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1.
Jakubowski JA Payne CD Li YG Farid NA Brandt JT Small DS Salazar DE Winters KJ 《Thrombosis and haemostasis》2008,99(1):215-222
Platelet 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 the VASP assay and LTA at the levels of P2Y(12) blockade after loading doses (LDs) of prasugrel or high dose clopidogrel (600 and 900 mg). The aim was to compare the VASP 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. P2Y(12) receptor blockade was estimated using the VASP assay, expressed as platelet reactivity index (VASP-PRI). Platelet aggregation was assessed by light transmission aggregometry (20 and 5 microM ADP). Twenty-four hours after prasgurel 60 mg or clopidogrel 300 mg and 600 mg, respectively, VASP-PRI decreased from approximately 80% to 8.9%, 54.7%, and 39.0%, and maximal platelet aggregation (MPA) decreased from approximately 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 microM ADP) for MPA (r = 0.86, p < 0.0001). VASP and LTA demonstrated concordance across the response range of P2Y(12) receptor blockade following thienopyridine LDs. 相似文献
2.
Cuisset T Frere C Quilici J Morange PE Saut N Lambert M Camoin L Vague IJ Bonnet JL Alessi MC 《Thrombosis research》2007,120(6):893-899
BACKGROUND: Variability in platelet response to clopidogrel and its clinical relevance have been well described. However, the underlying mechanisms remain unclear. Recently, the T744C polymorphism of the P2Y12 receptor gene has been associated with enhanced platelet aggregation in healthy volunteers, suggesting a possible mechanism for modulation of clopidogrel response. AIM OF THIS STUDY: To assess whether the clopidogrel response may be influenced by the T744C P2Y12 gene polymorphism in patients with non ST elevation acute coronary syndrome (NSTE ACS). METHODS: 597 NSTE ACS patients were included in our study and were divided into 3 groups: CC homozygotes, CT heterozygotes ad TT homozygotes. All patients received loading doses of 600 mg clopidogrel and 250 mg aspirin at least 12 hours before blood samples. Clopidogrel response was assessed by post-treatment ADP 10 micromol/L-induced platelet aggregation (ADP-Ag), VASP phosphorylation (PRI VASP) and P-selectin expression (PS). Clopidogrel resistance was defined by persistence of High Post-treatment Platelet Reactivity (HPPR=ADP-Ag>70%). RESULTS: Significant variability in the distribution of platelet parameters was observed in the overall study population. No significant difference in platelet parameter profiles was observed within patients having the same genotype, for ADP-Ag (p=0.39), PRI VASP (p=0.97) and PS (p=0.62). The genotype frequencies of the T744C polymorphism of the P2Y12 gene were similar in responders and non responders defining by HPPR (p=0.75). CONCLUSION: Our study did not show any influence of the T744C polymorphism of the P2Y12 receptor gene on clopidogrel response assessed by ADP-Ag, PRI VASP or P-selectin expression in NSTE ACS patients. 相似文献
3.
