Head-to-Head Comparison of Consensus-Recommended Platelet Function Tests to Assess P2Y12 Inhibition—Insights for Multi-Center Trials

The vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation level is a highly specific method to assess P2Y12 receptor inhibition. Traditionally, VASP phosphorylation is analyzed by flow cytometry, which is laborious and restricted to specialized laboratories. Recently, a simple ELISA kit has been commercialized. The primary objective of this study was to compare the performance of VASP assessment by ELISA and flow cytometry in relation to functional platelet aggregation testing by Multiplate® whole-blood aggregometry. Blood from 24 healthy volunteers was incubated with increasing concentration of a P2Y12 receptor inhibitor (AR-C 66096). Platelet function testing was carried out simultaneously by Multiplate® aggregometry and by VASP assessment through ELISA and flow cytometry. As expected, increasing concentrations of the P2Y12 receptor inhibitor induced a proportional inhibition of platelet aggregation and P2Y12 receptor activation across the modalities. Platelet reactivity index values of both ELISA- and flow cytometry-based VASP assessment methods correlated strongly (r = 0.87, p < 0.0001) and showed minimal bias (1.05%). Correlation with Multiplate® was slightly higher for the flow cytometry-based VASP assay (r = 0.79, p < 0.0001) than for the ELISA-based assay (r = 0.69, p < 0.0001). Intraclass correlation (ICC) was moderate for all the assays tested (ICC between 0.62 and 0.84). However, categorization into low, optimal, or high platelet reactivity based on these assays was strongly concordant (κ between 0.86 and 0.92). In conclusion, the consensus-recommended assays with their standardized cut-offs should not be used interchangeably in multi-center clinical studies but, rather, they should be standardized throughout sites.

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A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry

Thrombosis and Haemostasis ◽

10.1160/th07-09-0555 ◽

2008 ◽

Vol 99 (01) ◽

pp. 215-222 ◽

Cited By ~ 58

Author(s):

Christopher D Payne ◽

Ying G Li ◽

Nagy A Farid ◽

John T Brandt ◽

David S Small ◽

...

Keyword(s):

Platelet Aggregation ◽

Light Transmission ◽

Platelet Reactivity ◽

Platelet Inhibition ◽

P2y12 Receptor ◽

Reactivity Index ◽

High Dose ◽

Receptor Blockade ◽

Vasp Phosphorylation ◽

Light Transmission Aggregometry

SummaryPlatelet inhibition as measured by vasodilator-stimulated phosphoprotein (VASP) and light transmission aggregometry (LTA) have shown concordance following dosing of clopidogrel. No reports have directly compared theVASP assay and LTA at the levels of P2Y12 blockade after loading doses (LDs) of prasugrel or high dose clopidogrel (600 and 900 mg).The aim was to compare theVASP assay and LTA during the loading dose phase of a comparative study of prasugrel and clopidogrel. Prasugrel 60 mg LD/10 mg maintenance dose (MD) and clopidogrel 300 mg/75 mg and 600 mg/75 mg LD/MD regimens were compared in a 3-way crossover study in 41 healthy, aspirin-free subjects. Each LD was followed by seven daily MDs and a 14-day washout period. P2Y12 receptor blockade was estimated using theVASP assay, expressed as platelet reactivity index (VASP-PRI). Platelet aggregation was assessed by light transmission aggregometry (20 and 5 μM ADP).Twenty-four hoursafter prasgurel 60 mg or clopidogrel 300 mg and 600 mg, respectively, VASP-PRI decreased from ∼80% to 8.9%, 54.7%, and 39.0 %, and maximal platelet aggregation (MPA) decreased from ∼79% to 10.8%, 42.7%, and 31.2%, with an overall VASP:MPA correlation of 0.88 (p<0.01). VASP assay responses after the clopidogrel LDs showed a wider range of values (300 mg: 0–93%; 600 mg: 0–80%) than prasugrel (0–13%); MPA responses followed a similar trend. Pearson’s correlation suggested a strong agreement between VASP and LTA (20 μM ADP) for MPA (r=0.86, p<0.0001).VASP and LTA demonstrated concordance across the response range of P2Y12 receptor blockade following thienopyridine LDs.

