Cilostazol could ameliorate platelet responsiveness to clopidogrel in patients undergoing primary percutaneous coronary intervention.

BACKGROUND: Cilostazol increases the cyclic adenosine monophosphate levels in platelets and might ameliorate the antiplatelet activity of clopidogrel. This study investigated the additional effect of cilostazol on platelet aggregation measured by a VerifyNow analyzer and soluble CD40 ligand (sCD40L) as a marker of activated platelet in patients undergoing primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: Sixty cases of primary PCI were randomly assigned to dual (aspirin and clopidogrel) or triple (dual plus cilostazol) therapy. The antiplatelet effects of aspirin and clopidogrel were evaluated by VerifyNow tests. The plasma sCD40L levels at admission, 24 h and 21 days were measured by the ELISA method. The arachidonic acid induced platelet aggregation was similar in both groups. However, the triple group had a significantly lower P2Y12 reaction unit (dual 208.8+/-69.0 vs triple 168.2+/-79.2, p=0.041) and higher % inhibition of adenosine diphosphate (ADP)-induced platelet aggregation (dual 23.8+/-21.4% vs triple 40.5+/-21.0%, p=0.004). In the multivariate analysis, cilostazol was a negative predictor for low responders to clopidogrel (95% confidence interval 0.067-0.711). The plasma sCD40L levels were not significantly different between the 2 groups at the same point of time. CONCLUSIONS: The addition of cilostazol to the combination of aspirin plus clopidogrel significantly increases the inhibition of ADP-induced platelet aggregation. However, there was no additive effect on aspirin-induced antiplatelet activity or lowering of sCD40L.     

老年人冠状动脉介入治疗术后氯吡格雷抵抗与炎性因子的关系

目的 观察冠状动脉支架植入后发牛氯吡格霄抵抗的老年冠心病患者术前、术后血清炎症因子的变化,并探讨其临床意义. 方法 选择因冠心病不稳定心绞痛住院并成功接受冠状动脉支架植入术的老年患者93例,分别于术前和术后24 h、7 d、1个月抽取外周血,比浊法检测二磷酸腺苷诱导的血小板聚集率,氯吡格雷抵抗33例(抵抗组)和正常反应60例(非抵抗组).酶联免疫法测定C反应蛋白质(CRP)、可溶性CD40配体(sCD40L)和P-选择素(P-selectin),分析氯吡格雷抵抗与炎症因子的关系. 结果 冠状动脉介入术后24 h、7 d、30 d时氯吡格雷抵抗的发生率为35.5%(33例)、26.9%(25例)、20.4%(19例),抵抗组患者术后24 h、7 d时血CRP水平[(8.8±2.5)mg/L、(5.3±2.5)mg/L]与术前(2.1±1.0)mg/L和非抵抗组[(8.1±2.3)mg/L和(2.5±1.4)mg/L]比较,差异有统计学意义(均P<0.05),30 d时有增高趋势,但差异无统计学意义,术后不同时间点P-selectin水平均较非抵抗组增高(P<0.05).术后24 hsCD40L水平较术前升高(P<0.05).相关分析结果显示,P-selectin水平、吸烟与术后30 d时氯吡格雷抵抗呈正相关(r=1.334,r=1.053,均P<0.05). 结论 冠状动脉支架术后对氯吡格雷具有不同反应性的老年患者血CRP、sCD40L、P-selectin表达存在差异,可能与氯吡格雷抵抗有关,P-selectin水平和吸烟是老年人冠状动脉支架植入术后30 d时氯吡格雷抵抗发生的预测因素.     