Angiolillo DJ Fernandez-Ortiz A Bernardo E Ramírez C Cavallari U Trabetti E Sabaté M Jimenez-Quevedo P Hernández R Moreno R Escaned J Alfonso F Bañuelos C Costa MA Bass TA Pignatti PF Macaya C 《Thrombosis research》2005,116(6):491-497
INTRODUCTION: Clopidogrel inhibits the ADP subtype P2Y(12) receptor. Recently, polymorphisms of this receptor have been associated with different degrees of platelet aggregation in healthy volunteers and have been suggested to modulate clopidogrel response. However, the role of gene sequence variations of the P2Y(12) receptor in patients treated with clopidogrel has not yet been assessed. MATERIALS AND METHODS: The T744C polymorphism of the P2Y(12) receptor gene was assessed in 119 patients: 36 undergoing coronary stenting receiving a 300 mg loading dose (Group A) and 83 on long-term clopidogrel (75 mg/day) treatment (Group B). Patients were divided into 2 subgroups according to the presence or absence of the C allele: carriers (CT heterozygotes and CC homozygotes) and non-carriers (TT homozygotes). Platelet aggregation, assessed by light transmittance aggregometry following ADP, collagen, TRAP and epinephrine stimuli, and platelet activation (GP IIb/IIIa activation and P-selectin expression), assessed by whole blood flow cytometry in ADP and TRAP-stimulated platelets, were performed. Platelet function was assessed at baseline and 4 and 24 h following clopidogrel loading dose in Group A and when patients where on clopidogrel treatment for at least 1 month in Group B. RESULTS: The genotype distribution of Group A was: 22/36 (61.1%) non-carriers and 14/36 (38.9%) carriers of the C allele; Group B: 57/83 (68.7%) non-carriers and 26/83 (31.3%) carriers of the C allele. There were no differences between groups for all the assessed platelet function assays. CONCLUSIONS: The T744C polymorphism of the P2Y(12) receptor gene does not modulate platelet response to clopidogrel either in the early or long-term phases of treatment. This specific gene polymorphism alone is therefore unlikely to be the cause of variability in individual response to antiplatelet therapy. 相似文献
4.
Frelinger AL Michelson AD Wiviott SD Trenk D Neumann FJ Miller DL Jakubowski JA Costigan TM McCabe CH Antman EM Braunwald E 《Thrombosis and haemostasis》2011,106(2):219-226
It was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, two-phase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18-24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18-24 h and 15 day reactivity to ADP (correlations 0.24-0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade with high-dose clopidogrel or even higher level P2Y12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies. 相似文献
5.
Jakubowski JA Bourguet N Boulay-Moine D Sugidachi A Yamaguchi S Barragan P Zhou C Moulard M 《Thrombosis and haemostasis》2012,107(2):388-395
Thienopyridines and other agents target the platelet P2Y(12) 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 P2Y(12) 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 P2Y(12) blockade achieved in vitro by preincubation with P2Y(12) 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 P2Y(12) receptor blockade and may enable more extensive utilisation of the VASP assay in clinical studies. 相似文献
6.
Malinin A Pokov A Spergling M Defranco A Schwartz K Schwartz D Mahmud E Atar D Serebruany V 《Thrombosis research》2007,119(3):277-284
INTRODUCTION: Clopidogrel inhibits platelet P2Y12 ADP receptors, while ADP, as an inductor of aggregation, stimulates both P2Y12 and P2Y1 platelet receptors. Despite a clinical loading dose routine with clopidogrel, some patients still experience coronary stent thrombosis suggesting persistent platelet activation. The VerifyNow-P2Y12 is a rapid assay that test platelet activity over 3 min and uses of the combination of ADP and prostaglandin E1 (PGE1) to directly measure the effects of clopidogrel on the P2Y12 receptor. ADP is used to maximally activate the platelets by binding to the P2Y1 and P2Y12 platelet receptors, while PGE1 is used to suppress the ADP-induced P2Y1-mediated increase in intracellular calcium levels. OBJECTIVE: The VERIfy Thrombosis risk ASsessment (VERITAS) was a prospective study designed to measure platelet response to clopidogrel therapy in subjects with multiple risk factors or history of vascular disease using this novel point-of-care assay. METHODS: 166 participants were enrolled in 4 participating sites. Data from 147 participants were analyzed after exclusion of 19 patients due to protocol violations. Platelets were assessed twice at baseline (before clopidogrel) and at 24 h post-loading 450 mg (110 participants) or 7 days after chronic clopidogrel treatment (75 mg/day) (37 patients). All participants received aspirin 81-325 mg for at least 2 days before the study enrollment. Results from the VerifyNow-P2Y12 assay are reported in P2Y12 reaction units (PRU). RESULTS: Clopidogrel therapy resulted in a mean 64.0+/-25.3% PRU reduction. No participant reached PRU inhibition below 10% of baseline. Distribution of PRU values for the VerifyNow-P2Y12 assay shows a separation from baseline to post-clopidogrel assay values with some overlap due to high inter-individual variations in response. CONCLUSIONS: VerifyNow-P2Y12 is a reliable, fast and sensitive device suitable for monitoring of platelet inhibition during clopidogrel therapy. 相似文献
7.
