Platelet glycoprotein VI binds to polymerized fibrin and promotes thrombin generation

Mammadova‐Bach, Elmina; Ollivier, Véronique; Loyau, Stéphane; Schaff, Mathieu; Dumont, Bénédicte; Favier, Rémi; Freyburger, G.; Latger‐Cannard, Véronique; Nieswandt, Bernhard; Gachet, Christian; Mangin, P; Jandrot‐Perrus, Martine

doi:10.1182/blood-2015-02-629717

Cited by 214 publications

(177 citation statements)

References 40 publications

(43 reference statements)

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“…11,12 Here we demonstrate for the first time that fibrin-exposed platelets shed GPVI to an extent comparable to GPVI ligands. GPVI shedding was not a result of PAR engagement, as neither PAR-1-nor PAR-4-activating peptides induced GPVI shedding.…”

Section: Discussionmentioning

confidence: 89%

“…Fibrin generation is a potential consequence of disease for most patient cohorts studied here, and as fibrin engages GPVI, 11,12 we assessed whether fibrin stimulation induced GPVI shedding. Thrombin stimulation in the presence of fibrinogen consistently induced GPVI shedding, independent of fibrinogen interaction with integrin aIIbb3, as shedding occurred in the presence of eptifibatide.…”

Section: Discussionmentioning

confidence: 99%

“…Glycoprotein (GP) VI is the major platelet signaling receptor for collagen and fibrin, 11,12 and GPVI-fibrin engagement may underpin fibrin-related disease pathology. GPVI is expressed only on megakaryocytes and platelets 13 in association with the Fc receptor g-chain containing an immunoreceptor tyrosine-based activation motif (ITAM).…”

Section: Introductionmentioning

confidence: 99%

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Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Montague

Delierneux

Lecut³

et al. 2018

Blood Advances

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• Soluble GPVI is elevated in patients with thermal injury with sepsis, and sGPVI levels augment severity score prediction of mortality.• The GPVI ligand, fibrin, induces GPVI shedding without requirement for platelet activation or signaling Soluble glycoprotein VI (sGPVI) is shed from the platelet surface and is a marker of platelet activation in thrombotic conditions. We assessed sGPVI levels together with patient and clinical parameters in acute and chronic inflammatory conditions, including patients with thermal injury and inflammatory bowel disease and patients admitted to the intensive care unit (ICU)for elective cardiac surgery, trauma, acute brain injury, or prolonged ventilation. Plasma sGPVI was measured by enzyme-linked immunosorbent assay and was elevated on day 14 after thermal injury, and was higher in patients who developed sepsis. sGPVI levels were associated with sepsis, and the value for predicting sepsis was increased in combination with platelet count and Abbreviated Burn Severity Index. sGPVI levels positively correlated with levels of D-dimer (a fibrin degradation product) in ICU patients and patients with thermal injury. sGPVI levels in ICU patients at admission were significantly associated with 28-and 90-day mortality independent of platelet count. sGPVI levels in patients with thermal injury were associated with 28-day mortality at days 1, 14, and 21 when adjusting for platelet count. In both cohorts, sGPVI associations with mortality were stronger than D-dimer levels. Mechanistically, release of GPVI was triggered by exposure of platelets to polymerized fibrin, but not by engagement of G protein-coupled receptors by thrombin, adenosine 59-diphosphate, or thromboxane mimetics. Enhanced fibrin production in these patients may therefore contribute to the observed elevated sGPVI levels. sGPVI is an important platelet-specific marker for platelet activation that predicts sepsis progression and mortality in injured patients.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Montague

Delierneux

Lecut³

et al. 2018

Blood Advances

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“…As outlined in the abstract by Haining et al, studies in mice expressing a signaling defective mutant of CLEC2 (Y7A KI) suggest a signaling-independent contribution of the CLEC2 ectodomain to thrombus stability[38,39]. A similar signaling-independent, adhesive role was also reported for GPVI[36,66]. …”