Effect of clopidogrel discontinuation at 1?year after drug eluting stent placement on soluble CD40L, P-selectin and C-reactive protein levels: DECADES (Discontinuation Effect of Clopidogrel After Drug Eluting Stent): a multicenter, open-label study

Antiplatelet therapy with clopidogrel has been shown to reduce major adverse cardiac events in acute coronary syndromes and after percutaneous interventions. This effect is not only due to its anti-platelet effect but also possibly due to an anti-inflammatory effect. The effect of clopidogrel cessation after one year of therapy on markers of inflammation has been investigated in diabetics and showed an increase in platelet aggregation as well as hsCRP and surface P-selectin levels. This was an exploratory multicenter prospective open-label single arm study of 98 non-diabetic patients who had received one or more drug eluting stents and were coming to the end of their 12 months course of clopidogrel therapy. The effect of clopidogrel cessation on expression of biomarkers: sCD40L, soluble P-selectin and hsCRP was measured right before clopidogrel cessation (day 0), and subsequently at 1, 2, 3 and 4 weeks after drug withdrawal. A median increase in sCD40L expression from 224 to 324.5 pg/ml was observed between baseline and 4 weeks after clopidogrel cessation, which corresponded to a 39% mean percent change based on an ANCOVA model (P < 0.001). Over the 4 weeks observation period the change in sCD40L expression correlated weakly with soluble P-selectin levels (at 4 weeks Spearman’s correlation coefficient = 0.32; P = 0.0024). Increase in P-selectin expression from baseline was statistically significant at week 1 and 2. Conversely, hsCRP level decreased by 21% at 1 week (P = 0.008) and was still reduced by 18% by 4 weeks (P = 0.062). The change in sCD40L expression appeared to vary with the type of drug eluting stent. Patients treated with drug eluting stents at 1 year after implantation display significant increase in sCD40L and decrease in hsCRP after clopidogrel cessation. Further studies should elucidate if this increase in sCD40L levels reflects solely the removal of the inhibitory effects of clopidogrel on platelet activity or rather an increase in pro-inflammatory state. The latter hypothesis may be less likely given decrease in hsCRP levels. Randomized studies are urgently needed to establish potential link of clopidogrel discontinuation and vascular outcomes.     

Comparison of platelet function and morphology in patients undergoing percutaneous coronary intervention receiving bivalirudin versus unfractionated heparin versus clopidogrel pretreatment and bivalirudin

We hypothesized that direct thrombin inhibition could attenuate platelet activation and release of soluble CD40 ligand (sCD40L), a marker of inflammation, during percutaneous coronary intervention (PCI). To assess platelet function under flow conditions with bivalirudin versus unfractionated heparin (UFH), we employed the cone and plate(let) analyzer (CPA) assay in drug-spiked blood samples from volunteers (n = 3) in vitro, and then in PCI patients who received bivalirudin alone (n = 20), UFH alone (n = 15), and clopidogrel pretreatment plus bivalirudin (n = 15). Scanning electron microscopy was employed to image bivalirudin or UFH-treated platelets to determine whether platelet function observations had a morphologic explanation. Enzyme immunoassay was used to measure sCD40L levels in PCI patients. In vitro, bivalirudin decreased platelet surface coverage; UFH increased platelet surface coverage. In PCI patients, bivalirudin alone decreased platelet surface coverage, UFH alone increased platelet surface coverage, and clopidogrel pretreatment plus bivalirudin additively reduced platelet surface coverage. Unlike UFH, bivalirudin did not activate platelets in SEM studies. Bivalirudin alone or coupled with clopidogrel significantly reduced plasma sCD40L in PCI patients. In conclusion, our findings suggest that under flow conditions, bivalirudin alone or coupled with clopidogrel may have an antiplatelet effect versus UFH alone during PCI. These data suggest that bivalirudin and UFH may confer an anti-inflammatory effect by reducing sCD40L during PCI.     