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Effects of Strong P2Y12 Receptor Inhibition by Prasugrel on Platelet Inhibition During Endotoxemia: A Randomized Controlled Trial

Blood ◽

10.1182/blood.v118.21.1245.1245 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1245-1245

Author(s):

Alexander O Spiel ◽

Ulla Derhaschnig ◽

Petra Jilma-Stohlawetz ◽

Bernd Jilma

Keyword(s):

Platelet Aggregation ◽

Conflicts Of Interest ◽

Platelet Reactivity ◽

Controlled Trial ◽

Platelet Inhibition ◽

P2y12 Receptor ◽

Reactivity Index ◽

Double Blind ◽

Plug Formation ◽

Induced Aggregation

Abstract Abstract 1245 Background: P2Y12 receptor antagonists have become a mainstay for the treatment of cardiovascular diseases. Yet, they have rarely been evaluated under pathophysiological conditions apart from arterial diseases. Objectives: We hypothesized interactions between prasugrel and enhanced von Willebrand Factor (VWF) release in a model of systemic inflammation, and compared the pharmacodynamic effects of prasugrel versus placebo on agonist-induced platelet aggregation and shear-induced platelet plug formation. Subjects/Methods: Twenty healthy male volunteers were enrolled in a double-blind, placebo-controlled two-way cross-over trial. Each volunteer received either placebo or a 60 mg-loading dose of prasugrel two hours before endotoxin infusion. Platelet inhibition was measured with Multiple Electrode Aggregometry (MEA), the Platelet Function Analyzer-100 (PFA-100) and the Vasodilator Stimulated Phosphoprotein (VASP) phosphorylation assay, respectively. Results: Prasugrel reduced the platelet reactivity index in the VASP assay from 79% to 5–7%, and unequivocally prolonged the closure times of the Innovance cartridge to >300s, but also the CADP-CT to >300s in the majority of subjects. Prasugrel not only blunted platelet aggregation induced by ADP (−81%), but also other pathways including arachidonic acid (−60%), ristocetin (−75%; p<0.001 for all), and to a lesser degree collagen or thrombin receptor activating peptide (TRAP). Prasugrel decreased shear-induced platelet plug formation but VWF release during endotoxemia partly antagonized the inhibitory effect of prasugrel as measured with the PFA-100. Endotoxemia acutely decreased ristocetin and TRAP induced platelet aggregation, and enhanced ristocetin induced aggregation after 24h. Conclusions: These data for the first time demonstrate that strong in vivo blockade of P2Y12 by prasugrel inhibits a broad spectrum of platelet aggregation pathways. However, VWF release may reduce prasugrel's effects under high shear conditions. Disclosures: No relevant conflicts of interest to declare.

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Cross validation of the Multiple Electrode Aggregometry

Thrombosis and Haemostasis ◽

10.1160/th08-10-0669 ◽

2009 ◽

Vol 102 (08) ◽

pp. 397-403 ◽

Cited By ~ 43

Author(s):

Jolanta Siller-Matula ◽

Ghazaleh Gouya ◽

Michael Wolzt ◽

Bernd Jilma

Keyword(s):

Platelet Aggregation ◽

Platelet Function ◽

Cross Validation ◽

Platelet Reactivity ◽

Adenosine Diphosphate ◽

Multiple Electrode Aggregometry ◽

Vasp Phosphorylation ◽

Function Analyzer ◽

Platelet Function Analyzer ◽

Multiple Electrode

SummarySeveral test systems exist for assessment of platelet function in patients under clopidogrel or aspirin therapy. The objective was to cross-validate the Multiple Electrode Aggregometry (MEA) with three other methods used for determining platelet reactivity under treatment with clopidogrel and aspirin. Platelet function was assessed by the MEA, Vasodilator Stimulated Phosphoprotein (VASP) phosphorylation assay, Platelet Function Analyzer-100 (PFA-100) and the Cone and Platelet Analyzer. Measurements were performed in blood from nine healthy volunteers at baseline, 2, 4, 6 and 72 hours after clopidogrel and aspirin loading. The apparent effect size for clopidogrel and aspirin was greatest for the MEA: treatment induced a 19-fold difference in the arachidonic acid-induced platelet aggregation and an 11-fold difference in the adenosine diphosphate-induced platelet aggregation before/after treatment. For comparison, aspirin and clopidogrel induced only 2.0– to 2.6 -fold changes in other tests (VASP assay, Cone and Platelet Analyzer and PFA-100). Maximal effects were seen 2 hours after aspirin loading and shorter than 72 hours after clopidogrel loading. In conclusion, aspirin and clopidogrel produce stronger signals in the MEA compared to several other methods.

