Thromb Haemost 2024; 124(04): 297-306
DOI: 10.1055/s-0043-1772221
Atherosclerosis and Ischaemic Disease

Plasma Soluble Glycoprotein VI, Platelet Function, Bleeding, and Ischemic Events in Patients Undergoing Elective Percutaneous Coronary Intervention

Shqipdona Lahu*
1   Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
,
Kristin Adler*
2   AdvanceCOR GmbH, Martinsried, Germany
,
Katharina Mayer
1   Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
3   German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
,
Ralph Hein-Rothweiler
3   German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
4   Department of Cardiology, Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
,
Isabell Bernlochner
3   German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
5   Klinik und Poliklinik für Innere Medizin I, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
,
Gjin Ndrepepa
1   Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
,
Stefanie Schüpke
1   Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
3   German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
6   Privatpraxis für Kardiologie, Kaiserstr. 10, 60311 Frankfurt am Main, Germany
,
Stefan Holdenrieder
7   Institut für Laboratoriumsmedizin, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
,
Dario Bongiovanni
8   Klinik für Kardiologie, Pneumologie, Endokrinologie, Intensivmedizin, Universitätsklinikum Augsburg, Augsburg, Germany
,
Karl-Ludwig Laugwitz
3   German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
5   Klinik und Poliklinik für Innere Medizin I, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
,
Heribert Schunkert
1   Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
3   German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
,
Meinrad Gawaz
9   Department of Cardiology and Angiology, University of Tübingen, Tübingen, Germany
,
Steffen Massberg
3   German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
4   Department of Cardiology, Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany
,
1   Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
3   German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
,
Götz Münch
2   AdvanceCOR GmbH, Martinsried, Germany
› Author Affiliations
Funding German Centre for Cardiovascular Research (DZHK), Deutsches Herzzentrum München, Federal Ministry of Education and Research (BMBF), and advanceCOR GmbH.


Abstract

Background and Aims Glycoprotein VI (GPVI) is the major platelet-specific collagen receptor. GPVI shedding with generation of soluble GPVI (sGPVI) is an endogenous feedback mechanism preventing platelet overstimulation. sGPVI has not been investigated in patients with chronic coronary syndrome (CCS) undergoing percutaneous coronary intervention (PCI), especially regarding its potential value as a predictor of ischemic and bleeding risk.

Methods Baseline plasma sGPVI levels were available in 318 patients with CCS undergoing PCI. Platelet function was assessed by measuring both adenosine diphosphate (ADP) and collagen-induced platelet aggregation. Co-primary endpoints were a composite of death or myocardial injury at 48 hours after PCI, and Bleeding Academic Research Consortium (BARC) type 1 to 5 bleeding at 30 days.

Results There was no significant correlation between sGPVI and platelet function at baseline or at 48 hours after PCI and loading with antiplatelet drugs. Baseline plasma sGPVI levels were not associated with the ischemic risk: the incidence of the ischemic endpoint was 25.0% in the lower, 22.9% in the middle, and 26.7% in the upper sGPVI tertile (p = 0.82). There was a significant nonlinear relationship between sGPVI and the risk of bleeding: the incidence of the bleeding endpoint was 11.8% in the lower, 12.6% in the middle, and 26.4% in the upper sGPVI tertile (p = 0.006).

Conclusion In patients with CCS undergoing PCI, plasma levels of sGPVI did not correlate with ADP- or collagen-induced platelet aggregation. Patients with higher baseline levels of sGPVI may carry an increased risk of bleeding at 30 days after PCI but no excess risk of ischemic events.

* These authors contributed equally and are joint first authors.


