Protease activated receptor-1 (PAR-1) mediated platelet aggregation is dependant on clopidogrel response

Kreutz, Rolf P.; Breall, Jeffrey A.; Kreutz, Yvonne; Owens, Janelle; Lu, Dongsi; Bolad, Islam; Lohe, Elisabeth von der; Sinha, Anjan; Flockhart, David A.

doi:10.1016/j.thromres.2012.02.049

Cited by 15 publications

(16 citation statements)

References 32 publications

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“…If true, our results provide further insights into the molecular mechanisms of platelet signaling, and activation and targeting AHR may provide additional therapeutic options for patients with bleeding disorders. Our results also potentially explain recent findings indicating patient responses to clopidogrel are predictive to determining the ability of their platelets to aggregate in response to PAR‐1 . The correlation of clopridigrel response to platelet aggregation was initially viewed as a metabolic effect involving cytochrome P450 complex but could also result from the ability of AHR to activate target genes, as cytochrome P450 is a very well established AHR target .…”

Section: Discussionsupporting

confidence: 76%

Platelets from mice lacking the aryl hydrocarbon receptor exhibit defective collagen‐dependent signaling

Lindsey

Jiang

Woulfe

et al. 2014

Journal of Thrombosis and Haemostasis

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Background We previously identified AHR as a novel regulator of megakaryocytic differentiation and polyploidization and reported that AHR-null mice have ~15% fewer platelets than WT mice, yet exhibit a dramatic, unexplained bleeding phenotype. Objectives The current work tests our hypothesis that AHR-null platelets are functionally deficient, contributing to the previously reported (yet unexplained) bleeding phenotype present in AHR-null mice. Patients/Methods AHR-null bone marrow (BM) was ex vivo differentiated with thrombopoietin (TPO) with or without AHR ligands or AHR inhibitors and analyzed for degree of megakaryopoiesis and polyploidization. Platelet function of AHR-null mice was assessed by aggregation and spreading assays. Platelet signaling was examined by Western analysis and Rac activity assays. Results AHR ligands differentiate murine BM-derived progenitors into polyploid megakaryocytes in the absence of TPO and AHR inhibitors block TPO-induced megakaryocytic differentiation. Despite their responsiveness toward thrombin, AHR-null plate-lets demonstrate decreased aggregation and spreading in response to collagen compared to WT platelets. AHR-null platelets bind fibrinogen after stimulation with thrombin or AYPGFK and aggregate in response to AYP and ADP. Mechanistically, AHR absence led to down-regulation of Vav1 and Vav3, altered PLC-gamma2 phosphorylation, decreased Rac1 activation, and reduced platelet activation in response to collagen. Conclusions These results are consistent with a role for AHR in platelet function, especially as it relates to platelet aggregation and spreading in response to collagen. Our work suggests AHR is a critical component of the physiologic response platelets undergo in response to collagen and may provide novel treatment options for patients with bleeding disorders.

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Section: Discussionsupporting

confidence: 76%

Platelets from mice lacking the aryl hydrocarbon receptor exhibit defective collagen‐dependent signaling

Lindsey

Jiang

Woulfe

et al. 2014

Journal of Thrombosis and Haemostasis

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“…Within this donor population, T2MR again detected partial inhibition of the ADP signal with MeSAMP alone but complete inhibition with MeSAMP and MRS2779 combined Figure 5B . In addition, the PAR-1 inhibitor vorapaxar produced partial cross-inhibition with AA, ADP, and epinephrine as agonists, consistent with studies demonstrating crosstalk between the PAR-1 and P2Y12 ADP receptors, 13 , 14 as well as PAR-1 and the α2A-adrenergic pathway 15 . These data suggest that T2MR measurements may help to identify the activity of various components in the intracellular signaling pathways involved in platelet activation in healthy and dysfunctional platelets.…”

