Coping strategies for antiplatelet drug resistance in the prevention of ischemic stroke / 国际脑血管病杂志

Aspirin and clopidogrel are widely used in the prevention and treatment of cardiocerebrovascular diseases.Although some patients have received antiplatelet therapy,they still experience ischemic events.This phenomenon is called antiplatelet drug resistance.This article reviews the coping strategies for antiplatelet drug resistance in the prevention of ischemic stroke.

Influence of aspirin/clopidogrel treatment on platelet aggregation rate and analysis of drug resistance in the patients with coronary heart disease / 中国医师杂志

Objective To investigate the influence of aspirin and/or clopidogrel treatment on platelet aggregation rate in coronary heart disease (CHD) patients,and discuss the factors related to anti-platelet drug resistance.Methods A total of 160 patients with CHD and received aspirin and/or clopidogrel treatment were enrolled in the Second Xiangya Hospital,Central South University,and were divided into stable coronary heart disease (SCHD) group (n =90) and acute coronary syndrome (ACS) group (n =70).Meanwhile,non-coronary heart disease (NCHD) patients who did not receive anti-platelet drug treatment were enrolled as controls (n =50).Clinical data of the subjects were recorded.The maximum platelet aggregation rate induced by arachidonic acid (MAR-AA) and adenosine diphosphate (MAR-ADP) were evaluated with sequential platelet counting method.The factors related to drug resistance were analyzed with Logistic regression analysis.Results Compared to NCHD group,there were lower MAR-AA and MAR-ADP in two groups of CHD (all P ＜ 0.05).In ACS patients,MAR-AA and MAR-ADP are significantly lower (P ＜0.05) in patients who receive the aspirin and clopidogrel.The rate of anti-platelet drug resistance in ACS group was significantly higher than that in SCHD group (20.0％ vs 10.0％,P ＜ 0.05).Multivariate logistic regression analysis showed that low HDL-C (＜ 1.0 mmol/L) was an independent risk factor related to the anti-platelet drug resistance (OR =4.36,95 ％ CI:1.36-14.02,P =0.025).Conclusions The antiplatelet treatment with aspirin and/or clopidogrel can significantly reduce the platelet reactivity in CHD patients,but some patients still present anti-platelet drug resistance.The combination of aspirin and clopidogrel is better.The rate of drug resistance in ACS patients is high.Low HDL-C might be associated with anti-platelet drug resistance.

Influence of aspirin/clopidogrel treatment on platelet aggregation rate and analysis of drug resistance in the patients with coronary heart disease / 中国医师杂志

Objective To investigate the influence of aspirin and/or clopidogrel treatment on platelet aggregation rate in coronary heart disease (CHD) patients,and discuss the factors related to anti-platelet drug resistance.Methods A total of 160 patients with CHD and received aspirin and/or clopidogrel treatment were enrolled in the Second Xiangya Hospital,Central South University,and were divided into stable coronary heart disease (SCHD) group (n =90) and acute coronary syndrome (ACS) group (n =70).Meanwhile,non-coronary heart disease (NCHD) patients who did not receive anti-platelet drug treatment were enrolled as controls (n =50).Clinical data of the subjects were recorded.The maximum platelet aggregation rate induced by arachidonic acid (MAR-AA) and adenosine diphosphate (MAR-ADP) were evaluated with sequential platelet counting method.The factors related to drug resistance were analyzed with Logistic regression analysis.Results Compared to NCHD group,there were lower MAR-AA and MAR-ADP in two groups of CHD (all P ＜ 0.05).In ACS patients,MAR-AA and MAR-ADP are significantly lower (P ＜0.05) in patients who receive the aspirin and clopidogrel.The rate of anti-platelet drug resistance in ACS group was significantly higher than that in SCHD group (20.0％ vs 10.0％,P ＜ 0.05).Multivariate logistic regression analysis showed that low HDL-C (＜ 1.0 mmol/L) was an independent risk factor related to the anti-platelet drug resistance (OR =4.36,95 ％ CI:1.36-14.02,P =0.025).Conclusions The antiplatelet treatment with aspirin and/or clopidogrel can significantly reduce the platelet reactivity in CHD patients,but some patients still present anti-platelet drug resistance.The combination of aspirin and clopidogrel is better.The rate of drug resistance in ACS patients is high.Low HDL-C might be associated with anti-platelet drug resistance.

