scholarly journals Does the VerifyNow P2Y12 assay overestimate “therapeutic response” to clopidogrel?

2014 ◽  
Vol 111 (06) ◽  
pp. 1150-1159 ◽  
Author(s):  
Vikram Khanna ◽  
Alex Hobson ◽  
Rand Mikael ◽  
Nalyaka Sambu ◽  
Nicola Englyst ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Healthy Volunteers ◽  
Prostaglandin E1 ◽  
Therapeutic Response ◽  
Platelet Reactivity ◽  
Adenosine Diphosphate ◽  
Therapeutic Effects ◽  
P2y12 Inhibitors ◽  
High Platelet Reactivity

SummaryIn contrast to short thrombelastography (s-TEG) which utilises adenosine diphosphate (ADP) alone, the VerifyNow P2Y12 assay (VN-P2Y12) additionally uses prostaglandin E1 (PGE1) as agonist to assess response to P2Y12 inhibitors. Based upon previous observations, we hypothesised that VN-P2Y12 overestimates the therapeutic effects of clopidogrel. Simultaneous assay with s-TEG and VN-P2Y12 was performed in 43 healthy volunteers and 170 patients either on or off clopidogrel. Furthermore, in 27 patients on clopidogrel 75 mg we compared the effects of adding 22 nM PGE1 to ADP on platelet aggregation in s-TEG to ADP alone. A higher proportion of individuals had a result indicating high platelet reactivity (HPR) with s-TEG than VN-P2Y12 in (i) 43 clopidogrel naïve volunteers (95.3% vs 81.4%, p = NS); (ii) 28 volunteers loaded with clopidogrel 600 mg (39.3% vs 10.7 %, p = < 0.01); (iii) 123 clopidogrel naïve patients (93.5% vs 78%, p = < 0.0001); (iv) 47 patients on clopidogrel 75 mg (42.6% vs 4.3%, p = < 0.0001). In 59 patients loaded with clopidogrel 600 mg/900 mg, a greater proportion had a “therapeutic response” with VN-P2Y12 compared to s-TEG, regardless of the threshold for defining HPR with VN-PY12 (P2Y12 reaction units ≥ 230 or 208). Furthermore, adding PGE1 to ADP in s-TEG potentiated the anti-aggregatory effects of clopidogrel compared with ADP alone. In conclusion, VN-P2Y12 overestimates the functional effects of clopidogrel in some individuals, possibly because it utilises PGE1 in addition to ADP. This could have implications for the ability of VN-P2Y12 to stratify patients as “responders” or “non-responders” to clopidogrel.

Platelet aggregation in response to ADP is highly variable in normal donors and patients on anti-platelet medication

2016 ◽  
Vol 54 (7) ◽  
Author(s):  
Eimear Dunne ◽  
Karl Egan ◽  
Siobhán McFadden ◽  
David Foley ◽  
Dermot Kenny
Keyword(s):  
Platelet Aggregation ◽  
Therapeutic Response ◽  
Light Transmission ◽  
Platelet Reactivity ◽  
Coronary Intervention ◽  
P2y12 Inhibitors ◽  
Aggregation Response ◽  
Healthy Donors ◽  
Percutaneous Coronary ◽  
Light Transmission Aggregometry

AbstractP2Y12 inhibitors are indicated in patients following percutaneous coronary intervention. Several studies have demonstrated that high on treatment platelet reactivity is correlated with outcomes yet prospective studies of guided therapy have failed to show benefit. There is a paucity of studies on the platelet aggregation response to ADP before P2Y12 therapy is started. The aim of this study was to characterize platelet responses to 20 μM ADP by light transmission aggregometry (LTA) in a homogenous population.Platelet aggregation was assessed in 201 patients on dual antiplatelet therapy, 98 patients on aspirin alone and 47 normal, healthy volunteers free from anti-platelet medication.Consensus guidelines suggest that a platelet aggregation response in response to the agonist ADP of <57% is an adequate therapeutic response to P2Y12 inhibition. Seven healthy donors and 38 patients taking aspirin only had aggregation responses below 57%.The results of our study demonstrate that 15% of normal donors and 38% of patients taking aspirin only would be classified as having a therapeutic response to P2Y12 inhibition using current guidelines.

scholarly journals Comparison of Light Transmission Aggregometry With Impedance Aggregometry in Patients on Potent P2Y12 Inhibitors