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Comparison of a new ELISA assay with the flow cytometric assay for platelet vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation in whole blood to assess P2Y12 inhibition

Thrombosis and Haemostasis ◽

10.1160/th11-04-0282 ◽

2012 ◽

Vol 107 (02) ◽

pp. 388-395 ◽

Cited By ~ 16

Author(s):

Nicolas Bourguet ◽

Danièle Boulay-Moine ◽

Atsuhiro Sugidachi ◽

Shinji Yamaguchi ◽

Paul Barragan ◽

...

Keyword(s):

Clinical Studies ◽

Platelet Reactivity ◽

P2y12 Receptor ◽

Reactivity Index ◽

Blood Collection ◽

Variable Response ◽

Vasp Phosphorylation ◽

P2y12 Antagonists ◽

Wide Range

SummaryThienopyridines and other agents target the platelet P2Y12 receptor and inhibit several platelet activities mediated by adenosine diphosphate (ADP). The measurement of vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation, expressed as platelet reactivity index (PRI), mirrors the degree of P2Y12 receptor inhibition and can detect the well-known variable response to clopidogrel. The commercially available VASP assay uses flow cytometry (FC) and requires that the test be run within 48 hours of blood collection. A new ELISA VASP assay offers the advantages of using more widely available technology and the potential to freeze and store samples before analysis. The objectives of the present study were to compare the performance of the ELISA and FC methods and to describe the relative flexibility of the ELISA-based assay. Human blood samples encompassing a wide range of levels of P2Y12 blockade achieved in vitro by preincubation with P2Y12 antagonists or in vivo from patients treated with clopidogrel were included, reflecting the wide spread of values reported in clinical studies. The correlation between the PRI measured by ELISA and FC was highly significant (r=0.95, p<0.001), (n=80). After the initial activation, samples were stable for at least four weeks when frozen (−20°C) prior to analysis by ELISA. Frozen samples from patients treated with clopidogrel appeared stable for up to nine weeks. Based on these results, the ELISA-based assay appears to provide a reliable and more flexible alternative to the FC method to determine P2Y12 receptor blockade and may enable more extensive utilisation of the VASP assay in clinical studies.Note: All work done at BioCytex, Marseille, France and Daiichi Sankyo, Tokyo, Japan.

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ANTIPLATELET ADEQUACY OF CYCLOPENTYL TRIAZOLOPYRIMIDINE VERSUS CLOPIDOGREL IN-PATIENTS WITH CORONARY HEART DISEASE

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i12.29703 ◽

2018 ◽

Vol 11 (12) ◽

pp. 536

Author(s):

Feryal Hashim Rada

Keyword(s):