Efficacy of Clopidogrel and Clinical Outcome When Clopidogrel Is Coadministered With Atorvastatin and Lansoprazole: A Prospective,Randomized, Controlled Trial

This prospective, randomized, nonblind, controlled trial evaluated the effects of clopidogrel on platelet function upon coadministration with atorvastatin and lansoprazole.One hundred four adult patients with non-ST-segment elevated acute coronary syndrome (NSTE-ACS) who underwent percutaneous coronary intervention (PCI) with drug-eluting stent implantation were included. All patients were treated with standard dual antiplatelet therapy (DAPT) plus rosuvastatin 10 mg daily after the operation. On the sixth day after PCI, patients were randomly divided into 4 groups, Group A: DAPT + atorvastatin 20 mg daily (a change from rosuvastatin to atorvastatin) + lansoprazole 30 mg daily, Group B: DAPT + atorvastatin 20 mg daily (a change from rosuvastatin to atorvastatin), Group C: DAPT + lansoprazole 30 mg daily (continuing to take rosuvastatin), Group D is the control group. Additional drugs were used according to the situation of patients. Platelet function and concentrations of platelet activation markers (granular membrane protein 140 (P-selectin), thromboxane B2 (TXB2), and human soluble cluster of differentiation 40 ligand (sCD40L)) were assessed before randomization and at 15- and 30-day follow-up visits. All patients were maintained on treatment for 6 months and observed for bleeding and ischemic events.A total of 104 patients were enrolled, 27 patients in group A, 26 patients in Group B/C, 25 patients in Group D separately, and all the patients were analyzed. There were no differences in platelet function and the levels of platelet activation markers (P-selectin, TXB₂, and sCD40L) among or within the 4 groups at the 3 time points of interest (P > 0.05). In the subsequent 6 months, no significant bleeding events occurred, and 12 patients experienced ischemic events, these results were also not significantly different among the groups (P > 0.05).In patients diagnosed with NSTE-ACS who have had drug-eluting stent implantation, simultaneously administering clopidogrel, atorvastatin, and lansoprazole did not decrease the antiplatelet efficacy of clopidogrel or increase adverse event frequency over 6 months.     

Effects of triple antiplatelet therapy (aspirin, clopidogrel, and cilostazol) on platelet aggregation and P-selectin expression in patients undergoing coronary artery stent implantation

The purpose of this study was to determine the effect of the addition of cilostazol to aspirin plus clopidogrel on platelet aggregation after intracoronary stent implantation. Twenty patients who underwent coronary stent placement were randomly assigned to therapy with aspirin plus clopidogrel (dual-therapy group, n = 10) or aspirin plus clopidogrel plus cilostazol (triple-therapy group, n = 10). A loading dose of clopidogrel (300 mg) and cilostazol (200 mg) was administered immediately after stent placement, and clopidogrel (75 mg/day) and cilostazol (100 mg twice daily) were given for 1 month. Platelet aggregation in response to adenosine diphosphate (ADP; 5 and 20 micromol/L) or collagen and P-selectin (CD-62P) expression was assayed at baseline, 2 hours, 24 hours, 1 week, and 1 month after stent placement. Inhibition of ADP-induced platelet aggregation was significantly higher in patients receiving triple therapy than those receiving dual therapy from 24 hours after stent placement, and inhibition of collagen-induced platelet aggregation was significantly higher in the triple-therapy group beginning 1 week after stent placement. P-Selectin expression was significantly lower in the triple-therapy than dual-therapy group at 1 week and 30 days. In conclusion, compared with dual antiplatelet therapy, triple therapy after coronary stent placement resulted in more potent inhibition of platelet aggregation induced by ADP and collagen. These findings suggest that triple therapy may be used clinically to prevent thrombotic complications after coronary stent placement.     

