Center for Platelet Research Studies, Division of Hematology/Oncology, Children's Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Thromb Haemost. 2011 Aug;106(2):219-26. doi: 10.1160/TH11-03-0185. Epub 2011 Jun 28.
It was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, two-phase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18-24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18-24 h and 15 day reactivity to ADP (correlations 0.24-0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade with high-dose clopidogrel or even higher level P2Y12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.
本研究旨在确定在噻吩吡啶类药物暴露之前，ADP 对血小板的固有反应是否会导致尽管使用普拉格雷（60 毫克负荷剂量 [LD]，每天 10 毫克维持剂量 [MD]）或高剂量氯吡格雷（600 毫克 LD，每天 150 毫克 MD）进行了高水平的 P2Y12 抑制，但仍存在对 ADP 的残余血小板反应。氯吡格雷治疗期间高残余血小板功能与不良临床结局相关。尚不清楚在接受氯吡格雷（300 毫克 LD，每天 75 毫克 MD）治疗之前与治疗中残余血小板反应之间的关系在更有效的 P2Y12 抑制后是否保持。PRINCIPLE-TIMI 44 是一项普拉格雷与高剂量氯吡格雷在 201 例计划行经皮冠状动脉介入治疗的接受心脏导管插入术的患者中进行的随机、双盲、两阶段交叉研究。在治疗前、LD（6 小时和 18-24 小时）和 MD（15 天）期间测量 ADP 刺激的血小板-单核细胞聚集体、血小板表面 P-选择素和血小板聚集。通过 Spearman 等级相关确定治疗前与治疗期间值之间的相关性。普拉格雷对每种测量方法的血小板抑制作用均优于高剂量氯吡格雷。然而，对于这两种药物，ADP 预处理反应性均能预测 6 小时、18-24 小时和 15 天的 ADP 反应性（血小板-单核细胞聚集体和 P-选择素的相关性为 0.24-0.62）。总之，在接触噻吩吡啶类药物之前，患者对 ADP 的固有血小板反应有助于尽管使用高剂量氯吡格雷甚至更高水平的 P2Y12 抑制（普拉格雷）进行高水平的 P2Y12 抑制，但仍存在对 ADP 的残余血小板反应。对 ADP 预处理反应过度的患者在治疗中对 ADP 的反应过度的可能性更大，这可能与治疗策略有关。
