Targeting GPVI as a novel antithrombotic strategy

While platelet activation is essential to maintain blood vessel patency and minimize loss of blood upon injury, untimely or excessive activity can lead to unwanted platelet activation and aggregation. Resultant thrombosis has the potential to block blood vessels, causing myocardial infarction or stroke. To tackle this major cause of mortality, clinical therapies that target platelet responsiveness (antiplatelet therapy) can successfully reduce cardiovascular events, especially in people at higher risk; however, all current antiplatelet therapies carry an increased probability of bleeding. This review will evaluate new and emerging targets for antithrombotics, focusing particularly on platelet glycoprotein VI, as blockade or depletion of this platelet-specific receptor conveys benefits in experimental models of thrombosis and thromboinflammation without causing major bleeding complications.

• Publication year

  2014

• Venue

  Journal of Blood Medicine

• Publication date

  2014-05-21

• Fields of study

  Medicine

• Identifiers
  DOI 10.2147/JBM.S39220PMID 24899824PMCID 4039396
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Targeting platelet receptor function in thrombus formation: the risk of bleeding.

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• Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta‐analysis

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• Implications of glycoprotein VI for theranostics

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• Triple antithrombotic therapy in cardiac patients: more questions than answers.

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• Update on platelet glycoprotein IIb/IIIa inhibitors: recommendations for clinical practice

  2013cited by this paper
• Histone deacetylase inhibitors reduce glycoprotein VI expression and platelet responses to collagen related peptide.

  2013cited by this paper
• Testing platelet function.

  2013cited by this paper
• The novel NOX inhibitor 2‐acetylphenothiazine impairs collagen‐dependent thrombus formation in a GPVI‐dependent manner

  2013cited by this paper
• Differentiating haemostasis from thrombosis for therapeutic benefit

  2013cited by this paper
• Platelet ITAM signaling

  2013cited by this paper
• Integrin &agr;6&bgr;1 Is the Main Receptor for Vascular Laminins and Plays a Role in Platelet Adhesion, Activation, and Arterial Thrombosis

  2013cited by this paper
• Who decides when to cleave an ectodomain?

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• Platelet ITAM signaling is critical for vascular integrity in inflammation.

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• Updates in Antiplatelet Agents Used in Cardiovascular Diseases

  2013cited by this paper
• Bernard–Soulier Syndrome: An Update

  2013cited by this paper
• Integrin α 6 β 1 Is the Main Receptor for Vascular Laminins and Plays a Role in Platelet Adhesion, Activation, and Arterial Thrombosis

  2013cited by this paper
• Positron Emission Tomography/Computed Tomographic and Magnetic Resonance Imaging in a Murine Model of Progressive Atherosclerosis Using 64Cu-Labeled Glycoprotein VI-Fc

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• The GPVI-Fc Fusion Protein Revacept Improves Cerebral Infarct Volume and Functional Outcome in Stroke

  2013cited by this paper
• Novel antiplatelet drugs in clinical development

  2013cited by this paper
• Platelets as cellular effectors of inflammation in vascular diseases.

  2013cited by this paper
• The GPVI – Fc Fusion Protein Revacept Reduces Thrombus Formation and Improves Vascular Dysfunction in Atherosclerosis without Any Impact on Bleeding Times

  2013cited by this paper
• Impact of clopidogrel and potent P2Y12-inhibitors on mortality and stroke in patients with acute coronary syndrome or undergoing percutaneous coronary intervention

  2012cited by this paper
• The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways.

  2012influential reference
• Platelet GPVI: a target for antithrombotic therapy?!

  2012cited by this paper
• Mitochondrial Calcium and Reactive Oxygen Species Regulate Agonist-Initiated Platelet Phosphatidylserine Exposure

  2012cited by this paper
• Platelet Glycoprotein VI Dimerization, an Active Process Inducing Receptor Competence, Is an Indicator of Platelet Reactivity

  2012cited by this paper
• A Humanized Glycoprotein VI (GPVI) Mouse Model to Assess the Antithrombotic Efficacies of Anti-GPVI Agents

  2012cited by this paper
• Constitutive Dimerization of Glycoprotein VI (GPVI) in Resting Platelets Is Essential for Binding to Collagen and Activation in Flowing Blood

  2012cited by this paper
• ITAM receptor‐mediated generation of reactive oxygen species in human platelets occurs via Syk‐dependent and Syk‐independent pathways

  2012cited by this paper
• The future of glycoprotein VI as an antithrombotic target

  2012cited by this paper
• Evaluating the clinical usefulness of platelet function testing: Considerations for the proper application and interpretation of performance measures

  2012cited by this paper
• Focusing on plasma glycoprotein VI

  2012cited by this paper
• A disintegrin and metalloproteases: molecular scissors in angiogenesis, inflammation and atherosclerosis.

