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PubMed2005

Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and clopidogrel after percutaneous coronary intervention.

Increased platelet inhibition is achieved when clopidogrel is added to aspirin (acetylsalicylic acid [ASA]). A broad variability in platelet inhibition profiles during the early phases of treatment has been demonstrated and may be attributed to ASA resistance. However, the influence of ASA sensitivity on platelet function profiles of patients on long-term dual antiplatelet therapy has yet to be explored. A total of 135 patients who had previously undergone percutaneous coronary intervention on long-term (>1 month) ASA and clopidogrel therapy was included. The PFA-100 system was used to define ASA resistance. Platelet aggregation, after adenosine diphosphate (6 and 20 micromol/L) and collagen (6 microg/ml) stimuli, and platelet activation (glycoprotein IIb/IIIa activation and P-selectin expression), after adenosine diphosphate (2 micromol/L) and thrombin receptor-activating peptide (50 micromol/L) stimuli, were assessed by light transmittance aggregometry and flow cytometry, respectively. Patient variability in response to treatment was defined by the coefficient of variability. ASA resistance was found in 60 of 135 patients (44%). Patients with diabetes were more frequently ASA resistant. Collagen/epinephrine- and collagen/adenosine diphosphate-coated cartridges on the PFA-100 had shorter closure times in the ASA-resistant population compared with ASA-sensitive patients. Platelet aggregation and activation were significantly higher in ASA-resistant patients. A broad variability (coefficient of variation >0.25) in patient response to treatment was observed in ASA-resistant and -sensitive patients. In conclusion, ASA resistance is associated with increased platelet reactivity in patients on long-term dual antiplatelet treatment.

Adenosine Diphosphate↗
PubMed2006

Usefulness of aspirin resistance after percutaneous coronary intervention for acute myocardial infarction in predicting one-year major adverse coronary events.

Recently, great interest has focused on the phenomenon of aspirin resistance, which may be defined as clinical or laboratory resistance. Monitoring the antiplatelet effect appears to be relevant in the presence of clinical implications, but no data are available on the possible clinical implications of the failure of aspirin to inhibit tests of platelet function in the setting of acute coronary syndromes. This study evaluated the role of aspirin resistance in the occurrence of 1-year major adverse coronary events (MACEs) in patients with acute myocardial infarction (AMI) who have undergone percutaneous coronary intervention (PCI). We prospectively evaluated 146 patients (115 men and 31 women; median age 65 years, range 30 to 84) with AMI who underwent primary PCI. Exclusion criteria were the use of glycoprotein IIb/IIIa inhibitors, hematocrit <or=30%, and a platelet count <100,000/mm3. Platelet function analyzer-100 closure times by collagen-epinephrine were used for measuring platelet function in venous blood samples obtained 12 to 15 hours after revascularization. Patients were considered aspirin resistant in the presence of a collagen-epinephrine closure time of <203 seconds. After 1-year follow-up, MACEs were recorded in 44 of 146 patients (30.1%). A significantly higher percentage of patients with MACEs had aspirin resistance (39.1% vs 23.2%, p <0.05). A Kaplan-Meier survival curve showed that the overall risk of MACEs was significantly higher among patients with aspirin resistance (p = 0.02). A Cox regression analysis that adjusted for age, gender, traditional cardiovascular risk factors, systolic left ventricular function, number of stenosed coronary arteries, and previous AMI, PCI, or coronary artery bypass graft showed aspirin resistance to be a significant and independent risk factor for the future MACEs (hazard ratio 2.9, 95% confidence interval 1.1 to 9.2, p <0.05). In conclusion, our data demonstrate that aspirin resistance after PCI is a significant and independent predictor of MACEs in patients with AMI undergoing primary PCI.

Adult↗
PubMed2005

Comparison of sea turtle thrombocyte aggregation to human platelet aggregation in whole blood.