Section: Vascular Integrity Vs Hemostatic Plug Formation – Lesions Omentioning

confidence: 85%

“…Surprisingly, GPVI was shown to be more important for thrombus stabilization than for thrombus initiation[35], suggesting the existence of ligands other than collagen. Fibrin, a protein deposited throughout the hemostatic plug, could be this ligand[36,37]. At this ISTH meeting, Haining et al reported that CLEC-2 also appears to have a function in thrombus stabilization, independently of its signaling function and thus potentially by binding an unknown intravascular ligand[38,39].…”

Section: Classical Hemostasis – Balancing Platelet Adhesiveness In CImentioning

confidence: 99%

Platelets at the vascular interface

Bergmeier

Stefanini

2018

Research and Practice in Thrombosis and Haemostasis

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In this brief review paper, we will summarize the State-of-the-Art on how platelet reactivity is regulated in circulation and at sites of vascular injury. Our review discusses recent and ongoing work, presented at this year’s International Society on Thrombosis and Haemostasis (ISTH) meeting, on the role of platelets in (1) classical hemostasis at sites of mechanical injury, and (2) the maintenance of vascular integrity at sites of inflammation.

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Efficacy and Safety of Revacept, a Novel Lesion-Directed Competitive Antagonist to Platelet Glycoprotein VI, in Patients Undergoing Elective Percutaneous Coronary Intervention for Stable Ischemic Heart Disease

et al. 2021

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IMPORTANCEThe assessment of new antithrombotic agents with a favorable safety profile is clinically relevant. OBJECTIVE To test the efficacy and safety of revacept, a novel, lesion-directed antithrombotic drug, acting as a competitive antagonist to platelet glycoprotein VI. DESIGN, SETTING, AND PARTICIPANTSA phase 2 randomized clinical trial; patients were enrolled from 9 centers in Germany from November 20, 2017, to February 27, 2020; follow-up ended on March 27, 2020. The study included patients with stable ischemic heart disease (SIHD) undergoing elective percutaneous coronary intervention (PCI).INTERVENTIONS Single intravenous infusion of revacept, 160 mg, revacept, 80 mg, or placebo prior to the start of PCI on top of standard antithrombotic therapy. MAIN OUTCOMES AND MEASURESThe primary end point was the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin to at least 5 times the upper limit of normal within 48 hours from randomization. The safety end point was bleeding type 2 to 5 according to the Bleeding Academic Research Consortium criteria at 30 days. RESULTSOf 334 participants (median age, 67.4 years; interquartile range, 60-75.1 years; 253 men [75.7%]; and 330 White participants [98.8%]), 120 were allocated to receive the 160-mg dose of revacept, 121 were allocated to receive the 80-mg dose, and 93 received placebo. The primary end point showed no significant differences between the revacept and placebo groups: 24.4%, 25.0%, and 23.3% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .98). The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, with a median 26.5 AU × min (interquartile range, 0.5-62.2 AU × min) in the revacept, 160 mg, group; 43.5 AU × min (interquartile range, 22.8-99.5 AU × min) in the revacept, 80 mg, group; and 41.0 AU × min (interquartile range, 31.2-101.0 AU × min) in the placebo group (P = .02), while adenosine 5′-diphosphate-induced aggregation was not affected. Revacept did not increase Bleeding Academic Research Consortium type 2 or higher bleeding at 30 days compared with placebo: 5.0%, 5.9%, and 8.6% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .36). CONCLUSIONS AND RELEVANCERevacept did not reduce myocardial injury in patients with stable ischemic heart disease undergoing percutaneous coronary intervention. There were few bleeding events and no significant differences between treatment arms.

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Platelet glycoprotein VI binds to polymerized fibrin and promotes thrombin generation

Cited by 214 publications

References 40 publications

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI

Platelets at the vascular interface

Efficacy and Safety of Revacept, a Novel Lesion-Directed Competitive Antagonist to Platelet Glycoprotein VI, in Patients Undergoing Elective Percutaneous Coronary Intervention for Stable Ischemic Heart Disease

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