Amplified inhibition of atherosclerotic plaque-induced platelet activation by glenzocimab with dual antiplatelet therapy JTH

Fawaz Alenazy; Maan Harbi; Dean Kavanagh; Joshua Price; Paul Brady; Oscar Hargreaves; Paul Harrison; Alexandre Slater; Alok Tiwari; Pip Nicolson; Derek Connolly; Paulus Kirchhof; Neena Kalia; Martine Jandrot-Perrus; Pierre H Mangin; Steve Watson; Mark R. Thomas

doi:10.1016/j.jtha.2023.07.018

Amplified inhibition of atherosclerotic plaque-induced platelet activation by glenzocimab with dual antiplatelet therapy JTH

Fawaz Alenazy, Maan Harbi, Dean Kavanagh, Joshua Price, Paul Brady, Oscar Hargreaves, Paul Harrison, Alexandre Slater, Alok Tiwari, Pip Nicolson, Derek Connolly, Paulus Kirchhof, Neena Kalia, Martine Jandrot-Perrus, Pierre H Mangin, Steve Watson, Mark R. Thomas^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Background
Aspirin and platelet P2Y12 inhibitors, such as ticagrelor, suboptimally inhibit microvascular thrombosis during ST-elevation myocardial infarction. Glycoprotein (GP) IIb/IIIa inhibitors may further inhibit this but cause excessive bleeding.

Objectives
We investigated whether combination of glenzocimab, a GPVI inhibitor, with aspirin and ticagrelor provides additional antithrombotic effects, as GPVI has a critical role in atherothrombosis but minimal involvement in hemostasis.

Methods
We investigated the effects of glenzocimab (monoclonal antibody Fab fragment) using blood from healthy donors and patients with acute coronary syndrome treated with aspirin and ticagrelor. Platelets were stimulated with multiple agonists, including atherosclerotic plaque, from patients undergoing carotid endarterectomy.

Results
Aspirin and ticagrelor partially inhibited atherosclerotic plaque-induced platelet aggregation by 48% compared with control (34 ± 3 vs 65 ± 4 U; P < .001). Plaque-induced platelet aggregation, adhesion, secretion, and activation were critically dependent on GPVI activation. Glenzocimab alone reduced plaque-induced aggregation by 75% compared with control (16 ± 4 vs 65 ± 4 U; P < .001) and by >95% when combined with aspirin and ticagrelor (3 ± 1 vs 65 ± 4 U; P < .001). Glenzocimab reduced platelet aggregation, adhesion, and thrombin generation when added to blood of aspirin- and ticagrelor-treated patients with acute coronary syndrome. Glenzocimab shared several antithrombotic effects with the GPIIb/IIIa inhibitor eptifibatide with less effect on general hemostasis assessed by rotational thromboelastometry. In a murine intravital model of ST-elevation myocardial infarction, genetic depletion of GPVI reduced microvascular thrombosis.

Conclusion
Addition of glenzocimab to aspirin and ticagrelor enhances platelet inhibition via multiple mechanisms of atherothrombosis. Compared with a GPIIb/IIIa inhibitor, glenzocimab shares multiple antithrombotic effects, with less inhibition of mechanisms involved in general hemostasis.

Original language	English
Pages (from-to)	3236-3251
Number of pages	16
Journal	Journal of thrombosis and haemostasis : JTH
Volume	21
Issue number	11
Early online date	3 Aug 2023
DOIs	https://doi.org/10.1016/j.jtha.2023.07.018
Publication status	Published - 17 Oct 2023

Keywords

Acute Coronary Syndrome
antiplatelet therapy
atherosclerotic plaque
GPVI
pharmacology
platelets
Thrombosis
Translational research

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10.1016/j.jtha.2023.07.018Licence: Creative Commons: Attribution (CC BY)

AlenazyFO2023AmplifiedFinal published version, 4.21 MBLicence: Creative Commons: Attribution (CC BY)

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Fibrin at the interface of platelet activation and thrombus stabilisation
Watson, S.
THE WELLCOME TRUST
1/01/18 → 1/10/24
Project: Research
Inhibition on fibrin-mediated platelet responses
Thomas, M. R.
THE ACADEMY OF MEDICAL SCIENCES
1/04/18 → 31/03/20
Project: Research

Cite this

Alenazy, F., Harbi, M., Kavanagh, D., Price, J., Brady, P., Hargreaves, O., Harrison, P., Slater, A., Tiwari, A., Nicolson, P., Connolly, D., Kirchhof, P., Kalia, N., Jandrot-Perrus, M., Mangin, P. H., Watson, S., & Thomas, M. R. (2023). Amplified inhibition of atherosclerotic plaque-induced platelet activation by glenzocimab with dual antiplatelet therapy JTH. Journal of thrombosis and haemostasis : JTH, 21(11), 3236-3251. https://doi.org/10.1016/j.jtha.2023.07.018

