Benedict C R, Refino C J, Keyt B A, Pakala R, Paoni N F, Thomas G R, Bennett W F
Division of Cardiology, University of Texas Health Science Center, Houston 77030, USA.
Circulation. 1995 Nov 15;92(10):3032-40. doi: 10.1161/01.cir.92.10.3032.
The thrombolytic properties of a new variant of tissue plasminogen activator (TPA) (T103N, N117Q, KHRR 296-299 AAAA, or TNK-TPA) with longer plasma half-life, greater fibrin specificity, and increased resistance to inhibition by plasminogen activator inhibitor (PAI-1) were investigated in a rabbit thrombosed carotid artery model.
After 60 minutes of arterial occlusion, TPA (1.5, 3.0, 6.0, or 9.0 mg/kg as a front-loaded IV infusion for 90 minutes; n = 22) or TNK-TPA (0.38, 0.75, or 1.5 mg/kg as IV bolus; n = 16) was administered. Blood flow through the artery was monitored for an additional 120 minutes. Bleeding was assessed by weighing the amount of blood absorbed in a gauze pad placed in a subcutaneous muscular incision. Recanalization rates and duration of recanalization were dose dependent. The doses that produced > 80% recanalization rates with the longest duration of recanalization were 9.0 mg/kg for TPA and 1.5 mg/kg for TNK-TPA. At these doses, time to reperfusion (mean +/- SEM) was significantly faster (11 +/- 2 versus 23 +/- 7 minutes) and duration of recanalization longer (77 +/- 9 versus 51 +/- 18 minutes) for TNK-TPA compared with TPA (P < .025). Weights of the residual thrombi of the TPA group were greater than those of the TNK-TPA group (P = .004). Concentrations of fibrinogen, plasminogen, and alpha 2-antiplasmin at 120 minutes were significantly higher for TNK-TPA-treated animals compared with TPA-treated animals (P < .001). ANOVA of the blood loss data determined that there were significant differences between thrombolytic agents but not between doses. After correction for saline controls, total blood loss for pooled doses of TPA and TNK-TPA was 82 +/- 6 mg and 40 +/- 4 mg, respectively (P < .01).
From these data, we conclude that TNK-TPA, given as a bolus, produces faster and more complete recanalization of occluded arteries in a rabbit experimental model compared with TPA, without increasing systemic plasmin generation or peripheral bleeding. In addition, we observed that TNK-TPA, unlike TPA, did not potentiate collagen-induced aggregation of platelets obtained from human plasma. This lack of effect on platelet aggregation by TNK-TPA potentially could be associated with a decreased risk of reocclusion after successful thrombolysis.
在兔颈总动脉血栓形成模型中，研究了一种新型组织型纤溶酶原激活剂（TPA）变体（T103N、N117Q、KHRR 296 - 299 AAAA，即TNK - TPA）的溶栓特性，该变体具有更长的血浆半衰期、更高的纤维蛋白特异性以及对纤溶酶原激活剂抑制剂（PAI - 1）抑制作用的更高抗性。
动脉闭塞60分钟后，给予TPA（1.5、3.0、6.0或9.0 mg/kg，90分钟前负荷静脉输注；n = 22）或TNK - TPA（0.38、0.75或1.5 mg/kg静脉推注；n = 16）。额外监测动脉血流120分钟。通过称量置于皮下肌肉切口的纱布垫吸收的血量评估出血情况。再通率和再通持续时间呈剂量依赖性。产生再通率> 80%且再通持续时间最长的剂量，TPA为9.0 mg/kg，TNK - TPA为1.5 mg/kg。在这些剂量下，与TPA相比，TNK - TPA的再灌注时间（均值±标准误）显著更快（11±2对23±7分钟），再通持续时间更长（77±9对51±18分钟）（P <.025）。TPA组残余血栓重量大于TNK - TPA组（P =.004）。与TPA治疗的动物相比，TNK - TPA治疗的动物在120分钟时纤维蛋白原、纤溶酶原和α2 - 抗纤溶酶浓度显著更高（P <.001）。对失血数据进行方差分析确定，溶栓剂之间存在显著差异，但剂量之间无显著差异。校正生理盐水对照后，TPA和TNK - TPA合并剂量的总失血量分别为82±6 mg和40±4 mg（P <.01）。
从这些数据中，我们得出结论，与TPA相比，静脉推注TNK - TPA在兔实验模型中能使闭塞动脉更快、更完全地再通，且不增加全身纤溶酶生成或外周出血。此外，我们观察到，与TPA不同，TNK - TPA不会增强从人血浆中获得的血小板的胶原诱导聚集。TNK - TPA对血小板聚集缺乏这种作用可能与成功溶栓后再闭塞风险降低有关。
