Local glycoprotein IIb/IIIa receptor inhibitor delivery from the pump surface attenuates platelet adhesion in continuous flow ventricular assist devices

Shear-induced platelet activation (SIPA) has been identified to induce platelet adhesion and thrombus formation in continuous flow left ventricular assist devices (LVAD). Platelet glycoprotein (GP) IIb/IIIa receptor inhibitors are effective to prevent SIPA. However, systemic GP IIb/IIIa receptor inhibitor application is associated with severe bleeding complications. The aim of the study was to evaluate (i) the feasibility of absorption and elution of the GP IIb/IIIa receptor blocker TAK-029 from the Ti6Al4V surface of the pump; and (ii) the effect of local GP IIb/IIIa receptor blocker delivery regarding platelet adhesion on the surface of a continuous flow VAD model. Saturating concentrations of TAK-029 were adsorbed on the surface of a centrifugal pump. Whole human blood was perfused in circulatory mock loops using untreated (control), albumin-coated, or TAK-029-coated pumps. Peripheral resistance of the circulatory systems were adjusted accordingly to generate 5 L flow per min with impeller rotational speeds of 3500 (high-shear group) and 1500 rpm (low-shear group), respectively. Platelet adhesions on the respective impellers were quantified by ELISA and scanning electron microscopy (SEM). TAK-029 elution and half-life time were determined by ELISA. Compared with control, albumin-coated pumps showed 64 and 20% less platelet adhesions in the high- and low-shear group, respectively. TAK-029 coated pumps reduced platelet adhesion by additional 33 and 65%, respectively, compared with the albumin group. Elution of TAK 029 was initially very rapid and continued slowly. The results show that it is possible to adsorb and elute a small molecular weight GP IIb/IIIa receptor blocker from the pump surface. This drug elution reduced platelet adhesion on the pump significantly. Further studies are necessary to find a suitable drug bonding that will prolong the antiplatelet effect and preclude any bleeding complication caused by this procedure.     

Platelet Protective Effect of TAK-029, A Novel Glycoprotein IIb/IIIa Antagonist: An In Vitro Study

Previous studies have indicated that exposure of fibrinogen receptors associated with the glycoprotein IIb/IIIa complex contributes to platelet loss during cardiopulmonary bypass. TAK-029 is a newly developed reversible, nonpeptide inhibitor of platelet glycoprotein IIb/IIIa receptors. In this study, we tested the platelet preserving effect of TAK-029 in an in vitro model. The methods included the comparison of the release of β-thromboglobulin (β-TG) between a TAK-029 group (n = 5) and a control group (n = 5) in a mock circulation under a shear force generated by a centrifugal pump. To evaluate the degree of β-TG release, Δβ-TG/ΔT was calculated where Δβ-TG is the increase in βTG and ΔT is the time. The results showed that the value of Δβ-TG/ΔT in the TAK-029 group was significantly lower than it was in the control group (4.22 ± 0.27 × 10² ng/ml vs. 7.33 ± 0.66 × 10² ng/ml, respectively). In conclusion, TAK-029 reduced the platelet activation under the shear forces of an in vitro model, suggesting that TAK-029 is a potential candidate for platelet protection during cardiopulmonary bypass.     

吸入麻醉药对人血浆和血小板血栓素B2生成与血小板聚集的影响

目的：探讨吸入麻醉剂氟烷、安氟醚和异氟醚对人血浆血栓素Ｂ２（ＴＸＢ２），血小板ＴＸＢ２生成与血小板聚集的影响。方法：血浆ＴＸＢ２和血小板ＴＸＢ２的生成量用放免分析法测量，血小板聚集率用比浊法测量。结果：吸入１ＭＡＣ氟烷３０分钟后，血浆ＴＸＢ２浓度、二磷酸腺苷（ＡＤＰ）和肾上腺素（Ｅ）诱导的血小板ＴＸＢ２生成量与血小板聚集率显著下降，吸入１ＭＡＣ安氟醚３０分钟后，血浆ＴＸＢ２浓度和血小板ＴＸＢ２生成量与血小板聚集率亦显著下降，其降低的程度比氟烷轻。吸入１ＭＡＣ异氟醚对上述指标无明显影响。血小板ＴＸＢ２生成的减少与血小板聚集率的下降呈显著正相关。结论：氟烷显著抑制血小板聚集，安氟醚次之，异氟醚对血小板聚集无明显影响。其机制可能与氟烷和安氟醚通过抑制血小板上血栓素Ａ２受体的亲和力，降低ＡＤＰ和Ｅ诱导的血小板ＴＸＢ２的生成有关。