@article{f6e5e9a883e144d69df1fd2248cdd4f3,

title = "Amplified inhibition of atherosclerotic plaque-induced platelet activation by glenzocimab with dual antiplatelet therapy JTH",

abstract = "BackgroundAspirin and platelet P2Y12 inhibitors, such as ticagrelor, suboptimally inhibit microvascular thrombosis during ST-elevation myocardial infarction. Glycoprotein (GP) IIb/IIIa inhibitors may further inhibit this but cause excessive bleeding.ObjectivesWe investigated whether combination of glenzocimab, a GPVI inhibitor, with aspirin and ticagrelor provides additional antithrombotic effects, as GPVI has a critical role in atherothrombosis but minimal involvement in hemostasis.MethodsWe investigated the effects of glenzocimab (monoclonal antibody Fab fragment) using blood from healthy donors and patients with acute coronary syndrome treated with aspirin and ticagrelor. Platelets were stimulated with multiple agonists, including atherosclerotic plaque, from patients undergoing carotid endarterectomy.ResultsAspirin and ticagrelor partially inhibited atherosclerotic plaque-induced platelet aggregation by 48% compared with control (34 ± 3 vs 65 ± 4 U; P < .001). Plaque-induced platelet aggregation, adhesion, secretion, and activation were critically dependent on GPVI activation. Glenzocimab alone reduced plaque-induced aggregation by 75% compared with control (16 ± 4 vs 65 ± 4 U; P < .001) and by >95% when combined with aspirin and ticagrelor (3 ± 1 vs 65 ± 4 U; P < .001). Glenzocimab reduced platelet aggregation, adhesion, and thrombin generation when added to blood of aspirin- and ticagrelor-treated patients with acute coronary syndrome. Glenzocimab shared several antithrombotic effects with the GPIIb/IIIa inhibitor eptifibatide with less effect on general hemostasis assessed by rotational thromboelastometry. In a murine intravital model of ST-elevation myocardial infarction, genetic depletion of GPVI reduced microvascular thrombosis.ConclusionAddition of glenzocimab to aspirin and ticagrelor enhances platelet inhibition via multiple mechanisms of atherothrombosis. Compared with a GPIIb/IIIa inhibitor, glenzocimab shares multiple antithrombotic effects, with less inhibition of mechanisms involved in general hemostasis.",

keywords = "Acute Coronary Syndrome, antiplatelet therapy, atherosclerotic plaque, GPVI, pharmacology, platelets, Thrombosis, Translational research",

author = "Fawaz Alenazy and Maan Harbi and Dean Kavanagh and Joshua Price and Paul Brady and Oscar Hargreaves and Paul Harrison and Alexandre Slater and Alok Tiwari and Pip Nicolson and Derek Connolly and Paulus Kirchhof and Neena Kalia and Martine Jandrot-Perrus and Mangin, {Pierre H} and Steve Watson and Thomas, {Mark R.}",

year = "2023",

month = oct,

day = "17",

doi = "10.1016/j.jtha.2023.07.018",

language = "English",

volume = "21",

pages = "3236--3251",

journal = "Journal of thrombosis and haemostasis : JTH",

issn = "1538-7933",

publisher = "Wiley",

number = "11",

}

Alenazy, F, Harbi, M, Kavanagh, D, Price, J, Brady, P, Hargreaves, O, Harrison, P , Slater, A, Tiwari, A, Nicolson, P, Connolly, D, Kirchhof, P , Kalia, N, Jandrot-Perrus, M, Mangin, PH, Watson, S & Thomas, MR 2023, 'Amplified inhibition of atherosclerotic plaque-induced platelet activation by glenzocimab with dual antiplatelet therapy JTH', Journal of thrombosis and haemostasis : JTH, vol. 21, no. 11, pp. 3236-3251. https://doi.org/10.1016/j.jtha.2023.07.018

TY - JOUR

T1 - Amplified inhibition of atherosclerotic plaque-induced platelet activation by glenzocimab with dual antiplatelet therapy JTH

AU - Alenazy, Fawaz

AU - Harbi, Maan

AU - Kavanagh, Dean

AU - Price, Joshua

AU - Brady, Paul

AU - Hargreaves, Oscar

AU - Harrison, Paul

AU - Slater, Alexandre

AU - Tiwari, Alok

AU - Nicolson, Pip

AU - Connolly, Derek

AU - Kirchhof, Paulus

AU - Kalia, Neena

AU - Jandrot-Perrus, Martine

AU - Mangin, Pierre H

AU - Watson, Steve

AU - Thomas, Mark R.

