Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Guardian Therapeutics, Lexington, Massachusetts, United States.
Thromb Haemost. 2020 Sep;120(9):1282-1290. doi: 10.1055/s-0040-1713888. Epub 2020 Jul 17.
von Willebrand factor (VWF) is crucial for arterial thrombosis and its plasma levels are increased in acute coronary syndromes (ACSs). The effects of conventional platelet inhibitors are compromised by elevated VWF under high shear rates. BT200 is a third-generation aptamer that binds and inhibits the A1 domain of human VWF. This article aims to study whether VWF is a predictor of mortality in ACS patients under potent P2Y12 blocker therapy and to examine the effects of a VWF inhibiting aptamer BT200 and its concentrations required to inhibit VWF in plasma samples of patients with ACS.
VWF activity was measured in 320 patients with ACS, and concentration effect curves of BT200 were established in plasma pools containing different VWF concentrations.
Median VWF activity in patients was 170% (interquartile range % confidence interval [CI]: 85-255) and 44% of patients had elevated (> 180%) VWF activity. Plasma levels of VWF activity predicted 1-year (hazard ratio [HR]: 2.68; 95% CI: 1.14-6.31; < 0.024) and long-term (HR: 2.59; 95% CI: 1.10-6.09) mortality despite treatment with potent platelet inhibitors (dual-antiplatelet therapy with aspirin and prasugrel or ticagrelor). Although half-maximal concentrations were 0.1 to 0.2 µg/mL irrespective of baseline VWF levels, increasing concentrations (0.42-2.13 µg/mL) of BT200 were needed to lower VWF activity to < 20% of normal in plasma pools containing increasing VWF activity ( < 0.001).
VWF is a predictor of all-cause mortality in ACS patients under contemporary potent P2Y12 inhibitor therapy. BT200 effectively inhibited VWF activity in a target concentration-dependent manner.
血管性血友病因子（VWF）对动脉血栓形成至关重要，其血浆水平在急性冠脉综合征（ACS）中升高。在高剪切率下，升高的 VWF 会影响常规血小板抑制剂的作用。BT200 是一种第三代适体，可结合并抑制人 VWF 的 A1 结构域。本文旨在研究 VWF 是否可预测接受强效 P2Y12 抑制剂治疗的 ACS 患者的死亡率，并探讨 VWF 抑制剂 aptamer BT200 的作用，以及 BT200 抑制 ACS 患者血浆样本中 VWF 所需的浓度。
测量了 320 例 ACS 患者的 VWF 活性，并在含有不同 VWF 浓度的血浆池建立了 BT200 的浓度效应曲线。
患者的 VWF 活性中位数为 170%（四分位数间距%置信区间[CI]：85-255），44%的患者 VWF 活性升高（>180%）。VWF 活性的血浆水平预测了 1 年（危险比[HR]：2.68；95%CI：1.14-6.31；<0.024）和长期（HR：2.59；95%CI：1.10-6.09）死亡率，尽管接受了强效血小板抑制剂（阿司匹林和普拉格雷或替卡格雷的双联抗血小板治疗）治疗。尽管半最大浓度在 0.1 至 0.2 µg/mL 之间且与基线 VWF 水平无关，但在含有逐渐升高的 VWF 活性的血浆池中（<0.001），需要更高的 BT200 浓度（0.42-2.13 µg/mL）来将 VWF 活性降低至<20%正常水平。
VWF 是接受当代强效 P2Y12 抑制剂治疗的 ACS 患者全因死亡率的预测指标。BT200 以靶浓度依赖性方式有效抑制 VWF 活性。
