Consequences of inhibition of plasma carboxypeptidase B on in vivo thrombolysis, thrombosis and hemostasis

C.J. Refino , L. DeGuzman , D. Schmitt , R. Smyth , S. Jeet , M.T. Lipari , D. Eaton , S. Bunting
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引用次数: 37

Abstract

To further evaluate the role of plasma carboxypeptidase B (pCPB) in modulating fibrinolysis, we investigated the effects of inhibiting pCPB on tissue plasminogen activator (tPA) induced lysis of preformed whole blood clots and on thrombus formation in vivo. In a rabbit arterio-venous shunt model we observed that a systemic administration of potato carboxypeptidase inhibitor (PCI), an inhibitor of pCPB, accelerated the rate of clot lysis induced by therapeutic concentrations of tPA. This effect was equivalent to increasing the relative potency of tPA by more than a factor of two and was achieved even when PCI was administered systemically in the presence of heparin. The effect of pCPB inhibition on thrombus formation was evaluated in a novel rabbit model of venous thrombosis. In this model, systemic administration of PCI reduced thrombus weight to 33% of saline treated controls. However, this regimen resulted in a modest bleeding tendency, comparable to that seen in rabbits treated with an antithrombotic regimen of heparin. Taken together, these data further support the hypothesis that pCPB’s function is to attenuate fibrinolysis and may thereby play a role in hemostasis following vascular injury.

血浆羧肽酶B抑制对体内溶栓、血栓形成和止血的影响
为了进一步评估血浆羧肽酶B(pCPB)在调节纤维蛋白溶解中的作用,我们在体内研究了抑制pCPB对组织纤溶酶原激活剂(tPA)诱导的预制全血凝块溶解和血栓形成的影响。在兔动静脉分流模型中,我们观察到全身给予马铃薯羧肽酶抑制剂(PCI),一种pCPB抑制剂,加速了治疗浓度的tPA诱导的血栓溶解速率。这种效果相当于将tPA的相对效力提高了两倍以上,即使在肝素存在的情况下全身给予PCI也能实现。在一种新型的兔静脉血栓形成模型中评估了pCPB对血栓形成的抑制作用。在该模型中,经皮冠状动脉介入治疗的全身给药将血栓重量降至生理盐水治疗对照组的33%。然而,这种方案导致了适度的出血趋势,与用肝素抗血栓方案治疗的兔子的出血趋势相当。总之,这些数据进一步支持了pCPB的功能是减弱纤维蛋白溶解,从而可能在血管损伤后的止血中发挥作用的假设。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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