Platelet Aggregation ◽

Stable Angina ◽

Platelet Reactivity ◽

Stable Coronary Artery Disease ◽

Light Transmittance ◽

Reactivity Index ◽

Major Adverse Cardiovascular Events ◽

Vasp Phosphorylation ◽

Coronary Syndromes ◽

Artery Disease

Objective: Ticagrelor, cyclopentyl triazolopyrimidine drug, and Clopidogrel, second-generation thienopyridine drug are antiplatelet drugs indicated for the prevention of thrombotic events in patients with acute or chronic coronary syndromes. The aim of this study is to assess efficacy and safety outcomes of ticagrelor treatment versus Clopidogrel treatment in patients with stable coronary artery disease (stable angina) using maximal platelet aggregation percent (MPAP) method and platelet reactivity index percent (PRIP) method.Methods: A total of 42 patients (27 male and 15 female), their ages ranging (48±8) years with stable angina enrolled from Ibn Albitar Center for Cardiac Surgery for this crossover study. After satisfying, the properties of inclusion criteria they screened for clopidogrel treatment 75 mg daily for 2 weeks than after 2 weeks periods of wash off they treated with ticagrelor 90 mg twice daily for another 2 weeks. Platelet reactivity was tested at baseline (before treatment), after 2 weeks treatment with clopidogrel and after another 2 weeks treatment with ticagrelor. Platelet reactivity measured by light transmittance aggregometry test and by vasodilator-stimulated phosphoprotein (VASP) phosphorylation test.Results: The results of MPAP after 2 weeks treatment with clopidogrel or ticagrelor showed high significant reduction in platelet aggregation in patients with ticagrelor treatment as compared to clopidogrel treatment (30±6% vs. 44±8%). As well, the results of PRIP using VASP-phosphorylation after 2 weeks treatment with clopidogrel or ticagrelor showed high significant reduction in platelet aggregation in patients with ticagrelor treatment as compared to clopidogrel treatment (22±5% vs. 36±7%).Conclusion: Treatment with ticagrelor produced a reduction in platelet reactivity consistent with the reduction in major adverse cardiovascular events and improved survival without increasing major bleeding.

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Effects of Ticlopidine of Platelet Function in Men with Stable Angina Pectoris

Thrombosis and Haemostasis ◽

10.1055/s-0038-1660138 ◽

1985 ◽

Vol 54 (04) ◽

pp. 808-812 ◽

Cited By ~ 7

Author(s):

Ulf Berglund ◽

Henning von Schenck ◽

Lars Wallentin

Keyword(s):

Platelet Aggregation ◽

Angina Pectoris ◽

Platelet Function ◽

Plasma Levels ◽

Platelet Reactivity ◽

Inhibitory Effect ◽

Controlled Study ◽

Double Blind ◽

Platelet Factor

SummaryThe effects of ticlopidine (T) (500 mg daily) on platelet function were investigated in a double-blind placebo-controlled study in 38 middle-aged men with stable incapacitating angina pectoris. The in vitro platelet reactivity to aggregating agents, the platelet sensitivity to prostacyclin and the plasma levels of platelet specific proteins and fibrinogen were determined before and after 4 and 8 weeks of treatment. T exerted a potent inhibitory effect on ADP- and collagen-induced platelet aggregation. The effect of T was proportional to the pretreatment reactivity to ADP and collagen. The inhibitory effect of T on the epinephrine response was less pronounced. The plasma levels of beta-thromboglobulin, platelet factor 4 and fibrinogen were not influenced by T. The platelet inhibition of prostacyclin was potentiated by T, and it was demonstrated that T and prostacyclin had synergistic inhibitory effects on platelet aggregation.

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Association of Lipoprotein(a) levels with intrinsic and on-clopidogrel platelet reactivity

European Heart Journal ◽

10.1093/ehjci/ehaa946.1356 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

A Kille ◽

T Nuehrenberg ◽

C.M Valina ◽

F.J Neumann ◽

W Hochholzer

Keyword(s):

Flow Cytometry ◽

Platelet Function ◽

Platelet Reactivity ◽

Laboratory Data ◽

Secondary Analysis ◽

Structural Similarity ◽

Lipoprotein A ◽

Causal Risk Factor ◽

Premature Cardiovascular Disease ◽

Potential Association

Abstract Background Lipoprotein(a) [Lp(a)] is an independent, genetic, and causal risk factor for premature cardiovascular disease (CVD). Laboratory data have suggested an interaction of Lp(a) with platelet function, potentially caused by its structural similarity to plasminogen. So far, the potential association of Lp(a) with platelet activation and reactivity has not been well established in larger clinical cohorts. Methods This secondary analysis of the EXCELSIOR study analyzed intrinsic platelet reactivity before loading with clopidogrel 600mg and on-treatment platelet reactivity tested 24 hours following loading in patients undergoing elective coronary angiography. Platelet reactivity was tested by optical aggregometry as final aggregation after 5 min following stimulation with 5μM ADP. Platelet reactivity was also assessed by flow cytometry (expression of CD62P and PAC1) following stimulation with ADP and TRAP. Levels of Lp(a) on admission of each patient were immediately measured from fresh samples in a central laboratory. Results The present analysis included 2046 patients. Levels of Lp(a) ranged between 0 and 332 mg/dl. Results for intrinsic (p=0.80) and on-clopidogrel platelet reactivity (p=0.81) did not differ between quartiles of Lp(a) levels (Figure). Flow cytometry analyses confirmed these findings. Conclusion The present data do not support the hypothesis of an interaction of Lp(a) with platelet function. This finding might be important to define the safety of evolving therapeutic options for lowering Lp(a). Funding Acknowledgement Type of funding source: None

