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Thromb Haemost 2019; 119(11): 1720-1739
DOI: 10.1055/s-0039-1695770
Review Article
Georg Thieme Verlag KG Stuttgart · New York

From Patients to Platelets and Back Again: Pharmacological Approaches to Glycoprotein VI, a Thrilling Antithrombotic Target with Minor Bleeding Risks

Augusto Martins Lima   *
1   Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
,
Ana C. Martins Cavaco‡   *
2   Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany
,
Rodrigo A. Fraga-Silva
1   Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
,
Johannes A. Eble
2   Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany
,
Nikolaos Stergiopulos
1   Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
› Author Affiliations Funding A.C.M.C. was funded by EU under the People Program (Marie Curie Actions) of the European Union's Seventh Framework Program FP7/2007 -2013/ under the REA grant agreement n° (316610).
Further Information

Publication History

29 March 2019

09 July 2019

Publication Date:
29 September 2019 (online)

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Abstract

Despite significant advances in the treatment of thrombogenic diseases, antiplatelet therapies are still associated with a high bleeding risk. Consequently, potential benefits of preventing thromboembolic events by pharmacological agents need to be balanced with the potential harm of inducing hemorrhage. Glycoprotein VI (GPVI) is a platelet-specific receptor, which plays a crucial role in thrombus formation. GPVI deficiency has been identified in patients who suffer from significant reduction of collagen-induced thrombus formation, with a slight tendency for mild bleeding. However, an isolated GPVI deficiency can reduce thrombus formation while not resulting in severe bleeding. Together, these observations strongly suggest that physiological hemostasis does not require GPVI, but pharmacological GPVI modulation may provide novel “bleeding-free” antithrombotic therapies. In this review, we discuss recent findings regarding the biological role of GPVI in platelet-related disorders and highlight the efforts to develop potential therapeutic strategies based on its structure, signaling pathways, and biological effects.

Keywords

GPVI - antiplatelet therapy - drug discovery - protein–protein interaction

* These authors contributed equally to this work.


 

  • References

  • 1 World Health Organization. Disease Burden and Mortality Estimates: Disease Burden 2000–2016; 2016 . Available at: http://www.who.int/healthinfo/global_burden_disease/estimates/en/ . Accessed August 7, 2019
    PubMedSearch in Google Scholar
  • 2 Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nat Rev Drug Discov 2010; 9 (02) 154-169
    CrossrefPubMedSearch in Google Scholar
  • 3 Hansson GK. Inflammatory mechanisms in atherosclerosis. J Thromb Haemost 2009; 7 (Suppl. 01) 328-331
    CrossrefPubMedSearch in Google Scholar
  • 4 Koupenova M, Kehrel BE, Corkrey HA, Freedman JE. Thrombosis and platelets: an update. Eur Heart J 2017; 38 (11) 785-791
    PubMedSearch in Google Scholar
  • 5 Collaboration AT. Collaborative overview of randomised trials of antiplatelet therapy Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308 (6921): 81-106
    CrossrefPubMedSearch in Google Scholar
  • 6 Collaboration AT. ; Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324 (7329): 71-86
    CrossrefPubMedSearch in Google Scholar
  • 7 Investigators E. ; EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330 (14) 956-961
    CrossrefPubMedSearch in Google Scholar
  • 8 Serebruany VL, Malinin AI, Ferguson JJ, Vahabi J, Atar D, Hennekens CH. Bleeding risks of combination vs. single antiplatelet therapy: a meta-analysis of 18 randomized trials comprising 129,314 patients. Fundam Clin Pharmacol 2008; 22 (03) 315-321
    CrossrefPubMedSearch in Google Scholar
  • 9 Hansen ML, Sørensen R, Clausen MT. , et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010; 170 (16) 1433-1441
    PubMedSearch in Google Scholar
  • 10 Li L, Geraghty OC, Mehta Z, Rothwell PM. ; Oxford Vascular Study. Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study. Lancet 2017; 390 (10093): 490-499
    CrossrefPubMedSearch in Google Scholar
  • 11 Jiang P, Jandrot-Perrus M. New advances in treating thrombotic diseases: GPVI as a platelet drug target. Drug Discov Today 2014; 19 (09) 1471-1475
    CrossrefPubMedSearch in Google Scholar
  • 12 Andrews RK, Arthur JF, Gardiner EE. Targeting GPVI as a novel antithrombotic strategy. J Blood Med 2014; 5: 59-68
    PubMedSearch in Google Scholar
  • 13 Dumont B, Lasne D, Rothschild C. , et al. Absence of collagen-induced platelet activation caused by compound heterozygous GPVI mutations. Blood 2009; 114 (09) 1900-1903
    PubMedSearch in Google Scholar