Inhibidores del receptor plaquetario P2Y12. Parte 1 de 2: escenario de acción, farmacología, aplicación clínica y limitaciones de su uso / Platelet P2Y12 receptor inhibitors. Part 1 of 2: Scenario of action, pharmacology, clinical application, and limitations of its use

Resumen: las enfermedades cardiovasculares, incluidas las afecciones del corazón, del cerebro y de los vasos sanguíneos en general, representan la primera causa de muerte a nivel mundial, con diecisiete millones y medio de muertes cada año. La prevención primaria y secundaria de las enfermedades aterotrombóticas, como el infarto agudo de miocardio, el accidente cerebrovascular y las enfermedades trombóticas, además de las medidas generales para el control de los factores de riesgo tales como la obesidad, el sedentarismo, el tabaquismo, la hipertensión arterial y la diabetes, se han centrado en el control de la agregación plaquetaria. El antiagregante plaquetario por excelencia o universal, sobre todo en la prevención primaria, es la aspirina y la terapia dual con la combinación de aspirina y un inhibidor del receptor plaquetario P2Y12, principalmente el clopidogrel, es usada en la prevención secundaria y en los casos de resistencia a la aspirina. En el momento, se dispone para uso clínico de seis inhibidores del receptor plaquetario P2Y12: la ticlopidina, el clopidogrel, el prasugrel, el ticagrelor, el cangrelor y el elinogrel. En este primer módulo, de dos que serán presentados, se abordará el uso de los inhibidores del receptor plaquetario P2Y12 en la práctica del día a día en la prevención primaria y secundaria de las enfermedades aterotrombóticas, enfocado en el análisis del papel de las plaquetas en la fisiopatología de la enfermedad aterotrombótica y la descripción de los seis inhibidores del receptor plaquetario P2Y12 disponibles ahora y en el futuro. En un segundo módulo se hará una aproximación al concepto de la resistencia a los inhibidores del receptor plaquetario P2Y12, su diagnóstico desde el punto de vista del laboratorio y las diferentes alternativas de manejo cuando se presenta resistencia a uno de estos medicamentos. (AU)

Abstract: Cardiovascular diseases, including in general heart diseases, brain, and blood vessels are the leading cause of death worldwide with 17.000.000 of deaths each year. Primary and secondary prevention of atherothrombotic diseases, as acute myocardial infarction, stroke, and thrombotic disorders, besides to the general measures for risk factors control such as obesity, sedentary lifestyle, smoke, high blood pressure, and diabetes, have focused on platelet aggregation control. The antiplatelet agent par excellence or universal, especially in primary prevention, is aspirin, and dual therapy with the combination of aspirin and a platelet receptor inhibitor P2Y12, with clopidogrel as the most used, for secondary prevention and in cases of aspirin resistance. Currently, six P2Y12 platelet receptor inhibitors are available for clinical use: ticlopidine, clopidogrel, prasugrel, ticagrelor, cangrelor, and elinogrel. In this first of two modules, the use of P2Y12 receptor inhibitors in daily practice in the primary and secondary prevention of atherothrombotic diseases will be addressed focused on the analysis of the platelets role in atherothrombotic disease pathophysiology and description of the six P2Y12 platelet receptor inhibitors available now and in the future. In a second module, we will approach the concept of resistance to platelet P2Y12 receptor inhibitors, its diagnosis from the laboratory point of view and the different management alternatives when resistance to one of these drugs is present. (AU)

The association of genetic polymorphism with clopidogrel resistance among patients after ;percutaneous coronary intervention / 中华检验医学杂志