2020 ◽  
pp. 107424842096870
Author(s):  
Patricia P. Wadowski ◽  
Joseph Pultar ◽  
Constantin Weikert ◽  
Beate Eichelberger ◽  
Irene M. Lang ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Light Transmission ◽  
Platelet Reactivity ◽  
Adenosine Diphosphate ◽  
P2y12 Inhibitors ◽  
Coronary Syndrome ◽  
Multiple Electrode Aggregometry ◽  
Impedance Aggregometry ◽  
Light Transmission Aggregometry ◽  
Sensitivity Specificity

Since data on the agreement between light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA) in patients on the more potent P2Y12 inhibitors are missing so far, we investigated if the evaluation of the responsiveness to therapy by LTA can be replaced by MEA in 160 acute coronary syndrome (ACS) patients on dual antiplatelet therapy with aspirin and prasugrel or ticagrelor (n = 80 each). Cut-off values for high on-treatment residual platelet reactivity (HRPR) in response to adenosine diphosphate (ADP) or arachidonic acid (AA) were defined according to previous studies showing an association of HRPR with the occurrence of adverse ischemic outcomes. ADP- inducible platelet aggregation was 33% and 37% (p = 0.07) by LTA and 19 AU and 20 AU (p = 0.38) by MEA in prasugrel- and ticagrelor-treated patients, respectively. AA- inducible platelet aggregation was 2% and 3% by LTA and 15 AU and 16 AU by MEA, (all p ≥ 0.3) in patients on prasugrel and ticagrelor, respectively. By LTA, HRPR ADP and HRPR AA were seen in 5%/5% and in 4%/ 13% of patients receiving prasugrel- and ticagrelor, respectively. By MEA, HRPR ADP and HRPR AA were seen in 3%/ 25% and 0%/24% of prasugrel- and ticagrelor-treated patients, respectively. ADP-inducible platelet reactivity by MEA correlated significantly with LTA ADP in prasugrel-treated patients (r = 0.4, p < 0.001), but not in those receiving ticagrelor (r = 0.09, p = 0.45). AA-inducible platelet aggregation by LTA and MEA did not correlate in prasugrel- and ticagrelor-treated patients. Sensitivity/specificity of HRPR by MEA to detect HRPR by LTA were 25%/99% for MEA ADP and 100%/79% for MEA AA in prasugrel-treated patients, and 0%/100% for MEA ADP and 70%/83% for MEA AA in ticagrelor-treated patients. In conclusion, on-treatment residual ADP-inducible platelet reactivity by LTA and MEA shows a significant correlation in prasugrel- but not ticagrelor-treated patients. However, in both groups LTA and MEA revealed heterogeneous results regarding the classification of patients as responders or non-responders to P2Y12 inhibition.

Ticlopidine Facilitates the Deaggregation of Human Platelets Aggregated by Thrombin

1994 ◽  
Vol 71 (01) ◽  
pp. 091-094 ◽  
Author(s):  
M Cattaneo ◽  
B Akkawat ◽  
R L Kinlough-Rathbone ◽  
M A Packham ◽  
C Cimminiello ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Platelet Aggregation ◽  
Prostaglandin E1 ◽  
Human Platelet ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
Before And After ◽  
Normal Human ◽  
Platelet Aggregates ◽  
Induced Aggregation

SummaryNormal human platelets aggregated by thrombin undergo the release reaction and are not readily deaggregated by the combination of inhibitors hirudin, prostaglandin E1 (PGE1) and chymotrypsin. Released adenosine diphosphate (ADP) plays an important role in the stabilization of thrombin-induced human platelet aggregates. Since ticlopidine inhibits the platelet responses to ADP, we studied thrombin-induced aggregation and deaggregation of 14C-serotonin-labeled platelets from 12 patients with cardiovascular disease before and 7 days after the oral administration of ticlopidine, 250 mg b.i.d. Before and after ticlopidine, platelets stimulated with 1 U/ml thrombin aggregated, released about 80–90% 14C-serotinin and did not deaggregate spontaneously within 5 min from stimulation. Before ticlopidine, hirudin (5× the activity of thrombin) and PGE1 (10 μmol/1) plus chymotrypsin (10 U/ml) or plasmin (0.06 U/ml), added at the peak of platelet aggregation, caused slight or no platelet deaggregation. After ticlopidine, the extent of platelet deaggregation caused by the same inhibitors was significantly greater than before ticlopidine. The addition of ADP (10 μmol/1) to platelet suspensions 5 s after thrombin did not prevent the deaggregation of ticlopidine-treated platelets. Thus, ticlopidine facilitates the deaggregation of thrombin-induced human platelet aggregates, most probably because it inhibits the effects of ADP on platelets.

