von Willebrand Factor Predicts Mortality in ACS Patients Treated with Potent P2Y12 Antagonists and is Inhibited by Aptamer BT200 Ex Vivo

Katarina D. Kovacevic; Bernd Jilma; Shuhao Zhu; James C. Gilbert; Max-Paul Winter; Aurel Toma; Christian Hengstenberg; Irene Lang; Jacek Kubica; Jolanta M. Siller-Matula

doi:10.1055/s-0040-1713888

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2020; 120(09): 1282-1290
DOI: 10.1055/s-0040-1713888

Cellular Haemostasis and Platelets

von Willebrand Factor Predicts Mortality in ACS Patients Treated with Potent P2Y12 Antagonists and is Inhibited by Aptamer BT200 Ex Vivo

Authors

Katarina D. Kovacevic

¹Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
Bernd Jilma

¹Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
Shuhao Zhu

²Guardian Therapeutics, Lexington, Massachusetts, United States
James C. Gilbert

²Guardian Therapeutics, Lexington, Massachusetts, United States
Max-Paul Winter

³Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
Aurel Toma

³Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
Christian Hengstenberg

³Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
Irene Lang

³Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
Jacek Kubica

⁴Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Toruń, Poland
Jolanta M. Siller-Matula

³Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria

⁵Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland

Abstract

Background 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.

Methods VWF activity was measured in 320 patients with ACS, and concentration effect curves of BT200 were established in plasma pools containing different VWF concentrations.

Results 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; p < 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 (p < 0.001).

Conclusion 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.

Keywords

VWF - mortality - predictor - BT200 - ACS - prasugrel - ticagrelor

Full Text

References

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