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.     

Antithrombotic activity of Z4A5, a new platelet glycoprotein IIb/IIIa receptor antagonist evaluated in a rabbit arteriovenous shunt thrombosis model

Introduction

The antithrombotic effect of the glycopreotein IIb/IIIa (GP IIb/IIIa) receptor antagonist Z4A5, exert alone or combination with heparin, and/or aspirin, was examined in a rabbit arteriovenous shunt thrombosis model.

Materials and Methods

Thrombosis was induced by the insertion of a silk thread (thrombogenic substrate) into an extracorporeal shunt. Before and after drug administration (0, 5, and 15 min), ex vivo adenosine diphosphate (ADP)-induced platelet aggregation and coagulation parameters (prothrombin time (PT) and activated partial thromboplastin time (APTT)) were determined in platelet-rich plasma (PRP) and platelet poor-plasma (PPP), respectively.

Results

Our data demonstrated that, compared to the control, Z4A5 decreased the thrombus weight (31-65%) in a dose-dependent manner and inhibited ADP-induced platelet aggregation (47-98%) 5 min after Z4A5 administration (25-100 mg/kg). However, PT and APTT remained stable, even at the highest dose (100 mg/kg). Heparin (100 U/kg) and aspirin (15 mg/kg) also significantly reduced thrombus mass, but this effect was accompanied by an increase of APTT by heparin. Furthermore, the combination of heparin (100 U/kg) and a low dose of Z4A5 (25 mg/kg) failed to produce an additional benefit beyond that provided by heparin or Z4A5 alone, whereas Z4A5 (25 mg/kg) plus aspirin (15 mg/kg) potentiated the antithrombotic effects of both compounds without further increasing the values of coagulation.

Conclusions

Our results indicate that Z4A5 is an effective antithrombotic agent with no significant effects on values of coagulation. Furthermore, Z4A5 can potentiate these antithrombotic effects when prescribed with aspirin.     

血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂治疗急性缺血性卒中的研究进展

血小板活化在血栓形成中起着重要作用,虽然阿替普酶（alteplase,rtPA）静脉溶栓是治疗 急性缺血性卒中（acute ischemic stroke,AIS）的标准治疗,但国内外一直在探索联合或单独使用各类 抗血小板药物在治疗AIS中的作用。抑制血小板聚集过程最后共同通路的新型抗血小板药物血小板 糖蛋白（GP）Ⅱb/Ⅲa受体拮抗剂,在急性冠脉综合征（acute coronary syndrome,ACS）等心血管疾病 中的安全性和有效性已得到验证,但在AIS中的作用尚存争议,本文拟就相关临床研究作一综述。     

The state of platelets preserved in extracorporeal circulation with a glycoprotein IIb/IIIa inhibitor

INTRODUCTION: Temporary inhibition of platelet function during extracorporeal circulation (platelet anesthesia) can preserve platelet count. We hypothesized that platelet anesthesia with a glycoprotein IIb/IIIa inhibitor could preserve activated platelets. MATERIALS AND METHODS: Fresh human blood from donors was recirculated for 120 min in a simulated extracorporeal circuit. Heparin and FK633, a short-acting platelet glycoprotein IIb/IIIa inhibitor, were added to recirculated blood in one group (group F, n=5) whereas only heparin was used in controls (group C, n=5). Blood samples were obtained from the donors, and at 0, 5, 15, 30, 60, and 120 min of recirculation. Platelet counts, beta-thromboglobulin, thrombin-antithrombin complex, and aggregation to adenosine diphosphate were measured. Flow cytometry was performed for measurement of fibrinogen binding, platelet surface expression of P-selectin, and microparticles. RESULTS AND CONCLUSIONS: In the FK633 group, platelet counts were preserved and beta-thromboglobulin levels remained unchanged, whereas in group C, platelet counts decreased significantly and beta-thromboglobulin increased significantly from 30 and 60 min, respectively. FK633 inhibited platelet aggregation and fibrinogen binding to platelets throughout recirculation. A significant difference between groups with respect to microparticle parameters and thrombin-antithrombin complex levels was evident by 120 min. P-selectin expression increased at 0 min in both groups, and was preserved significantly at 5 min and reduced at 120 min in group F. Platelet counts were preserved by platelet anesthesia during recirculation without platelet activation. These results suggest that FK633 inhibits the amplification loop by reducing the binding of fibrinogen to glycoprotein IIb/IIIa and platelet aggregation.     