Objects To investigate the correlation of the single nucleotide polymorphism ( SNP) of clopidogrel related gene CYP2C19, ABCB1, PON1 to the occurrence of clopidogrel resistance ( CR) and TEG among patients after percutaneous coronary intervention.Methods A total of 299 patients after PCI were enrolled from April 2015 to December 2015.It genotyped the CYP2C19(rs4244285,rs4986893)ABCB1 ( rs1045642 ) and PON1 ( rs662 ) gene, measured clopidogrel response by TEG.Accordingly, all the enrolled 299 patients were then divided into CR group (n=17) +non-CR (NCR) group (n=282) or CLR group (n=54) +non-CR (NCR) group (n=245) by TEG(%).All the patients were divided into EM、IM and PM group by CYP2C19 genotype.The age of patient in CR (71.1 ±11.1) years old is higher than NCR (65.02 ±10.51) years old (t=2.559, P0.05).There was no significant difference between CR(χ2 =0.175,P=0.916) CLR(χ2 =1.589,P=0.452)and the level of TEG(ADP) (Z=-0.030,P=0.976) in PON1(rs662) polymorphism.There was no significant difference between CR(χ2 =1.722,P=0.423) CLR(χ2 =0.176,P=0.916) and the level of TEG(ADP) (Z=-0.331,P=0.741) in ABCB1(rs1045642) polymorphism.Conclusions CYP2C19 PM is associated with decreased of TEG(ADP).It is considered that no correlation exists between ABCB1(rs1045642) and PON1(rs662) polymorphism and clopidogrel resistance in patients with coronary heart diseases.The loss of function of ABCB1 ( rs1045642 ) and PON1 ( rs662 ) is not associated with decreased of TEG(ADP) in CYP2C19 PM patients.

The diagnostic value and clinical relevance of thrombelastography and light transmission aggregometry based identification of low response to clopidogrel in ACS patients after percutaneous coronary intervention / 中华检验医学杂志

Objective To obtain the incidence of “clopidogrel low response”( CLR ) of acute coronary syndrome ( ACS ) patients after percutaneous coronary intervention ( PCI ) by Thrombelastography ( TEG) and Light transmission aggregometry( LTA) ,and explore the correlation of CLR with clinical related factors and major adverse cardiac events.Methods This study is a cohort study.214 ACS patients in the Department of Cardiology of Peking University People′s Hospital,who were ready to treat with PCI between May 2014 and November 2014 were enrolled.Among them, 168 cases(78.5%) were male with an average age of (61.32 ±10.79) years;46 cases(21.5%) were female with an average age of (68.72 ±8.38) years.The clinical data were recorded, such as history of present illness, the past medical history, clinical medication, and the results of coronary angiography.After taken clopidogrel 75 mg per day at least for 4 days,all patients were detected the contribution from ADP-stimulated platelets to maximal clot strength by TEG( TEG-ADP-Inhib), and detected ADP induced maximal platelet aggregation ratio by LTA ( LTA-ADPMAX ) .The occurrence rate of CLR was calculated, and the correlation between results of the two assays were anylysed.Patients were divided into two groups according to CLR.Univariate analysis was used to compare the difference of clinical data between CLR group and non-CLR group, then Logistic regression analysis was conducted to find out the related risk factors that may influence the occurrence rate of CLR.Compare the correlation between CLR and MACE according to 6-month followed-up.Results There was negative correlations between LAT and TEG in the adenosine diphosphate induced platelet reactivity ( r=-0.282,P=0.000).CLR was found in 115 (53.7%) patients by LTA and in 74(34.6%) patients by TEG and the difference between the two CLR ratio was significant (χ2 =10.486, P =0.001 ) .There were significant differences in age,smoking history and prior PCI/CABG history between CLR group and non-CLR group according to LTA grouping(t=2.829,P=0.005;χ2 =11.058,P=0.001;χ2 =4.252,P=0.039), and there was significant differences in history of cerebrovascular accident between CLR group and non-CLR group according to TEG grouping (χ2 =4.584, P=0.032 ).Logistic regression analysis showed smoking history was the protective factor for CLR ( OR=0.390,P=0.001) , while history of cerebrovascular accident was the independent risk factor (OR=2.499,P=0.037) for CLR.According to 6-month followed-up, the incidence of clinical ischemic events and bleeding events in CLRLTA group was 5.2%and 0 respectively, in N-CLRLTA group was 10.1% and 3% respectively;the occurrence rate of clinical ischemic events and bleeding events was no significant difference between two groups(χ2 =1.834,P=0.176;χ2 =1.682,P=0.195).The incidence of clinical ischemic events and bleeding events in CLRTEG group was 8.1% and 0 respectively, in N-CLRTEG group was 7.1%and 2.1%respectively;the occurrence rate of clinical ischemic events and bleeding events was no significant difference between two groups(χ2 =0.065,P=0.798;χ2 =0.432,P=0.511 ).Conclusions The correlation between the testing results of TEG and LTA in ACS patients treated with clopidogrel was poor, CLR ratios detected by two assays were significantly different.Smoking history was the protective factor for CLR , while history of cerebrovascular accident was the independent risk factor for CLR.CLR was not the risk factor for MACE in ACS patients.

