Inhibition of growth of thrombus on fresh mural thrombus. Targeting optimal therapy.
Inhibition of growth of thrombus on fresh mural thrombus. Targeting optimal therapy.
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DOI：
10.1161/01.cir.90.5.2432
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发表时间：
1994-11
期刊：
影响因子：
37.8
通讯作者：
Beat J. Meyer;J. Badimón;A. Mailhac;Antonio Fernández-Ortiz;J. Chesebro;V. Fuster;L. Badimón
中科院分区：
文献类型：
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作者：
Beat J. Meyer;J. Badimón;A. Mailhac;Antonio Fernández-Ortiz;J. Chesebro;V. Fuster;L. Badimón
严重损伤的动脉壁上残留的附壁血栓非常易形成血栓。我们检验了直接凝血酶抑制比间接凝血酶抑制、环氧合酶抑制或两者都能更好地阻断新鲜血栓上血栓生长的假设。方法和结果在一个良好表征的离体灌注系统中，以高剪切速率将新鲜猪血直接灌注在严重受损的动脉壁上5分钟，形成新鲜附壁血栓。5分钟内达到的平均血小板（P）和纤维蛋白原（F）沉积（D）分别为382 +/- 32 x 10（6）血小板/cm 2和296 +/- 36 x 10（12）纤维蛋白原分子/cm 2。通过在预先形成的附壁血栓上直接灌注来自猪的具有111 In标记的血小板和125 I标记的纤维蛋白原的血液另外5分钟来定量新鲜附壁血栓上的血栓生长。治疗包括重组水蛭素（1 mg/kg/h IV）作为凝血酶探针，阿司匹林（5 mg/kg IV）作为环氧合酶的血小板抑制剂，肝素（中等剂量，100 IU/kg/h IV;高剂量，250 IU/kg/h IV）作为间接凝血酶抑制剂，肝素（100 IU/kg/h）加阿司匹林（5 mg/kg IV）。与基线（分别为1113 +/- 67和545 +/- 52）相比，阿司匹林（分别为1034 +/- 92和436 +/- 78）轻度但不显著降低了血栓生长（通过标记PD（x 10（6）/cm 2）和FD（x 10（12）分子/cm 2）测量）。肝素对血栓生长的抑制具有剂量依赖性。回归分析显示PD和FD与平均血浆肝素浓度呈负相关（分别为r = -.81，P = .0001和r = -.49，P = .0007）。重组水蛭素导致血栓生长的显著抑制（PD，30 +/- 12; FD，109 +/- 21），与所有组相比，即使是最高剂量的肝素（250 IU/kg/h）也是显著的。结论：特异性凝血酶抑制剂可显著抑制高剪切速率下血小板和纤维蛋白原在新鲜附壁血栓上的沉积。阿司匹林单独使用或与肝素联合使用对血栓形成的影响很小。肝素剂量依赖性地减少血栓生长，但即使是最高剂量也不如水蛭素有效。凝血酶似乎是新鲜血栓血小板的主要激活剂。
BACKGROUND 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. METHODS AND RESULTS 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). CONCLUSIONS 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.