A defined peptide that inhibits the formation of the glycoprotein IIb and IIIa complex

Collagen–platelet interaction plays an important role in hemostasis and pathological thrombosis. The proposed mechanism of the interaction was the activation of platelets→releasing of contents from granules→aggregation. The common end point is the platelets and fibrin aggregates. Platelet glycoprotein (GP) IIb/IIIa (the IIbβ3 integrin) complexes serve as a receptor for the binding of fibrinogen to form firmed aggregates. Blockading of GP IIb/IIIa has been proposed to prevent platelet aggregation independent of the substance(s) responsible for activating the platelets. The development of various forms of GP IIb/IIIa inhibitor has resulted in the inhibition of platelet aggregation, although studies of IIbβ3 receptor function and various GP IIb/IIIa inhibitors have demonstrated the potential for these agents to produce effects on other aspects of platelet function as well as having nonplatelet effects. This study investigated platelet inhibition provided by blocking the GP IIb/IIIa complex formation by using a peptide derived from the GP IIIa molecule. The peptide inhibits both types I and III collagen-induced platelet aggregation in a dose-dependent manner. The defined peptide interferes with the formation of the GP IIb/IIIa complex by inhibiting the binding of FITC–PAC-1 onto ADP-, type I collagen-, and type III collagen-activated platelets. However, P-selectin secretion is not affected by the peptide. In addition, the peptide is not interfering with the binding of FITC–PAC-1 to platelets that were preincubated with indomethacin. Results from this study may suggest that the defined peptide is an effective agent to block the interaction of types I and III collagen with platelets.     

Deaggregation of human platelets in vitro by an RGD analog antagonist of platelet glycoprotein IIb/IIIa receptors

Binding of fibrinogen to platelet glycoprotein (GP) IIb/IIIa receptors is essential for normal platelet aggregation. We investigated whether inhibition of GP IIb/IIIa receptors with arginine-glycine-aspartate-O-methyltyrosine amide (RGDY), an analog of the receptor recognition sequence found in fibrinogen, is associated with platelet deaggregation. Platelets from five healthy human subjects that were maximally aggregated by addition of adenosine diphosphate to platelet-rich plasma were deaggregated in a dose-dependent manner by subsequent addition of RGDY (86.5 ± 6.2%, 68.2 ± 4.3%, 44.9 ± 6.4%, and 31.6 ± 4.1% for RGDY concentrations of 400, 200, 133, and 67 μM, respectively vs. 7.8 ± 2.9% for saline control samples, p < 0.0001). The extent of deaggregation was decreased as the time of addition of RGDY (400 μM) after maximal aggregation increased (85.6 ± 6.7%, 58.5 ± 12.6%, 47.1 ± 2.7%, and 37.1 ± 4.2% for 0, 1, 3, and 5 minute intervals, respectively, vs. 8.3 ± 3.1% in control samples, N = 4, p < 0.0001) consistent with the occurrence of irreversible aggregation. Thus, RGDY can rapidly and extensively deaggregate human platelets under certain conditions which may enhance its antithrombotic efficacy.     