The endangered sea turtles are living "fossils" that afford us an opportunity to study the hemostatic process as it likely existed millions of years ago. There are essentially no data about turtle thrombocyte aggregation prior to our studies. Thrombocytes are nucleated cells that serve the same hemostatic functions as the anucleated mammalian platelet. Sea turtle thrombocytes aggregate in response to collagen and beta-thrombin. Ristocetin induces an agglutination/aggregation response indicating the presence of a von Willebrand-like receptor, GPIb, found in all mammalian platelets. Samples treated with alpha-thrombin plus gamma-thrombin followed by ristocetin results in a rapid, stronger response than ristocetin alone. These responses are inhibited by the RGDS peptide that blocks fibrinogen cross-linking of mammalian platelets via the fibrinogen receptor, GPIIb/IIIa. Three platelet-like proteins, GPIb, GPIIb/IIIa and P-selection are detected in sea turtle thrombocytes by fluorescence activated cell sorting. Turtle thrombocytes do not respond to ADP, epinephrine, serotonin, thromboxane A2 mimetic, U46619, trypsin, or alpha-thrombin and gamma-thrombin added alone. Comparison of hemostasis in sea turtles to other vertebrates could provide a framework for understanding the structure/function and evolution of these pathways and their individual components.

Animals↗
PubMed2005

Evaluation of platelet function under high shear condition in the small-sized collagen bead column.

We previously reported that platelet retention rates as measured with collagen-coated bead columns (the conventional column) reflect the processes of platelet adhesion and aggregation under low shear stress, and that this system could serve as an easy-to-use platelet aggregometry. With this column, platelet glycoprotein (GP) VI and GPIIb/IIIa, but not the GPIb-von Willebrand factor (VWF) interaction, play major roles in platelet activation. To develop a system that can better reflect the GPIb-VWF interaction under high shear stress, we designed a column containing small-sized beads (125-212 microm) coated with porcine collagen type I. As expected, the GPIb-VWF interaction played a crucial role in platelet retention rates at higher flow rates. Adenosine 5'-diphosphate, but not thromboxane A2, appears to support platelet activation in this system. The platelet retention rates among healthy individuals with the new columns are in the range wider than the conventional columns, and this diversity could be attributed to the broad range of the VWF antigen and/or its activity. It is suggested that this new column can serve as an easy-to-use method for evaluating the VWF antigen levels and its activity and for monitoring patients with thrombotic or bleeding disorders related to the VWF-GPIb interaction.

Antibodies↗
PubMed2004

Lack of uniform platelet activation in patients after ischemic stroke and choice of antiplatelet therapy.

INTRODUCTION: Platelets play an important role in the natural history of ischemic stroke, and are known to be activated in the acute phase. Although aspirin reduces risks of myocardial infarction, stroke and cardiovascular death, the extent of platelet action and the effect of aspirin on platelet function in patients recovering from stroke remain unclear. METHODS: We studied 120 individuals divided into three equal groups: aspirin-free patients after ischemic stroke, post-stroke patients receiving aspirin (81-650 mg/daily), and aspirin-free subjects with multiple risk factors for vascular disease. Conventional platelet aggregation induced by 5 microM ADP and 5 microM epinephrine, cartridge-based analyzers (Ultegra, and PFA-100) readings, and expression of CD31, CD41a, CD42b, GPIIb/IIIa activity, CD51/CD61, CD62p, CD63, CD107a, CD154, CD165, formation of platelet-monocyte aggregates, intact (SPAN12), and cleaved (WEDE15) PAR-1 thrombin receptors by flow cytometry were analyzed. RESULTS: There were no differences between aspirin-free post-stroke patients and aspirin-free controls. Although aggregation was slightly higher, 12 out of the 14 receptor analyses, were surprisingly lower in the post-stroke cohort. Aspirin-treated patients exhibited highly significant inhibition of epinephrine-induced aggregation (p=0.0001), prolongation of the closure time (p=0.03), and reduction of the aspirin reactive units (p=0.02) measured by the Ultegra device. In addition, surface platelet expression of thrombospondin (p=0.001), GPIIb/IIIa activity (p=0.04), P-selectin (p=0.03), CD40-ligand (p=0.04), CD165 (p=0.02), the formation of the platelet-monocyte aggregates (p=0.01), and intact epitope of PAR-1 thrombin receptor (p=0.03) were significantly lower in the aspirin-treated group. CONCLUSIONS: Platelets are not activated in aspirin-free patients after ischemic stroke. Platelet function is significantly inhibited in those treated with aspirin when compared with healthy subjects with risk factors for vascular disease. Bleeding complications and hemorrhagic transformations after aggressive antiplatelet regimens could be related to the decreased or normal baseline platelet characteristics in such patients. Further analysis of platelet heterogeneity and its clinical significance remains to be determined in randomized trials.

