Krupski W C, Bass A, Cadroy Y, Kelly A B, Harker L A, Hanson S R
Department of Medicine, Emory University School of Medicine, Atlanta, Ga.
Surgery. 1992 Aug;112(2):433-9; discussion 439-40.
Because the adhesive glycoprotein von Willebrand Factor (vWF) mediates initial platelet attachment at sites of vascular injury and may also contribute to shear-dependent platelet thrombus formation, we have determined in vivo the relative antithrombotic efficacy and hemostatic safety of infusing murine monoclonal antibodies against vWF.
In baboons with chronic arteriovenous shunts, thrombus formation was initiated by interposition of thrombogenic Dacron vascular grafts (VG) and endarterectomized baboon aortic segments (EAS). Thrombus formation on VG and EAS was assessed by use of real-time scintillation camera imaging of indium 111-labeled platelet deposition. In control and treated animals (anti-vWF antibody) platelet hemostatic competence was evaluated by means of serial measurements of platelet count, bleeding time, and ex vivo platelet aggregation in response to adenosine diphosphate and ristocetin.
Although bolus antibody infusions did not affect circulating platelet counts, bleeding times were immediately prolonged to 28 +/- 4 minutes (vs 4.7 +/- 0.4 minutes before treatment, p = 0.01). Bleeding times normalized within 24 hours after antibody administration. Platelet aggregation in response to adenosine diphosphate was unchanged by antibody therapy, whereas ristocetin-induced platelet aggregation was abolished acutely and remained impaired for 24 hours. Platelet deposition on VG after 60 minutes of exposure to flowing blood was 2.95 +/- 0.74 x 10(9) platelets/cm in six control animals as compared to 1.86 +/- 0.16 x 10(9) platelets/cm in five treated animals (p = 0.04). Similarly, platelet deposition on EAS averaged 4.40 +/- 0.89 x 10(9) platelets/cm in control studies and was reduced significantly by antibody therapy (1.52 +/- 0.50 x 10(9) platelets/cm, p = 0.02).
Despite profound interruption of platelet hemostatic functions, therapeutic targeting of vWF modestly inhibits platelet-dependent thrombosis.
由于黏附糖蛋白血管性血友病因子（vWF）介导血小板在血管损伤部位的初始黏附，并且可能也有助于剪切力依赖性血小板血栓形成，我们已在体内确定了输注抗vWF鼠单克隆抗体的相对抗血栓形成疗效和止血安全性。
在患有慢性动静脉分流的狒狒中，通过插入致血栓形成的涤纶血管移植物（VG）和狒狒主动脉内膜切除段（EAS）来启动血栓形成。通过对铟111标记的血小板沉积进行实时闪烁相机成像来评估VG和EAS上的血栓形成。在对照动物和治疗动物（抗vWF抗体）中，通过连续测量血小板计数、出血时间以及体外血小板对二磷酸腺苷和瑞斯托霉素的聚集反应来评估血小板止血能力。
尽管推注抗体未影响循环血小板计数，但出血时间立即延长至28±4分钟（治疗前为4.7±0.4分钟，p = 0.01）。抗体给药后24小时内出血时间恢复正常。抗体治疗未改变血小板对二磷酸腺苷的聚集反应，而瑞斯托霉素诱导的血小板聚集被急性消除并在24小时内仍受损。在暴露于流动血液60分钟后，六只对照动物的VG上的血小板沉积为2.95±0.74×10⁹血小板/cm，而五只治疗动物为1.86±0.16×10⁹血小板/cm（p = 0.04）。同样，在对照研究中，EAS上的血小板沉积平均为4.40±0.89×10⁹血小板/cm，并且抗体治疗使其显著降低（1.52±0.50×10⁹血小板/cm，p = 0.02）。
尽管血小板止血功能受到严重干扰，但以vWF为治疗靶点适度抑制了血小板依赖性血栓形成。