CD32-dependent platelet activation by a drug-dependent antibody to glycoprotein IIb/IIIa antagonists

Thrombocytopenia is observed with a frequency of up to 2% in patients treated with glycoprotein (GP) IIb/IIIa antagonists. We recently provided evidence that thrombocytopenia is caused by antibody binding to drug-induced conformational changes in GP IIb/IIIa. Here, we report that a murine monoclonal antibody binds to GP IIb/IIIa in an antagonist-dependent manner and activates platelets. Platelet stimulation is associated with a disruption of the phospholipid asymmetry, resulting in the assembly of catalytic active intrinsic Xase and prothrombinase complexes. Further mechanistic studies revealed that this response is (I) mediated in cis, (II) not associated with the formation of prothrombotic microparticles, and (III) requires intact platelet signaling and (IV) is blocked by increases in cAMP. The prothrombotic response is not observed using F(ab')2 fragments and is blocked by incubation of platelets with neutralizing antibodies to the platelet FcgammaRIIa receptor (CD 32).Taken together, these observations suggest that GPIIb/IIIa antagonist-dependent antibody binding to the platelet fibrinogen receptor has the propensity to lead to CD32-mediated platelet activation and accelerated platelet clearance, leading to thrombocytopenia.     

Platelet GPIIb/IIIa receptor occupancy studies using a novel fluoresceinated cyclic Arg-Gly-Asp peptide

DMP 728 is a potent and specific platelet GPIIb/IIIa antagonist. Like all GPIIb/IIIa antagonists, DMP 728 has a steep dose-response relationship in inhibiting platelet aggregation. In this study the relationships between receptor occupancy, platelet aggregation and bleeding time was determined in anesthetized dogs after intravenous infusion of DMP 728 (0.01 and 0.1 mg/kg/2h). Receptor occupancy was determined by flow cytometry using XL086, a novel fluorescent cyclic RGD peptide that binds to GPIIb/IIIa with high specificity and affinity (k_d ~55 nM). Mean number of GPIIb/IIIa as determined by flow cytometric assay was ~53,800 and 79,000 on unactivated and ADP-activated platelets respectively. After DMP 728 intravenous infusion, there was a dose and time-dependent increase in receptor occupancy, inhibition of platelet aggregation and bleeding time. The two methods of receptor occupancy determination correlate with each other with an r² = 0.78. The present data suggest that blockade of only 40–60% (~40,000 receptors) of the total platelet GPIIb/IIIa was required to achieve >90% inhibition of platelet aggregation and >15 min bleeding time. Our results showed the potential clinical utility of this approach in the study of GPIIb/IIIa dose-response relationship.     

Antithrombotic effects of aspirin based on PLA1/A2 glycoprotein IIIa polymorphism in patients with coronary artery disease

OBJECTIVE: The diallelic glycoprotein IIIa polymorphism P1A1/A2 was attributed to be an inherited risk factor for coronary events. Whether this polymorphism affects response to aspirin in patients with coronary artery disease is not known. METHODS: We assessed thrombin generation (prothrombin fragment F1+2) in consecutive blood samples collected from bleeding-time wounds in 28 men with coronary artery disease; P1A2 carriers, n=9; P1A1/A1, n=19. Thrombin generation and bleeding time were measured before and after 2 weeks of aspirin 300 mg/day. RESULTS: Aspirin-depressed thrombin generation in A1 homozygotes (p=0.04), but not in A2 carriers. Bleeding time after aspirin was also prolonged in A1 subjects only (p=0.02). CONCLUSION: Genotyping for glycoprotein IIIa polymorphism might be helpful in predicting antithrombotic action of aspirin in secondary prevention of coronary artery disease.     

Differential inhibitory effects of platelet glycoprotein IIb/IIIa antagonists on aggregation induced by procoagulant agonists