  • 14 Bigalke B, Stellos K, Geisler T. , et al. Expression of platelet glycoprotein VI is associated with transient ischemic attack and stroke. Eur J Neurol 2010; 17 (01) 111-117
    CrossrefPubMedSearch in Google Scholar
  • 15 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Vélez P, Ocaranza-Sánchez R, López-Otero D. , et al. Alteration of platelet GPVI signaling in ST-elevation myocardial infarction patients demonstrated by a combination of proteomic, biochemical, and functional approaches. Sci Rep 2016; 6: 39603
    CrossrefPubMedSearch in Google Scholar
  • 17 Kato K, Kanaji T, Russell S. , et al. The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion. Blood 2003; 102 (05) 1701-1707
    CrossrefPubMedSearch in Google Scholar
  • 18 Penz S, Reininger AJ, Brandl R. , et al. Human atheromatous plaques stimulate thrombus formation by activating platelet glycoprotein VI. FASEB J 2005; 19 (08) 898-909
    CrossrefPubMedSearch in Google Scholar
  • 19 Schulte V, Reusch HP, Pozgajová M, Varga-Szabó D, Gachet C, Nieswandt B. Two-phase antithrombotic protection after anti-glycoprotein VI treatment in mice. Arterioscler Thromb Vasc Biol 2006; 26 (07) 1640-1647
    CrossrefPubMedSearch in Google Scholar
  • 20 Walker A, Pugh N, Garner SF. , et al; Bloodomics Consortium. Single domain antibodies against the collagen signalling receptor glycoprotein VI are inhibitors of collagen induced thrombus formation. Platelets 2009; 20 (04) 268-276
    CrossrefPubMedSearch in Google Scholar
  • 21 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
    CrossrefPubMedSearch in Google Scholar
  • 22 Kojima H, Moroi M, Jung SM. , et al. Characterization of a patient with glycoprotein (GP) VI deficiency possessing neither anti-GPVI autoantibody nor genetic aberration. J Thromb Haemost 2006; 4 (11) 2433-2442
    CrossrefPubMedSearch in Google Scholar
  • 23 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
    CrossrefPubMedSearch in Google Scholar
  • 24 Arai M, Yamamoto N, Moroi M, Akamatsu N, Fukutake K, Tanoue K. Platelets with 10% of the normal amount of glycoprotein VI have an impaired response to collagen that results in a mild bleeding tendency. Br J Haematol 1995; 89 (01) 124-130
    CrossrefPubMedSearch in Google Scholar
  • 25 Hermans C, Wittevrongel C, Thys C, Smethurst PA, Van Geet C, Freson K. A compound heterozygous mutation in glycoprotein VI in a patient with a bleeding disorder. J Thromb Haemost 2009; 7 (08) 1356-1363
    CrossrefPubMedSearch in Google Scholar
  • 26 Ryo R, Yoshida A, Sugano W. , et al. Deficiency of P62, a putative collagen receptor, in platelets from a patient with defective collagen-induced platelet aggregation. Am J Hematol 1992; 39 (01) 25-31
    CrossrefPubMedSearch in Google Scholar
  • 27 Takahashi H, Moroi M. Antibody against platelet membrane glycoprotein VI in a patient with systemic lupus erythematosus. Am J Hematol 2001; 67 (04) 262-267
    CrossrefPubMedSearch in Google Scholar
  • 28 Boylan B, Chen H, Rathore V. , et al. Anti-GPVI-associated ITP: an acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FcRgamma-chain complex from the human platelet surface. Blood 2004; 104 (05) 1350-1355
    CrossrefPubMedSearch in Google Scholar
  • 29 Nurden P, Jandrot-Perrus M, Combrié R. , et al. Severe deficiency of glycoprotein VI in a patient with gray platelet syndrome. Blood 2004; 104 (01) 107-114
    CrossrefPubMedSearch in Google Scholar
  • 30 Gardiner EE, Al-Tamimi M, Mu F-T. , et al. Compromised ITAM-based platelet receptor function in a patient with immune thrombocytopenic purpura. J Thromb Haemost 2008; 6 (07) 1175-1182
    CrossrefPubMedSearch in Google Scholar
  • 31 Akiyama M, Kashiwagi H, Todo K. , et al. Presence of platelet-associated anti-glycoprotein (GP)VI autoantibodies and restoration of GPVI expression in patients with GPVI deficiency. J Thromb Haemost 2009; 7 (08) 1373-1383
    CrossrefPubMedSearch in Google Scholar
  • 32 Matus V, Valenzuela G, Sáez CG. , et al. An adenine insertion in exon 6 of human GP6 generates a truncated protein associated with a bleeding disorder in four Chilean families. J Thromb Haemost 2013; 11 (09) 1751-1759
    CrossrefPubMedSearch in Google Scholar
  • 33 Nieswandt B, Schulte V, Bergmeier W. , et al. Long-term antithrombotic protection by in vivo depletion of platelet glycoprotein VI in mice. J Exp Med 2001; 193 (04) 459-469
    CrossrefPubMedSearch in Google Scholar
  • 34 Boilard E, Nigrovic PA, Larabee K. , et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327 (5965): 580-583
    CrossrefPubMedSearch in Google Scholar
  • 35 Jain S, Russell S, Ware J. Platelet glycoprotein VI facilitates experimental lung metastasis in syngenic mouse models. J Thromb Haemost 2009; 7 (10) 1713-1717
    CrossrefPubMedSearch in Google Scholar
  • 36 Berlanga O, Bobe R, Becker M. , et al. Expression of the collagen receptor glycoprotein VI during megakaryocyte differentiation. Blood 2000; 96 (08) 2740-2745
