Collet J P, Montalescot G, Lesty C, Soria J, Mishal Z, Thomas D, Soria C
Department of Cardiology, Hematology Research Center, Pitié-Salpêtrière Hospital, Paris, France.
Arterioscler Thromb Vasc Biol. 2001 Jan;21(1):142-8. doi: 10.1161/01.atv.21.1.142.
The glycoprotein IIb/IIIa receptor inhibitor abciximab has been shown to facilitate the rate and the extent of pharmacological thrombolysis with recombinant tissue plasminogen activator (rtPA) in patients with acute myocardial infarction. However, the underlying mechanisms remain not fully determined. We sought to demonstrate that this facilitating effect of abciximab could be related to its potential to modify the clot architecture and the clot physical properties. Compared with fibrin-rich clots, platelets dramatically modified the in vitro properties of the fibrin network, leading to a significant increase of the permeability (K(s)) and the viscoelasticity (G') indexes but also leading to the appearance of platelet aggregates (surface area [S.ag]). These modifications resulted in a 2.6-fold decrease of the fibrinolysis rate when rtPA (1 nmol/L) was added before the initiation of clotting. Adding aspirin (100 microgram/mL) or abciximab (0.068 micromol/L) before the clotting of platelet-rich clots (PRCs) lowered K(s) by 50% and 70%, respectively (P<0.01), G' by 41% and 66%, respectively (P<0.01), and S.ag by 32% and 61%, respectively (P<0.01). As a consequence, the lysis speed was increased by 21% with aspirin (P<0.01) and 45% with abciximab (P<0.01). However, unlike aspirin, permeation of preformed PRCs with abciximab (0.068 micromol/L) decreased G' (37%, P<0.01), K(s) (35%, P<0.001) and S.ag (25%, P=NS) and resulted in a 27% (P<0.01) increase of the lysis speed when abciximab and rtPA (0.2 micromol/L) were simultaneously permeated. This effect was found to be time dependent and was observed only with early permeation, starting within the first 10 minutes of clotting. These changes in the physical properties of the PRC architecture suggest that fibrin is removed from the platelet-fibrin aggregates and reexposed into the surrounding fibrin network, increasing rtPA access to fibrin and therefore the fibrinolysis rate. The superiority of abciximab over aspirin in accelerating fibrinolysis of forming and preformed PRCs is related to its ability to modulate the interactions of fibrinogen and fibrin with platelets. These findings provide new mechanistic information on reperfusion therapy.
糖蛋白IIb/IIIa受体抑制剂阿昔单抗已被证明可促进急性心肌梗死患者使用重组组织型纤溶酶原激活剂（rtPA）进行药理溶栓的速度和程度。然而，其潜在机制仍未完全明确。我们试图证明阿昔单抗的这种促进作用可能与其改变血凝块结构和血凝块物理特性的潜力有关。与富含纤维蛋白的凝块相比，血小板显著改变了纤维蛋白网络的体外特性，导致通透性（K(s)）和粘弹性（G'）指数显著增加，但也导致血小板聚集体的出现（表面积[S.ag]）。当在凝血开始前加入rtPA（1 nmol/L）时，这些改变导致纤溶速率降低了2.6倍。在富含血小板的凝块（PRC）凝血前加入阿司匹林（100微克/毫升）或阿昔单抗（0.068微摩尔/升），分别使K(s)降低了50%和70%（P<0.01），G'分别降低了41%和66%（P<0.01），S.ag分别降低了32%和61%（P<0.01）。因此，阿司匹林使溶解速度提高了21%（P<0.01），阿昔单抗使溶解速度提高了45%（P<0.01）。然而，与阿司匹林不同的是，用阿昔单抗（0.068微摩尔/升）渗透预先形成的PRC会降低G'（37%，P<0.01）、K(s)（35%，P<0.001）和S.ag（25%，P=无统计学意义），并且当阿昔单抗和rtPA（0.2微摩尔/升）同时渗透时，溶解速度会提高27%（P<0.01）。发现这种作用具有时间依赖性，并且仅在凝血开始后的前10分钟内开始的早期渗透时才观察到。PRC结构物理特性的这些变化表明，纤维蛋白从血小板 - 纤维蛋白聚集体中被去除并重新暴露于周围的纤维蛋白网络中，增加了rtPA与纤维蛋白的接触，从而提高了纤溶速率。阿昔单抗在加速形成的和预先形成的PRC的纤溶方面优于阿司匹林，这与其调节纤维蛋白原和纤维蛋白与血小板相互作用的能力有关。这些发现为再灌注治疗提供了新的机制信息。