Research on detection method and clinical countermeasure of clopidogrel-resisted metabolism-related genes after interventional operation of coronary heart disease (CHD) / 中国医师杂志

Objective Study on cytochrome P450 (CYP) 2C19 gene single nucleotide polymorphism and the clinical prognosis of coronary heart disease (CHD) patients with percutaneous coronary intervention (PCI) after long-term use of clopidogrel.Methods A total of 150 cases of CHD patients was chosen prospectively between January 2013 and June 2014 who were hospitalized and PCI.All patients accepted dual antiplatelet therapy.Platelet aggregation rate and platelet aggregation inhibition rate were detected before taking the medicine and after PCI,which were used to classify the patients into clopidogrel-resistance groups (CR) and non-clopidogrel-resistance group (NCR).CYP2C19 gene single nucleotide polymorphism type was determined.The patients in CR group accepted clinical intervention countermeasures and NCR group was used as control,and postoperative recurrence angina and bleeding at the one year of operation were observed.Results About 24.67％ of patients with CHD with clopidogrel treatment,platelet aggregation rate cannot recover to normal.The correlation analysis showed CYP2C19* 2 carriers had a significantly higher platelet aggregation rate.Comprehensive analysis found that CYP2C19 * 2,long-term smoking,increased platelet count,and diabetes were the independent risk factors that platelet aggregation rate cannot recover to normal.No significant differences were found in primary end point,secondary end points,and bleeding events between CR group after clinical intervention countermeasures and NCR group.Conclusions CYP2C19 * 2,long-term smoking,increased platelet count,and diabetes are the independent risk factors that platelet aggregation rate cannot be developed to standard.Patients with clopidogrel resistance,the clinical intervention countermeasures to strengthen antiplatelet therapy can improve high platelet reactivity after PCI in CHD patients,and does not increase the risk of bleeding.

The effect of combined use of antiplatelet drugs on late-onset bleeding in elderly patients after high frequency electric resection of the colon polyps on colonoscopy / 中国医师杂志

Objective To explore the effect of combined use of antiplatelet drugs on late-onset bleeding in elderly patients after high frequency electric resection of the colon polyps on colonoscopy.Methods Data with late-onset bleeding after high frequency electric resection of the colon polyps on colonoscopy were collected from 64 elderly patients using antiplatelet drugs from January 2010 to December 2013.Those 64 elderly patiets using antiplatelet drugs were divided into aspirin,clopidogrel,and aspirin + clopidogrel groups.The clinical situation,blood-coagulation time,bleeding-occurrence time,emergency colonoscopy hemostatic rate of demand,and hemostatic time in hospital were analyzed.Results No statistically significant differences were found in the blood-coagulation time,bleeding-occurrence time,and hemostatic time in hospital among aspirin,clopidogrel,and aspirin + clopidogrel groups.However,the clinical situation,and emergency colonoscopy hemostatic rate of demand in aspirin + clopidogrel group were significantly more serious and higher than those of the aspirin or clopidogrel groups (P ＜ 0.01).Conclusions There are more serious clinical situation and higher emergency colonoscopy hemostatic demand in patients with combined use of antiplatelet drugs relative to the use of single antiplatelet drug.The clinicians should pay attention to the combined use of antiplatelet drugs for late-onset bleeding in elderly patients after high frequency electric resection of the colon polyps on colonoscopy.

Effects of eradication of Helicobacter pylori on upper gastrointestinal rebleeding rate in patients with long-term aspirin and clopidogrel combination therapy / 中华消化杂志