Supplementary Material



Publication History

Received: 21 May 2023

Accepted: 14 July 2023

Article published online:
17 August 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Moroi M, Jung SM, Okuma M, Shinmyozu K. A patient with platelets deficient in glycoprotein VI that lack both collagen-induced aggregation and adhesion. J Clin Invest 1989; 84 (05) 1440-1445
  • 2 Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor?. Blood 2003; 102 (02) 449-461
  • 3 Sugiyama T, Okuma M, Ushikubi F, Sensaki S, Kanaji K, Uchino H. A novel platelet aggregating factor found in a patient with defective collagen-induced platelet aggregation and autoimmune thrombocytopenia. Blood 1987; 69 (06) 1712-1720
  • 4 Goto S, Tamura N, Handa S, Arai M, Kodama K, Takayama H. Involvement of glycoprotein VI in platelet thrombus formation on both collagen and von Willebrand factor surfaces under flow conditions. Circulation 2002; 106 (02) 266-272
  • 5 Al-Tamimi M, Tan CW, Qiao J. et al. Pathologic shear triggers shedding of vascular receptors: a novel mechanism for down-regulation of platelet glycoprotein VI in stenosed coronary vessels. Blood 2012; 119 (18) 4311-4320
  • 6 Gardiner EE, Arthur JF, Kahn ML, Berndt MC, Andrews RK. Regulation of platelet membrane levels of glycoprotein VI by a platelet-derived metalloproteinase. Blood 2004; 104 (12) 3611-3617
  • 7 Stephens G, Yan Y, Jandrot-Perrus M, Villeval JL, Clemetson KJ, Phillips DR. Platelet activation induces metalloproteinase-dependent GP VI cleavage to down-regulate platelet reactivity to collagen. Blood 2005; 105 (01) 186-191
  • 8 Nurden AT. Clinical significance of altered collagen-receptor functioning in platelets with emphasis on glycoprotein VI. Blood Rev 2019; 38: 100592
  • 9 Al-Tamimi M, Mu FT, Moroi M, Gardiner EE, Berndt MC, Andrews RK. Measuring soluble platelet glycoprotein VI in human plasma by ELISA. Platelets 2009; 20 (03) 143-149
  • 10 Naitoh K, Hosaka Y, Honda M, Ogawa K, Shirakawa K, Furusako S. Properties of soluble glycoprotein VI, a potential platelet activation biomarker. Platelets 2015; 26 (08) 745-750
  • 11 Chen H, Locke D, Liu Y, Liu C, Kahn ML. The platelet receptor GPVI mediates both adhesion and signaling responses to collagen in a receptor density-dependent fashion. J Biol Chem 2002; 277 (04) 3011-3019
  • 12 Gardiner EE, Al-Tamimi M, Andrews RK, Berndt MC. Platelet receptor shedding. Methods Mol Biol 2012; 788: 321-339
  • 13 Bigalke B, Elvers M, Schönberger T, Gawaz M. Platelet and soluble glycoprotein VI - novel applications in diagnosis and therapy. Curr Drug Targets 2011; 12 (12) 1821-1830
  • 14 Bigalke B, Geisler T, Stellos K. et al. Platelet collagen receptor glycoprotein VI as a possible novel indicator for the acute coronary syndrome. Am Heart J 2008; 156 (01) 193-200
  • 15 Bigalke B, Haap M, Stellos K. et al. Platelet glycoprotein VI (GPVI) for early identification of acute coronary syndrome in patients with chest pain. Thromb Res 2010; 125 (05) e184-e189
  • 16 Bigalke B, Lindemann S, Ehlers R. et al. Expression of platelet collagen receptor glycoprotein VI is associated with acute coronary syndrome. Eur Heart J 2006; 27 (18) 2165-2169
  • 17 Bigalke B, Pötz O, Kremmer E. et al. Sandwich immunoassay for soluble glycoprotein VI in patients with symptomatic coronary artery disease. Clin Chem 2011; 57 (06) 898-904
  • 18 Bigalke B, Schuster A, Sopova K, Wurster T, Stellos K. Platelets in atherothrombosis–diagnostic and prognostic value of platelet activation in patients with atherosclerotic diseases. Curr Vasc Pharmacol 2012; 10 (05) 589-596
  • 19 Bigalke B, Stellos K, Geisler T. et al. Glycoprotein VI for diagnosis of acute coronary syndrome when ECG is ambiguous. Int J Cardiol 2011; 149 (02) 164-168
  • 20 Bigalke B, Stellos K, Geisler T, Lindemann S, May AE, Gawaz M. Glycoprotein VI as a prognostic biomarker for cardiovascular death in patients with symptomatic coronary artery disease. Clin Res Cardiol 2010; 99 (04) 227-233