Aged↗
PubMed2005

In vivo platelet redistribution and acute transient thrombocytopenia after eptifibatide injection in baboons.

BACKGROUND: The occurrence of thrombocytopenia has been reported during clinical eptifibatide (Integrilin) therapy, but the exact mechanism is not yet established to explain the varied duration and severity of thrombocytopenia associated with glycoprotein (GP) IIb/IIIa inhibitors. We assessed the redistribution of platelets in juvenile baboons during acute transient thrombocytopenia that was observed after eptifibatide injection. METHODS: Eptifibatide was administered intravenously to eight baboons by infusion at 20 microg/kg/min or a bolus injection of 10 mg. Platelet distribution was measured with a gamma scintillation camera using 111In-labeled autologous platelets. Platelet function and GP IIb/IIIa receptor inhibition were evaluated using the Plateletworks system. The effects of pretreatment with abciximab (0.4 mg/kg) or human immunoglobulin concentrate (0.75 g/kg) were also investigated. RESULTS: Eptifibatide, administered as an infusion or a bolus, caused transient thrombocytopenia with uptake of platelets predominantly by the liver. The recovery of platelet aggregation was associated with the re-entry of platelets from the liver into the systemic circulation. Pretreatment with either abciximab (0.4 mg/kg) or human intravenous immunoglobulin (IVIG, 0.75 g/kg) attenuated eptifibatide-induced thrombocytopenia and the hepatic uptake of radiolabeled platelets. CONCLUSION: Acute thrombocytopenia after eptifibatide injection was caused by the transient redistribution of platelets to the liver. Attenuation of the decrease in platelet count and hepatic sequestration by abciximab and IVIG suggests that thrombocytopenia may have been caused by ligand-induced binding site antigen induction and recognition by the reticuloendothelial system.

Abciximab↗
PubMed2005

Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting.

BACKGROUND: Although patients undergoing coronary stenting routinely receive dual antiplatelet treatment to reduce the risk of stent thrombosis, this undesired event still occurs. A suboptimal response to clopidogrel treatment (low responders) has been suggested to contribute to stent thrombosis. In the present study, platelet function profiles were assessed in patients undergoing coronary stenting receiving a standard 300-mg clopidogrel loading dose with the aim to identify low clopidogrel responders. MATERIALS AND METHODS: Platelet aggregation was assessed by light transmittance aggregometry following 6 microM ADP stimuli in 48 patients before and 10 min, 4 and 24 h after receiving clopidogrel front-loading. Patients having > or =40% inhibition of platelet aggregation 24 h after clopidogrel administration were defined as normal responders, whereas those having <40% inhibition were low responders. Glycoprotein (GP) IIb/IIIa activation and P-selectin expression were assessed by whole blood flow cytometry following 2 microM ADP stimuli at the same time points. Platelet function profiles were compared between normal and low clopidogrel responders. RESULTS: Twenty-seven patients (56%) were normal responders and 21 (44%) low responders. Baseline GP IIb/IIIa activation was higher in low responders (74.6+/-16.6% vs. 58.2+/-24.5%, p=0.03). Although GP IIb/IIIa activation reduced following clopidogrel front-loading in both groups, it remained increased among low responders at 24 h (58.6+/-21.3% vs. 40.2+/-28.7%, p=0.05) and during the overall study time course (p=0.02). There were no differences in P-selectin expression. CONCLUSIONS: A considerable proportion of patients have an early suboptimal response to a 300-mg clopidogrel loading dose. An increased GP IIb/IIIa activation before intervention may identify this group of patients suggesting the use of a more aggressive antithrombotic treatment in these individuals.