Objective To investigate the significance of H.pylori infection on upper gastrointestinal rebleeding in patients with long-term (≥ three months) aspirin and clopidogrel combination therapy.Methods From September 2007 to September 2011,at Yijishan Hospital of Wannan Medical College 78 patients with upper gastrointestinal bleeding and receiving long-term (≥ three months) aspirin and clopidogrel combined therapy were selected and treated with esomeprazole.The results of rapid urease test and gastric mucosal biopsy Giemsa staining of selected patients indicated 55 patients were H.pylori positive (positive group) and the other 23 cases were in negative group.The patients of positive group were randomly divided into intervention group (28 cases) and control group (22 cases) by the random allocation table method.The patients of intervention group received H.pylori eradiation treatment and the situation of H.pylori eradication was checked by 14C breath test.After treatment all patients were followed up for six months and clinical symptoms and the situation of rebleeding were observed.Categorical variables were expressed as percentage,intentional analysis and in accordance with protocol analysis were performed separately and analyzed by chi-square test.Results One patient in negative group with gastric cancer withdraw from the study.Two patients in intervention group lost.And one patient in control group lost.H.pylori of intervention group was all eradiated.In accordance with protocol analysis,the rebleeding rates of intervention group and control group were 7.69％ (2/26) and 34.62％ (9/26),respectively,and the difference was statistically significant (x2 =5.650,P=0.017).There was no significant difference between negative group (18.18％,4/22) and intervention group and no significant difference between negative group and control group (both P ＞ 0.05).In intentional analysis,the rebleeding rates of intervention group and control group were 7.14％ (2/28) and 33.33％ (9/27),respectively,and the difference was statistically significant (x2 =5.893,P =0.015).There was no significant difference between negative group (17.39 ％,4/23) and intervention group and no significant difference between negative group and control group (both P ＞ 0.05).Conclusion Eradication of H.pylori can reduce the rate of upper gastrointestinal rebleeding in patients with long-term aspirin and clopidogrel combination therapy.

A View on Combination Antiplatelet Agents in Ischemic Stroke.

The evaluation of antiplatelet agents for prevention of ischemic stroke is being focused as a strategy for stroke reduction. The aim of this analysis was to focus specifically on the necessity of combination antiplatelet agents for secondary prevention of ischemic strokes. Aspirin, clopidogrel, ticlopidine and the combination of aspirin plus extended-release dipyridamole are all effective in reducing the risk of recurrent ischemic strokes and transient ischemic attack. Furthermore, the combinations of all above drugs show some merits and demerits in one or more condition. National guideline endorses any of these antiplatelet agents as appropriate treatment options but more research into this strategy is needed. Choosing a single antiplatelet agent or the combination must be tailored according to patient characteristics, cost, disease condition and tolerability. Other classes of antiplatelet drugs should undergo clinical trials to optimize antiplatelet therapy.

Research advances in monitoring platelet function in patients with coronary artery disease / 中华检验医学杂志

Antiplatelet therapy and stent implantation have been the dominant treatment to reduce the mortality of patients with coronary artery disease.Recently,studies have showed that adverse cardiac events still occur in part of patients with coronary artery disease after the antiplatelet treatment with aspirin and/or clopidogrel.Thus,resistance to aspirin and clopidogrel has attracted increasing attention.It will be great benefit to these patients who were identified resistance and made tailoring antiplatelet therapy So far many platelet function tests has been used in clinical to monitor the reaction of the antiplatelet drugs for prevention and treatment of thrombosis in patients with coronary artery disease.These monitoring tests may be chosen based on different antiplatelet drugs including aspirin,clopidogrel and GP Ⅱ b/Ⅲ a antagonist.The results of antiplatelet drug resistance may be different due to different platelet function methods,thus the related clinical adverse events needs further verification.

The study on the mechanim of clopidogrel in human gastric epithelial GES-1 cell line injury / 中华消化杂志

ObjectiveTo explore the mechanism of clopidogrel in human gastric epithelial cell line (GES-1) injury.MethodsSet up GES-1 cells monolayer culture model.Then the GES-1 cells were divided into negative control group,U0126 intervented group,clopidogrel intervented group and combined intervented group (U0t26 treated firstly then clopidogrel intervented).The cell proliferation and apoptosis in each group was examined by methyl thiazolyl tetrazolium (MTT) assay and Flow cytometry.TheexpressionofphosphorylatedERK1/2ineachgroupwasdetectedby immunocytochemistry method,and the expression quantity of phosphorylated ERK1/2 in each group was measured by western blot.ResultsThe result of MTT assay showed that compared with negative control group,the proliferation of GES-1 cells was inhibited in U0126 group,clopidogrel group and combined intervented group,and the inhibition percentage was 21.8％ ±2.7％,46.3％ ± 3.4％ and 82.9 ％ ± 0.8 ％ respectively ( F=615.556,P =0.000 ).The result of immunocytochemistry indicated that the expression of p-ERK in U0126 group,Clopidogrel group and combined intervented group decreased compared with negative control group,which was 10.80±1.64,7.20± 1.64,4.40±0.89and 1.40±0.55 respecitively (F=49.426,P=0.000).The result of western blot and immunocytochemistry was of the same trend.Conclusion In GES-1 cell model,clopidogrel may injureGES-1 cells through MAPK/EPK signal transduction pathway.