    CrossrefPubMedSearch in Google Scholar
  • 37 Ichinohe T, Takayama H, Ezumi Y, Yanagi S, Yamamura H, Okuma M. Cyclic AMP-insensitive activation of c-Src and Syk protein-tyrosine kinases through platelet membrane glycoprotein VI. J Biol Chem 1995; 270 (47) 28029-28036
    CrossrefPubMedSearch in Google Scholar
  • 38 Ichinohe T, Takayama H, Ezumi Y. , et al. Collagen-stimulated activation of Syk but not c-Src is severely compromised in human platelets lacking membrane glycoprotein VI. J Biol Chem 1997; 272 (01) 63-68
    CrossrefPubMedSearch in Google Scholar
  • 39 Kehrel B, Wierwille S, Clemetson KJ. , et al. Glycoprotein VI is a major collagen receptor for platelet activation: it recognizes the platelet-activating quaternary structure of collagen, whereas CD36, glycoprotein IIb/IIIa, and von Willebrand factor do not. Blood 1998; 91 (02) 491-499
    CrossrefPubMedSearch in Google Scholar
  • 40 Sugiyama T, Ishibashi T, Okuma M. Functional role of the antigen recognized by an antiplatelet antibody specific for a putative collagen receptor in platelet-collagen interaction. Int J Hematol 1993; 58 (1-2): 99-104
    PubMedSearch in Google Scholar
  • 41 Tsuji M, Ezumi Y, Arai M, Takayama H. A novel association of Fc receptor gamma-chain with glycoprotein VI and their co-expression as a collagen receptor in human platelets. J Biol Chem 1997; 272 (38) 23528-23531
    CrossrefPubMedSearch in Google Scholar
  • 42 Moroi M, Jung SM, Shinmyozu K, Tomiyama Y, Ordinas A, Diaz-Ricart M. Analysis of platelet adhesion to a collagen-coated surface under flow conditions: the involvement of glycoprotein VI in the platelet adhesion. Blood 1996; 88 (06) 2081-2092
    CrossrefPubMedSearch in Google Scholar
  • 43 Qiao J, Al-Tamimi M, Baker RI, Andrews RK, Gardiner EE. The platelet Fc receptor, FcγRIIa. Immunol Rev 2015; 268 (01) 241-252
    CrossrefPubMedSearch in Google Scholar
  • 44 Matsumoto Y, Takizawa H, Gong X. , et al. Highly potent anti-human GPVI monoclonal antibodies derived from GPVI knockout mouse immunization. Thromb Res 2007; 119 (03) 319-329
    CrossrefPubMedSearch in Google Scholar
  • 45 Lecut C, Feeney LA, Kingsbury G. , et al. Human platelet glycoprotein VI function is antagonized by monoclonal antibody-derived Fab fragments. J Thromb Haemost 2003; 1 (12) 2653-2662
    CrossrefPubMedSearch in Google Scholar
  • 46 Onselaer M-B, Hardy AT, Wilson C. , et al. Fibrin and D-dimer bind to monomeric GPVI. Blood Adv 2017; 1 (19) 1495-1504
    CrossrefPubMedSearch in Google Scholar
  • 47 Lima AM, Wegner SV, Martins Cavaco AC. , et al. The spatial molecular pattern of integrin recognition sites and their immobilization to colloidal nanobeads determine α2β1 integrin-dependent platelet activation. Biomaterials 2018; 167: 107-120
    CrossrefPubMedSearch in Google Scholar
  • 48 Nieuwenhuis HK, Akkerman JWN, Houdijk WPM, Sixma JJ. Human blood platelets showing no response to collagen fail to express surface glycoprotein Ia. Nature 1985; 318 (6045): 470-472
    CrossrefPubMedSearch in Google Scholar
  • 49 Nieuwenhuis HK, Sakariassen KS, Houdijk WP, Nievelstein PF, Sixma JJ. Deficiency of platelet membrane glycoprotein Ia associated with a decreased platelet adhesion to subendothelium: a defect in platelet spreading. Blood 1986; 68 (03) 692-695
    CrossrefPubMedSearch in Google Scholar
  • 50 Kehrel B, Balleisen L, Kokott R. , et al. Deficiency of intact thrombospondin and membrane glycoprotein Ia in platelets with defective collagen-induced aggregation and spontaneous loss of disorder. Blood 1988; 71 (04) 1074-1078
    CrossrefPubMedSearch in Google Scholar
  • 51 Handa M, Watanabe K, Kawai Y. , et al. Platelet unresponsiveness to collagen: involvement of glycoprotein Ia-IIa (alpha 2 beta 1 integrin) deficiency associated with a myeloproliferative disorder. Thromb Haemost 1995; 73 (03) 521-528
    Thieme ConnectPubMedSearch in Google Scholar
  • 52 Moroi M, Jung SM. Platelet glycoprotein VI: its structure and function. Thromb Res 2004; 114 (04) 221-233
    CrossrefPubMedSearch in Google Scholar
  • 53 Ezumi Y, Uchiyama T, Takayama H. Molecular cloning, genomic structure, chromosomal localization, and alternative splice forms of the platelet collagen receptor glycoprotein VI. Biochem Biophys Res Commun 2000; 277 (01) 27-36
    CrossrefPubMedSearch in Google Scholar
  • 54 Pollitt AY, Hughes CE, Watson SP. . GPVI and CLEC-2. In: Platelets. Elsevier; 2013. :215–231. Available at: http://linkinghub.elsevier.com/retrieve/pii/B9780123878373000110 . Accessed August 7, 2019
  • 55 Bori-Sanz T, Inoue KS, Berndt MC, Watson SP, Tulasne D. Delineation of the region in the glycoprotein VI tail required for association with the Fc receptor gamma-chain. J Biol Chem 2003; 278 (38) 35914-35922
    CrossrefPubMedSearch in Google Scholar