INTRODUCTION: In addition to mediating the final common pathway of aggregation, the glycoprotein (GP) IIb/IIIa receptor participates in the activation of coagulation on the platelet surface. High-affinity conformation of GP IIb/IIIa in response to collagen-induced inside-out signalling seems to be mediated by GP VI(-FcRgamma) and reinforced by release of soluble mediators. METHODS: We assessed the effects of the three currently available GP IIb/IIIa antagonists--abciximab, tirofiban and eptifibatide--on platelet aggregation induced by various procoagulant and GP VI-related agonists, i.e. collagen-related peptide (CRP), convulxin and collagen fibrils, in PPACK-anticoagulated platelet-rich plasma. RESULTS: At concentrations that equally inhibited 80% of ADP-induced maximal aggregation abciximab-inhibited GP VI-mediated platelet responses to CRP or convulxin significantly more than the low-molecular-weight antagonists (CRP: abciximab 75+/-18%, tirofiban 41+/-7% and eptifibatide 41+/-6%; convulxin: abciximab 90+/-6%, tirofiban 64+/-20%, eptifibatide 61+/-14%, p<0.01 for all). In contrast, aggregation induced by collagen was equally abolished with all antagonists under the similar conditions. During CRP- or convulxin-triggered platelet activation, inhibition of fibrin polymerisation with GPRP potentiated the antiaggregatory effects of tirofiban and eptifibatide to reach that of abciximab. GPRP as such did not affect platelet aggregation. CONCLUSIONS: GP IIb/IIIa antagonists exhibit distinct inhibition profiles in platelet aggregation, depending on fibrin polymerization and calcium. Specifically, the ability of procoagulant platelet agonists to expose pre-activated and ligand-bound GP IIb/IIIa from the internal pool seems important.     

Arginyl-glycyl-aspartyl (RGD) epitope of human apolipoprotein (a) inhibits platelet aggregation by antagonizing the IIb subunit of the fibrinogen (GPIIb/IIIa) receptor

An unknown epitope of apolipoprotein (a) antagonizes fibrinogen binding to agonist-stimulated platelet's fibrinogen (GPIIb/IIIa) receptor yielding lipoprotein (a) mediated decreased platelet aggregation. The purpose of this study was to test the hypothesis that human apolipoprotein (a)'s single arginyl-glycyl-aspartyl (RGD) epitope, unique to apolipoprotein (a) in lipoprotein (a) binds to the RGD binding motif on the IIb subunit of the GPIIb/IIIa receptor thus reducing platelet-bound fibrinogen and consequently decreasing agonist-stimulated platelet aggregation. Platelets (N=30 subjects) were prepared from fresh plasma, washed three times in Tyrode's buffer and stimulated using 10 microM ADP or 2 microg/ml collagen. Lipoprotein (a) was isolated from plasma using lectin affinity chromatography followed by ultracentrifugation. The peptide RGDS inhibited (125)I-labelled lipoprotein (a) binding to autologous platelets with IC-50's of 25.1+/-2.2 (mean+/-SEM) and 15.4+/-1.3 microM for collagen- and ADP-stimulation respectively. Further, RGDS reduced platelet binding of (125)I-labelled fibrinogen IC-50's of 35.5+/-3.2 (mean+/-SEM) and 20.7+/-2.2 microM for collagen- and ADP-stimulation respectively. The monoclonal antibody PAC-1, uniquely directed at the RGD binding motif on the IIb subunit on collagen- and ADP-stimulated platelets, inhibited binding of (125)I-labelled lipoprotein (a) with IC-50's of 6.4+/-0.7 and 2.5+/-2.2 microg/10(8) platelets for collagen- and ADP-stimulation respectively. Additionally, PAC-1 reduced platelet bound of (125)I-labelled fibrinogen with IC-50's of 9.0+/-1.4 and 4.1+/-2.2 microg/10(8) platelets for collagen- and ADP-stimulation respectively. In a dose-related fashion, a polyclonal antibody, specific for the RGD epitope on apolipoprotein (a), restored platelet aggregation to control levels, inhibited (125)I-labelled lipoprotein (a) binding, and increased (125)I-labelled fibrinogen by displacing lipoprotein (a) from the GPIIb/IIIa receptor. Thus a never before demonstrated aspect of the mechanism of lipoprotein (a)'s suggested novel role as an endogenous regulator of fibrinogen binding to collagen- and ADP-stimulated platelets has been shown. In conclusion, lipoprotein (a), via apolipoprotein (a)'s RGD epitope, binds to the RGD binding motif on the IIb protein of the GPIIb/IIIa receptor consequently reducing platelet-bound fibrinogen which results in decreased platelet aggregation.     

