to evaluate the safety and efficacy of aprotinin in pediatric neuromuscular scoliosis patients undergoing spinal fusion. The medical records of all patients undergoing initial spinal fusions for neuromuscular scoliosis between January 1999 and March 2003 were reviewed to determine demographic data, perioperative data, wound drainage and number of transfusion required. Cases were compared to a matched group of historical controls. We had 14 patients in the aprotinin group and 17 in the control group. Total blood loss in the aprotinin group was significantly lower compared to the control group (715 vs. 2,110 ml; P = 0.007). Significantly less blood loss occurred in the aprotinin group when blood loss per kilogram was evaluated as well (23 vs. 60 ml/kg, respectively; P = 0.002). Intra-operative packed red blood cell (PRBC) transfusions were also significantly lower in the aprotinin group (1.25 vs. 3.16 units; P = 0.001). No clinical evidence of anaphylaxis, deep vein thrombosis (DVT) or renal failure was observed in the aprotinin group. After considering the price of drug therapy, operating room time, and the cost of blood products, the use of aprotinin saved an average of $8,577 per patient. In our series, the use of aprotinin resulted in decreased blood loss and a decreased rate of transfusions in children with neuromuscular scoliosis undergoing extensive spinal fusion. At out institution, the use of aprotinin is safe and cost effective for patients with neuromuscular scoliosis.     

两种抑肽酶制剂抑制纤溶活性和保护血小板功能作用的比较

使用大剂量的抑肽酶能显著改善体外循环心内直视手术后的止血功能,减少术后创面的渗血量。本实验通过尿激酶诱导的纤溶活性和抗血小板聚集作用,比较两种抑肽酶制剂(5万和50万单位/瓶)对此的保护作用。结果表明,两种抑肽酶制剂对纤溶活性的抑制作用和对血小板功能的保护作用是有同等的浓度依赖性,提示它们的临床作用也应该一致。     

抑肽酶对围术期急性失血性休克DIC转归的保护作用

目的 :探讨抑肽酶对围术期急性失血性休克弥漫性血管内凝血 (DIC)转归的保护作用。方法 :选择外伤后失血较多并出现急性失血性休克病人 2 7例 ,随机分为 2组 ,Ⅰ组 (15例 )为静脉应用抑肽酶组 ;Ⅱ组 (12例 )为立止血对照组 ,静脉应用立止血。两组患者于术前、术中低容量期、术中容量恢复期、术后 1小时、术后 1天分别观测血小板计数 (PLC)以及凝血功能检查 ,包括凝血酶原时间 (PT)、激活部分促凝血酶原激酶时间 (APTT)、凝血酶凝结时间 (TT)、纤维蛋白原(FIB)。结果 :抑肽酶组术中容量恢复期、术后 1小时、术后 1天PLC、PT、APTT、TT、FIB均正常或接近正常 ,而对照组则出现明显异常 ,其中 4例病人出现PLC低于 5 0× 10 9/L ,FIB低于 1 5g ,PT、APTT明显延长的DIC诊断指征。结论 :严重失血性休克患者应用抑肽酶对休克转归DIC具有保护作用。     

Pulmonary vascular resistance index during coronary artery bypass surgery with aprotinin

Low pulmonary vascular resistance index (PVRI) reflects favorable redundant pulmonary circulation following coronary artery bypass grafting with cardiopulmonary bypass surgery (CPB). This randomized study investigated whether aprotinin given in different modalities impacts PVRI after coronary artery bypass grafting. A total of 40 patients undergoing coronary artery bypass grafting were randomized to four groups according to aprotinin dose: (1) high dose, (2) early low dose, (3) late low dose, and (4) without aprotinin. Oxygenation index, pulmonary shunt, alveolar-arterial oxygen gradient and PVRI were determined. PVRI was calculated as the transpulmonary pressure gradient divided by cardiac index multiplied by 80. The results showed that PVRI remained relative low in all patients provided aprotinin regardless of treatment dosage; PVRI increased at 4?h after restarting ventilation after CPB in patients without aprotinin as compared with aprotinin (266?±?137, 266?±?115, 244?±?86 vs. 386?±?121, dynes-s-cm^?5, respectively, p?=?.047). Elevated postoperative PVRI was predictive for patients without aprotinin (AUC 0.668; SE 0.40; p?相似文献   

