Platelet hyperreactivity generalizes to multiple forms of stimulation

Abstract

Summary. Background: Although platelet hyperreactivity constitutes an important cardiovascular risk factor, standardized methods for its measurement are lacking. We recently reported that aggregometry using a submaximal concentration of epinephrine identifies individuals with in vitro platelet hyperreactivity; this hyperreactivity was reproducible on multiple occasions over long periods of time. Objective and methods: To better understand this aberrant reactivity, we studied in a large group of subjects (n ¼ 386) the relationship between healthy individualsÕ platelet reactivity to epinephrine and their platelet phenotype as measured by other functional assays. Results: Subjects with hyperreactivity to epinephrine were more likely to exhibit hyperfunction in each major aspect of platelet activity, including adhesion (response to low-dose ristocetin; P < 0.001), activation (surface P-selectin expression and PAC-1 binding after stimulation; P £ 0.003) and aggregation to other agonists [no agonist, adenosine diphosphate (ADP), arachidonic acid, collagen, collagen-related peptide and ristocetin; P £ 0.025] and to applied shear stress (PFA-100 and cone-and-plate viscometer; P < 0.05). These differences persisted after adjusting for demographic and hematologic differences between groups. We studied candidate genes relevant to epinephrine-mediated platelet activation and found that hyperreactivity to epinephrine was associated with a polymorphism on the gene (GNB3) encoding the beta-3 subunit of G proteins (P ¼ 0.03). Conclusions: Robust aggregation to a submaximal concentration of epinephrine establishes a true hyperreactive platelet phenotype that is ÔglobalÕ as opposed to agonist specific; detection of this phenotype could be useful for studying patients at risk for arterial thrombosis. The mechanisms underlying hyperreactivity to different types of platelet stimulation may share common signaling pathways, some of which may involve specific G protein subunits.

A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways

“…[2][3][4][5][6][7][8] Interestingly the level of responsiveness within an individual is remarkably consistent over time, regardless of agonist, or function outcome measure. [2][3][4][8][9][10] This, coupled with evidence from studies in siblings, 11 twins, 12 and in families with a history of premature coronary artery disease (CAD), 13 suggests a high level of heritability of platelet response.…”

The genetics of normal platelet reactivity

“…The 1780AA genotype was associated with a shorter CT (ie, platelet hyperreactivity). Even though the SNP designations are different in Yabe et el 29 and Yee et al, 6 it is probable that these represent the same SNPs because the flanking sequence of the major allele in each case (TTTAAA) represents a DraI restriction site. According to the current dbSNP database (Build 131), this polymorphism is located at chr10:112,839,580 but has not been named.…”

“…Several assays have been selected that fulfill these criteria, including light transmission aggregometry (LTA), 6 the Platelet Function Analyzer-100 (PFA-100; Siemens Diagnostics), 44 and the measurement of platelet activation events by flow cytometry, 2 but each is used in association studies under carefully considered conditions that may not be identical to those used in the routine clinical laboratory.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12] At the same time, these and other studies of siblings, twins, and families with a history of coronary artery disease (CAD) have documented that intraindividual responsiveness is highly reproducible over time, regardless of the agonist tested or the chosen method of assessment. These findings strongly suggest that there is a high level of heritability of platelet function, and this has prompted numerous attempts to define the genetic basis for platelet function variability.…”

Platelet-Mediated Thrombosis

“…Based on the considerable interindividual and intraindividual variation in response to various agonists in a healthy population, it was hypothesized that subjects with maximal aggregation induced by low agonist concentrations may exhibit hyperreactive platelet phenotype that is associated with an increased risk for thrombotic complications. 17,18 Faraday et al demonstrated that heritable factors indirectly related to COX-1 contribute prominently to variability in residual platelet function after aspirin therapy in 1880 asymptomatic subjects from families with premature coronary heart disease. They showed that the same factors that contribute to the variability in indirect COX-1 pathways (described later) during aspirin therapy also contribute to the variability before aspirin therapy.…”