  2012cited by this paper
• An Acquired Defect Associated with Abnormal Signaling of the Platelet Collagen Receptor Glycoprotein VI

  2012cited by this paper
• Pathologic shear triggers shedding of vascular receptors: a novel mechanism for down-regulation of platelet glycoprotein VI in stenosed coronary vessels.

  2012cited by this paper
• The evolution of antiplatelet therapy in cardiovascular disease

  2011cited by this paper
• Structural Basis for FcγRIIa Recognition of Human IgG and Formation of Inflammatory Signaling Complexes

  2011cited by this paper
• Soluble Glycoprotein VI Is Raised in the Plasma of Patients With Acute Ischemic Stroke

  2011cited by this paper
• LXR as a novel antithrombotic target.

  2011cited by this paper
• TNF receptor‐associated factor 4 (TRAF4) is a novel binding partner of glycoprotein Ib and glycoprotein VI in human platelets

  2011cited by this paper
• Novel Antiplatelet Drug Revacept (Dimeric Glycoprotein VI-Fc) Specifically and Efficiently Inhibited Collagen-Induced Platelet Aggregation Without Affecting General Hemostasis in Humans

  2011cited by this paper
• Arterial thrombosis—insidious, unpredictable and deadly

  2011cited by this paper
• Genetic and antibody‐induced glycoprotein VI deficiency equally protects mice from mechanically and FeCl3‐induced thrombosis

  2011cited by this paper
• Design and reshaping of an scFv directed against human platelet glycoprotein VI with diagnostic potential.

  2011cited by this paper
• Glycoprotein VI for diagnosis of acute coronary syndrome when ECG is ambiguous.

  2011cited by this paper
• Coagulation-induced shedding of platelet glycoprotein VI mediated by factor Xa.

  2011cited by this paper
• GPVI and CLEC‐2 in hemostasis and vascular integrity

  2010cited by this paper
• Bleeding Complications With Dual Antiplatelet Therapy Among Patients With Stable Vascular Disease or Risk Factors for Vascular Disease: Results From the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial

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• Platelets Amplify Inflammation in Arthritis via Collagen-Dependent Microparticle Production

  2010cited by this paper
• New oral anticoagulant drugs in cardiovascular disease

  2010cited by this paper
• Identification of novel downstream targets of platelet glycoprotein VI activation by differential proteome analysis: implications for thrombus formation.

  2010cited by this paper
• GPIbα-selective activation of platelets induces platelet signaling events comparable to GPVI activation events

  2010cited by this paper
• Expression of platelet glycoprotein VI is associated with transient ischemic attack and stroke

  2010cited by this paper
• Diagnostic and Therapeutic Potentials of Platelet Glycoprotein VI

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• Glycoprotein VI as a prognostic biomarker for cardiovascular death in patients with symptomatic coronary artery disease

  2010influential reference
• Platelet recruitment to the inflamed glomerulus occurs via an alphaIIbbeta3/GPVI-dependent pathway.

  2010cited by this paper
• Regulation of platelet glycoprotein VI (GPVI) surface expression and of soluble GPVI in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS)

  2009cited by this paper
• Single domain antibodies against the collagen signalling receptor glycoprotein VI are inhibitors of collagen induced thrombus formation

  2009cited by this paper
• Complementary roles of platelets and coagulation in thrombus formation on plaques acutely ruptured by targeted ultrasound treatment: a novel intravital model

  2009cited by this paper
• A compound heterozygous mutation in glycoprotein VI in a patient with a bleeding disorder

  2009cited by this paper
• Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo.

  2009cited by this paper
• The novel Syk inhibitor R406 reveals mechanistic differences in the initiation of GPVI and CLEC‐2 signaling in platelets

  2009cited by this paper
• A small-molecule inhibitor of integrin α2β1 introduces a new strategy for antithrombotic therapy

  2009cited by this paper
• Regulation of the proteolytic disintegrin metalloproteinases, the 'Sheddases'.

  2009cited by this paper
• Absence of collagen-induced platelet activation caused by compound heterozygous GPVI mutations.

  2009cited by this paper
• Rapid Procoagulant Phosphatidylserine Exposure Relies on High Cytosolic Calcium Rather Than on Mitochondrial Depolarization

  2009cited by this paper
• Small-molecule inhibitors of integrin α2β1 that prevent pathological thrombus formation via an allosteric mechanism

  2009cited by this paper
• Design and humanization of a murine scFv that blocks human platelet glycoprotein VI in vitro

  2009cited by this paper
• Dual ITAM-mediated proteolytic pathways for irreversible inactivation of platelet receptors: de-ITAM-izing FcgammaRIIa.

  2008cited by this paper
• A novel antiplatelet antibody therapy that induces cAMP-dependent endocytosis of the GPVI/Fc receptor gamma-chain complex.