Section: Resultssupporting

confidence: 80%

Rapid Evaluation of Platelet Function With T2 Magnetic Resonance

Cuker¹,

Husseinzadeh²,

Lebedeva³

et al. 2016

Am J Clin Pathol

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Objectives: The clinical diagnosis of qualitative platelet disorders (QPDs) based on light transmission aggregometry (LTA) requires significant blood volume, time, and expertise, all of which can be barriers to utilization in some populations and settings. Our objective was to develop a more rapid assay of platelet function by measuring platelet-mediated clot contraction in small volumes (35 µL) of whole blood using T2 magnetic resonance (T2MR).Methods: We established normal ranges for platelet-mediated clot contraction using T2MR, used these ranges to study patients with known platelet dysfunction, and then evaluated agreement between T2MR and LTA with arachidonic acid, adenosine diphosphate, epinephrine, and thrombin receptor activator peptide.Results: Blood from 21 healthy donors was studied. T2MR showed 100% agreement with LTA with each of the four agonists and their cognate inhibitors tested. T2MR successfully detected abnormalities in each of seven patients with known QPDs, with the exception of one patient with a novel mutation leading to Hermansky-Pudlak syndrome. T2MR appeared to detect platelet function at similar or lower platelet counts than LTA.Conclusions: T2MR may provide a clinically useful approach to diagnose QPDs using small volumes of whole blood, while also providing new insight into platelet biology not evident using plasma-based platelet aggregation tests.

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“…This may explain why this study's results regarding COL-Agg max mirrored those obtained with AA. There is a correlation between the degree of P2Y 12 inhibition and low dose TRAP-induced platelet aggregation [21] that may thus explain the results regarding TRAP-Agg max mirroring those obtained with ADP-Agg max .…”

Section: Discussionmentioning

confidence: 70%

Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An ex vivo study

et al. 2015

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Managing bleeding in patients receiving P2Y12 inhibitors is challenging. Few data are available regarding the efficacy of platelet transfusion in patients treated with prasugrel or ticagrelor. The aim of this study was to evaluate the minimal amount of platelet supplementation (in terms of ratio of non-inhibited platelets to inhibited platelets) necessary to restore platelet reactivity in platelet-rich plasma (PRP) of patients treated with aspirin and a prasugrel or ticagrelor loading dose for an acute coronary syndrome. PRP samples from patients were mixed ex vivo with increasing proportions of pooled PRP from healthy volunteers. Platelet reactivity was challenged with adenosine diphosphate (ADP), arachidonic acid, collagen or thrombin receptor activating peptide using light transmission aggregometry. The primary endpoint was the proportion of patient samples recovering an ADP-induced maximal aggregation (ADP-Aggmax) value above 40%. In patients treated with prasugrel (n = 32), ADP-Aggmax increased progressively with supplements of pooled PRP, with an average increase of 7.9% (95% CI [7.1; 8.8], p < 0.001) per each 20% increase in the ratio of non-inhibited platelets to inhibited platelets. A ratio of 60% was associated with 90% of patients reaching the primary endpoint. In patients treated with ticagrelor (n = 15), ADP-Aggmax did not significantly increase with any level of supplements. In conclusions, ex vivo addition of non-inhibited platelets significantly improved ADP-Aggmax in patients treated with prasugrel with a dose-dependent effect. There was no evidence of such a reversal in patients treated with ticagrelor. These results suggest that platelet transfusion may be more effective in blunting bleeding in patients treated with prasugrel, than those treated with ticagrelor.

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Protease activated receptor-1 (PAR-1) mediated platelet aggregation is dependant on clopidogrel response

Cited by 15 publications

References 32 publications

Platelets from mice lacking the aryl hydrocarbon receptor exhibit defective collagen‐dependent signaling

Platelets from mice lacking the aryl hydrocarbon receptor exhibit defective collagen‐dependent signaling

Rapid Evaluation of Platelet Function With T2 Magnetic Resonance

Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An ex vivo study

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