Aged↗
PubMed2004

Pharmacodynamics and pharmacokinetics of the platelet GPIIb/IIIa inhibitor tirofiban in patients undergoing percutaneous coronary intervention: implications for adjustment of tirofiban and clopidogrel dosage.

INTRODUCTION: Despite extensive data supporting the use of platelet glycoprotein (GP) IIb/IIIa (GPIIb/IIIa) inhibitors in the therapy of patients with acute coronary syndromes (ACS), there is considerable debate as to the optimal choice of antiplatelet regimen. The objective of this study was to conduct a detailed time-resolved analysis of the effects of the GPIIb/IIIa inhibitor tirofiban with concomitant clopidogrel in ACS patients undergoing percutaneous coronary intervention (PCI) to improve the dosing regimen of these two commonly used antiplatelet drugs. METHODS: The study was performed in 14 patients with non-ST-segment elevation (NSTE) ACS who underwent PCI while being treated with the current typically utilized regimen of tirofiban (10 microg/kg bolus, 0.15 microg/kg/min infusion) and clopidogrel (300 mg). Platelet function was assessed before, during, and after tirofiban infusion using a panel of agonists for ADP receptors, PAR1 and PAR4 thrombin receptors, and collagen receptors. RESULTS: Measurements of circulating tirofiban levels demonstrated a trough, which paralleled a reduction in platelet inhibition for all platelet agonists during the time when PCI was being performed. Interestingly, younger ACS patients (<55 years) exhibited less inhibition of platelet function both during the PCI procedure and after termination of the tirofiban infusion. These apparent age differences were primarily attributed to a decreased responsiveness of the younger patients to clopidogrel. CONCLUSIONS: This study shows that the currently utilized tirofiban dosage is suboptimal and suggests that patients may benefit from a higher dose regimen.

Age Factors↗
PubMed2006

Upregulation of GP IIb/IIIa receptors during platelet activation: influence on efficacy of receptor blockade.

INTRODUCTION: GP IIb/IIIa inhibitor doses high enough to inhibit platelet macroaggregation may not completely prevent formation of microaggregates. Platelets contain an internal pool of GP IIb/IIIa receptors which externalizes with activation and supports microaggregation. This study assesses microaggregation in the presence of the two GP IIb/IIIa inhibitors abciximab and tirofiban. METHODS: Citrated whole blood was preincubated with abciximab (5 microg/ml), tirofiban (50 ng/ml), or saline as control and activated with TRAP (5 microM) or ADP (2 microM) at 37 degrees C under constant stirring. Microaggregate formation and receptor expression were determined with flow cytometry. RESULTS: Within few seconds after TRAP-activation the platelet count dropped from 266,000/microl to 20,000/microl, the number of microaggregates increased from 3700/microl to 10,100/microl and the mean number of GP IIb/IIIa receptors increased from 53,000 to 65,000/platelet. With TRAP+abciximab the platelet count dropped from 259,000 to 113,000/microl, microaggregates increased from 2500 to 9300/microl, GP IIb/IIIa receptors from 56,000 to 77,000/platelet. Platelet microaggregate formation was reversible. With TRAP and tirofiban platelet count dropped to only 190,000/microl, there was no increase in platelet microaggregates, receptors increased to 66,000/platelet. Platelet activation with ADP gave similar results. CONCLUSIONS: During the early phase of activation additional GP IIb/IIIa receptors externalize to the platelet surface. Abciximab does not block these new receptors sufficiently to prevent microaggregate formation. However, the number of unblocked receptors is not high enough to maintain a stable aggregate, microaggregation is reversible. With tirofiban there is no microaggregate formation, possibly because the inhibitor rapidly binds to newly externalized receptors.

