Platelet glycoprotein VI‐related clinical defects

Abstract

SummaryHuman patients with defects associated with the platelet collagen receptor, glycoprotein (GP)VI, are rare and usually described as having a mild bleeding disorder. However, here we review clinical profiles of patients with familial or acquired GPVI defects, revealing the bleeding defect is often severe and associated with immune dysfunction. GPVI is a member of the immunoreceptor family, and co-expressed on platelets with Fc receptor c-chain (FcRc). Ligand binding to GPVI leads to activation of platelet integrins, in particular a IIb b 3 that mediates platelet aggregation; and activation of endogenous platelet metalloproteinases resulting in ectodomain shedding and release of a soluble GPVI fragment. Increasing evidence supports the functional importance of GPVI/FcRc in thrombus formation at arterial shear rates, and expression levels of platelet GPVI may be a marker of thrombotic risk. Over the past 20 years, patients have been reported with GPVI-related defects involving: (i) an acquired deficiency, resulting from (a) anti-GPVI autoantibodies or (b) other causes; or (ii) a congenital deficiency, where (c) GPVI is not expressed or (d) is expressed in a dysfunctional form with defective signalling to a IIb b 3 . Clinical consequences of GPVI-related defects may be uniquely informative about the role of platelet GPVI in health and disease.

Sandwich Immunoassay for Soluble Glycoprotein VI in Patients with Symptomatic Coronary Artery Disease

“…However, as Arthur et al (31 ) have critically observed, although the study by Ollikainen et al (30 ) found that C-allele carriers were associated with coronary thrombosis, there has been no differentiation between homozygotes and heterozygotes, and only 1.4% presented a homozygote genotype (30,31 ). Therefore, the relevance and frequency of innate issues of GPVI remain low.…”

“…Although we performed an adjustment for possible confounders, a limitation of this study is that patients had not been examined for genetic polymorphisms and GPVI-related clinical defects (30,31 ). However, as Arthur et al (31 ) have critically observed, although the study by Ollikainen et al (30 ) found that C-allele carriers were associated with coronary thrombosis, there has been no differentiation between homozygotes and heterozygotes, and only 1.4% presented a homozygote genotype (30,31 ).…”

Inhibitors of Platelet Adhesion

“…36 Ligands for the GP VI receptor include collagen, collagen-related peptide, and convulxin, a protein found in tropical rattlesnake venom, with collagen being the most relevant ligand for platelet adhesion in vivo. 37 The functional role of the GP VI receptor in platelet aggregation takes place in the early stages of platelet adhesion, and much like the GP Ib/V/IX receptor complex, it is instrumental in facilitating platelet adhesion at sites of endothelial injury. 5 An element of redundancy in platelet adhesion receptors may offer an attractive construct for attenuating or tempering thrombosis while maintaining hemostatic capacity.…”

Platelet receptors and signaling in the dynamics of thrombus formation

“…37 Thus, it is widely recognized that α2β1 and GP VI act synergistically for optimal platelet adhesion and activation by collagen, and that their relative contribution to the dynamics of thrombus formation depends on the nature of the vascular lesion, flow conditions, and other still unknown factors. Even though deficiency of α2β1 and GP VI in humans does not seem to be associated with major hemostatic defects, 30,38 targeting α2β1, and the collagen itself, is being considered as a potential antithrombotic strategy. …”