  • 56 Andrews RK, Suzuki-Inoue K, Shen Y, Tulasne D, Watson SP, Berndt MC. Interaction of calmodulin with the cytoplasmic domain of platelet glycoprotein VI. Blood 2002; 99 (11) 4219-4221
    CrossrefPubMedSearch in Google Scholar
  • 57 Suzuki-Inoue K, Tulasne D, Shen Y. , et al. Association of Fyn and Lyn with the proline-rich domain of glycoprotein VI regulates intracellular signaling. J Biol Chem 2002; 277 (24) 21561-21566
    CrossrefPubMedSearch in Google Scholar
  • 58 Smethurst PA, Joutsi-Korhonen L, O'Connor MN. , et al. Identification of the primary collagen-binding surface on human glycoprotein VI by site-directed mutagenesis and by a blocking phage antibody. Blood 2004; 103 (03) 903-911
    CrossrefPubMedSearch in Google Scholar
  • 59 O'Connor MN, Smethurst PA, Farndale RW, Ouwehand WH. Gain- and loss-of-function mutants confirm the importance of apical residues to the primary interaction of human glycoprotein VI with collagen. J Thromb Haemost 2006; 4 (04) 869-873
    CrossrefPubMedSearch in Google Scholar
  • 60 Lecut C, Arocas V, Ulrichts H. , et al. Identification of residues within human glycoprotein VI involved in the binding to collagen: evidence for the existence of distinct binding sites. J Biol Chem 2004; 279 (50) 52293-52299
    CrossrefPubMedSearch in Google Scholar
  • 61 Kunicki TJ, Cheli Y, Moroi M, Furihata K. The influence of N-linked glycosylation on the function of platelet glycoprotein VI. Blood 2005; 106 (08) 2744-2749
    CrossrefPubMedSearch in Google Scholar
  • 62 Arthur JF, Shen Y, Kahn ML, Berndt MC, Andrews RK, Gardiner EE. Ligand binding rapidly induces disulfide-dependent dimerization of glycoprotein VI on the platelet plasma membrane. J Biol Chem 2007; 282 (42) 30434-30441
    CrossrefPubMedSearch in Google Scholar
  • 63 Horii K, Kahn ML, Herr AB. Structural basis for platelet collagen responses by the immune-type receptor glycoprotein VI. Blood 2006; 108 (03) 936-942
    CrossrefPubMedSearch in Google Scholar
  • 64 Feitsma LJ, Brondijk THC, Jarvis G. , et al. Structural insights into collagen-binding by platelet receptor Glycoprotein VI. Doi: 10.2210/pdb5OU7/pdb
    PubMed
  • 65 Gibbins JM, Okuma M, Farndale R, Barnes M, Watson SP. Glycoprotein VI is the collagen receptor in platelets which underlies tyrosine phosphorylation of the Fc receptor γ-chain. FEBS Lett 1997; 413 (02) 255-259
    CrossrefPubMedSearch in Google Scholar
  • 66 Berlanga O, Tulasne D, Bori T. , et al. The Fc receptor gamma-chain is necessary and sufficient to initiate signalling through glycoprotein VI in transfected cells by the snake C-type lectin, convulxin. Eur J Biochem 2002; 269 (12) 2951-2960
    CrossrefPubMedSearch in Google Scholar
  • 67 Berlanga O, Bori-Sanz T, James JR. , et al. Glycoprotein VI oligomerization in cell lines and platelets. J Thromb Haemost 2007; 5 (05) 1026-1033
    CrossrefPubMedSearch in Google Scholar
  • 68 Miura Y, Takahashi T, Jung SM, Moroi M. Analysis of the interaction of platelet collagen receptor glycoprotein VI (GPVI) with collagen. A dimeric form of GPVI, but not the monomeric form, shows affinity to fibrous collagen. J Biol Chem 2002; 277 (48) 46197-46204
    CrossrefPubMedSearch in Google Scholar
  • 69 Plenz GAM, Deng MC, Robenek H, Völker W. Vascular collagens: spotlight on the role of type VIII collagen in atherogenesis. Atherosclerosis 2003; 166 (01) 1-11
    CrossrefPubMedSearch in Google Scholar
  • 70 Watson SP, Herbert JMJ, Pollitt AY. GPVI and CLEC-2 in hemostasis and vascular integrity. J Thromb Haemost 2010; 8 (07) 1456-1467
    CrossrefPubMedSearch in Google Scholar
  • 71 Jung SM, Takemura Y, Imamura Y, Hayashi T, Adachi E, Moroi M. Collagen-type specificity of glycoprotein VI as a determinant of platelet adhesion. Platelets 2008; 19 (01) 32-42
    CrossrefPubMedSearch in Google Scholar
  • 72 Mizuno K, Adachi E, Imamura Y, Katsumata O, Hayashi T. The fibril structure of type V collagen triple-helical domain. Micron 2001; 32 (03) 317-323
    CrossrefPubMedSearch in Google Scholar
  • 73 Jarvis GE, Atkinson BT, Snell DC, Watson SP. Distinct roles of GPVI and integrin alpha(2)beta(1) in platelet shape change and aggregation induced by different collagens. Br J Pharmacol 2002; 137 (01) 107-117
    CrossrefPubMedSearch in Google Scholar
  • 74 Hechler B, Nonne C, Eckly A. , et al. Arterial thrombosis: relevance of a model with two levels of severity assessed by histologic, ultrastructural and functional characterization. J Thromb Haemost 2010; 8 (01) 173-184
    CrossrefPubMedSearch in Google Scholar
  • 75 Knight CG, Morton LF, Onley DJ. , et al. Collagen-platelet interaction: Gly-Pro-Hyp is uniquely specific for platelet Gp VI and mediates platelet activation by collagen. Cardiovasc Res 1999; 41 (02) 450-457
    CrossrefPubMedSearch in Google Scholar