Abciximab↗
PubMed2003

Effects of roxifiban on platelet aggregation and major receptor expression in patients with coronary artery disease for the Roxifiban Oral Compound Kinetics Evaluation Trial-I (ROCKET-I Platelet Substudy).

BACKGROUND: It has been expected that therapy with oral glycoprotein (GP) IIb/IIIa blockers including roxifiban will reduce mortality and vascular complications in a long-term. However, platelet-related properties of roxifiban in the clinical setting are not well known. We measured platelet characteristics during chronic treatment in patients with coronary artery disease enrolled in the Roxifiban Oral Compound Kinetics Evaluation Trial (ROCKET-I). METHODS: ROCKET-I was designed as a randomized, double blind, multicenter, dose-ranging study of roxifiban, administered either as monotherapy or concomitantly with aspirin, compared with aspirin alone. Thirty-one patients were assigned for 24 weeks of therapy with aspirin (n = 7), roxifiban (n = 9), or roxifiban plus aspirin (n = 15). Platelets were assessed 5 times in each patient at baseline, and at weeks 2, 4, 12, 18, and 24 thereafter with aggregometry and flow cytometry. RESULTS: Baseline platelet characteristics were similar in all 3 groups. There was a consistent significant decrease of adenosine diphosphate- (P =.0001) and collagen-induced (P =.002) platelet aggregation in the patients treated with roxifiban when compared with patients treated with aspirin alone. Flow cytometry revealed paradoxical late activation of GP IIb/IIIa expression (P =.007) when roxifiban was used without aspirin, which was significant compared with the aspirin and aspirin-roxifiban groups. There were no differences among groups in GP Ib expression, although its rise was more profound in the patients treated with roxifiban. There were substantial differences in the P-selectin expression. Although aspirin time dependently decreased the percent of P-selectin positive platelets (P =.02), treatment with roxifiban resulted in the phasic changes with the early inhibition (P =.01) and then 2-fold activation (P =.0001) starting at week 12 of the therapy. There was an early transient activation of platelet endothelial cell adhesion molecule-1 expression (P =.008) at week 2, followed by the later inhibition of this receptor (P =.003) in patients treated with roxifiban. CONCLUSION: Despite achieving sustained inhibition of platelet aggregation, therapy with roxifiban has been associated with over expression or phasic changes of major platelet receptors. These data may explain clinical concerns about the use of oral GP IIb/IIIa inhibitors linking higher mortality rates and incidence of thrombotic episodes with paradoxical switching to alternative passways of platelet activation.

Amidines↗
PubMed2001

Clinical utility of the platelet function analyzer (PFA-100) for the assessment of the platelet status in patients with congestive heart failure (EPCOT trial).

BACKGROUND: Data from small studies have shown the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of platelet function analyzer (PFA-100) in the CHF population. METHODS: Blood samples were obtained for measurement of adenosine diphosphate (ADP)/collagen and epinephrine/collagen shear-induced closure time (CT), whole blood aggregation, platelet contractile force, activity of glycoprotein (GP) IIb/IIIa, and P-selectin receptors in 100 consecutive outpatients with CHF. RESULTS: Substantial interindividual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were divided by the incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Aspirin use did not affect instrument readings as well. CT correlates well with whole blood aggregometry (r(2)=.587) and less with GP IIb/IIIa activity (r(2)=.326). No correlation has been observed for the CT with the platelet-bound P-selectin (r(2)=.041) and platelet contractile force measures (r(2)=.028). CONCLUSIONS: PFA-100 is indeed capable to serve as a platelet analyzer and may be successfully used as a screening device. However, patients with heart failure enrolled in the EPCOT trial exhibited a marginal, sometimes oppositely directed changes in the platelet function, challenging the diagnostic utility of PFA-100 to serve as a useful tool for the identification of platelet abnormalities, predicting clinical outcomes, or for the monitoring of antiplatelet strategies in this population.

Adenosine Diphosphate↗
PubMed2002

Assessment of omega-fatty-acid-supplemented human platelets for potential improvement in long-term storage.