Platelet Function Assay for Clopidogrel and Ticlopidine in Patients With Ischemic Stroke

BACKGROUND: The rapid platelet function assay (RPFA) has recently been developed and used to monitor the antiplatelet effects on the P2Y12 ADP receptor. We describe the platelet response to clopidogrel and ticlopidine using the RPFA and identify the clinical factor related to laboratory resistance in patients with ischemic stroke. METHODS: Of the 172 outpatients with ischemic stroke or transient ischemic attack (TIA) enrolled in this study, 86 were taking clopidogrel (75 mg/day) and 86 were taking ticlopidine (500 mg/day). Demographic data, vascular risk factors, stroke subtypes, and the results of blood tests were recorded. Inhibition is described as the percentage change from baseline aggregation, and is calculated from the P2Y12 reaction unit (PRU) and the base PRU on the RPFA. Those patients who displayed ineffective aggregation-inhibition (inhibition <20%) on the RPFA were defined as nonresponders. RESULTS: The response of platelet aggregation-inhibition to clopidogrel and ticlopidine exhibited a variable distribution (PRU; coefficient of variability, 0.477). Ineffective platelet inhibition was detected in 25.6% of the clopidogrel group and 3.5% of the ticlopidine group (p<0.001). In addition to clopidogrel, TIA and diabetes exhibited significantly higher ineffective platelet inhibition in a univariate analysis. In the multivariate analysis, clopidogrel and TIA remained significant, and diabetes fell to borderline significance (p=0.061). CONCLUSIONS: The response to clopidogrel and ticlopidine can vary between patients. Platelet inhibition is lower for clopidogrel than for ticlopidine on the platelet function test in patients with ischemic stroke. The clinical impact of these results remains uncertain; further investigations are needed.

Prevención de la enfermedad cerebrovascular: uso de tienopiridinas: [revisión] / Thienopirydines in stroke treatment: [review]

Las tienopiridnas son anitiagregantes plaquetarios con una efectividad igual o superior a la del ASA (ácido acetilsalílico), son metabolizadas en el hígado a través del sistema de la Citocromo P-450, lo cual puede determinar la resistencia a su efecto e interacciones cuestionadas con algunos inhibidores de la bomba de protones. La ticlopidina fue la la primera molécula de esta familia y se usó ampliamente hasta finales de los noventa. Fue remplazada por el clopidogrel el cual es 100 veces más potente. En la enfermedad coronaria se usa el clopidogrel en combinación con el ASA tanto en el evento agudo como luego de la angioplastia, en la enfermedad cerebrovascular por el contrario el uso de la terapia dual no ha demostrado ser efectivo y conlleva un incremento en las tasas de sangrado. Actualmente hay estudios en curso para la administración de terapia dual en pacientes con ACV isquémico agudo, igualmente está en curso otro estudio en prevención secundaria del ACV isquémico con terapia dual. Su mecanismo de acción es sobre el receptor P2Y (12), el cual es el principal receptor en la agregación plaquetaria mediada por ADP, lo bloquean en forma indirecta a través de sus tiolactonas, las cuales se unen covalentemente a este en forma irreversible generando antiagregación plaquetaria. Este receptor es en la actualidad el centro de investigación en la generación de nuevos fármacos que modulan la agregación plaquetaria, en forma tanto indirecta (Tienopiridinas) como directa, ticagrelor de uso oral y cangrelor de uso I.V.

The thienopiryidines are antiplatelet agents with effectiveness similar or superior to ASA (Acetil salicylic acid), metabolized by the cytochrome P-450 system in the liver which can determines the resistance to their effect and questioned interactions with some proton pump inhibitors. Ticlopidine was the first molecule of this family and it was used until the end of nineties. Clopidogrel was the second molecule, 100 times potent. In the coronary disease the use of clopidogrel plus ASA in the acute event and after angioplasty is approved. In the cerebrovascular disease the dual antiplatelet therapy has not shown benefit and an increase in the bleeding complications rate has been reported. Actually there are several trials of dual therapy in the context of acute ischemic stroke and one trial in the secondary stroke prevention. The mechanism of action is over the P2Y(12) receptor which is the main receptor for ADP mediated platelet aggregation, they block it in an indirect way through tiolactones with an irreversible covalently binding. This receptor is actually the investigation core for new platelet aggregation modulating drugs development in indirect (Thienopirydines) and direct blockade as ticagrelor (oral uses) and cangrelor (I.V. use).

