Relative antithrombotic effects of monoclonal antibodies targeting different platelet glycoprotein-adhesive molecule interactions in nonhuman primates.
Relative antithrombotic effects of monoclonal antibodies targeting different platelet glycoprotein-adhesive molecule interactions in nonhuman primates.
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DOI：
10.1182/blood.v83.11.3218.bloodjournal83113218
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发表时间：
1994-06
期刊：
影响因子：
20.3
通讯作者：
Y. Cadroy;S. Hanson;A. Kelly;U. Marzec;B. Evatt;T. Kunicki;R. Montgomery;L. Harker
中科院分区：
文献类型：
--
作者：
Y. Cadroy;S. Hanson;A. Kelly;U. Marzec;B. Evatt;T. Kunicki;R. Montgomery;L. Harker
靶向糖蛋白（GP）Ib依赖性血小板相互作用与GPIIb-IIIa依赖性血小板相互作用的相对抗血栓形成有效性已在狒狒中通过在输注可比抗止血剂量的抗血管性血友病因子（vWF）单克隆抗体（MoAb）BB 3-BD 5、抗GPIb MoAb AP 1、和抗GPIIb-IIIa MoAb LJ-CP 8在动脉和静脉流动条件下（剪切速率分别为750至1，000秒-1和100秒-1）。血栓形成被量化为111 In-血小板沉积和125 I-纤维蛋白积聚在插入慢性外置动静脉（AV）分流器40分钟的胶原涂层管段上。在体外，抗vWF单抗BB 3 BD 5（IgG）和抗GPIb单抗AP 1 [IgG或F（ab）2片段]均能抑制瑞斯托霉素诱导的血小板聚集（IC 50分别为50 nmol/L和1 mumol/L），但均不能抑制ADP诱导的血小板聚集（P > 0.5）。抗GPIIb-IIIa单克隆抗体LJ-CP 8可抑制ADP诱导的血小板聚集（IC_（50）1 μ mol/L），但不能阻断瑞斯托霉素诱导的血小板聚集（P > 0.5）。在体内，将抗vWF MoAb BB 3 BD 5或抗GPIIb-IIIa MoAb LJ-CP 8以消除相应激动剂诱导的离体聚集的剂量静脉输注到狒狒中，（分别推注0.5 mg/kg和10 mg/kg）将模板出血时间从基线值4.0 +/-0.3分钟延长至> 27 +/-4分钟，和> 26 +/- 4分钟（P .5）。然而，注射抗GPIb MoAb AP 1 [10 mg/kg IgG或1 mg/kg F（ab）2片段]可立即产生不可逆的血小板减少症（<40，000血小板/微升）。抗GPIIb-IIIa MoAb LJ-CP 8在动脉和静脉流动条件下均消除胶原片段上的血小板沉积和纤维蛋白积聚（在所有情况下P <0.01），而MoAb BB 3 BD 5在动脉剪切速率下产生对血小板沉积的最小抑制，并且纤维蛋白积聚没有减少，并且在低剪切下产生不可检测的抗血栓形成结果。因此，抑制GPIIb-IIIa依赖性血小板募集在静脉和动脉剪切速率下消除血栓形成和血小板止血功能。相比之下，干扰GPIb-vWF依赖性血小板相互作用会破坏血小板止血功能，而不会产生相应的抗血栓形成作用。
The relative antithrombotic effectiveness of targeting glycoprotein (GP) Ib-dependent versus GPIIb-IIIa-dependent platelet interactions has been determined in baboons by measuring thrombus formation after infusing comparable antihemostatic doses of anti-von Willebrand factor (vWF) monoclonal antibody (MoAb) BB3-BD5, anti-GPIb MoAb AP1, and anti-GPIIb-IIIa MoAb LJ-CP8 under conditions of arterial and venous flow (shear rates of 750 to 1,000 seconds-1 and 100 seconds-1, respectively). Thrombus formation was quantified as 111In-platelet deposition and 125I-fibrin accumulation on segments of collagen-coated tubing interposed in chronic exteriorized arteriovenous (AV) shunts for 40 minutes. In vitro, anti-vWF MoAb BB3 BD5 (IgG) and anti-GPIb MoAb AP1 [IgG or F(ab)2 fragments] inhibited ristocetin-induced platelet aggregation (IC50 50 nmol/L and 1 mumol/L, respectively), but neither of these MoAbs blocked platelet aggregation induced by adenosine diphosphate (ADP) (P > .5). Conversely, anti-GPIIb-IIIa MoAb LJ-CP8 inhibited platelet aggregation induced by ADP (IC50 1 mumol/L, but failed to block ristocetin-induced platelet aggregation (P > .5). In vivo, the intravenous infusion of anti-vWF MoAb BB3 BD5 or anti-GPIIb-IIIa MoAb LJ-CP8 into baboons at doses that abolished corresponding agonist-induced aggregation ex vivo (bolus injections of 0.5 mg/kg and 10 mg/kg, respectively) prolonged template bleeding times from baseline values of 4.0 +/- 0.3 minutes to > 27 +/- 4 minutes, and to > 26 +/- 4 minutes, respectively (P .5). However, injection of anti-GPIb MoAb AP1 [10 mg/kg as IgG or 1 mg/kg as F(ab)2 fragments] produced immediate irreversible thrombocytopenia (< 40,000 platelets/microL). Anti-GPIIb-IIIa MoAb LJ-CP8 abolished platelet deposition and fibrin accumulation on collagen segments under both arterial and venous flow conditions (P < .01 in all cases), whereas MoAb BB3 BD5 produced minimal inhibition of platelet deposition and no decrease in fibrin accumulation at arterial shear rates and undetectable antithrombotic outcomes at low shear. Thus, inhibiting GPIIb-IIIa-dependent platelet recruitment abrogates both thrombus formation and platelet hemostatic function at both venous and arterial shear rates. By contrast, interfering with GPIb-vWF-dependent platelet interactions abolishes platelet hemostatic function without producing corresponding antithrombotic effects.