Soluble CD40 ligand and atrial fibrillation: relationship to platelet activation, and endothelial damage/dysfunction

Increased plasma soluble CD40L (sCD40L) is present in many cardiovascular diseases and predicts poor outcome, but levels in atrial fibrillation (AF) are unknown. Although the platelet is frequently cited as the source of sCD40L, this view is not universal. We hypothesised (a) raised sCD40L in non-rheumatic AF, and (b) that sCD40L correlates with platelet, but not endothelial, markers, thus suggesting a platelet origin. Plasma sCD40L, platelet marker soluble P-selectin and endothelial markers von Willebrand factor (vWf) and soluble E-selectin were measured by ELISA in 54 AF patients free of diabetes or major cardiovascular disease, and in 28 age/sex matched controls. Median (inter-quartile range) sCD40L in AF was 0.82 (0-4.8) ng/mL compared to 0.21 (0-5.5 ng/mL) in controls (p=0.0397). vWf and soluble P-selectin (p<0.005), but not soluble E-selectin, were raised in AF, but none of the indices inter-correlated significantly. We find that sCD40L is marginally raised in AF but the stimulus for this is unclear. The lack of clear correlation with relevant plasma markers suggests that the source is unlikely to be the endothelium or platelet alone.     

氯吡格雷抑制急性冠状动脉综合征患者血小板释放可溶性CD40配体

目的探讨在非ST段抬高急性冠状动脉综合征（non—ST-segment elevation acute coronary syndromes，NSTEACS）患者短期应用氯吡格雷是否有抑制ADP诱导血小板释放可溶性CD40配体（sCD40L）的作用。方法NSTEACS42例，患者服用氯吡格雷6—8d，治疗前后采静脉血。提取富含血小板血浆（platelet rich plasma，PRP）并用二磷腺苷诱导血小板聚集和释放sCD40L，在不同时间点终止反应，用酶联免疫法测量sCD40L浓度，进行自身前后对照。结果治疗前后血浆sCD40L分别为（0．20±0．16）μg／L和（0．19±0．18）μg/L（P〉0．05）；治疗前后PRP受ADP诱导后20min释放的sCD40L浓度分别为（4．3±2．5）μg／L和（2.8±1．9）μg／L（P〈0．001），诱导后40min释放的sCD40L浓度分别为（5．3±3．1）μg／L和（2．9±1．6）μg／L（P〈0．001）。结论短期应用氯吡格雷可能对非sT段抬高急性冠状动脉综合征患者血小板炎症因子sCD40L释放具有抑制作用，提示氯吡格雷很可能具有抗炎效应．     

The effects of antiplatelet agents on platelet–leukocyte aggregations in patients with acute cerebral infarction

Background Studies have shown that platelet-leukocyte aggregates (PLA) are sensitive to platelet activation which might exist before the onset of cerebral infarction. In this study, we investigated the formation of PLA in patients with cerebral infarction and the effects of antiplatelet agents on PLA. Methods The level of soluble P-selectin, C-reaction protein, platelet aggregation rate and leukocyte-platelet aggregations were measured in 40 patients with acute cerebral infarction and 20 normal controls. The 40 patients were randomly assigned to two treatment groups: aspirin group (n = 20) and clopidogrel group (n = 20). Both groups were monitored for Scandinavian stroke scale (SNSS), soluble P-selectin, serum C-reaction protein, platelet aggregation rate and PLA before and after the treatment. Flow cytometry was used to detect the levels of PLA in the blood. Results The percentage of platelet-monocyte aggregates (PMA) in patients with cerebral infarction was significantly increased compared with the controls (P < 0.001), which was positively correlated to soluble P-selectin, C-reaction protein and platelet aggregation rate (P < 0.05). After the treatment, the levels of PMA and platelet aggregation rate were decreased in both groups (P < 0.05). The level of PMA and platelet aggregation rate in the clopidogrel group was significantly lower than that in the aspirin group (P < 0.05). Conclusions PMA are a sensitive biomarker to platelet activation in patients with cerebral infarction. In addition, although both aspirin and clopidogrel lowered the level of PMA, clopidogrel is a more effective treatment than aspirin in inhibiting platelet activation.     