抑肽酶对体外循环围术期白介素-2 分泌细胞和可溶性受体表达的影响

目的：白介素和其受体介导的反应在免疫功能中有重要地位，我们着重观察白介素－２分泌细胞（ＩＬ－２Ｃ）和可溶性白介素－２受体（ｓＩＬ－２Ｒ）在体外循环（ＣＰＢ）中和术后的变化，以及抑肽酶对其影响。方法：２１例瓣膜替换手术患者分两组，对照组（１０例），抑肽酶组（１１例），体外循环中给２００万单位抑肽酶。结果：两组ＩＬ－２Ｃ在体外循环１０分钟时明显降低，３０分钟时明显增加，６０分钟时继续增加，术后达到高峰，术后１天和术后３天明显低于术前。ＩＬ－２Ｃ和库血应用呈负相关。两组ｓＩＬ－２Ｒ变化基本和ＩＬ－２Ｃ相似。但抑肽酶组在体外循环６０分钟时、术后即刻、术后１天、术后３天ｓＩＬ－２Ｒ的增加幅度低于对照组。抑肽酶组术后胸腔引流量明显低于对照组。结论：体外循环对ＩＬ－２Ｃ开始为刺激，术后转为抑制状态。ｓＩＬ－２Ｒ在体外循环后期和术后增加，这对免疫功能有不利影响，抑肽酶除改善凝血功能外，还可能改善白介素介导的免疫反应。     

体外循环时心肌细胞上粘附分子的变化及抑肽酶对其表达的影响

目的：观察行心脏瓣膜置换术的病人在体外循环（CPB）前，后心肌细胞间粘附分-1(ICAM-1）及血管细胞间粘附分子－1（VCAM－1）的表达，并探讨抑肽酶对其表面的影响，方法：20例病人被随机均分为抑肽酶组和对照组，分别于手术开始及结束时取右心房心肌标本，采用免疫组化法检测心肌细胞及心肌血管内皮细胞上ICAM－1及VCAM－1的表达（IOD值）。结果：对照组心脏瓣膜我术病人CPB后心肌细胞上和心肌血管内皮细胞（EC）上ICAM－1及VCAM－1的表达较术前有明显增加（P＜0．05），而在抑肽酶组则无明显变化，组间比较，差异有具有显著意义，P＜0．05，结论：CPB时心肌细胞及心肌血管EC上ICAM－1及VCAM－1的表达增高，抑肽酶可通过抑制这些粘附分子的表达而减轻CPB所致的炎症反应。     

Aprotinin Reduces the Expression of P-Selectin on the Surface of Platelet and Leukocyte-Platelet Conjugates

P-Selectin, an adhesion molecule expressed on the surfaces of activated platelets and the vascular endothelium, mediates platelet binding to monocytes and neutrophils. Monocytes and neutrophils produce superoxide anion by activated platelets through p-selectin. Aprotinin, a serine protease inhibitor, inhibits plasmin to activate platelets during cardiopulmonary bypass (CPB). A total of 25 patients were studied to clarify the effects of aprotinin on p-selectin expression during CPB. Nine patients were not given aprotinin (control group), and 16 were given aprotinin of 2 million U in the priming solution (aprotinin group). The platelet count and soluble p-selectin in the plasma, p-selectin on the surface membranes of platelets, and leukocyte-platelet conjugate levels were measured during and after CPB. The platelet count was maintained well in the aprotinin group. The increases of soluble p-selectin in the plasma, platelet surface p-selectin, and leukocyte-platelet conjugates were less in the aprotinin group than in the control group (p < 0.05). In conclusion, aprotinin in patients undergoing CPB may reduce the early inflammatory reactions induced by p-selectin.     

小剂量抑肽酶对体外循环中血小板的保护

选择４５例心脏瓣膜置换术患者，其中２３例应用小剂量抑肽酶作为用药组，观察体外循环期间小剂量抑肽酶降低术后失血量的作用。结果显示：用药组术后失血量比对照组减少了５０．２％，输血量减少了６７．０％。抑肽酶可减缓血小板计数的骤然下降趋势，但并不阻止其下降。血小板聚集功能及粘附功能的下降在用药组明显较轻，而胞浆游离［Ｃａ２＋」ｉ、膜磷脂酶Ａ２和环氧化酶活性的上升明显被抑制。结论：小剂量抑肽酶可明显减少术后失血量及输血量，具有与大剂量抑肽酶同样的临床效果。对于血小板胞浆游离［Ｃａ２＋］ｉ及膜磷脂酶Ａ２、环氧化酶活性升高的抑制作用是抑肽酶作用机制的一个重要方面。