  • 76 Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor?. Blood 2003; 102 (02) 449-461
    CrossrefPubMedSearch in Google Scholar
  • 77 Morton LF, Hargreaves PG, Farndale RW, Young RD, Barnes MJ. Integrin alpha 2 beta 1-independent activation of platelets by simple collagen-like peptides: collagen tertiary (triple-helical) and quaternary (polymeric) structures are sufficient alone for alpha 2 beta 1-independent platelet reactivity. Biochem J 1995; 306 (Pt 2): 337-344
    CrossrefPubMedSearch in Google Scholar
  • 78 Poulter NS, Pollitt AY, Owen DM. , et al. Clustering of glycoprotein VI (GPVI) dimers upon adhesion to collagen as a mechanism to regulate GPVI signaling in platelets. J Thromb Haemost 2017; 15 (03) 549-564
    CrossrefPubMedSearch in Google Scholar
  • 79 Slater A, Perrella G, Onselaer MB. , et al. Does fibrin(ogen) bind to monomeric or dimeric GPVI, or not at all?. Platelets 2019; 30 (03) 281-289
    CrossrefPubMedSearch in Google Scholar
  • 80 Alshehri OM, Hughes CE, Montague S. , et al. Fibrin activates GPVI in human and mouse platelets. Blood 2015; 126 (13) 1601-1608
    PubMedSearch in Google Scholar
  • 81 Mangin PH, Onselaer M-B, Receveur N. , et al. Immobilized fibrinogen activates human platelets through glycoprotein VI. Haematologica 2018; 103 (05) 898-907
    CrossrefPubMedSearch in Google Scholar
  • 82 Riba R, Hughes CE, Graham A, Watson SP, Naseem KM. Globular adiponectin induces platelet activation through the collagen receptor GPVI-Fc receptor γ chain complex. J Thromb Haemost 2008; 6 (06) 1012-1020
    CrossrefPubMedSearch in Google Scholar
  • 83 Inoue O, Suzuki-Inoue K, McCarty OJT. , et al. Laminin stimulates spreading of platelets through integrin alpha6beta1-dependent activation of GPVI. Blood 2006; 107 (04) 1405-1412
    CrossrefPubMedSearch in Google Scholar
  • 84 Inoue O, Suzuki-Inoue K, Ozaki Y. Redundant mechanism of platelet adhesion to laminin and collagen under flow: involvement of von Willebrand factor and glycoprotein Ib-IX-V. J Biol Chem 2008; 283 (24) 16279-16282
    CrossrefPubMedSearch in Google Scholar
  • 85 Schaff M, Tang C, Maurer E. , et al. Integrin α6β1 is the main receptor for vascular laminins and plays a role in platelet adhesion, activation, and arterial thrombosis. Circulation 2013; 128 (05) 541-552
    CrossrefPubMedSearch in Google Scholar
  • 86 Reth M. Antigen receptor tail clue. Nature 1989; 338 (6214): 383-384
    PubMedSearch in Google Scholar
  • 87 Boulaftali Y, Hess PR, Kahn ML, Bergmeier W. Platelet ITAM signaling and vascular integrity. Circ Res 2014; 114 (07) 1174-1184
    CrossrefPubMedSearch in Google Scholar
  • 88 Rayes J, Watson SP, Nieswandt B. Functional significance of the platelet immune receptors GPVI and CLEC-2. J Clin Invest 2019; 129 (01) 12-23
    CrossrefPubMedSearch in Google Scholar
  • 89 Boylan B, Gao C, Rathore V, Gill JC, Newman DK, Newman PJ. Identification of FcgammaRIIa as the ITAM-bearing receptor mediating alphaIIbbeta3 outside-in integrin signaling in human platelets. Blood 2008; 112 (07) 2780-2786
    CrossrefPubMedSearch in Google Scholar
  • 90 Watson SP, Auger JM. , McCarty OJT, Pearce AC. GPVI and integrin αIIbβ3 signaling in platelets. J Thromb Haemost 2005; 3 (08) 1752-1762
    CrossrefPubMedSearch in Google Scholar
  • 91 Locke D, Chen H, Liu Y, Liu C, Kahn ML. Lipid rafts orchestrate signaling by the platelet receptor glycoprotein VI. J Biol Chem 2002; 277 (21) 18801-18809
    CrossrefPubMedSearch in Google Scholar
  • 92 Zhang W, Trible RP, Samelson LE. LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation. Immunity 1998; 9 (02) 239-246
    CrossrefPubMedSearch in Google Scholar
  • 93 Quinter PG, Dangelmaier CA, Quinton TM, Kunapuli SP, Daniel JL. Glycoprotein VI agonists have distinct dependences on the lipid raft environment. J Thromb Haemost 2007; 5 (02) 362-368
    CrossrefPubMedSearch in Google Scholar
  • 94 Schmaier AA, Zou Z, Kazlauskas A. , et al. Molecular priming of Lyn by GPVI enables an immune receptor to adopt a hemostatic role. Proc Natl Acad Sci U S A 2009; 106 (50) 21167-21172
    CrossrefPubMedSearch in Google Scholar
  • 95 Quek LS, Pasquet JM, Hers I. , et al. Fyn and Lyn phosphorylate the Fc receptor gamma chain downstream of glycoprotein VI in murine platelets, and Lyn regulates a novel feedback pathway. Blood 2000; 96 (13) 4246-4253
    CrossrefPubMedSearch in Google Scholar
  • 96 Asazuma N, Wilde JI, Berlanga O. , et al. Interaction of linker for activation of T cells with multiple adapter proteins in platelets activated by the glycoprotein VI-selective ligand, convulxin. J Biol Chem 2000; 275 (43) 33427-33434
    CrossrefPubMedSearch in Google Scholar
  • 97 Gross BS, Lee JR, Clements JL. , et al. Tyrosine phosphorylation of SLP-76 is downstream of Syk following stimulation of the collagen receptor in platelets. J Biol Chem 1999; 274 (09) 5963-5971
    CrossrefPubMedSearch in Google Scholar
