Abstract:
:Shear-induced platelet aggregation (SIPA) involves the sequential interaction of von Willebrand factor (VWF) with both glycoprotein Ib (GPIb) and alphaIIbbeta3 receptors. Type 2B recombinant VWF (2B-rVWF), characterized by an increased affinity for GPIb, induces strong SIPA at a high shear rate (4000 s-1). Despite the increased affinity of 2B-rVWF for GPIb, patients with type 2B von Willebrand disease have a paradoxical bleeding disorder, which is not well understood. The purpose of this study was to determine if SIPA induced by 2B-rVWF was associated with alphaIIbbeta3-dependent platelet activation. To this end, we have addressed the influence of 2B-rVWF (Val553Met substitution) on SIPA-dependent variations of tyrosine protein phosphorylation (P-Tyr) and the effect of alphaIIbbeta3 blockers. At a high shear rate, 2B-rVWF induced a strong SIPA, as shown by a 92.7% +/- 0.4% disappearance of single platelets (DSP) after 4.5 minutes. In these conditions, increased P-Tyr of proteins migrating at positions 64 kd, 72 kd, and 125 kd were observed. The band at 125 kd was identified as pp125FAK using anti-phospho-FAK antibody. This effect, which required a high level of SIPA (> 70% DSP), was observed at 4000 s-1 but not at 200 s-1. Monoclonal antibodies (MoAbs) 6D1 (anti-GPIb) and 328 (anti-VWF A1 domain), completely abolished SIPA and p125FAK phosphorylation mediated by 2B-rVWF. In contrast, neither RGDS peptide nor MoAb 7E3, both known to block alphaIIbbeta3 engagement, had any effect on SIPA and pp125FAK. The size of aggregates formed at a high shear rate in the presence of 2B-rVWF was decreased by genistein, demonstrating the biologic relevance of pp125FAK. These findings provide a unique mechanism whereby the enhanced interaction of 2B-rVWF with GPIb, without engagement of alphaIIbbeta3, is sufficient to induce SIPA but does not lead to stable thrombus formation.
journal_name
Bloodjournal_title
Bloodauthors
Mekrache M,Bachelot-Loza C,Ajzenberg N,Saci A,Legendre P,Baruch Ddoi
10.1182/blood-2002-06-1879subject
Has Abstractpub_date
2003-06-01 00:00:00pages
4363-71issue
11eissn
0006-4971issn
1528-0020pii
2002-06-1879journal_volume
101pub_type
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