PY - 2023/10/17

Y1 - 2023/10/17

N2 - BackgroundAspirin and platelet P2Y12 inhibitors, such as ticagrelor, suboptimally inhibit microvascular thrombosis during ST-elevation myocardial infarction. Glycoprotein (GP) IIb/IIIa inhibitors may further inhibit this but cause excessive bleeding.ObjectivesWe investigated whether combination of glenzocimab, a GPVI inhibitor, with aspirin and ticagrelor provides additional antithrombotic effects, as GPVI has a critical role in atherothrombosis but minimal involvement in hemostasis.MethodsWe investigated the effects of glenzocimab (monoclonal antibody Fab fragment) using blood from healthy donors and patients with acute coronary syndrome treated with aspirin and ticagrelor. Platelets were stimulated with multiple agonists, including atherosclerotic plaque, from patients undergoing carotid endarterectomy.ResultsAspirin and ticagrelor partially inhibited atherosclerotic plaque-induced platelet aggregation by 48% compared with control (34 ± 3 vs 65 ± 4 U; P < .001). Plaque-induced platelet aggregation, adhesion, secretion, and activation were critically dependent on GPVI activation. Glenzocimab alone reduced plaque-induced aggregation by 75% compared with control (16 ± 4 vs 65 ± 4 U; P < .001) and by >95% when combined with aspirin and ticagrelor (3 ± 1 vs 65 ± 4 U; P < .001). Glenzocimab reduced platelet aggregation, adhesion, and thrombin generation when added to blood of aspirin- and ticagrelor-treated patients with acute coronary syndrome. Glenzocimab shared several antithrombotic effects with the GPIIb/IIIa inhibitor eptifibatide with less effect on general hemostasis assessed by rotational thromboelastometry. In a murine intravital model of ST-elevation myocardial infarction, genetic depletion of GPVI reduced microvascular thrombosis.ConclusionAddition of glenzocimab to aspirin and ticagrelor enhances platelet inhibition via multiple mechanisms of atherothrombosis. Compared with a GPIIb/IIIa inhibitor, glenzocimab shares multiple antithrombotic effects, with less inhibition of mechanisms involved in general hemostasis.

AB - BackgroundAspirin and platelet P2Y12 inhibitors, such as ticagrelor, suboptimally inhibit microvascular thrombosis during ST-elevation myocardial infarction. Glycoprotein (GP) IIb/IIIa inhibitors may further inhibit this but cause excessive bleeding.ObjectivesWe investigated whether combination of glenzocimab, a GPVI inhibitor, with aspirin and ticagrelor provides additional antithrombotic effects, as GPVI has a critical role in atherothrombosis but minimal involvement in hemostasis.MethodsWe investigated the effects of glenzocimab (monoclonal antibody Fab fragment) using blood from healthy donors and patients with acute coronary syndrome treated with aspirin and ticagrelor. Platelets were stimulated with multiple agonists, including atherosclerotic plaque, from patients undergoing carotid endarterectomy.ResultsAspirin and ticagrelor partially inhibited atherosclerotic plaque-induced platelet aggregation by 48% compared with control (34 ± 3 vs 65 ± 4 U; P < .001). Plaque-induced platelet aggregation, adhesion, secretion, and activation were critically dependent on GPVI activation. Glenzocimab alone reduced plaque-induced aggregation by 75% compared with control (16 ± 4 vs 65 ± 4 U; P < .001) and by >95% when combined with aspirin and ticagrelor (3 ± 1 vs 65 ± 4 U; P < .001). Glenzocimab reduced platelet aggregation, adhesion, and thrombin generation when added to blood of aspirin- and ticagrelor-treated patients with acute coronary syndrome. Glenzocimab shared several antithrombotic effects with the GPIIb/IIIa inhibitor eptifibatide with less effect on general hemostasis assessed by rotational thromboelastometry. In a murine intravital model of ST-elevation myocardial infarction, genetic depletion of GPVI reduced microvascular thrombosis.ConclusionAddition of glenzocimab to aspirin and ticagrelor enhances platelet inhibition via multiple mechanisms of atherothrombosis. Compared with a GPIIb/IIIa inhibitor, glenzocimab shares multiple antithrombotic effects, with less inhibition of mechanisms involved in general hemostasis.

KW - Acute Coronary Syndrome

KW - antiplatelet therapy

KW - atherosclerotic plaque

KW - GPVI

KW - pharmacology

KW - platelets

KW - Thrombosis

KW - Translational research

U2 - 10.1016/j.jtha.2023.07.018

DO - 10.1016/j.jtha.2023.07.018

M3 - Article

C2 - 37541591

SN - 1538-7933

VL - 21

SP - 3236

EP - 3251

JO - Journal of thrombosis and haemostasis : JTH

JF - Journal of thrombosis and haemostasis : JTH

IS - 11

ER -

Amplified inhibition of atherosclerotic plaque-induced platelet activation by glenzocimab with dual antiplatelet therapy JTH

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Fibrin at the interface of platelet activation and thrombus stabilisation

Inhibition on fibrin-mediated platelet responses

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