Krupski W C, Bass A, Kelly A B, Ruggeri Z M, Harker L A, Hanson S R
Department of Surgery, University of Colorado School of Medicine, Denver 80262.
J Vasc Surg. 1993 Feb;17(2):294-303; discussion 303-4. doi: 10.1067/mva.1993.42303.
Because the platelet membrane receptor glycoprotein IIb/IIIa plays a central role in the recruitment of platelets into forming thrombus, therapeutic inhibition of this receptor complex may be particularly useful to prevent thrombosis after small vessel arterial manipulation.
The relative hemostatic safety and antithrombotic efficacy for thrombus formation at sites of endarterectomy and implanted prosthetic vascular graft of a murine monoclonal antibody (LJ-CP8) against platelet glycoprotein IIb/IIIa have been determined in baboons after bolus injections in doses (10 mg/kg) that block platelet receptor function for fibrinogen and other adhesive glycoproteins (absent platelet aggregation and bleeding times > 30 minutes without affecting circulating platelet counts).
Thrombus formation was eliminated by LJ-CP8 at sites of surgical endarterectomy in fresh segments of homologous aorta incorporated into chronic exteriorized arteriovenous femoral shunts (accumulation of indium 111-labeled platelets fell from 4.40 +/- 0.89 x 10(9) platelets/cm in control animals [n = 6] to 0.23 +/- 0.01 x 10(9) platelets/cm in treated animals [n = 4]; p < 0.005). The formation of thrombus was also abolished by LJ-CP8 at sites of 1 cm prosthetic vascular grafts (4 mm inner diameter polytetrafluoroethylene grafts) interposed into common carotid arteries (deposition of indium 111-labeled platelets decreased from 2.57 +/- 0.43 x 10(9) platelets/cm [n = 5] to 0.16 +/- 0.06 x 10(9) platelets/cm, [n = 4]; p = 0.004). However, LJ-CP8 injections produced substantial bleeding in the surgical wound during the first few hours after operation. Thirty days after operation all four graft implants were patent in JJ-CP8-treated animals compared with two of five in control animals (p = 0.06).
We conclude that profound inhibition of platelet glycoprotein IIb/IIIa receptor function by single bolus injection of LJ-CP8 monoclonal antibody transiently abolishes platelet hemostatic function, eliminates acute thrombus formation at sites of endarterectomy and prosthetic vascular graft implants, and may improve vascular patency.
由于血小板膜受体糖蛋白IIb/IIIa在血小板募集形成血栓过程中起核心作用，对该受体复合物进行治疗性抑制可能对预防小血管动脉操作后的血栓形成特别有用。
在狒狒体内，静脉注射剂量为10mg/kg的抗血小板糖蛋白IIb/IIIa鼠单克隆抗体（LJ-CP8），该剂量可阻断血小板对纤维蛋白原和其他黏附糖蛋白的受体功能（无血小板聚集，出血时间>30分钟，且不影响循环血小板计数），之后测定其在内膜切除术部位和植入的人工血管移植物处形成血栓的相对止血安全性和抗血栓疗效。
在纳入慢性体外股动静脉分流术的同种异体主动脉新鲜节段的手术内膜切除部位，LJ-CP8消除了血栓形成（对照组动物[n = 6]中铟111标记血小板的积累量为4.40±0.89×10⁹血小板/cm，治疗组动物[n = 4]中为0.23±0.01×10⁹血小板/cm；p<0.005）。在插入颈总动脉的1cm人工血管移植物（内径4mm的聚四氟乙烯移植物）部位，LJ-CP8也消除了血栓形成（铟111标记血小板的沉积量从2.57±0.43×10⁹血小板/cm[n = 5]降至0.16±0.06×10⁹血小板/cm[n = 4]；p = 0.004）。然而，LJ-CP8注射在术后最初几个小时内在手术伤口处导致大量出血。术后30天，LJ-CP8治疗的动物中所有四个移植物植入物均保持通畅，而对照组动物中五个中有两个通畅（p = 0.06）。
我们得出结论，单次静脉注射LJ-CP8单克隆抗体对血小板糖蛋白IIb/IIIa受体功能的深度抑制可短暂消除血小板止血功能，消除内膜切除术部位和人工血管移植物植入处的急性血栓形成，并可能改善血管通畅性。