  • 98 Hughes CE, Auger JM, McGlade J, Eble JA, Pearce AC, Watson SP. Differential roles for the adapters Gads and LAT in platelet activation by GPVI and CLEC-2. J Thromb Haemost 2008; 6 (12) 2152-2159
    CrossrefPubMedSearch in Google Scholar
  • 99 Zhou Z, Gushiken FC, Bolgiano D. , et al. Signal transducer and activator of transcription 3 (STAT3) regulates collagen-induced platelet aggregation independently of its transcription factor activity. Circulation 2013; 127 (04) 476-485
    CrossrefPubMedSearch in Google Scholar
  • 100 Oda A, Ikeda Y, Ochs HD. , et al. Rapid tyrosine phosphorylation and activation of Bruton's tyrosine/Tec kinases in platelets induced by collagen binding or CD32 cross-linking. Blood 2000; 95 (05) 1663-1670
    PubMedSearch in Google Scholar
  • 101 Atkinson BT, Ellmeier W, Watson SP. Tec regulates platelet activation by GPVI in the absence of Btk. Blood 2003; 102 (10) 3592-3599
    CrossrefPubMedSearch in Google Scholar
  • 102 Pleines I, Elvers M, Strehl A. , et al. Rac1 is essential for phospholipase C-gamma2 activation in platelets. Pflugers Arch 2009; 457 (05) 1173-1185
    CrossrefPubMedSearch in Google Scholar
  • 103 Pearce AC, Senis YA, Billadeau DD, Turner M, Watson SP, Vigorito E. Vav1 and vav3 have critical but redundant roles in mediating platelet activation by collagen. J Biol Chem 2004; 279 (52) 53955-53962
    CrossrefPubMedSearch in Google Scholar
  • 104 Manganaro D, Consonni A, Guidetti GF. , et al. Activation of phosphatidylinositol 3-kinase β by the platelet collagen receptors integrin α2β1 and GPVI: The role of Pyk2 and c-Cbl. Biochim Biophys Acta 2015; 1853 (08) 1879-1888
    PubMedSearch in Google Scholar
  • 105 Gilio K, Munnix ICA, Mangin P. , et al. Non-redundant roles of phosphoinositide 3-kinase isoforms α and β in glycoprotein VI-induced platelet signaling and thrombus formation. J Biol Chem 2009; 284 (49) 33750-33762
    CrossrefPubMedSearch in Google Scholar
  • 106 Auger JM, Best D, Snell DC, Wilde JI, Watson SP. c-Cbl negatively regulates platelet activation by glycoprotein VI. J Thromb Haemost 2003; 1 (11) 2419-2426
    CrossrefPubMedSearch in Google Scholar
  • 107 Yacoub D, Théorêt J-F, Villeneuve L. , et al. Essential role of protein kinase C delta in platelet signaling, alpha IIb beta 3 activation, and thromboxane A2 release. J Biol Chem 2006; 281 (40) 30024-30035
    CrossrefPubMedSearch in Google Scholar
  • 108 Senis YA, Tomlinson MG, Ellison S. , et al. The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis. Blood 2009; 113 (20) 4942-4954
    CrossrefPubMedSearch in Google Scholar
  • 109 Ming Z, Hu Y, Xiang J, Polewski P, Newman PJ, Newman DK. Lyn and PECAM-1 function as interdependent inhibitors of platelet aggregation. Blood 2011; 117 (14) 3903-3906
    CrossrefPubMedSearch in Google Scholar
  • 110 Colonna M, Samaridis J, Angman L. Molecular characterization of two novel C-type lectin-like receptors, one of which is selectively expressed in human dendritic cells. Eur J Immunol 2000; 30 (02) 697-704
    CrossrefPubMedSearch in Google Scholar
  • 111 Suzuki-Inoue K, Fuller GLJ, García A. , et al. A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood 2006; 107 (02) 542-549
    CrossrefPubMedSearch in Google Scholar
  • 112 Suzuki-Inoue K, Kato Y, Inoue O. , et al. Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J Biol Chem 2007; 282 (36) 25993-26001
    CrossrefPubMedSearch in Google Scholar
  • 113 Christou CM, Pearce AC, Watson AA. , et al. Renal cells activate the platelet receptor CLEC-2 through podoplanin. Biochem J 2008; 411 (01) 133-140
    CrossrefPubMedSearch in Google Scholar
  • 114 Astarita JL, Acton SE, Turley SJ. Podoplanin: emerging functions in development, the immune system, and cancer. Front Immunol 2012; 3: 283
    PubMedSearch in Google Scholar
  • 115 May F, Hagedorn I, Pleines I. , et al. CLEC-2 is an essential platelet-activating receptor in hemostasis and thrombosis. Blood 2009; 114 (16) 3464-3472
    PubMedSearch in Google Scholar
  • 116 Hughes CE, Navarro-Núñez L, Finney BA, Mourão-Sá D, Pollitt AY, Watson SP. CLEC-2 is not required for platelet aggregation at arteriolar shear. J Thromb Haemost 2010; 8 (10) 2328-2332
    CrossrefPubMedSearch in Google Scholar
  • 117 Suzuki-Inoue K, Inoue O, Ding G. , et al. Essential in vivo roles of the C-type lectin receptor CLEC-2: embryonic/neonatal lethality of CLEC-2-deficient mice by blood/lymphatic misconnections and impaired thrombus formation of CLEC-2-deficient platelets. J Biol Chem 2010; 285 (32) 24494-24507
    CrossrefPubMedSearch in Google Scholar
  • 118 Hatakeyama K, Kaneko MK, Kato Y. , et al. Podoplanin expression in advanced atherosclerotic lesions of human aortas. Thromb Res 2012; 129 (04) e70-e76
    CrossrefPubMedSearch in Google Scholar
