Abstract | BACKGROUND: 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.
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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)
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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
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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
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