  • 21 Bigalke B, Stellos K, Weig HJ. et al. Regulation of platelet glycoprotein VI (GPVI) surface expression and of soluble GPVI in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS). Basic Res Cardiol 2009; 104 (03) 352-357
  • 22 Villmann JM, Burkhardt R, Teren A, Villmann T, Thiery J, Drogies T. Atherosclerosis, myocardial infarction and primary hemostasis: Impact of platelets, von Willebrand factor and soluble glycoprotein VI. Thromb Res 2019; 180: 98-104
  • 23 Al-Tamimi M, Grigoriadis G, Tran H. et al. Coagulation-induced shedding of platelet glycoprotein VI mediated by factor Xa. Blood 2011; 117 (14) 3912-3920
  • 24 Pishko AM, Andrews RK, Gardiner EE, Lefler DS, Cuker A. Soluble glycoprotein VI is a predictor of major bleeding in patients with suspected heparin-induced thrombocytopenia. Blood Adv 2020; 4 (18) 4327-4332
  • 25 Muthiah K, Connor D, Ly K. et al. Longitudinal changes in hemostatic parameters and reduced pulsatility contribute to non-surgical bleeding in patients with centrifugal continuous-flow left ventricular assist devices. J Heart Lung Transplant 2016; 35 (06) 743-751
  • 26 Mayer K, Hein-Rothweiler R, Schüpke S. et al. 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: the randomized, double-blind, placebo-controlled ISAR-PLASTER phase 2 trial. JAMA Cardiol 2021; 6 (07) 753-761
  • 27 Schüpke S, Hein-Rothweiler R, Mayer K. et al; ISAR-PLASTER-Trial Investigators. Revacept, a novel inhibitor of platelet adhesion, in patients undergoing elective PCI-design and rationale of the randomized ISAR-PLASTER trial. Thromb Haemost 2019; 119 (09) 1539-1545
  • 28 Ungerer M, Rosport K, Bültmann A. et al. Novel antiplatelet drug revacept (dimeric glycoprotein VI-Fc) specifically and efficiently inhibited collagen-induced platelet aggregation without affecting general hemostasis in humans. Circulation 2011; 123 (17) 1891-1899
  • 29 Neumann FJ, Sousa-Uva M, Ahlsson A. et al; ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019; 40 (02) 87-165
  • 30 Bigalke B, Stellos K, Stakos D. et al. Influence of platelet count on the expression of platelet collagen receptor glycoprotein VI (GPVI) in patients with acute coronary syndrome. Thromb Haemost 2009; 101 (05) 911-915
  • 31 Al-Tamimi M, Gardiner EE, Thom JY. et al. Soluble glycoprotein VI is raised in the plasma of patients with acute ischemic stroke. Stroke 2011; 42 (02) 498-500
  • 32 Wurster T, Poetz O, Stellos K. et al. Plasma levels of soluble glycoprotein VI (sGPVI) are associated with ischemic stroke. Platelets 2013; 24 (07) 560-565
  • 33 Montague SJ, Delierneux C, Lecut C. et al. Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI. Blood Adv 2018; 2 (03) 240-251
  • 34 Ndrepepa G, Colleran R, Braun S. et al. High-sensitivity troponin T and mortality after elective percutaneous coronary intervention. J Am Coll Cardiol 2016; 68 (21) 2259-2268
  • 35 Tantry US, Bonello L, Aradi D. et al; Working Group on On-Treatment Platelet Reactivity. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 2013; 62 (24) 2261-2273
  • 36 Chatterjee M, Gawaz M. Clinical significance of receptor shedding-platelet GPVI as an emerging diagnostic and therapeutic tool. Platelets 2017; 28 (04) 362-371
  • 37 Vulliamy P, Montague SJ, Gillespie S. et al. Loss of GPVI and GPIbα contributes to trauma-induced platelet dysfunction in severely injured patients. Blood Adv 2020; 4 (12) 2623-2630
  • 38 Ndrepepa G, Berger PB, Mehilli J. et al. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 2008; 51 (07) 690-697
  • 39 Ndrepepa G, Stephan T, Fiedler KA, Guerra E, Kufner S, Kastrati A. Procedure-related bleeding in elective percutaneous coronary interventions. Eur J Clin Invest 2015; 45 (03) 263-273
  • 40 Costa F, van Klaveren D, James S. et al; PRECISE-DAPT Study Investigators. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet 2017; 389 (10073): 1025-1034
  • 41 Urban P, Mehran R, Colleran R. et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention: a consensus document from the Academic Research Consortium for High Bleeding Risk. Eur Heart J 2019; 40 (31) 2632-2653