Activating profile of platelet receptors in patients with coronary disease after clopidogrel intake / 中华检验医学杂志

Objective To study the characteristic of inhibition on platelet P2Y12 and short-term change after clopidogrel intake in patients with cardiovascular disease. Methods Thirty-two patients with cardiovascular disease were enrolled. Samples at baseline, 10 h and 36 h after 300 mg loading dose and 75 mg/d maintenance dose of clopidogrel with 100 mg/d Aspirin intake were measured respectively. Platelet aggregation (PAgT) was measured on thromboelastograph(TEG) induced by ADP/AA. INH was detected and calculated activated by Kaolin, AA, ADP and Activator((R)) in the TEG reagent. CD62p and VASP phosphorylation (PRI), platelet activation markers were tested with FACSCalibur Flow Cytometry, and platelet secretion activity and suppression of P2Y12 receptor were detected respectively. The changes of indicators were compared before and after clopidogrel intake, and evaluate their function in platelet receptor activation. Results INHADP at baseline was (11.5 ±9.3)%, and increased to (42.5 ±29.1)% statistically (t =3.155, P<0.05) after taking the P2Y12 at 10 h, but decreased to (20.4±13.1)% at 36 h, non-statistical to baseline (t = 2.078, P > 0. 05) , INHAA increases from baseline level (56. 6 ± 36. 6) % to (83.0 ±27. 3)% at 10h(t=2.086,P>0.05) and (85. 4 ±20. 8)% at 36 h (t= 1. 888, P>0.05), no statistical defferences were found. Inhibition on platelet activativation induced by ADP function well till 36 h after 300 mg loading dose. PAgTADP decrease from (53. 7 ± 14. 1)% at baseline to (49. 2 ±22. 8)% at 10 h non-statistically (t=0.656, P>0.05), and (40.7±12.8)% at 36 h statistically (t=2.418, P<0.05), however PAgTAA decrease at both 10 h and 36 h statiscally, from (34. 3 ± 18. 1) % to (17.4 ± 13. 1) % , (t=3.134, P<0.05) and (14.6±5.1)%, (t=2.532, P<0.05), respectively. Data of PAgT was not corresponding to that from TEG for the difference in sample type partly. PRI in VASP assay was (78. 6 ± 22.3)% before loading dose, and decreased to (70.7 ±9.4)% at 10 h without significance (t = l. 194, P>0.05) and (59.6 ±28.0)% at 36 h (t=1.930,P<0.05) statistically, similarly to INHADP,indicating that within 36 h clopidogrel did not have strong inhibitory effect on the ADP receptor. On the contrary, CD62p changed from (7. 5 ± 1. 4) % at baseline to (4. 2 ± 1. 1) % statistically (10 h, t = 18. 027, P < 0. 05) and ( 4. 3 ± 0. 2 ) % non-statistically (36 h, t = 2. 908, P > 0. 05 ). Inhibition of secretion activity reflected by CD62p was significant. In contrast, it was more obvious inhibition in COX-1 passway, while the inhibition of P2Y12 receptor varied due to assay difference. Conclusions AA-induced platelet activation is significantly decreased in the inhibition of clopidogrel and aspirin, while ADP receptor is significantly inhibited until 36 h after the loading dose of clopidogrel. Platelet function in whole blood reflects total activity of platelet interaction with other components, in which no significant inhibition could be witnessed within 10 h.

OPCAB after Placement of Drug-Eluting Stent : A Case of Cardiac Tamponade Developing after Resumption of Ticlopidine Administration in the Early Postoperative Period / 日本心臓血管外科学会雑誌

