Abendschein D R, Meng Y Y, Torr-Brown S, Sobel B E
Cardiovascular Division, Washington University School of Medicine, St Louis, MO 63110, USA.
Circulation. 1995 Aug 15;92(4):944-9. doi: 10.1161/01.cir.92.4.944.
Pharmacological coronary fibrinolysis induces procoagulant effects that contribute to delayed recanalization and early reocclusion. This study was designed to determine whether brief inhibition of activation of the coagulation cascade with tissue factor pathway inhibitor, a physiological inhibitor of activated factor X and its activation by the tissue factor/factor VII complex, would facilitate fibrinolysis, sustain patency of recanalized arteries, or both.
Platelet-rich coronary thrombi were induced with anodal current that elicited intimal injury in 21 conscious dogs. Each was randomized to human recombinant tissue-type plasminogen activator (rTPA 1.0 mg/kg IV over 1 hour) with infusion of 50 micrograms.kg-1.min-1 of human recombinant tissue factor pathway inhibitor (rTFPI, n = 7), 100 micrograms.kg-1.min-1 of rTFPI (n = 8), or 300 mmol/L arginine phosphate buffer as a control (n = 6) concomitant with and for 1 hour after infusion of the plasminogen activator. Recanalization, verified with proximal Doppler flow probes, occurred in all but 1 dog given the high dose of rTFPI. It was not accelerated by conjunctive rTFPI. Reocclusion occurred within 90 minutes after infusion of rTPA in all 6 control dogs. However, reocclusion was delayed and patency was sustained for the entire 24-hour observation interval in 2 of 6 dogs (excluding 1 that did not survive) given the low dose and in 4 of 6 dogs (excluding 1 that did not receive the desired amount) given the high dose of rTFPI (P < .05 compared with controls). Cyclic flow variations indicative of platelet aggregation and disaggregation locally were virtually eliminated by rTFPI (3 +/- 4[SD]/h in dogs given the low dose and 2 +/- 2/h in those given the high dose of rTFPI compared with 13 +/- 12/h in controls, P < .05). In addition, rTFPI increased activated partial thromboplastin time and prothrombin time only at the high dose (1.4 +/- 0.3 and 2.1 +/- 0.9 times baseline) and had no effects on platelet aggregation assayed ex vivo and only minimal effects on bleeding time assayed in vivo.
Brief inhibition of the coagulation system by administration of rTFPI sustains patency of arteries recanalized by pharmacological fibrinolysis without markedly perturbing hemostatic mechanisms.
药物性冠状动脉纤溶会诱导促凝作用，这会导致再通延迟和早期再闭塞。本研究旨在确定用组织因子途径抑制剂短暂抑制凝血级联反应的激活是否会促进纤溶、维持再通动脉的通畅，或两者兼具。组织因子途径抑制剂是活化因子X及其被组织因子/因子VII复合物激活的生理性抑制剂。
在21只清醒犬中，通过阳极电流诱导富含血小板的冠状动脉血栓形成，该电流会引发内膜损伤。每只犬被随机分为接受人类重组组织型纤溶酶原激活剂（rTPA，1.0 mg/kg静脉注射，1小时以上）并输注50微克·千克-1·分钟-1的人类重组组织因子途径抑制剂（rTFPI，n = 7）、100微克·千克-1·分钟-1的rTFPI（n = 8）或300 mmol/L精氨酸磷酸盐缓冲液作为对照（n = 6），在输注纤溶酶原激活剂的同时及之后1小时内给药。除1只接受高剂量rTFPI的犬外，其余所有犬经近端多普勒血流探头验证均实现再通。联合使用rTFPI并未加速再通。所有6只对照犬在输注rTPA后90分钟内均发生再闭塞。然而，在接受低剂量rTFPI的6只犬中有2只（不包括1只未存活的犬）以及接受高剂量rTFPI的6只犬中有4只（不包括1只未接受所需剂量的犬）在整个24小时观察期内再闭塞延迟且通畅得以维持（与对照组相比，P <.05）。rTFPI几乎消除了指示局部血小板聚集和解聚的周期性血流变化（接受低剂量rTFPI的犬为3±4[标准差]/小时，接受高剂量rTFPI的犬为2±2/小时，而对照组为13±12/小时，P <.05）。此外，rTFPI仅在高剂量时增加活化部分凝血活酶时间和凝血酶原时间（分别为基线的1.4±0.3倍和2.1±0.9倍），对体外测定的血小板聚集无影响，对体内测定的出血时间影响极小。
通过给予rTFPI短暂抑制凝血系统可维持药物性纤溶再通动脉的通畅，而不会明显干扰止血机制。
