Differential Inhibition of Human Atherosclerotic Plaque-Induced Platelet Activation by Dimeric GPVI-Fc and Anti-GPVI Antibodies: Functional and Imaging Studies.

Abstract

BACKGROUND:

Glycoprotein VI (GPVI) is the essential platelet collagen receptor in atherothrombosis, but its inhibition causes only a mild bleeding tendency. Thus, targeting this receptor has selective antithrombotic potential.

OBJECTIVES:

This study sought to compare compounds interfering with platelet GPVI-atherosclerotic plaque interaction to improve current antiatherothrombotic therapy.

METHODS:

Human atherosclerotic plaque-induced platelet aggregation was measured in anticoagulated blood under static and arterial flow conditions (550/s, 1,100/s, and 1,500/s). Inhibition by dimeric GPVI fragment crystallizable region of IgG (Fc) masking GPVI binding sites on collagen was compared with that of 3 anti-GPVI antibodies: BLO8-1, a human domain antibody; 5C4, a fragment antigen-binding (Fab fragment) of monoclonal rat immunoglobulin G; and m-Fab-F, a human recombinant sFab against GPVI dimers.

RESULTS:

GPVI-Fc reduced plaque-triggered platelet aggregation in static blood by 51%, BLO8-1 by 88%, and 5C4 by 93%. Under arterial flow conditions, BLO8-1 and 5C4 almost completely inhibited platelet aggregation while preserving platelet adhesion on plaque. Inhibition by GPVI-Fc, even at high concentrations, was less marked but increased with shear rate. Advanced optical imaging revealed rapid persistent GPVI-Fc binding to collagen under low and high shear flow, upstream and downstream of plaque fragments. At low shear particularly, platelets adhered in plaque flow niches to GPVI-Fc-free segments of collagen fibers and recruited other platelets onto aggregates via ADP and TxA2 release.

CONCLUSIONS:

Anti-GPVI antibodies inhibit atherosclerotic plaque-induced platelet aggregation under static and flow conditions more effectively than GPVI-Fc. However, potent platelet inhibition by GPVI-Fc at a higher shear rate (1,500/s) suggests localized antithrombotic efficacy at denuded or fissured stenotic high-risk lesions without systemic bleeding. The compound-specific differences have relevance for clinical trials targeting GPVI-collagen interaction combined with established antiplatelet therapies in patients with spontaneous plaque rupture or intervention-associated plaque injury.

• Authors: Janina Jamasbi, Remco T A Megens, Mariaelvy Bianchini, Götz Münch, Martin Ungerer, Alexander Faussner, Shachar Sherman, Adam Walker, Pankaj Goyal, Stephanie Jung, Richard Brandl, Christian Weber, Reinhard Lorenz, Richard Farndale, Natalie Elia, Wolfgang Siess
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 65 Issue 22 Pg. 2404-15 (Jun 09 2015) ISSN: 1558-3597 [Electronic] United States
• PMID: 26046734 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Immunoglobulin Fab Fragments
• Immunologic Factors
• Platelet Membrane Glycoproteins
• platelet membrane glycoprotein VI

Topics

• Animals
• Blood Flow Velocity (drug effects, physiology)
• Carotid Arteries (drug effects, pathology, physiopathology)
• Carotid Stenosis (drug therapy, etiology, physiopathology)
• Humans
• Immunoglobulin Fab Fragments (pharmacology)
• Immunologic Factors (pharmacology)
• Plaque, Atherosclerotic (complications, diagnosis, drug therapy)
• Platelet Activation (drug effects)
• Platelet Membrane Glycoproteins (pharmacology)
• Rats