Interactions Between Blood Platelets and Vascular Endothelium in vitro Studies

1979 ◽  
Author(s):  
M.A. Gimbrone ◽  
K.D. Curwen ◽  
R. I. Handin
Keyword(s):  
Platelet Aggregation ◽  
Vascular Endothelium ◽  
Potent Inhibitor ◽  
Platelet Reactivity ◽  
Blood Platelets ◽  
Primary Cultures ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
Platelet Adherence

Endothelial cells (EC) can actively influence the hemostatic response at sites of vascular injury through multiple mechanisms. For example, EC can degrade adenosine diphosphate, release plasminogen activator, and synthesize prostacyclin (PGI2), a potent inhibitor of platelet aggregation. We have examined whether PGI2 also might account for the normal lack of platelet adherence to the uninjured EC surface. In a monolayer adherence assay, radiolabeled human platelets in citrated plasma showed minimal interaction with primary cultures of human EC (<1 platelet adhering per cell). Platelets from aspirin-treated and untreated donors behaved similarly. However, aspirin pretreatment of EC consistently resulted in ~2-fold increases in platelet adherence which could be completely abolished by exogenous PGI2 (0.5–1.0 μg/ml). SV40-transformed human EC (SVHEC), which are deficient in PGI2 production compared to primary EC, showed 10-30 times more platelet adherence. Exogenous PGI2 produced a dose - related (.001-1.0 μg/ml) decrease in platelet adherence to SVHEC but did not result in the basal levels observed with normal EC monolayers. These data suggest that : 1) In addition to its effects on platelet aggregation, PGI2 can influence platelet endothelial cell interactions; 2) The increased platelet reactivity of transformed EC is associated with, but not completely attributable, to decreased PGI2 production; and 3) Factors other than PGI2 may play a role in the thromboresistance of normal vascular endothelium.

scholarly journals Protease-Activated Receptor-Mediated Platelet Aggregation In Patients With Type 2 Diabetes On Potent P2Y12 Inhibitors

2021 ◽  
Author(s):  
Benjamin Panzer ◽  
Patricia P Wadowski ◽  
Kurt Huber ◽  
Simon Panzer ◽  
Thomas Gremmel
Keyword(s):  
Type 2 Diabetes ◽  
Platelet Aggregation ◽  
Platelet Reactivity ◽  
Coronary Intervention ◽  
The Body ◽  
Diabetic Patients ◽  
P2y12 Inhibitors ◽  
Platelet Aggregometry

Abstract Background: Dual antiplatelet therapy is a cornerstone in the secondary prevention of ischemic events following percutaneous coronary intervention (PCI) with stent implantation. The new, more potent adenosine diphosphate (ADP) P2Y12 receptor inhibitors prasugrel and ticagrelor have been shown to improve patients’ outcomes. Whether or not these drugs have equal efficacy in diabetic as in non-diabetic individuals is disputed. Furthermore, platelets can be activated by thrombin, which is, at least in part, independent of ADP-inducible activation. Protease-activated receptor (PAR)-1 and -4 are thrombin receptors on human platelets activated by the agonists SFLLRN and AYPGKF, respectively. In the current study, we sought to compare the in vitro efficacy of prasugrel (n=121) and ticagrelor (n=99) to inhibit PAR-mediated platelet activation in patients with type 2 diabetes (n=55).Materials and Methods: We compared P2Y12-, PAR-1- and PAR-4-mediated platelet aggregation as assessed by multiple electrode platelet aggregometry between prasugrel- and ticagrelor-treated patients without and with type 2 diabetes who underwent acute PCI. Results: There were no significant differences of on-treatment platelet aggregation in response to ADP, SFLLRN and AYPGKF between patients on prasugrel or on ticagrelor. Diabetic and non-diabetic patients responded equally. There was no significant correlation between either; ADP-, SFLLRN-, or AYPGKF-inducible platelet aggregation and levels of HbA1c or the body mass index. However, we observed patients with high residual platelet reactivity to SFLLRN and AYPGKF in all cohorts.Conclusion: Prasugrel and ticagrelor inhibit platelet aggregation in diabetic and non-diabetic patients to a similar extent.