  2008cited by this paper
• Dual ITAM-mediated proteolytic pathways for irreversible inactivation of platelet receptors: de-ITAM-izing FcγRIIa

  2008cited by this paper
• Triggers, targets and treatments for thrombosis

  2008cited by this paper
• Compromised ITAM‐based platelet receptor function in a patient with immune thrombocytopenic purpura

  2008cited by this paper
• Mechanisms of thrombus formation.

  2008cited by this paper
• The Modifier of hemostasis (Mh) locus on chromosome 4 controls in vivo hemostasis of Gp6-/- mice.

  2008cited by this paper
• Targeting Platelets in Acute Experimental Stroke: Impact of Glycoprotein Ib, VI, and IIb/IIIa Blockade on Infarct Size, Functional Outcome, and Intracranial Bleeding

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• Antiplatelet therapy for the prevention of recurrent stroke and other serious vascular events: a review of the clinical trial data and guidelines

  2007cited by this paper
• Controlled shedding of platelet glycoprotein (GP)VI and GPIb–IX–V by ADAM family metalloproteinases

  2007influential reference
• Thrombin-initiated platelet activation in vivo is vWF independent during thrombus formation in a laser injury model.

  2007cited by this paper
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  2007cited by this paper
• Platelet glycoprotein VI‐related clinical defects

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• Diverging signaling events control the pathway of GPVI down-regulation in vivo.

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• GPVI-deficient mice lack collagen responses and are protected against experimentally induced pulmonary thromboembolism.

  2006cited by this paper
• Glycoprotein VI-dependent and -independent pathways of thrombus formation in vivo.

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• Local delivery of soluble platelet collagen receptor glycoprotein VI inhibits thrombus formation in vivo

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• Laminin stimulates spreading of platelets through integrin α6β1–dependent activation of GPVI

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• Structural basis for platelet collagen responses by the immune-type receptor glycoprotein VI.

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  2006cited by this paper
• Thrombin overcomes the thrombosis defect associated with platelet GPVI/FcRgamma deficiency.

  2006cited by this paper
• Thrombin overcomes the thrombosis defect associated with platelet GPVI/FcRγ deficiency. Commentary

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• Evidence for a Role of ADAM17 (TACE) in the Regulation of Platelet Glycoprotein V*

  2005cited by this paper
• Platelet GPIb‐IX‐V‐dependent signaling

  2005cited by this paper
• Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules.

  2005cited by this paper
• Relative antithrombotic effect of soluble GPVI dimer compared with anti-GPVI antibodies in mice.

  2005cited by this paper
• Contribution of platelet glycoprotein VI to the thrombogenic effect of collagens in fibrous atherosclerotic lesions.

  2005cited by this paper
• Glycoproteins VI and Ib-IX-V stimulate tyrosine phosphorylation of tyrosine kinase Syk and phospholipase Cgamma2 at distinct sites.

  2004cited by this paper
• Anti-glycoprotein VI treatment severely compromises hemostasis in mice with reduced alpha2beta1 levels or concomitant aspirin therapy.

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• Identification of Residues within Human Glycoprotein VI Involved in the Binding to Collagen

  2004cited by this paper
• Defective collagen-induced platelet activation in two patients with malignant haemopathies is related to a defect in the GPVI-coupled signalling pathway

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• Influence of short-term refrigeration on collagen-dependent signalling mechanisms in stored platelets.

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• Chemical profile and antithrombotic activity of the essential oil of Levisticum officinale W.D.J.Koch (Apiaceae)

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• GPVI inhibition: Advancing antithrombotic therapy in cardiovascular disease

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• Fragmented Thrombi, Targeted Solutions: Exploring GPVI Inhibition in High-Shear Environments.

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• Differential effects of plant and animal fats on obesity‐induced dyslipidemia and atherosclerosis in Ldlr−/−.Leiden mice

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• Illustrated Abstracts of the 5th EUPLAN International Conference

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• Perspective: Collagen induced platelet activation via the GPVI receptor as a primary target of colchicine in cardiovascular disease

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• Characterizing the binding of glycoprotein VI with nanobody 35 reveals a novel monomeric structure of glycoprotein VI where the conformation of D1+D2 is independent of dimerization.

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• Fibrin-glycoprotein VI interaction increases platelet procoagulant activity and impacts clot structure.

  2022cites this paper
• Evaluation of the effect of eltrombopag therapy on the platelet collagen receptor glycoprotein VI (GPVI) expression and soluble GPVI levels in young patients with immune thrombocytopenia

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• Modulation of Glycoprotein VI and Its Downstream Signaling Pathways as an Antiplatelet Target

  2022cites this paper
• Colchicine as a Modulator of Platelet Function: A Systematic Review.