  • 119 Hughes CE, Pollitt AY, Mori J. , et al. CLEC-2 activates Syk through dimerization. Blood 2010; 115 (14) 2947-2955
    CrossrefPubMedSearch in Google Scholar
  • 120 Fuller GLJ, Williams JAE, Tomlinson MG. , et al. The C-type lectin receptors CLEC-2 and Dectin-1, but not DC-SIGN, signal via a novel YXXL-dependent signaling cascade. J Biol Chem 2007; 282 (17) 12397-12409
    CrossrefPubMedSearch in Google Scholar
  • 121 Judd BA, Myung PS, Obergfell A. , et al. Differential requirement for LAT and SLP-76 in GPVI versus T cell receptor signaling. J Exp Med 2002; 195 (06) 705-717
    CrossrefPubMedSearch in Google Scholar
  • 122 Pollitt AY, Grygielska B, Leblond B, Désiré L, Eble JA, Watson SP. Phosphorylation of CLEC-2 is dependent on lipid rafts, actin polymerization, secondary mediators, and Rac. Blood 2010; 115 (14) 2938-2946
    CrossrefPubMedSearch in Google Scholar
  • 123 Bender M, May F, Lorenz V. , et al. Combined in vivo depletion of glycoprotein VI and C-type lectin-like receptor 2 severely compromises hemostasis and abrogates arterial thrombosis in mice. Arterioscler Thromb Vasc Biol 2013; 33 (05) 926-934
    CrossrefPubMedSearch in Google Scholar
  • 124 Chang CH, Chung CH, Tu YS. , et al. Trowaglerix venom polypeptides as a novel antithrombotic agent by targeting immunoglobulin-like domains of glycoprotein VI in platelet. Arterioscler Thromb Vasc Biol 2017; 37 (07) 1307-1314
    CrossrefPubMedSearch in Google Scholar
  • 125 Hsu CC, Wu WB, Huang TF. A snake venom metalloproteinase, kistomin, cleaves platelet glycoprotein VI and impairs platelet functions. J Thromb Haemost 2008; 6 (09) 1578-1585
    PubMedSearch in Google Scholar
  • 126 Fuentes M, Sepúlveda C, Alarcón M, Palomo I, Fuentes E. Buddleja globosa (matico) prevents collagen-induced platelet activation by decreasing phospholipase C-gamma 2 and protein kinase C phosphorylation signaling. J Tradit Complement Med 2017; 8 (01) 66-71
    PubMedSearch in Google Scholar
  • 127 Li W, Tang X, Yi W. , et al. Glaucocalyxin A inhibits platelet activation and thrombus formation preferentially via GPVI signaling pathway. PLoS One 2013; 8 (12) e85120
    CrossrefPubMedSearch in Google Scholar
  • 128 Fuentes EJ, Astudillo LA, Gutiérrez MI. , et al. Fractions of aqueous and methanolic extracts from tomato (Solanum lycopersicum L.) present platelet antiaggregant activity. Blood Coagul Fibrinolysis 2012; 23 (02) 109-117
    CrossrefPubMedSearch in Google Scholar
  • 129 Hsiao G, Wang Y, Tzu N-H. , et al. Inhibitory effects of lycopene on in vitro platelet activation and in vivo prevention of thrombus formation. J Lab Clin Med 2005; 146 (04) 216-226
    CrossrefPubMedSearch in Google Scholar
  • 130 Yoshida S, Sudo T, Niimi M. , et al. Inhibition of collagen-induced platelet aggregation by anopheline antiplatelet protein, a saliva protein from a malaria vector mosquito. Blood 2008; 111 (04) 2007-2014
    CrossrefPubMedSearch in Google Scholar
  • 131 Yao Y, Chen Y, Adili R. , et al. Plant-based food cyanidin-3-glucoside modulates human platelet glycoprotein VI signaling and inhibits platelet activation and thrombus formation. J Nutr 2017; 147 (10) 1917-1925
    CrossrefPubMedSearch in Google Scholar
  • 132 Massberg S, Konrad I, Bültmann A. , et al. Soluble glycoprotein VI dimer inhibits platelet adhesion and aggregation to the injured vessel wall in vivo. FASEB J 2004; 18 (02) 397-399
    CrossrefPubMedSearch in Google Scholar
  • 133 Bültmann A, Herdeg C, Li Z. , et al. Local delivery of soluble platelet collagen receptor glycoprotein VI inhibits thrombus formation in vivo. Thromb Haemost 2006; 95 (05) 763-766
    Thieme ConnectPubMedSearch in Google Scholar
  • 134 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
    CrossrefPubMedSearch in Google Scholar
  • 135 Takayama H, Hosaka Y, Nakayama K. , et al. A novel antiplatelet antibody therapy that induces cAMP-dependent endocytosis of the GPVI/Fc receptor gamma-chain complex. J Clin Invest 2008; 118 (05) 1785-1795
    CrossrefPubMedSearch in Google Scholar
  • 136 Muzard J, Bouabdelli M, Zahid M. , et al. Design and humanization of a murine scFv that blocks human platelet glycoprotein VI in vitro. FEBS J 2009; 276 (15) 4207-4222
    CrossrefPubMedSearch in Google Scholar
  • 137 Matsumoto Y, Takizawa H, Nakama K. , et al. Ex vivo evaluation of anti-GPVI antibody in cynomolgus monkeys: dissociation between anti-platelet aggregatory effect and bleeding time. Thromb Haemost 2006; 96 (02) 167-175
    Thieme ConnectPubMedSearch in Google Scholar
  • 138 Li H, Lockyer S, Concepcion A. , et al. The Fab fragment of a novel anti-GPVI monoclonal antibody, OM4, reduces in vivo thrombosis without bleeding risk in rats. Arterioscler Thromb Vasc Biol 2007; 27 (05) 1199-1205
    CrossrefPubMedSearch in Google Scholar
