Herbert J M, Bernat A, Maffrand J P
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
Blood. 1992 Nov 1;80(9):2281-6.
Venous thrombosis was induced by ligature of the inferior vena cava in rats whose blood was made hypercoagulable by intravenous (IV) administration of tissue thromboplastin. From a dose-response showing that the administration of increasing doses of tissue thromboplastin resulted in a subsequent progressive increase of thrombus weight, two concentrations of tissue thromboplastin were chosen: a high dose (550 microL/kg, IV) where thrombus formation was optimal and a concentration (7 microL/kg, IV) where tissue thromboplastin-hypercoagulability was intermediate. In both experimental conditions, leukopenia provoked by a myelotoxic drug did not influence the development of venous thrombosis. However, after thrombocytopenia induced by an antiplatelet antiserum, a dramatic decrease in thrombus formation was observed in animals that had been pre-challenged with the lower dose of tissue thromboplastin, whereas decrease in platelet count did not affect venous thrombosis under high thrombogenic challenge. When administered orally 2 hours before thrombosis induction, the ticlopidine analogue clopidogrel showed dose-dependent inhibition of thrombus formation in animals that were pre-challenged with a low dose of tissue thromboplastin (ED50 = 7.9 +/- 1.5 mg/kg, orally) but remained ineffective against high tissue thromboplastin-induced venous thrombosis. We further determined the effect of heparin and hirudin, and showed that both of these drugs exhibited a more potent antithrombotic activity after injection of the lower dose of tissue thromboplastin than after injection of a high dose of tissue thromboplastin. Therefore, using our model of stasis and hypercoagulability, platelet activation played a major role in the development of venous thrombosis when the thrombogenitic stimulus was mild.
通过结扎大鼠下腔静脉诱导静脉血栓形成，这些大鼠通过静脉注射组织凝血活酶使其血液呈现高凝状态。从剂量反应来看，给予递增剂量的组织凝血活酶会导致随后血栓重量逐渐增加，据此选择了两种组织凝血活酶浓度：一种高剂量（550微升/千克，静脉注射），此时血栓形成最佳；另一种浓度（7微升/千克，静脉注射），此时组织凝血活酶诱导的高凝状态处于中等水平。在这两种实验条件下，骨髓毒性药物引发的白细胞减少均不影响静脉血栓的形成。然而，在抗血小板抗血清诱导血小板减少后，在预先用较低剂量组织凝血活酶激发的动物中观察到血栓形成显著减少，而血小板计数降低在高血栓形成刺激下并不影响静脉血栓形成。在血栓形成诱导前2小时口服给药时，噻氯匹定类似物氯吡格雷在预先用低剂量组织凝血活酶激发的动物中呈现剂量依赖性的血栓形成抑制作用（半数有效剂量=7.9±1.5毫克/千克，口服），但对高剂量组织凝血活酶诱导的静脉血栓形成仍然无效。我们进一步测定了肝素和水蛭素的作用，结果显示这两种药物在注射较低剂量组织凝血活酶后比注射高剂量组织凝血活酶后表现出更强的抗血栓活性。因此，利用我们的血流淤滞和高凝模型，当血栓形成刺激较轻时，血小板活化在静脉血栓形成过程中起主要作用。