Laurent Bonello Nathalie Bonello-Palot Caroline Bonello Stéphane Arques Laurence Camoin-Jau Franck Paganelli 《Thrombosis research》2010,125(4):e167
Introduction
High on-treatment platelet reactivity (HTPR) after clopidogrel loading dose (LD) is associated with a high risk of thrombotic events after percutaneous coronary intervention(PCI). We have demonstrated that HTPR could be overcome in the majority of cases using LD adjustment resulting in an improved clinical outcome. However this strategy failed in nearly 10% of patients with HTPR. We aimed to determine if P2Y12-ADP receptor polymorphisms were associated with failed dose adjustment.Materiel and method
Forty-three patients undergoing PCI were included in this prospective study. A VASP index ≥ 50% after a 600 mg LD of clopidogrel defined HTPR. Dose adjustment was performed according to PR monitoring to reach a VASP index < 50%. Genetic polymorphism of the P2Y12-ADP receptor was determined by direct sequencing.Results
Patients with successful dose-adjustment (SDA) (n = 33) and failed (FDA) (n = 10) dose-adjustment groups were compared. The 2 groups were similar in terms of cardiovascular risk factors including diabetes mellitus (SDA vs FDA: 42 vs 20%; p = 0.3). The prevalence of the H2 allele of the P2Y12-ADP receptor was also similar between the 2 groups (p = 0.3). The H2 allele was found in 6 patients which are all included in the SDA group. After the first 600 mg loading dose of clopidogrel, patients carrying at least one H2 allele had similar VASP index compared to those carrying two copies of the wild type allele (H1) (SDA vs FDA: 44.9 ± 14.9 vs 43.5 ± 10%; p = 0.8).Conclusion
The present study suggests that the H2 allele of the P2Y12-ADP receptor is not involved in clopidogrel failed dose adjustment according to platelet reactivity monitoring. 相似文献8.
Blindt R Stellbrink K de Taeye A Müller R Kiefer P Yagmur E Weber C Kelm M Hoffmann R 《Thrombosis and haemostasis》2007,98(6):1329-1334
Low-response to the P2Y12 adenosine diphosphate (ADP)-receptor antagonist clopidogrel was suggested to correspond to a higher incidence of stent thrombosis (ST). This prospective observational study assessed the capability of two platelet function assays, e.g. direct measurement of the phosphorylation status of vasodilator-stimulated phosphoprotein (VASP) and ADP-induced platelet aggregation for definition of the individual risk to develop ST. Ninety-nine patients with an elevated high risk to develop ST were enrolled. All patients received a dual antiplatelet therapy consisting of 100 mg aspirin and 75 mg clopidogrel during an observation period of six months. Flow cytometry of VASP phosphorylation and densitometrically-determined measurement of ADP-induced platelet aggregation was performed 72-96 hours after stent implantation. These data were related to angiographically confirmed ST. Nine patients suffered from angiographically confirmed ST (9.1%). The meanVASP-platelet reactivity indices (VASP-PRI) and values for ADP-induced platelet aggregation in the ST group were significantly higher (60.8 +/- 13.0 and 60.9 +/- 13.1, respectively) compared to patients without ST (41.3 +/- 14.0 and 50.8 +/- 14.4, P < 0.001 vs. 0.048, respectively). There was a fair correlation between both methods using non-linear regression analysis (r = 0.332). In a multivariate analysis, VASP was the only independent predictor of ST and was superior to previously identified angiographic parameters. Receiver- operator characteristic (ROC) curve analysis revealed a cut-off value for VASP-PRI of <48% to be associated with low risk of ST. In conclusion, determination of VASP phosphorylation is superior to conventional platelet aggregometry and angiographic parameters for assessing the risk of ST. Patients with a VASP-PRI >48% seem to have a significantly increased risk. 相似文献
9.
