Pharmacological Inhibition of Glycoprotein VI- and Integrin α2β1-Induced Thrombus Formation Modulated by the Collagen Type.
| Autor: | Jooss NJ; Department of Biochemistry, Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands.; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom., Henskens YMC; Central Diagnostic Laboratory, Maastricht University Medical Centre, Maastricht, The Netherlands., Watson SP; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Midlands, United Kingdom., Farndale RW; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.; CambCol Laboratories, Ely, United Kingdom., Gawaz MP; Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany., Jandrot-Perrus M; UMR_S1148, Laboratory for Vascular Translational Science, INSERM, University Paris Cité, Paris, France., Poulter NS; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Midlands, United Kingdom., Heemskerk JWM; Department of Biochemistry, Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands.; Synapse Research Institute, Maastricht, The Netherlands. |
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| Jazyk: | angličtina |
| Zdroj: | Thrombosis and haemostasis [Thromb Haemost] 2023 Jun; Vol. 123 (6), pp. 597-612. Date of Electronic Publication: 2023 Feb 17. |
| DOI: | 10.1055/s-0043-1761463 |
| Abstrakt: | Background: In secondary cardiovascular disease prevention, treatments blocking platelet-derived secondary mediators pose a risk of bleeding. Pharmacological interference of the interaction of platelets with exposed vascular collagens is an attractive alternative, with clinical trials ongoing. Antagonists of the collagen receptors, glycoprotein VI (GPVI), and integrin α2β1, include recombinant GPVI-Fc dimer construct Revacept, 9O12 mAb based on the GPVI-blocking reagent Glenzocimab, Syk tyrosine-kinase inhibitor PRT-060318, and anti-α2β1 mAb 6F1. No direct comparison has been made of the antithrombic potential of these drugs. Methods: Using a multiparameter whole-blood microfluidic assay, we compared the effects of Revacept, 9O12-Fab, PRT-060318, or 6F1 mAb intervention with vascular collagens and collagen-related substrates with varying dependencies on GPVI and α2β1. To inform on Revacept binding to collagen, we used fluorescent-labelled anti-GPVI nanobody-28. Results and Conclusion: In this first comparison of four inhibitors of platelet-collagen interactions with antithrombotic potential, we find that at arterial shear rate: (1) the thrombus-inhibiting effect of Revacept was restricted to highly GPVI-activating surfaces; (2) 9O12-Fab consistently but partly inhibited thrombus size on all surfaces; (3) effects of GPVI-directed interventions were surpassed by Syk inhibition; and (4) α2β1-directed intervention with 6F1 mAb was strongest for collagens where Revacept and 9O12-Fab were limitedly effective. Our data hence reveal a distinct pharmacological profile for GPVI-binding competition (Revacept), GPVI receptor blockage (9O12-Fab), GPVI signaling (PRT-060318), and α2β1 blockage (6F1 mAb) in flow-dependent thrombus formation, depending on the platelet-activating potential of the collagen substrate. This work thus points to additive antithrombotic action mechanisms of the investigated drugs. Competing Interests: M.P.G. is a co-inventor of Revacept and M.J.P. is a founder and scientific adviser for Acticor Biotech. S.P.W. and N.S.P. own a patent (WO2022/136457) for Nb28. R.W.F. is the Chief Scientific Officer of CambCol Laboratories Ltd., Ely, United Kingdom. J.W.M.H. is a consultant of Synapse B.V. (Thieme. All rights reserved.) |
| Databáze: | MEDLINE |
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