Straub A, Azevedo R, Beierlein W, Wendel H P, Dietz K, Ziemer G
Department of Thoracic, Cardiac and Vascular Surgery, University of Tübingen, Tübingen, Germany.
Thorac Cardiovasc Surg. 2006 Apr;54(3):162-7. doi: 10.1055/s-2005-872952.
Extracorporeal circulation (ECC) induces platelet activation and inflammation with potentially life-threatening organ dysfunction. Short-acting GP IIb/IIIa inhibitors like tirofiban and eptifibatide protect platelets during ECC without increasing bleeding complications and may reduce inflammation. This study investigates anti-thrombotic and anti-inflammatory effects of different platelet inhibitors.
Control (untreated) and treated (using either 150 ng/mL tirofiban, 2.5 microg/mL eptifibatide, 0.7 microg/mL milrinone, 15 microg/mL dipyridamol, or 300 KIU/mL aprotinin) heparinized blood of healthy volunteers (n = 6) was recirculated in a well-established ECC model (Chandler loop). Percentage of platelet aggregates, P-selectin-expressing (activated) platelets, CD15-positive aggregates (indicating proinflammatory platelet-granulocyte binding), and platelet counts were determined before (baseline) and after 30 minutes recirculation in unstimulated and ADP-stimulated samples using flow cytometry. Statistical analysis was performed using multifactor ANOVA after transforming the data (logarithms for counts and log odds for percentages). Least square means were backtransformed to obtain appropriate means and their 95 % confidence intervals. Multiple post-hoc comparisons were performed by Tukey's HSD test with a global alpha of 5 %.
Significant inhibition was observed for: 1) ECC-induced platelet aggregation by tirofiban (unstimulated: 2.2-fold/stimulated: 2.46-fold), eptifibatide (unstimulated: 1.96-fold/stimulated: 2.65-fold), and milrinone (unstimulated: 1.87-fold/stimulated: 1.37-fold); 2) ECC-induced P-selectin expression by tirofiban (unstimulated: 3.95-fold/stimulated: 2.54-fold), and eptifibatide (unstimulated: 5.87-fold/stimulated: 3.28-fold); 3) ECC-induced platelet loss by tirofiban (1.27-fold), and eptifibatide (1.25-fold); 4) ECC-induced platelet-granulocyte binding by tirofiban (unstimulated: 2.25-fold/stimulated: 1.59-fold), but not by eptifibatide.
Amongst the investigated drugs only GP IIb/IIIa inhibitors decreased activation, aggregation, and loss of platelets during ECC but acted differently on platelet-granulocyte interaction. A short-acting GP IIb/IIIa inhibitor with the potential to inhibit platelet activation and platelet-leukocyte interaction should be considered both for platelet protection and inhibition of platelet-mediated inflammation during ECC.
体外循环（ECC）可诱导血小板活化和炎症反应，并可能导致危及生命的器官功能障碍。短效糖蛋白IIb/IIIa抑制剂，如替罗非班和依替巴肽，可在ECC期间保护血小板，且不会增加出血并发症，还可能减轻炎症反应。本研究旨在探究不同血小板抑制剂的抗血栓形成和抗炎作用。
将健康志愿者（n = 6）的肝素化血液分为对照组（未治疗）和治疗组（分别使用150 ng/mL替罗非班、2.5 μg/mL依替巴肽、0.7 μg/mL米力农、15 μg/mL双嘧达莫或300 KIU/mL抑肽酶），在一个成熟的ECC模型（钱德勒环路）中进行再循环。使用流式细胞术测定未刺激和ADP刺激样本在再循环30分钟之前（基线）和之后的血小板聚集体百分比、表达P-选择素（活化）的血小板、CD15阳性聚集体（表明促炎性血小板-粒细胞结合）以及血小板计数。在对数据进行转换（计数的对数和百分比的对数优势）后，使用多因素方差分析进行统计分析。将最小二乘均值进行反变换以获得合适的均值及其95%置信区间。通过Tukey's HSD检验进行多重事后比较，全局α水平为5%。
观察到以下显著抑制作用：1）替罗非班（未刺激：2.2倍/刺激：2.46倍）、依替巴肽（未刺激：1.96倍/刺激：2.65倍）和米力农（未刺激：1.87倍/刺激：1.37倍）对ECC诱导的血小板聚集的抑制作用；2）替罗非班（未刺激：3.95倍/刺激：2.54倍）和依替巴肽（未刺激：5.87倍/刺激：3.28倍）对ECC诱导的P-选择素表达的抑制作用；3）替罗非班（1.27倍）和依替巴肽（1.25倍）对ECC诱导的血小板损失的抑制作用；4）替罗非班（未刺激：2.25倍/刺激：1.59倍）对ECC诱导的血小板-粒细胞结合的抑制作用，而依替巴肽无此作用。
在所研究的药物中，只有糖蛋白IIb/IIIa抑制剂可降低ECC期间血小板的活化、聚集和损失，但对血小板-粒细胞相互作用的作用不同。一种具有抑制血小板活化和血小板-白细胞相互作用潜力的短效糖蛋白IIb/IIIa抑制剂，在ECC期间对于血小板保护和抑制血小板介导的炎症反应均应予以考虑。