Background
Non-responsiveness to anti-platelet therapy has been reported and has been linked to the occurrence of adverse events. No standard method to monitor clopidogrel efficacy is available at present. We aimed at comparing the utility of whole blood impedance aggregometry for the assessment of clopidogrel action using the novel Multiplate® analyzer with two flow cytometric methods.Methods
Platelet function was determined before and after the initiation of clopidogrel therapy (300 mg loading dose, followed by 75 mg qd) in 40 patients (observational study). Furthermore, 77 patients and 77 referents with and without clopidogrel treatment (75 mg qd) were evaluated (case control study). Platelet function was assessed by Multiplate® ADP and ADP + PG tests, by P-selectin (CD62P) expression, and by vasodilator stimulated phosphoprotein (VASP) phosphorylation status.Results
The observational study revealed that platelet reactivity decreased significantly after clopidogrel administration with all 4 methods (p < 0.001 for each). In the case control study the median values of all 4 tests were significantly higher in the referents without clopidogrel treatment than in the patients on clopidogrel therapy (p < 0.001 for each). Applying test specific lower reference limits as criterion for the differentiation between responders and non-responders to clopidogrel treatment, 57% of the patients on clopidogrel therapy were classified as non-responders with the Multiplate® ADP test, 38% with the Multiplate® ADP + PG test, 55% with the P-selectin assay, 9% with the PLT VASP/P2Y12 assay.Conclusions
The VASP phosphorylation assay appeared to be advantageous for the assessment of clopidogrel action compared to the Multiplate® ADP + PG test, the P-selectin assay, and the Multiplate® ADP test (listed in descending order). However, our method comparison study underscores the critical nature of the dependence of results on the techniques used in specific studies, and it remains to be elucidated which method correlates best with the occurrence of adverse events. 相似文献10.
The inhibitory platelet effect of clopidogrel is insufficient in approximately 5 to 30% of patients. These low responders (LR) face a significantly higher risk of cardiovascular complications. The therapeutic management of LR is still undefined. In the present study, we evaluate a novel therapeutic algorithm to reduce the incidence of clopidogrel resistance. One hundred sixty-one patients on 100 mg of aspirin co-medication underwent elective coronary stenting and were given an initial dosage of 600 mg clopidogrel, followed by 75 mg clopidogrel daily. 48 h later, the platelet responsiveness was tested with ADP (5-20 microM) stimulation by impedance aggregometry (Chronolog 590). A significant rise in impedance (>5 Omega after 6 minutes, aggregation index >65%) was defined as LR. In this subgroup, platelets were stimulated with the selective P2Y(12)-ADP receptor antagonist 2-MeS-AMP. One hundred twenty-three patients were clopidogrel-responders (76.4%) and 38 patients were LR (23.6%). A defect of the ADP-receptor P2Y(12) was found in three out of 38 LR (7.9%). Inhibition of platelet aggregation indicating clopidogrel-responsiveness was achieved with either a clopidogrel high-dose regimen (22/38, 57.9%); a repeat loading dose, doubling the maintenance dose) or with an alternative therapy with ticlopidine (8/38 (21.1%); 250 mg twice daily). Thus the incidence of LR was reduced from 23.6% to 5.0%. Our aggregometer-guided therapeutic algorithm reduced the relative percentage of clopidogrel LR by 78.9%. This approach could prove to be helpful in achieving a further decrease in the incidence of clopidogrel resistance. 相似文献
11.
