Department of Cardiology and Angiology I, Heart Centre, University of Freiburg, Germany.
Vitrisa Therapeutics, Durham, NC, USA.
Eur Heart J Acute Cardiovasc Care. 2019 Sep;8(6):520-526. doi: 10.1177/2048872617703065. Epub 2017 Apr 13.
Residual platelet reactivity is a predictor of poor prognosis in patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention. Thrombin is a major platelet activator and upon initiation of the coagulation cascade, it is subsequently produced downstream of factor IXa, which itself is known to be increased in ACS. Pegnivacogin is a novel RNA-aptamer based factor IXa inhibitor featuring a reversal agent, anivamersen. We hypothesized that pegnivacogin could reduce platelet reactivity.
Whole blood samples from healthy volunteers were incubated in vitro in the presence and absence of pegnivacogin and platelet reactivity was analysed. In addition, platelet aggregometry was performed in blood samples from ACS patients in the RADAR trial featuring the intravenous administration of pegnivacogin as well as reversal by anivamersen.
In vitro, pegnivacogin significantly reduced adenosine diphosphate-induced CD62P-expression (100% . 89.79±4.04%, =0.027, =9) and PAC-1 binding (100% . 83.02±4.08%, =0.010, =11). Platelet aggregation was reduced (97.71±5.30% . 66.53±9.92%, =0.013, =10) as evaluated by light transmission aggregometry. In the presence of the RNA-aptamer reversal agent anivamersen, neither CD62P-expression nor platelet aggregation was attenuated. In patients with ACS treated with aspirin and clopidogrel, residual platelet aggregation was significantly reduced 20 min after intravenous bolus of 1 mg/kg pegnivacogin (100% versus 43.21±8.23%, =0.020).
Inhibition of factor IXa by pegnivacogin decreases platelet activation and aggregation in vitro. This effect was negated by anivamersen. In ACS patients, platelet aggregation was significantly reduced after intravenous pegnivacogin. An aptamer-based anticoagulant inhibiting factor IXa therefore might be a promising antithrombotic strategy in ACS patients.
残余血小板反应性是经皮冠状动脉介入治疗的急性冠脉综合征（ACS）患者预后不良的预测因子。凝血酶是血小板的主要激活剂，在凝血级联反应开始时，它是因子 IXa 的下游产物，而因子 IXa 在 ACS 中已知会增加。Pegnivacogin 是一种新型的基于 RNA 适体的因子 IXa 抑制剂，具有逆转剂 anivamersen。我们假设 pegnivacogin 可以降低血小板反应性。
将健康志愿者的全血样本在体外与或不与 pegnivacogin 孵育，并分析血小板反应性。此外，还在 RADAR 试验中进行了 ACS 患者的血小板聚集试验，该试验中静脉给予 pegnivacogin 以及用 anivamersen 逆转。
在体外，pemnivacogin 显著降低了二磷酸腺苷诱导的 CD62P 表达（100%. 89.79±4.04%，=0.027，=9）和 PAC-1 结合（100%. 83.02±4.08%，=0.010，=11）。通过透光比浊法评估，血小板聚集减少（97.71±5.30%. 66.53±9.92%，=0.013，=10）。在 RNA 适体逆转剂 anivamersen 的存在下，CD62P 表达和血小板聚集均未减弱。在接受阿司匹林和氯吡格雷治疗的 ACS 患者中，静脉注射 1mg/kg pegnivacogin 20 分钟后，残余血小板聚集明显降低（100% 与 43.21±8.23%，=0.020）。
Pegnivacogin 抑制因子 IXa 可降低体外血小板的激活和聚集。这一作用被 anivamersen 所否定。在 ACS 患者中，静脉注射 pegnivacogin 后血小板聚集明显减少。因此，基于适体的抑制因子 IXa 的抗凝剂可能是 ACS 患者有前途的抗血栓形成策略。