Platelet anaesthesia during extracorporeal circulation: differential effects of GP IIb/IIIa blockers on platelet activation marker P-selectin expression at hypothermia

INTRODUCTION: Blood contact with artificial surfaces of extracorporeal circulation (ECC) and hypothermia as applied in cardiac surgery cause platelet dysfunction possibly followed by bleeding complications. "Platelet anaesthesia" is a pharmacological strategy to protect platelets against ECC-induced damage using a GP IIb/IIIa blocker, which should be short acting to achieve maximal therapy control thereby avoiding post-ECC haemorrhage. However, GP IIb/IIIa blockers can paradoxically induce platelet activation, which may limit their efficiency as anti-platelet drugs. This in-vitro study investigated potentially platelet-activating effects of short-acting GP IIb/IIIa blockers during normothermic and hypothermic ECC. MATERIALS AND METHODS: Control (untreated) and treated (using either FK633 [half-life: 0.52 h], tirofiban [half-life: 1.5-2 h], or eptifibatide [half-life: 1.5 h]) heparinized blood was circulated in an ECC-model at normothermia (37 degrees C) and hypothermia (18 degrees C). Percentages of platelet aggregates and P-selectin-expressing (activated) platelets, platelet-counts and Thrombin-Antithrombin (TAT) complex formation were determined before (baseline) and after ECC. Statistical analysis was performed using multifactorial ANOVA after log-transforming the data. RESULTS: GP IIb/IIIa blockade inhibited ECC-induced platelet aggregation and platelet loss and decreased P-selectin expression at normothermia. During hypothermic ECC P-selectin was decreased by tirofiban but augmented by FK633 and eptifibatide. TAT formation was only decreased by FK633. CONCLUSIONS: Especially regarding its ultra-short half-life FK633 has the best properties for platelet protection during normothermic ECC. However, at hypothermia FK633 and eptifibatide induce platelet activation. In relation with "platelet anaesthesia" possible hypothermia-associated prothrombotic side effects of GP IIb/IIIa blockers should be considered.     

Blockade of glycoprotein IIb/IIIa by crotavirin, a member of disintegrins, prevents platelet from activation and aggregation by Staphylococcus aureus bacteria

Interaction with circulating platelets is considered an important virulent mechanism for Staphylococcus aureus (S. aureus) bacteria to induce endocarditis, a severe infectious disease with high incidence of systemic thrombosis. It therefore represents an important target for pharmacological intervention. In this study, we found that the clinical isolate S. aureus 30326 induced activation and aggregation of washed human platelets in a fibrinogen-dependent manner and this platelet reactivity was abrogated by crotavirin, a snake venom-derived glycoprotein (GP) IIb/IIIa antagonist, indicating that crotavirin is able to protect platelets from activation and aggregation by S. aureus 30326. When tested at a concentration that prevented the platelet reactivity of S. aureus 30326, crotavirin also interfered with the binding of bacteria to washed human platelets supplemented with fibrinogen. The fibrinogen-binding activity of S. aureus has been shown to be essential for S. aureus to trigger platelet activation and aggregation. Crotavirin failed to affect the fibrinogen binding of S. aureus 30326 and neither did it bind to this microbe, suggesting that the inhibitory action of crotavirin on the S. aureus 30326-platelet interaction resulted from the occupation of platelet GPIIb/IIIa. Taken together, these results demonstrate an important role for GPIIb/IIIa in mediating the interaction of platelets with S. aureus in the presence of fibrinogen and platelet GPIIb/IIIa thus appears to be a new target for the intervention of S. aureus-platelet interaction.     

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.     

