Agonists-induced platelet activation varies considerably in healthy male individuals: studies by flow cytometry

Abstract

Flow cytometric evaluation of platelet function extends our understanding of platelets' role in various clinical conditions associated with either bleeding disorders, thrombosis, or monitoring of antiplatelet therapy. The use of suboptimal concentrations of various agonists may allow assessing the "activatability" of platelets. We determined platelet responsiveness to thrombin-receptor-activating peptide-6, arachidonic acid, adenosine 5c-diphosphate (ADP), epinephrine, collagen, and ristocetin at suboptimal concentrations by determination of P-selectin expression and binding of PAC-1 in 26 healthy male individuals. The response varied considerably from one individual to the next. However, within individuals, responses to all agonists except collagen correlated strongly (p<0.05), suggesting a global variability of platelet responses. Moreover, P-selectin expression and PAC-1 binding were strongly correlated (p<0.05). Interestingly, with epinephrine, PAC-1 positive events outnumbered P-selectin positive events, while this was not seen with the other agonists. Thus, epinephrine may specifically affect the conformational switch mechanism and receptor clustering. Our data indicate that the in vitro response to suboptimal concentrations of agonists varies, but individuals with selective platelet defects may still be identified based on data obtained with the various agonists.

Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function

“…Platelet response, volume, and count are independent risk factors for MI, particularly in the immediate postevent period, supported by compelling evidence of increased morbidity and mortality in patients undergoing percutaneous intervention with hyperactive platelets, despite antiplatelet therapy. 32 The response of platelets to activatory signals from agonists, such as collagen and ADP, ranges widely, [1][2][3]33 and this variation is, to a large extent, inherited. 3 Until recently, the number of robustly validated genetic variants affecting the platelet functional phenotype has remained small, but in the era of large-scale "-omics" strategies, novel genes and variants are emerging.…”

“…These cells are also intimately involved in the pathological processes associated with atherothrombotic diseases, in particular, the thrombotic response to plaque rupture seen in myocardial infarction (MI). The platelet response to agonist stimulation shows a wide interindividual variation 1,2 that is reproducible over time 1 and shows substantial heritability, 3 suggesting regulation through genetic variation.…”

The genetics of normal platelet reactivity

“…[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.…”

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.…”