scholarly journals Use of increased concentrations of adenosinediphosphate for high residual platelet reactivity in patients with coronary heart disease

2021 ◽  
Vol 70 (1) ◽  
pp. 129-132
Author(s):  
O.A. Trubacheva ◽  
S.N. Belyaeva ◽  
T.E. Suslova ◽  
I.V. Petrova
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Platelet Aggregation ◽  
Antiplatelet Therapy ◽  
Light Transmission ◽  
Platelet Reactivity ◽  
Platelet Rich Plasma ◽  
Adenosine Diphosphate ◽  
Transmission Curve ◽  
Platelet Suspension

Detection of a tendency to increased thrombosis in patients with coronary heart disease (CHD) is of important prognostic value in the selection of drugs aimed at achieving a persistent antithrombotic effect. The aim of the study was to evaluate the use of elevated ADP inducer concentrations to improve the accuracy of ADP-induced platelet aggregation in patients with coronary heart disease. Material and method. Material and method. We studied 48 patients with CHD who were on continuous double antiplatelet therapy for 6 months (aspirin 75mg and clopidogrel 75mg per day). The aggregation activity of the platelet suspension was studied using the Born method G. in the modification of Gabbasov Z. A. Platelet activity was evaluated by the degree of aggregation of platelet-rich plasma along the light transmission curve under the influence of the inducer adenosine diphosphate (ADP) at a concentration of 2 mmol/l and by its own patented method against the background of additional ADP application. Results. In patients, platelet aggregation decreased to 5-35% (p<0.005) compared to the standard values, which are 50-60%. The values of platelet aggregation with the additional introduction of the inducer of aggregation ADP in a ratio of 2:1 to 2 µmol/l for 1, 2, 3, and 4-minute registration of platelet aggregation, resulted in increased aggregation from 55% to 75% (p<0.001), indicating high residual platelet reactivity on the background of double antiplatelet therapy. Correlations of the degree of aggregation for elevated ADP concentrations with multivessel arterial lesion and dyslipidemia were also found, r=0.86 and r=0.92, respectively. Conclusion. The use of elevated concentrations of adenosine diphosphate in platelet aggregation in patients with ischemic heart disease increases the accuracy of assessing ADP-induced platelet aggregation against the background of dual antiplatelet therapy and contributes to the detection of high residual platelet reactivity.

Whole blood platelet aggregation kinetics under cardiopulmonary bypass: A pilot study

2019 ◽  
Vol 43 (3) ◽  
pp. 208-214
Author(s):  
Tobias Petzold ◽  
Erik Bagaev ◽  
Helen Herzog ◽  
Frank Born ◽  
Dominik Hoechter ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Platelet Aggregation ◽  
Life Support ◽  
Platelet Reactivity ◽  
Extracorporeal Life Support ◽  
Adenosine Diphosphate ◽  
Thrombin Receptor ◽  
Electrode Impedance ◽  
Platelet Counts ◽  
Impedance Aggregometry

Assessing the platelets’ functional status during surgery on cardiopulmonary bypass is challenging. This study used multiple electrode impedance aggregometry (Multiplate®) to create a timeline of platelet aggregation changes as induced by cardiopulmonary bypass in antiplatelet-naive patients undergoing elective surgery for mitral valve regurgitation. We performed six consecutive measurements (T1: pre-operatively, T2: after heparinization, T3: 3 min after establishment of cardiopulmonary bypass, T4: immediately after administration of cardioplegia, T5: 5 min after administration of cardioplegia, and T6: 45 min after administration of cardioplegia). Platelet aggregation was determined after stimulation with 3.2-μg/mL collagen, 6.4-μM adenosine diphosphate, and 32-μM thrombin receptor activating peptide. Five patients were included (age: 64 ± 10 years, one female). We observed a decrease in hematocrit levels by −17.1% ± 3.7% (T1 vs T6) with a drop after establishment of cardiopulmonary bypass (T2 vs T3) and slightly decreasing platelet counts by −6.2% ± 7.7% (T1 vs T6). Immediately after establishment of cardiopulmonary bypass (T2 vs T3), we observed reduced platelet aggregation responses for stimulation with adenosine diphosphate (−19.7% ± 12.8%) and thrombin receptor activating peptide (−19.3% ± 6.3%). Interestingly, we found augmented platelet aggregation for all stimuli 45 min after administration of cardioplegia (T5 vs T6) with the strongest increase for collagen (+83.4% ± 42.8%; adenosine diphosphate: +39.0% ± 37.2%; thrombin receptor activating peptide: +34.5% ± 18.5%). Thus, after an initial drop due to hemodilution upon establishment of cardiopulmonary bypass, platelet reactivity increased over time which was not outweighed by decreasing platelet counts due to mechanical platelet destruction and absorption. These findings have implications for rational transfusion, peri-operative antiplatelet therapy, and for the management of patients on other extracorporeal support, such as extracorporeal life support or extracorporeal membrane oxygenation.