Interactions between thrombolytic agents and platelets: Effects of plasmin on platelet glycoproteins Ib and IIb/IIIa

The mechanisms by which thrombolytic agents affect platelet function are not yet elucidated. The aim of the present study was to investigate the effects of plasmin, generated by thrombolytic agents in plasma, on platelet glycoproteins (GP) Ib and IIb/IIIa. Platelet-rich plasma was incubated with pharmacological amounts of streptokinase, anistreplase and tissue-type plasminogen activator and the platelet surface GP's were investigated with a panel of monoclonal antibodies using flow cytometry. As assessed from the mean fluorescence intensity of incubated and control platelets, no significant changes in the binding of antibodies to GP Ib and GP IIb/IIIa were found. The functional integrity of these glycoproteins was severely impaired by treatment with the thrombolytic agents, as shown by significant inhibition of ADP- and ristocetin-induced platelet aggregation. Experiments with purified plasmin and washed platelets indicated significant degradation of GP IIb/llla and upregulation of GP Ib, which is in agreement with previous findings. In addition, platelet activation by plasmin was shown using two monoclonal antibodies to activation-specific antigens. We conclude that degradation of platelet GP's by plasmin offers no likely explanation for the defect in platelet function, which is induced by thrombolytic agents in platelet-rich plasma.     

Effects of a monoclonal antibody to glycoprotein IIb/IIIa (P256) and of enzymically derived fragments of P256 on human platelets

The anti-platelet monoclonal antibody P256 is currently undergoing development for in vivo detection of thrombus. We have examined the actions of P256 and two fragments on human platelet function. P256, and its divalent fragment, caused aggregation at concentrations of 10(-9)-3 x 10(-8) M. A monovalent fragment of P256 did not cause aggregation at concentrations up to 10(-7) M. P256-induced platelet aggregation was dependent upon extracellular calcium ions as assessed by quin2 fluorescence. Indomethacin partially inhibited platelet aggregation and completely inhibited intracellular calcium mobilisation. Apyrase caused partial inhibition of aggregation. Aggregation induced by the divalent fragment was dependent upon fibrinogen and was inhibited by prostacyclin. Aggregation induced by the whole antibody was only partially dependent upon fibrinogen, but was also inhibited by prostacyclin. P256 whole antibody was shown, by flow cytometry, to induce fibrinogen binding to indomethacin treated platelets. Monovalent P256 was shown to be a specific antagonist for aggregation induced by the divalent forms. In-111-labelled monovalent fragment bound to gel-filtered platelets in a saturable and displaceable manner. Monovalent P256 represents a safer form for in vivo applications.     

Influence of platelet reactivity and response to clopidogrel on myocardial damage following percutaneous coronary intervention in patients with non-st-segment elevation acute coronary syndrome

Introduction

A wide variability in the response to clopidogrel and magnitude of post-treatment platelet reactivity has been described. However, this has been demonstrated by light transmittance aggregometry, a method too laborious for daily practice. Point-of-care devices may overcome this limitation, but little is known on the predictive value of such measurements. Our objective was to determine the relationship between platelet reactivity and the incidence of myocardial damage following percutaneous coronary intervention (PCI) in patients with Non-ST-segment Elevation Acute Coronary Syndrome (NSTEACS).

Materials and Methods

This prospective study included 93 patients with NSTEACS and PCI. All patients received a loading dose of 300 mg of clopidogrel and 250 mg of aspirin. Myocardial damage was defined as any elevation above upper limit of normal or previous levels of troponin T, assessed every 6 h for at least 24 h following PCI. Platelet reactivity not related to clopidogrel (BASE reactivity), related to P2Y12 inhibition (P2Y12 reactivity) and inhibition of platelet aggregation (IPA) were assessed immediately pre-PCI with the VerifyNow® device.

Results

Myocardial damage was detected in 60 patients (64.5%). Higher BASE reactivity was associated with myocardial damage (287.8 ± 62.6 vs. 260 ± 55.9 units, p = 0.043) while a trend was found for P2Y12 reactivity (173.4 ± 70.3 vs. 149.2 ± 58.4 units, p = 0.109). No relationship was detected for IPA. Multivariate logistic regression analysis confirmed that BASE reactivity (p = 0.04) and P2Y12 reactivity (p = 0.03) were independent predictors of myocardial damage.

Conclusions

Platelet reactivity before PCI appears to be better predictor of myocardial damage than does response to clopidogrel.