Schäfer A Flierl U Kössler J Seydelmann N Kobsar A Störk S Bauersachs J 《Thrombosis and haemostasis》2011,106(1):141-148
While acute myocardial infarction (MI) is associated with impaired clopidogrel responsiveness, systematic evaluation is lacking due to the inability of functional aggregation-based assays to analyse clopidogrel responsiveness in the presence of glycoprotein IIb/IIIa inhibitors. Using the P2Y12-specific, non-aggregation-based platelet-reactivity-index (PRI) we assessed clopidogrel responsiveness in patients with acute MI. Clopidogrel responsiveness was determined 24 hours (h) after loading with 600 mg clopidogrel in 54 patients with acute MI admitted for coronary intervention. A PRI >50% was considered as suboptimal inhibition. Overall response in MI patients was suboptimal with a median PRI of 58%. Diabetes, low high-density lipoprotein and pre-hospital clopidogrel loading were associated with impaired clopidogrel responsiveness. Patients loaded at first medical contact had a significantly weaker platelet inhibition by clopidogrel after 24 h (PRI 63%) compared to those loaded peri-interventionally (PRI 54%, p=0.014). Clinical outcome was assessed as a combination of cardiac death, non-fatal MI, stent thrombosis, ischaemic stroke, and urgent target vessel revascularisation after 12 months. The pre-selected cut-off of PRI ≤50% yielded a sensitivity of 87% at a specificity of 26%, whereas a PRI ≤57% determined by receiver-operating characteristics (ROC)-analysis yielded a sensitivity of 80% at a specificity of 56% (event rate: PRI ≤57%: 12.0%; PRI >57%: 41.4%, p=0.0136). In conclusion, PRI detects clopidogrel responsiveness in acute MI patients requiring glycoprotein IIb/IIIa antagonism; and impaired clopidogrel responsiveness predisposes to clinical events. Pre-hospital clopidogrel loading was associated with impaired response and more adverse events challenging the concept of earliest oral clopidogrel loading in MI patients. 相似文献
12.
There 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 microM). Platelet aggregation was induced by ADP (1.25, 2.5 and 5 microM). 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 %lt; 0.0001) and with aggregation induced 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 micro M 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. 相似文献
13.
Iyú D Glenn JR White AE Fox SC van Giezen H Nylander S Heptinstall S 《Thrombosis and haemostasis》2011,105(1):96-106
P2Y(12) receptor antagonists are antithrombotic agents that inhibit platelet function by blocking the effects of adenosine diphosphate (ADP) at P2Y (12)receptors. However, some P2Y(12) receptor antagonists may affect platelet function through additional mechanisms. It was the objective of this study to investigate the possibility that P2Y(12) antagonists inhibit platelet function through interaction with G-protein-coupled receptors other than P2Y(12) receptors. We compared the effects of cangrelor, ticagrelor and the prasugrel active metabolite on platelet aggregation and on phosphorylation of vasodilator-stimulated phosphoprotein (VASP). We compared their effects with those of selective IP, EP4 and A2A agonists, which act at Gs-coupled receptors. All three P2Y(12) antagonists were strong inhibitors of ADP-induced platelet aggregation but only partial inhibitors of aggregation induced by thrombin receptor activating peptide (TRAP) or the thromboxane A2 mimetic U46619. Further, after removing ADP and its metabolites using apyrase and adenosine deaminase, the P2Y(12) antagonists produced only minor additional inhibition of TRAP or U46619-induced aggregation. Conversely, the Gs-coupled receptor agonists always produced strong inhibition of aggregation irrespective of whether ADP was removed. Other experiments using selective receptor agonists and antagonists provided no evidence of any of the P2Y(12) antagonists acting through PAR1, TP, IP, EP4, A2A or EP3 receptors. All three P2Y (12)antagonists enhanced VASP-phosphorylation to a small and equal extent but the effects were much smaller than those of the IP, EP4 and A2A agonists. The effects of cangrelor, ticagrelor and prasugrel on platelet function are mediated mainly through P2Y(12)receptors and not through another G-protein-coupled receptor. 相似文献
14.