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Comparison of VASP-phosphorylation assay to light-transmission aggregometry in assessing inhibition of the platelet ADP P2Y12 receptor

Thrombosis and Haemostasis ◽

10.1160/th06-09-0491 ◽

2006 ◽

Vol 96 (12) ◽

pp. 767-773 ◽

Cited By ~ 29

Author(s):

Agnieszka Pampuch ◽

Giovanni de Gaetano ◽

Chiara Cerletti

Keyword(s):

Light Transmission ◽

Platelet Reactivity ◽

Flow Cytometric Analysis ◽

Individual Variability ◽

P2y12 Receptor ◽

Reactivity Index ◽

Drug Induced ◽

Light Transmission Aggregometry ◽

Adp Receptor

SummaryThere is need to improve platelet function testing to monitor the response to antiplatelet drugs. We compared flow-cytometric analysis of intraplatelet vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) to light-transmission aggregometry for the detection of drug-induced in-vitro inhibition of the platelet P2Y12 ADP receptor on 22 healthy subjects (10 males, 12 females, 28.5 ± 6.6 years). The platelet reactivity index (PRI) of VASP was calculated both from mean fluorescence intensity (MFI) and percent of fluorescence-positive platelets in the presence of PGE1 with or without ADP (10 µM). Platelet aggregation was induced by ADP (1.25, 2.5 and 5 µM). Cangrelor, a competitive inhibitor of the P2Y12 receptor, preincubated 5 minutes, induced a concentration-dependent inhibition of platelet ADP-receptor function in both tests. Indeed PRI (%) based on either MFI or percent platelets gated were highly correlated with each other (r = 0.97, p<0.0001) and with aggregation in- duced by ADP. The IC50 of cangrelor against each of the three ADP concentrations used in aggregometry increased from 5.8 ± 3.4 nM to 23.1 ± 4.0 nM and to 98 ± 25 nM, respectively. The IC50 of cangrelor based on VASP-P was within the same range (25.5 ± 7.7 nM). No correlation was observed between IC50 values of cangrelor and ADP concentrations giving 50% effect (EC50) in the absence of the drug. However, at 10 nM cangrelor seven subjects could be identified by the VASP-P assay as “low responders” to the drug (PRI> 50%), and six of them also had an aggregation response to 5 µM ADP > 50%. These six subjects showed the lowest ADP EC50 values in the absence of the drug, possibly reflecting high sensitivity of their platelet P2Y12 receptors to ADP. In conclusion, both the VASP-P assay and light-transmission aggregometry detect in a comparable way in-vitro pharmacological inhibition of the platelet P2Y12 ADP receptor and its individual variability.

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Role of VASP Phosphorylation Assay in Monitoring the Antiplatelet Therapy

Acta Medica Martiniana ◽

10.2478/acm-2013-0008 ◽

2013 ◽

Vol 13 (1) ◽

pp. 21-26 ◽

Cited By ~ 2

Author(s):

Marian Fedor ◽

R. Simonova ◽

J. Fedorova ◽

I. Skornova ◽

L. Duraj ◽

...

Keyword(s):