Uptake of omega (omega)-3 fatty acids can influence membrane stability and cell mobility. We investigated the effects of omega-3 and -6 fatty acids on the hemostatic efficacy of human platelets using an in vivo rabbit bleeding model. In vitro assays such as platelet aggregation, vWF bead-mediated ATP release and platelet adhesion to beads (measured by the residual platelet count [RPC] [free platelet count after reacting with the beads]/[baseline platelet count]x 100=%RPC; a high %RPC indicates reduced platelet function) were conducted on platelets treated with 1% fish oil (omega-3); 2% fish oil emulsion or 1% soy oil (omega-6). Oil treatment of platelets reduced the vWF bead-induced ATP release insignificantly. Addition of omega-3 agents reduced physical reactivity (%RPC) with the vWF beads by a factor of 1.2 (oil) and 1.9 (emulsion). The omega-6 oil enhanced reactivity by a factor of 1.7. After washing to remove excess reagent, platelet resuspension was most efficient with the omega-3 emulsion. Platelet function was higher with the omega-3-treated platelets (%RPC=52.3%, omega-3 oil; 63.3%, omega-3 emulsion vs. 85%, omega-6 oil; 82% untreated platelets). Ethyl-palmitate-treated thrombocytopenic rabbits were infused with human platelets. Survival times of the treated platelets, as monitored by flow cytometry (6.2-8.2 h) were comparable to untreated platelets (8.6 h). In the rabbit kidney injury model, blood loss after infusion of the treated platelets was similar to that of saline-infused rabbits (75.3+/-3.4 g). However, platelets washed prior to infusion reduced blood loss to a value comparable to that of fresh platelets (48.3+/-5 g). Furthermore, the presence of the infused platelets at the injury site was clearly visualized using FITC-tagged anti CD42a antibody. Thus, the omega-3-based agents protect the platelets from damage during the washing procedure as demonstrated in vitro by improved platelet resuspension, low %RPC, high stimulus-responsive ATP secretion and a reduction in blood loss in vivo.

Animals↗
PubMed2003

Is platelet aggregation a more important contributor than platelet adhesion to the overall platelet-related primary haemostasis measured by PFA-100?

BACKGROUND: Platelet-related primary haemostasis (PRPH), measured in PFA-100 as a closure time (CT), reflects platelets' combined ability to adhere and aggregate under higher shear stress. The inputs of platelet aggregation and platelet adhesion into the real values of CT remain unknown, and this poor discrimination results in the complexity of the PFA-100 measurement. OBJECTIVE: To estimate the particular contributions of two physiological phenomena, platelet aggregation and adhesion, and the importance of various membrane receptors underlying platelets' capability of the plug formation in PFA-100 cartridges. MATERIALS AND METHODS: Effects of various blockers antagonizing ligands binding to platelet surface membrane receptors (antagonists of GPIIb-IIIa complex, collagen receptors and purinoreceptors), and aurintricarboxylic acid (ATA), the antagonist of GPIb-von Willebrand factor (vWF) interaction, were monitored in 47 healthy donors with the use of PFA-100 and whole blood electrical aggregometry (WBEA). RESULTS: PFA-100 collagen/ADP CT was the most sensitive in probing the effect of platelet membrane receptor antagonists acting via the blockade of GPIIb-IIIa complex and those antagonizing GPIb-vWF interaction (GR144053F, Integrilin, ATA), whereas the other blockers, acting on collagen receptors or purinoreceptors, remained much less efficient. For the examined GPIIb-IIIa and GPIb antagonists, the overall variability in WBEA explained a very significant part (30-60%) of the overall variability in PFA-100 CT. CONCLUSIONS: GPIIb-IIIa-mediated platelet aggregation and von Willebrand factor interactions with GPIb and/or GPIIb-IIIa seem to be the major determinants of PFA-100 CT. On the contrary, other platelet receptors participating in platelet aggregation and/or platelet adhesion are of secondary importance and minor significance in blood flow at higher shear stress monitored in PFA-100.

Adult↗