A 72-year-old man presented with a chief complaint of chest pain. Since ECG showed ST elevation in leads III and _aV_F, suggestive of acute myocardial infarction, we performed emergency coronary angiography which revealed total occlusion of RCA#3, 75% stenosis of LAD#6, and 99% stenosis of LAD#7. Thus, RCA occlusion was the likely cause of the chest pain, and a drug-eluting stent (DES) was placed in RCA#3. OPCAB of the LITA to the LAD (LITA-LAD) was performed 44 days later. The volume of postoperative drainage was very low, and, since the DES was in place, the administration of aspirin 100 mg once daily and ticlopidine 200 mg twice daily was started on the first morning after surgery. On the second morning after surgery, the CVP rose rapidly to 16, and then to 23 mmHg. Chest CT revealed massive hemopericardium and hemomediastinum, and re-thoracotomy was performed for hematoma removal. There was no bleeding at the anastomosis or graft sites, with minimal bleeding from mediastinal adipose tissue. Thereafter, his condition improved uneventfully, and he was discharged on the 19th postoperative day. Since the DES was in place, the administration of antiplatelet agents was resumed in the early postoperative period to prevent occlusion, which resulted in the development of cardiac tamponade due to bleeding. We report the case of severe postoperative complication due to DES placement.

Ticlopidine Induced Bullous Pemphigoid / 대한피부과학회지

Bullous pemphigoid (BP) is an acquired autoimmune disease that's characterized by subepidermal vesicles and bullae. The etiology for BP is mostly idiopathic, but numerous observations have suggested the role of certain drugs in the occurrence of bullous pemphigoid. Drugs such as penicillamine, furosemide, captopril, enalapril, sulfasalazine and ampicilline have been reported to be associated with bullous pemphigoid. We report here on a new case of bullous pemphigoid that was probably induced by ticlopidine (thienopyridine, adenosine diphosphate receptor inhibitor) in a 78 year old female patient.

A case of ticlopidine induced acute cholestatic hepatitis and pure red cell aplasia / 대한간학회지

Ticlopidine inhibits platelet aggregation and provides beneficial secondary prevention of cerebrovascular and coronary artery disease. Frequently reported adverse effects of ticlopidine include diarrhea, nausea, and rash. However, to our knowledge, there are only a few published reports of the simultaneous occurrence of cholestatic hepatitis and pure red cell aplasia. Here we report a patient with simultaneous severe cholestatic hepatitis and pure red cell aplasia associated with ticlopidine. Although these adverse effects are rare, periodic hematological and liver function tests are recommended after starting ticlopidine.

Strengthen the application of platelet function tests in monitoring antiplatelet drug treatment / 中华检验医学杂志

Many platelet function tests can be used for monitoring antiplatelet drug for the prevention and treatment of thrombotic diseases.These monitoring tests may be chosen based on different antiplatelet drugs which include aspirin,clopidogrel and GP Ⅱ b/Ⅲ a antagonist.There is difference of the drug resistance which is validated by different platelet function tests,and the relation with clinical adverse events should be farther clarifled.

The Number of Lives Saved and Quality-adjusted Life Years Prolonged by Ticlopidine Hydrochloride over the Past 20 years in Japan / General Medicine

PURPOSE: Ticlopidine hydrochloride, an antiplatelet agent, is believed to have saved life years in many patients with ischemic cerebral vascular diseases in Japan. But severe adverse events have also been reported. The current investigation aimed to compare two hypothetical cohorts treated with and without ticlopidine in terms of risks and benefits of ticlopidine treatment using Markov model.<BR>METHODS: We conducted Markov decision analysis to estimate the number of lives saved and the increase in quality-adjusted life years (QALYs) over the past 20 years by ticlopidine in Japan. Two cohorts of 60-year-old male patients with previous histories of cerebral infarction, one of which treated with ticlopidine and the other not treated with ticlopidine, were compared with respect to the number of deaths and quality of life (QOL) . Data incorporated were the probabilities of the recurrence of cerebral infarction and the associated mortality, adverse events of the drug, and the utility of health status treated with ticlopidine.<BR>RESULTS: Approximately 1, 630, 000 patients were estimated to be on ticlopidine for variable periods of time during the past 20 years in Japan. With treatment, 17, 130 lives were saved, while 1, 338 patients died because of cerebral bleeding, agranulocytosis, severe hepatic dysfunction, or thrombotic thrombocytic purpura, resulting in a net benefit of 15, 792 lives saved by ticlopidine over the past 20 years. In terms of QOL, there was a total increase of 382, 191 QALYs. Sensitivity analyses showed that the older the patients when ticlopidine therapy was started, the smaller the benefits that were gained by treatment.<BR>CONCLUSIONS: Ticlopidine is considered to have made a great contribution in savingmany lives and improving QALYs in the past 20 years in Japan. This kind of analysis based on Markov model can be employed to demonstrate effectiveness of drugs and medical technologies in terms of population health outcomes.