The Genotypic Combination of Homozygous Carriers of Both H1 Haplotype and 34C Shows a Significantly Lower Responsiveness to ADP-Induced Platelet Aggregation Than Others in Healthy Volunteers.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3560-3560
Author(s):  
Koji Isobe ◽  
Yumiko Matsubara ◽  
Shinichi Takahashi ◽  
Miho Iwashita ◽  
Risa Komine ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Platelet Aggregation ◽  
Healthy Volunteers ◽  
Platelet Reactivity ◽  
Direct Sequencing ◽  
Allele Frequencies ◽  
Complete Linkage Disequilibrium ◽  
Receptor Expression ◽  
Complete Linkage ◽  
Genotypic Combination

Abstract BACKGROUND: The adenosine diphosphate (ADP) receptor, P2Y12, plays a central role in platelet activation and its blocker clopidogrel reduces the incidence of cardiovascular events. Recently, the polymorphisms of the P2Y12 gene (H1 and H2 haplotype) was shown to be associated with increased ADP-induced platelet aggregation in healthy volunteers. In addition, the polymorphism (C34T) of the P2Y12 gene was reportedly associated with higher numbers of cerebrovascular events in patients with PAD receiving clopidgrel therapy. However, it is totally unknown if there is any association between polymorphisms combination and platelet reactivity. In this study, we aimed to investigate in detail about the association between ADP-induced platelet aggregation and the polymorphisms of P2Y12 gene, haplotype and C34T, in healthy volunteers. METHODS AND RESULTS: We determined P2Y12 genotype and platelet reactivity in 267 healty volunteers. Genotyping was performed using direct sequencing or a single nucleotide primer extension (SNuPE). In previous study, H1 and H2 haplotype were defined by 4 polymorphisms, C139T, T744C and insertion801A in intron1 and G52T in exon2, and there were in complete linkage disequilibrium. Result of genotyping of haplotype, however, G52T was found not to be in complete linkage disequilibrium. Allele frequencies of H1 and H2 were 0.83 and 0.17, respectively. For C34T, allele frequencies of 34C and 34T were 0.75 and 0.25, respectively. Platelet reactivity was evaluated by optical aggregometry in platelet-rich plasma. Aggregation was induced by 2 or 5 μmol/L ADP to evaluate maximal aggregation (%) and the area under the aggregate curve (AUC) for 6 min. Maximal aggregation induced by 2 μmol/L ADP was similar in homozygous carriers of H1 haplotype and carriers of H2 haplotype (p=0.262). AUC induced by 2 μmol/L ADP was lower in homozygous carriers of H1 haplotype than carriers of H2 haplotype (p=0.074). However, haplotype was not associated with platelet reactivity induced by 5 μmol/L ADP. For C34T, whereas, maximal aggregation and AUC induced by 2 or 5 μmol/L ADP was lower in homozygous carriers of 34C than carriers of 34T (p=0.009 and p=0.006 or p=0.002 and p=0.003, respectively). Furthermore, for the genotypic combination of haplotype and genotype (C34T), maximal aggregation and AUC induced by 2 or 5 μmol/L ADP was significantly lower in homozygous carriers of both H1 haplotype and 34C than others (p=0.003 and p&lt;0.001 or p=0.05 and p=0.007, respectively). When platelet aggregation was induced by 1 mg/mL Collagen, the same trends were observed. CONCLUSIONS: We demonstrated that polymorphisms of the P2Y12 gene are associated with increased ADP-induced platelet aggregation, moreover, that group with genotypic combination of homozygous carriers of both H1 haplotype and 34C shows a significantly lower responsiveness to ADP-induced platelet aggregation than others in healthy volunteers. This suggests the possibility that polymorphisms of the P2Y12 gene are related to the receptor expression of P2Y12.

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