BACKGROUND: Controversy surrounds the optimal platelet aggregation measurement to assess clopidogrel non-responsiveness. The P2Y12 reactivity ratio (PRR) determined by vasodilator-stimulated phosphoprotein phosphorylation levels has been used to indicate the extent of P2Y(12) blockade. OBJECTIVES: We sought to compare the prevalence of non-responsiveness measured by maximum (MA) and 6 min aggregation (FA) and correlate these measurements with PRR in patients with non-responsiveness. METHODS: MA and FA were measured in stented patients (n=100) before and after clopidogrel treatment. The PRR was determined in 22 non-responsive patients. Responsiveness was defined as pre-treatment minus post-treatment aggregation; and non-responsiveness was defined as <10% change in platelet aggregation. RESULTS: Responsiveness was greater as determined by FA, p=0.006 (5 microM ADP) and p=0.003 (20 microM ADP)). There was a strong correlation between MA and FA stimulated by 5 microM (r=0.84, p<0.0001) and 20 microM ADP (r=0.90, p<0.001). The prevalence of non-responsiveness rose with agonist concentration but did not differ significantly between methods: 5 microM ADP [22% (MA) vs. 17% (FA), p=0.186] and 20 microM ADP [33% (MA) vs. 29% (FA), p=0.270]. PRR correlated with both MA (r=0.66, p<0.001) and FA (r=0.74, p<0.001) in non-responsive patients indicating incomplete receptor blockade. CONCLUSION: Clopidogrel responsiveness is higher when measured by FA as compared to MA. However, these measurements are equivalent in determining the prevalence of non-responsiveness: FA and MA are affected to the same degree in patients with non-responsiveness. These findings are relevant to ongoing studies assessing platelet inhibition by P2Y(12) inhibitors and support previous studies that employed MA to assess non-responsiveness. 相似文献
15.
Braun OO Johnell M Varenhorst C James S Brandt JT Jakubowski JA Winters KJ Wallentin L Erlinge D Siegbahn A 《Thrombosis and haemostasis》2008,100(4):626-633
Prasugrel, a novel P2Y(12) ADP-receptor antagonist, has been reported to achieve greater inhibition of platelet aggregation compared to clopidogrel as assessed by light transmission aggregometry. It was the objective of this study to investigate the effect of prasugrel on alternative markers of platelet activation in comparison to a high loading dose and the approved maintenance dose of clopidogrel. One hundred ten aspirin-treated patients with stable coronary artery disease were randomized to a loading dose (LD, day 1)/ maintenance dose (MD, days 2-29) of prasugrel 60 mg/10 mg or clopidogrel 600 mg/75 mg. Platelet activation markers were analyzed by whole blood flow cytometry pre-dose and at 2 and 24 hours after LD and pre-dose at 14 and 29 days. After stimulation with 20 muM ADP, 2 hours after LD, significantly lower expression of activated GPIIb/IIIa (4.3 vs. 21.8 [mean fluorescent intensity (MFI)], p < 0.001) and P-selectin (2.0 vs. 11.7 MFI, p < 0.001) along with decreased formation of platelet-monocyte aggregates (16.4% vs. 29.6% positive cells, p < 0.001) was observed with prasugrel versus clopidogrel. All these effects were maintained through 24 hours and during the MD period. In conclusion, prasugrel 60 mg LD and 10 mg MD inhibit several markers of platelet activation and the formation of platelet-monocyte aggregates more effectively than a 600 mg LD and 75 mg MD of clopidogrel. Attenuated platelet aggregation and reduced expression of platelet pro-coagulant and pro-inflammatory markers with prasugrel suggest the potential to reduce cardiovascular events both in the acute setting and in long-term treatment. 相似文献
16.
Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect 总被引:1,自引:0,他引:1
Steinhubl SR Oh JJ Oestreich JH Ferraris S Charnigo R Akers WS 《Thrombosis research》2008,121(4):527-534
BACKGROUND: Cangrelor is a direct, parenteral, and reversible inhibitor of the platelet P2Y12 receptor currently undergoing Phase III testing. As many individuals treated acutely with cangrelor will often be treated long-term with a thienopyridine, it is important to determine the effects of concurrent cangrelor and clopidogrel administration. METHODS AND RESULTS: Ten healthy volunteers received a 600 mg oral loading dose of clopidogrel and then underwent serial platelet function monitoring for 6 h. Two weeks later these same individuals received a 600 mg clopidogrel loading dose simultaneously with a cangrelor IV bolus (30 microg/kg) and a 2-hour infusion (4 microg/kg/min). A separate group of ten volunteers received a 600 mg clopidogrel loading dose after administration of a cangrelor bolus and a 1-hour infusion. The effects on ADP-induced platelet activation and aggregation were evaluated by flow cytometry, whole-blood electrical impedance, and light-transmittance aggregometry. Cangrelor and clopidogrel alone achieved the expected levels of platelet inhibition. However, the sustained platelet inhibition anticipated for clopidogrel treatment did not occur when cangrelor was initiated simultaneously. No such effect was found when clopidogrel was started upon completion of the cangrelor infusion. CONCLUSION: To achieve sustained platelet P2Y12 inhibition in patients treated with cangrelor, clopidogrel administration should be started when the cangrelor infusion is terminated. 相似文献
17.
INTRODUCTION: There is wide variability in the responses of individual patients to aspirin and clopidogrel. Polymorphisms of several platelet receptors have been related to increased platelet aggregation. We therefore aimed to evaluate whether these polymorphisms are related to altered response to aspirin or clopidogrel. MATERIALS AND METHODS: Patients (n=120) undergoing percutaneous coronary intervention who received aspirin for > or =1 week but not clopidogrel were included. Blood samples were drawn at baseline and 20-24h after a 300-mg clopidogrel dose. Aspirin insensitivity was defined as 5 microM ADP-induced aggregation > or =70% and 0.5 mg/mL arachidonic acid-induced aggregation > or =20%. Clopidogrel insensitivity was defined as baseline minus post-treatment aggregation < or =10% in response to 5 and 20 microM ADP. PlA polymorphism of glycoprotein IIIa, T744C polymorphism of the P2Y(12) gene and the 1622A>G polymorphism of the P2Y(1) gene were genotyped by polymerase chain reaction. RESULTS: There were no differences in polymorphism frequencies between drug-insensitive vs. drug-sensitive patients. There were also no significant differences in response to aspirin (assessed by arachidonic acid-induced aggregation) or to clopidogrel (assessed by ADP-induced aggregation or activation markers) when patients were grouped according to genotype. The only trend observed was lower reduction in PAC-1 binding following clopidogrel in PlA(2) carriers (P=0.065). CONCLUSIONS: We did not find an association between polymorphisms in the platelet receptors GP IIIa, P2Y(12) or P2Y(1) and response to aspirin or clopidogrel in cardiac patients. These findings suggest that the variability in response to anti-platelet drugs is multi-factorial and is not caused only by single gene mutations. 相似文献
18.
Cuisset T Frere C Quilici J Morange PE Saut N Romero-Barra M Camoin L Lambert M Juhan-Vague I Bonnet JL Alessi MC 《Thrombosis and haemostasis》2007,97(2):212-217
Variability in platelet response to antiplatelet therapy and its clinical relevance have been well described. However, the underlying mechanisms remain unclear. It was the aim of the present study to assess whether the response to aspirin and clopidogrel may be influenced by the 807 C/T polymorphism of the glycoprotein Ia (GpIa) gene in patients with non-ST elevation acute coronary syndrome (NSTE ACS). Six hundred one NSTE ACS patients were included in our study and were divided into three groups: CC homozygotes, CT heterozygotes ad TT homozygotes. All patients received loading doses of 600 mg clopidogrel and 250 mg aspirin at least 12 hours before blood samples were drawn. Post-treatment platelet reactivity was assessed by post treatment ADP 10 microM-induced platelet aggregation (ADP-Ag), VASP phosphorylation (PRI VASP) and P-selectin expression. Non-response to dual antiplatelet therapy was defined by high post-treatment platelet reactivity (HPPR=ADP-Ag > 70%). Significant variability in the distribution of platelet parameters was observed in the overall study population. No significant difference in platelet parameters profiles was observed within patients having the same genotype, for ADP-Ag (p=0.33), PRIVASP (p=0.72) and P-selectin expression (p=0.37). The genotype frequencies of the 807 C/T polymorphism of the GpIa gene were similar in responders and non-responders defined by persistent HPPR (p=0.104). In conclusion, our study did not show any influence of 807 C/T polymorphism of GpIa gene on post-treatment platelet reactivity assessed by ADP-Ag, PRI VASP or P-selectin expression in 601 NSTE ACS patients. 相似文献
19.
