Meyer B J, Badimon J J, Mailhac A, Fernández-Ortiz A, Chesebro J H, Fuster V, Badimon L
Cardiovascular Biology Research Laboratory, Massachusetts General Hospital, Boston.
Circulation. 1994 Nov;90(5):2432-8. doi: 10.1161/01.cir.90.5.2432.
Residual mural thrombus on severely damaged arterial wall is very thrombogenic. We tested the hypothesis that direct thrombin inhibition will block thrombus growth on fresh thrombus better than indirect thrombin inhibition, cyclooxygenase inhibition, or both.
A fresh mural thrombus was formed by directly perfusing fresh porcine blood for 5 minutes over severely damaged arterial wall at a high shear rate in a well-characterized ex vivo perfusion system. The average platelet (P) and fibrinogen (F) deposition (D) achieved in 5 minutes were 382 +/- 32 x 10(6) platelets/cm2 and 296 +/- 36 x 10(12) fibrinogen molecules/cm2, respectively. Thrombus growth on the fresh mural thrombus was quantitated by directly perfusing blood from pigs with 111In-labeled platelets and 125I-labeled fibrinogen for an additional 5 minutes over the preformed mural thrombus. Treatment included recombinant hirudin (1 mg/kg per hour IV) as a probe for thrombin, aspirin (5 mg/kg IV) as a platelet inhibitor of cyclooxygenase, heparin (moderate, 100 IU/kg per hour IV; high-dose, 250 IU/kg per hour IV) as an indirect thrombin inhibitor, and heparin (100 IU/kg per hour) plus aspirin (5 mg/kg IV). Thrombus growth as measured by labeled PD (x 10(6)/cm2) and FD (x 10(12) molecules/cm2) was mildly but not significantly reduced by aspirin (1034 +/- 92 and 436 +/- 78, respectively) compared with baseline (1113 +/- 67 and 545 +/- 52, respectively). Inhibition of thrombus growth with heparin was dose dependent. A regression analysis showed an inverse correlation of PD and FD with mean plasma heparin concentrations (r = -.81, P = .0001 and r = -.49, P = .0007, respectively). Recombinant hirudin led to a profound inhibition of thrombus growth (PD, 30 +/- 12; FD, 109 +/- 21), which was significant compared with all groups, even the highest dosage of heparin (250 IU/kg per hour).
Specific thrombin inhibition markedly inhibits platelet and fibrinogen deposition onto fresh mural thrombus at a high shear rate. Aspirin alone or in combination with heparin has little effect on evolving thrombosis. Heparin dose dependently reduces thrombus growth, but even the highest dosage is less effective than hirudin. Thrombin appears to be the primary activator of platelets by fresh thrombus.
严重受损动脉壁上的残余壁血栓具有很强的致血栓形成性。我们检验了这样一个假设，即直接凝血酶抑制在阻止新鲜血栓上的血栓生长方面比间接凝血酶抑制、环氧合酶抑制或两者联合更有效。
在一个特征明确的体外灌注系统中，以高剪切速率将新鲜猪血液直接灌注在严重受损的动脉壁上5分钟，形成新鲜壁血栓。5分钟内平均血小板（P）和纤维蛋白原（F）沉积量（D）分别为382±32×10⁶个血小板/cm²和296±36×10¹²个纤维蛋白原分子/cm²。通过将含¹¹¹In标记血小板和¹²⁵I标记纤维蛋白原的猪血再直接灌注在预先形成的壁血栓上5分钟，对新鲜壁血栓上的血栓生长进行定量。治疗包括使用重组水蛭素（1mg/kg每小时静脉注射）作为凝血酶的探针、阿司匹林（5mg/kg静脉注射）作为环氧合酶的血小板抑制剂、肝素（中等剂量，100IU/kg每小时静脉注射；高剂量，250IU/kg每小时静脉注射）作为间接凝血酶抑制剂，以及肝素（100IU/kg每小时）加阿司匹林（5mg/kg静脉注射）。与基线相比（分别为1113±67和545±52），阿司匹林使通过标记的PD（×10⁶/cm²）和FD（×10¹²分子/cm²）测量的血栓生长轻度但无显著降低（分别为1034±92和436±78）。肝素对血栓生长的抑制呈剂量依赖性。回归分析显示PD和FD与平均血浆肝素浓度呈负相关（r = -0.81，P = 0.0001；r = -0.49，P = 0.0007）。重组水蛭素导致血栓生长显著抑制（PD，30±12；FD，109±21），与所有组相比均有显著差异，甚至与最高剂量的肝素（250IU/kg每小时）相比也是如此。
特异性凝血酶抑制在高剪切速率下能显著抑制血小板和纤维蛋白原在新鲜壁血栓上的沉积。单独使用阿司匹林或与肝素联合使用对正在形成的血栓几乎没有影响。肝素剂量依赖性地减少血栓生长，但即使是最高剂量也比水蛭素效果差。凝血酶似乎是新鲜血栓激活血小板的主要因素。
