Principal Role of Glycoprotein VI in 2 1 and IIb 3 Activation During Collagen-Induced Thrombus Formation

Department of Biochemistry, Maastricht University, Maestricht, Limburg, Netherlands
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 10/2004; 24(9):1727-33. DOI: 10.1161/01.ATV.0000137974.85068.93
Source: PubMed


High-shear perfusion of blood over collagen results in rapid platelet adhesion, aggregation, and procoagulant activity. We studied regulation of alpha2beta1 and alphaIIbbeta3 integrin activation during thrombus formation on collagen.
Blockade of glycoprotein (GP) VI by 9O12 antibody or of P2Y purinergic receptors permitted platelet adhesion but reduced aggregate formation, fibrinogen binding, and activation of alpha2beta1 and alphaIIbbeta3, as detected with antibodies IAC-1 and PAC1 directed against activation-dependent epitopes of these integrins. Combined blockade of GPVI and P2Y receptors and thromboxane formation abolished integrin activation but still allowed adhesion of morphologically unstimulated, nonprocoagulant platelets. Exogenous ADP partly restored the suppressive effect of GPVI blockade on integrin alpha2beta1 and alphaIIbbeta3 activation. Adhesion was fully inhibited only with simultaneous blocking of GPVI and alpha2beta1, indicating that the integrin can support platelet-collagen binding in the absence of its activation. Blockade or absence of GPIbalpha only moderately influenced integrin activation and adhesion unless GPVI was inhibited.
GPVI- and autocrine-released ADP induce affinity changes of alpha2beta1 and alphaIIbbeta3 during thrombus formation on collagen under flow. These integrin changes are dispensable for adhesion but strengthen platelet-collagen interactions and thereby collagen-induced platelet activation. Integrin activation during thrombus formation on collagen was studied using fluorescent-labeled antibodies IAC-1 and PAC1 directed against activation-dependent epitopes of alpha2beta1 and alphaIIbbeta3 integrin, respectively. Glycoprotein VI blockade by 9O12 antibody or P2Y ADP receptors reduced integrin activation along with aggregate formation and fibrinogen binding but not alpha2beta1-dependent adhesion.

Download full-text


Available from: Martine Jandrot-Perrus, Sep 08, 2015
  • Source
    • "The -granules contain autocrine acting proteins (Gas6) together with a reservoir of receptor proteins (Gas6 receptors, P-selectin) that support the autocrine responses [17]. The autocrine mediators are of key importance for the establishment of rapid platelet-platelet interactions in plug formation (hemostasis) as well as arterial thrombus formation (thrombosis) [7] [9]. The -granules are also packed with many other proteins with a variety of functions, including coagulation factors, adhesive proteins as well as growth factors, cytokines, chemokines and proteases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Atherosclerosis with ensuing atherothrombosis is an inflammatory disease of the large arteries with high mortality and morbidity. Interactions between blood cells and the arterial vessel wall are considered to determine the progression of atherosclerotic plaques and the thrombotic complications. There is increasing evidence for important roles of activated platelets and platelet-derived microparticles in this disease process by contact with leukocytes, endothelial cells and smooth muscle cells. This paper gives an overview of newly described interactions of platelets and microparticles with other cells of the cardiovascular system via direct contact or via mediator release. The possible significance of these interactions is discussed within the context of vascular inflammation.
    Full-text · Article · Nov 2010
  • [Show abstract] [Hide abstract]
    ABSTRACT: This paper is confined to the use of human musculoskeletal tissue in the treatment of patients. Its focus is on the safety and quality dimension of human tissue transplantation, including the ethical and legal aspects, the regulations and standards from the European perspective, quality assurance and quality management in tissue banking and as a special subject, tissue sterilisation and the validation of sterilisation methods.
    No preview · Article · Feb 1999 · Annales chirurgiae et gynaecologiae
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The occurrence of a thrombocytopathy concomitantly to the development of a malignant haemopathy has been reported for some time, but little is known about the mechanism(s) involved in the platelet dysfunction. Platelet glycoprotein VI (GPVI) has now been identified as a principal platelet receptor for collagen. In this paper, we report the cases of two patients with a myelodysplasia and a B lymphopathy, respectively, who presented with thrombocytopathy in relation to a defective GPVI-mediated platelet reactivity to collagen. Thus, with regard to the different steps of adhesion, activation secretion or aggregation, patients' platelet responses to collagen and to the GPVI specific agonists, collagen related peptide (CRP) or convulxin were null or dramatically impaired. Platelet responses to other agonists ADP, TRAP, Arachidonic acid were normal or showed only a moderate decrease. GPVI content was repeatedly normal, and binding of specific ligands, such as convulxin, satisfactory. Nevertheless, specific activating monoclonal antibodies and convulxin failed to induce platelet secretion; collagen, CRP or convulxin were unable to provoke calcium mobilisation. Furthermore, using a perfusion chamber model, we showed that ex vivo collagen-induced thrombi formation was very impaired. Taken together, these data provide evidence, for the first time, of an acquired defect in GPVI-mediated platelet reactivity to collagen, which reflects data observed in constitutional GPVI deficiencies, in two patients with malignant haemopathies.
    Full-text · Article · Feb 2005 · Thrombosis and Haemostasis
Show more