目的用血栓弹力图(thromboelastograms,TEG)评价合并糖尿病的急性脑梗死患者正规使用氯吡格雷后血小板抑制率的变化及氯吡格雷抵抗情况。方法收集住院的急性脑梗死患者80例,其中糖尿病患者33例,非糖尿病患者47例,所有患者予以顿服氯吡格雷负荷量300 mg继以75 mg/d维持,在服用氯吡格雷3 d后和7 d后空腹抽取肘静脉血标本,用血栓弹力图(thromboelastograms,TEG)测定10μmol/L二磷酸腺苷(adenosine diphosphate,ADP)受体途径诱导的血小板抑制率,分析比较两组患者临床特征、血小板抑制率的差异和氯吡格雷抵抗情况。结果糖尿病组的空腹血糖(Fasting plasma glucose,FPG)和糖化血红蛋白(%)显著高于非糖尿病组,差异具有统计学意义(P<0.05)。糖尿病组3 d后和7 d的血小板抑制率显著低于非糖尿病组,差异具有统计学意义(P<0.05)。糖尿病组3 d和7 d后分别有11例(33.3%)、12例(36.4%)患者出现氯吡格雷抵抗的现象,显著高于非糖尿病组的6例(12.8%)、5例(10.6%),差异具有统计学意义(P<0.05)。结论糖尿病患者的血小板抑制率明显低于非糖尿病患者,更容易发生氯吡格雷抵抗现象。 相似文献
20.
Dovlatova N Wijeyeratne YD Fox SC Manolopoulos P Johnson AJ White AE Latif ML Ralevic V Heptinstall S 《Thrombosis and haemostasis》2008,100(2):261-270
mRNA encoding the recently discovered P2Y(14) receptor has been reported in platelets, but the presence of P2Y(14) receptor protein and its functionality have not been studied. If P2Y(14) is expressed along with P2Y(1) and P2Y(12) receptors it may have a role in haemostasis. It was the objective of this study to investigate the presence of the P2Y(14) receptor in platelets and its role in platelet function. The effects of the agonist UDP-glucose were compared with those of sulprostone, a selective EP(3) receptor agonist. Expression of P2Y(14) receptor was investigated by immunoblotting and confocal microscopy. Platelet aggregation in platelet-rich plasma (PRP) and whole blood was measured using light absorbance and platelet counting. VASP phosphorylation was investigated using flow cytometry. Immunoblotting provided evidence for P2Y(14) receptor protein and microscopy confirmed its presence on platelets. Despite this, UDP-glucose (up to 100 muM) did not induce platelet aggregation in either PRP or whole blood, and did not potentiate aggregation induced by other agonists. P2Y(14) did not substitute for P2Y(12) in experiments using the P2Y(12) antagonist AR-C69931. No effect of UDP-glucose was seen on adenylate cyclase activity as measured by VASP phosphorylation. In contrast, sulprostone acting via the EP(3) receptor promoted platelet aggregation with effects on adenylate cyclase activity. EP(3) also partially substituted for P2Y(12) receptor. We have demonstrated the presence of P2Y(14) receptor protein in platelets, but no contribution of this receptor to several measures of platelet function has been observed. Further studies are necessary to determine whether the P2Y(14) receptor in platelets has any functionality. 相似文献