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• Human milk oligosaccharide, 2′-Fucosyllactose, attenuates platelet activation in arterial thrombosis

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• Elevated Soluble Podoplanin Associates with Hypercoagulability in Patients with Nephrotic Syndrome

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• Spatial Environment Affects HNF4A Mutation-Specific Proteome Signatures and Cellular Morphology in hiPSC-Derived β-Like Cells

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• Pharmacological Inhibition of Glycoprotein VI- and Integrin α2β1-Induced Thrombus Formation Modulated by the Collagen Type

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• A fibrinolytic snake venom metalloproteinase, mutalysin-II, with antiplatelet activity and targeting capability toward glycoprotein GPIbα and glycoprotein GPVI.

  2021cites this paper
• Interspecies differences in protein expression do not impact the spatiotemporal regulation of GPVI mediated activation

  2021cites this paper
• Temporal Roles of Platelet and Coagulation Pathways in Collagen- and Tissue Factor-Induced Thrombus Formation

  2021cites this paper
• Structural characterisation of a novel GPVI nanobody-complex reveals a biologically active domain-swapped GPVI dimer.

  2021cites this paper
• Glanzmann thrombasthenia complicated by frequent myeloproliferative neoplasm‐related thromboembolism: thrombosis occurring regardless of αIIbβIII integrin deficiency

  2021cites this paper
• Colchicine inhibits ROS generation in response to glycoprotein VI stimulation

  2021cites this paper
• Overcoming challenges in developing small molecule inhibitors for GPVI and CLEC-2

  2021cites this paper
• Immobilized collagen prevents shedding and induces sustained GPVI clustering and signaling in platelets

  2021cites this paper
• The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential

  2021cites this paper
• Cancer-associated-platelet-inspired nanomedicines for cancer therapy.

  2021cites this paper
• Novel antiplatelet strategies targeting GPVI, CLEC-2 and tyrosine kinases

  2020cites this paper
• The CEACAM1-derived peptide QLSN impairs collagen-induced human platelet activation through glycoprotein VI

  2020cites this paper
• Progress Towards a Glycoprotein VI Modulator for the Treatment of Thrombosis.

  2020cites this paper
• Immobilised collagen prevents shedding and induces sustained GPVI clustering and signalling in platelets

  2020cites this paper
• From Patients to Platelets and Back Again: Pharmacological Approaches to Glycoprotein VI, a Thrilling Antithrombotic Target with Minor Bleeding Risks

  2019cites this paper
• Epigenetic modulation of glycoprotein VI gene expression by DNA methylation.

  2019cites this paper
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  2019cites this paper
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  2018cites this paper
• Tyrosine Kinase Inhibitor Pazopanib Inhibits Platelet Procoagulant Activity in Renal Cell Carcinoma Patients

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• Proteolytic processing of platelet receptors

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• Novel aspects of antiplatelet therapy in cardiovascular disease

  2018cites this paper
• Acquired platelet antagonism: off‐target antiplatelet effects of malignancy treatment with tyrosine kinase inhibitors

  2018cites this paper
• Increased platelet reactivity as measured by plasma glycoprotein VI in gout

  2018cites this paper
• Platelet Signaling Pathways and New Inhibitors.

  2018cites this paper
• Clinical significance of receptor shedding-platelet GPVI as an emerging diagnostic and therapeutic tool

  2017cites this paper
• Basic mechanisms of platelet receptor shedding

  2017cites this paper
• Direct Fibrinolytic Snake Venom Metalloproteinases Affecting Hemostasis: Structural, Biochemical Features and Therapeutic Potential

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  2017cites this paper
• Plant-based Food Cyanidin-3-Glucoside Modulates Human Platelet Glycoprotein VI Signaling and Inhibits Platelet Activation and Thrombus Formation.

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• Platelet receptors as therapeutic targets: Past, present and future

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• Liver-mediated shedding of platelet GPVI

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• Tetraspanin Tspan9 regulates platelet collagen receptor GPVI lateral diffusion and activation

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• A novel fibrinolytic metalloproteinase, barnettlysin-I from Bothrops barnetti (Barnett´s pitviper) snake venom with anti-platelet properties.

  2016cites this paper
• Liver-mediated shedding of platelet GPVI.

  2016cites this paper
• Beyond antiplatelets: The role of glycoprotein VI in ischemic stroke

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• Platelet Hyperreactivity in Diabetes: Focus on GPVI Signaling—Are Useful Drugs Already Available?

  2016cites this paper
• A-Disintegrin-And-Metalloproteinase (ADAM) 10 Activity on Resting and Activated Platelets.

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• An atypical IgM class platelet cold agglutinin induces GPVI-dependent aggregation of human platelets

  2015cites this paper
• Current State and Novel Approaches of Antiplatelet Therapy

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