  • 139 Florian P, Wonerow P, Harder S, Kuczka K, Dubar M, Graff J. Anti-GPVI Fab SAR264565 effectively blocks GPVI function in ex vivo human platelets under arterial shear in a perfusion chamber. Eur J Clin Pharmacol 2017; 73 (08) 949-956
    CrossrefPubMedSearch in Google Scholar
  • 140 Jung SM, Tsuji K, Moroi M. Glycoprotein (GP) VI dimer as a major collagen-binding site of native platelets: direct evidence obtained with dimeric GPVI-specific Fabs. J Thromb Haemost 2009; 7 (08) 1347-1355
    CrossrefPubMedSearch in Google Scholar
  • 141 Lebozec K, Jandrot-Perrus M, Avenard G, Favre-Bulle O, Billiald P. Design, development and characterization of ACT017, a humanized Fab that blocks platelet's glycoprotein VI function without causing bleeding risks. MAbs 2017; 9 (06) 945-958
    CrossrefPubMedSearch in Google Scholar
  • 142 O'Connor MN, Smethurst PA, Davies LW. , et al. Selective blockade of glycoprotein VI clustering on collagen helices. J Biol Chem 2006; 281 (44) 33505-33510
    CrossrefPubMedSearch in Google Scholar
  • 143 Uckun FM, Vassilev A, Bartell S, Zheng Y, Mahajan S, Tibbles HE. The anti-leukemic Bruton's tyrosine kinase inhibitor alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl) propenamide (LFM-A13) prevents fatal thromboembolism. Leuk Lymphoma 2003; 44 (09) 1569-1577
    PubMedSearch in Google Scholar
  • 144 Spalton JC, Mori J, Pollitt AY, Hughes CE, Eble JA, Watson SP. The novel Syk inhibitor R406 reveals mechanistic differences in the initiation of GPVI and CLEC-2 signaling in platelets. J Thromb Haemost 2009; 7 (07) 1192-1199
    CrossrefPubMedSearch in Google Scholar
  • 145 Reilly MP, Sinha U, André P. , et al. PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model. Blood 2011; 117 (07) 2241-2246
    CrossrefPubMedSearch in Google Scholar
  • 146 Spyridon M, Moraes LA, Jones CI. , et al. LXR as a novel antithrombotic target. Blood 2011; 117 (21) 5751-5761
    CrossrefPubMedSearch in Google Scholar
  • 147 Bishton MJ, Gardiner EE, Harrison SJ, Prince HM, Johnstone RW. Histone deacetylase inhibitors reduce glycoprotein VI expression and platelet responses to collagen related peptide. Thromb Res 2013; 131 (06) 514-520
    CrossrefPubMedSearch in Google Scholar
  • 148 Vara D, Campanella M, Pula G. The novel NOX inhibitor 2-acetylphenothiazine impairs collagen-dependent thrombus formation in a GPVI-dependent manner. Br J Pharmacol 2013; 168 (01) 212-224
    CrossrefPubMedSearch in Google Scholar
  • 149 Grothusen C, Umbreen S, Konrad I. , et al. EXP3179 inhibits collagen-dependent platelet activation via glycoprotein receptor-VI independent of AT1-receptor antagonism: potential impact on atherothrombosis. Arterioscler Thromb Vasc Biol 2007; 27 (05) 1184-1190
    CrossrefPubMedSearch in Google Scholar
  • 150 Lin K-H, Lu W-J, Wang S-H. , et al. Characteristics of endogenous γ-aminobutyric acid (GABA) in human platelets: functional studies of a novel collagen glycoprotein VI inhibitor. J Mol Med (Berl) 2014; 92 (06) 603-614
    PubMedSearch in Google Scholar
  • 151 Kamiguti AS. Platelets as targets of snake venom metalloproteinases. Toxicon 2005; 45 (08) 1041-1049
    CrossrefPubMedSearch in Google Scholar
  • 152 Fuentes E, Fuentes F, Palomo I. Mechanism of the anti-platelet effect of natural bioactive compounds: role of peroxisome proliferator-activated receptors activation. Platelets 2014; 25 (07) 471-479
    CrossrefPubMedSearch in Google Scholar
  • 153 Akbiyik F, Ray DM, Gettings KF, Blumberg N, Francis CW, Phipps RP. Human bone marrow megakaryocytes and platelets express PPARgamma, and PPARgamma agonists blunt platelet release of CD40 ligand and thromboxanes. Blood 2004; 104 (05) 1361-1368
    CrossrefPubMedSearch in Google Scholar
  • 154 Moraes LA, Spyridon M, Kaiser WJ. , et al. Non-genomic effects of PPARgamma ligands: inhibition of GPVI-stimulated platelet activation. J Thromb Haemost 2010; 8 (03) 577-587
    CrossrefPubMedSearch in Google Scholar
  • 155 Reimann A, Li Z, Goebel S. , et al. Combined administration of the GPVI-Fc fusion protein Revacept with low-dose thrombolysis in the treatment of stroke. Heart Int 2016; 11 (01) e10-e16
    PubMedSearch in Google Scholar
  • 156 Nieswandt B, Bergmeier W, Schulte V, Rackebrandt K, Gessner JE, Zirngibl H. Expression and function of the mouse collagen receptor glycoprotein VI is strictly dependent on its association with the FcRgamma chain. J Biol Chem 2000; 275 (31) 23998-24002
    CrossrefPubMedSearch in Google Scholar
  • 157 Stegner D, Haining EJ, Nieswandt B. Targeting glycoprotein VI and the immunoreceptor tyrosine-based activation motif signaling pathway. Arterioscler Thromb Vasc Biol 2014; 34 (08) 1615-1620
    CrossrefPubMedSearch in Google Scholar
  • 158 Martins Lima A, Bragina ME, Burri O. , et al. An optimized and validated 384-well plate assay to test platelet function in a high-throughput screening format. Platelets 2019; 30 (05) 563-571
    CrossrefPubMedSearch in Google Scholar