Myocardial Infarction ◽

Stent Thrombosis ◽

Cardiac Death ◽

P2y12 Receptor ◽

Response To Treatment ◽

Reactivity Index ◽

Inadequate Response ◽

Vasp Phosphorylation ◽

Platelet Receptor ◽

Increased Risk

Abstract Dual antiplatelet treatment with clopidogrel and aspirin represents standard regimen in prevention of thromboembolic events in patients with ischemic heart disease undergoing percutaneous coronary intervention (PCI). One of the greatest pitfalls of clopidogrel treatment is large inter-individual variability in response. Large amount of patients does not respond adequately and therefore are not „protected“ even in spite of receiving the therapy. Poor responders are exposed to three-fold increased risk of myocardial infarction, stent thrombosis and cardiac death. Clopidogrel is an antiplatelet prodrug, whose active metabolite inhibits platelet function by irreversible binding to the (adenosine diphosphate) platelet receptor P2Y12. Receptor P2Y12 plays primal role in ADP-mediated platelet activation, and also in mechanism of action of ADP inhibitors such as clopidogrel, prasugrel etc. Reasons stated above, raised the necessity for implementing reliable laboratory test in order to identify the unprotected patients. In an ideal scenario, such test would serve to adjust the dose and guide the individual tailored treatment. Vasodilator Stimulated Phosphoprotein (VASP) is an intracellular platelet protein which is non phosphorylated at basal state. Since its relation in cascade with P2Y12 receptor, VASP phosphorylation corerlates with inhibition of P2Y12 which is the receptor of prime importance in ADP mediated activation of platelets and as is primary target of ADP inhibitors action. Outcome of the assay is represented as the value of platelet reactivity index (PRI), where PRI values above 50% are considered inadequate response to treatment and signal exposure to increased risk of myocardial infarction, post-PCI stent thrombosis and cardiac death. VASP-P flow cytometric assay is emerging into the spotlight as the promising method, mostly for its specificity for ADP inhibitors, better outlook for standardising results and lesser sample manipulation compared to multiple electrode aggregometry.

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ADP-Mediated Upregulation of Expression of CD62P on Human Platelets Is Critically Dependent on Co-Activation of P2Y1 and P2Y12 Receptors

Pharmaceuticals ◽

10.3390/ph13120420 ◽

2020 ◽

Vol 13 (12) ◽

pp. 420

Author(s):

Ronald Anderson ◽

Annette J. Theron ◽

Helen C. Steel ◽

Jan G. Nel ◽

Gregory R. Tintinger

Keyword(s):

Flow Cytometry ◽

Platelet Rich Plasma ◽

Receptor Activation ◽

Human Platelets ◽

P2y12 Receptor ◽

Phosphatidylinositol 3 Kinase ◽

Pi3k Activity ◽

Potent Inhibition ◽

Co Activation ◽

Adult Humans

This study probed the differential utilization of P2Y1 and P2Y12 receptors in mobilizing CD62P (P-selectin) from intracellular granules following activation of human platelets with adenosine 5′-diphosphate (ADP, 100 µmol·L−1) Platelet-rich plasma (PRP) was prepared from the blood of adult humans. CD62P was measured by flow cytometry following activation of PRP with ADP in the absence and presence of the selective antagonists of P2Y1 and P2Y12 receptors, MRS2500 and PSB0739 (both 0.155–10 µmol·L−1), respectively. Effects of the test agents on ADP-activated, CD62P-dependent formation of neutrophil:platelet (NP) aggregates were also measured by flow cytometry, while phosphatidylinositol 3-kinase (PI3K) activity was measured according to Akt1 phosphorylation in platelet lysates. Treatment with MRS2500 or PSB0739 at 10 µmol·L−1 almost completely attenuated (94.6% and 86% inhibition, respectively) ADP-activated expression of CD62P and also inhibited NP aggregate formation. To probe the mechanisms involved in P2Y1/P2Y12 receptor-mediated expression of CD62P, PRP was pre-treated with U73122 (phospholipase C (PLC) inhibitor), 2-aminoethoxy-diphenyl borate (2-APB, inositol triphosphate receptor antagonist), calmidazolium chloride (calmodulin inhibitor), or wortmannin (PI3K inhibitor). U73122, 2-APB, and wortmannin caused almost complete inhibition of ADP-activated expression of CD62P, while calmidazolium chloride caused statistically significant, partial inhibition. PSB0739, but not MRS2500, caused potent inhibition of PI3K-mediated phosphorylation of Akt1. Optimal mobilization of CD62P by ADP-stimulated platelets is critically dependent on the co-activation of platelet P2Y1 and P2Y12 receptors. P2Y12 receptor activation is the key event in activation of PI3K, while activation of the P2Y1 receptor appears to create a high cytosolic Ca2+ environment conducive to optimum PI3K activity.

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