Platelet function profile post-clopidogrel therapy in patients with type 2 diabetes undergoing coronary stent implantation

Platelet dysfunction contributes to the increased risk of thromboischemic complications after percutaneous coronary intervention (PCI), particularly in type 2 diabetes. Little is known about the effects of glycemic control on platelet reactivity. We assessed adenosine diphosphate-induced platelet aggregation and flow cytometric expression of P-selectin in 90 patients (56 diabetic and 34 nondiabetic patients) undergoing coronary stent implantation after administration of clopidogrel as a potential predictor of poststent complications and its relation to glycemic control. Posttreatment platelet reactivity was significantly elevated in diabetic compared with nondiabetic participants and was associated with smoking, hypercholesterolemia, overweight, and cardiovascular ischemic events. A linear relationship was found between hemoglobin A1c in diabetic patients and platelet reactivity. Both methods (standard aggregometry and P-selectin expression) used for assessment of platelet function were positively correlated. Low responsiveness to clopidogrel detected by posttreatment platelet reactivity is a risk factor for ischemic events after PCI in diabetic patients.     

Enhanced P-selectin expression and increased soluble CD40 Ligand in patients with Type 1 diabetes mellitus and microangiopathy: evidence for platelet hyperactivity and chronic inflammation

Aims/hypothesis Platelet activation, endothelial dysfunction and inflammation may be involved in early stages of diabetic microangiopathy. We therefore investigated patients with Type 1 diabetes mellitus, without (n=19) and with (n=20) microangiopathy, matched for glycaemic control and duration of disease, and matched with healthy control subjects (n=27).Methods Platelet activation was measured as platelet P-selectin expression using whole blood flow cytometry and as soluble P-selectin by immunoassay. Von Willebrand factor antigen in plasma, serum soluble E-selectin, CD40 ligand (sCD40L) and C-reactive protein (CRP) served as markers for endothelial function and inflammation.Results Thrombin-induced platelet P-selectin expression was enhanced, and soluble P-selectin and sCD40L concentrations were increased in patients with microangiopathy compared with the control subjects (p<0.01 for both) and with patients without microangiopathy (p<0.05 for P-selectin expression and sP-selectin), whereas all three parameters were similar in patients without microangiopathy and in the control subjects. CRP and soluble E-selectin were increased in patients with microangiopathy, compared with the control subjects (p<0.01 and p<0.05), whereas von Willebrand factor did not differ between the groups.Conclusions/interpretation Microangiopathy in Type 1 diabetes is associated with platelet hyperactivity, endothelial dysfunction and low-grade inflammation, indicating an increased risk for cardiovascular disease.Abbreviations sP-selectin Soluble P-selectin - sCD40L soluble CD40 Ligand - CRP C-reactive protein     

Plasma, serum, and platelet expression of CD40 ligand in adults with cardiovascular disease

The application of soluble CD40 ligand (sCD40L) as a biomarker has garnered great scientific and clinical interest. However, there are many uncertainties with regard to the biology of sCD40L. Although presumed to be a marker of platelet activation, relative levels in plasma, serum, and platelet expression are unknown, as is the optimal method for its measurement. We measured CD40L from serum, platelet-poor plasma, and platelet surface in adults who had stable cardiovascular disease (CVD) and those who had unstable CVD (n = 40). Plasma sCD40L did not differ significantly between groups. Serum sCD40L was significantly lower (1.4 +/- 1.3 vs 5.2 +/- 3.7 ng/ml, p <0.001) and platelet membrane CD40L expression was higher (1.4 +/- 0.7% vs 0.9 +/- 0.6%, p = 0.03) in unstable compared with stable CVD. When the 2 groups were considered together, there was a significant correlation between plasma and serum sCD40L levels (rho = 0.4, p = 0.02) and negative correlations between plasma (rho = -0.3, p = 0.04) and serum (rho = -0.4, p = 0.01) sCD40L levels with platelet membrane CD40L expression. In unstable CVD, the correlation between sCD40L measurements was poor. Consistent with enhanced platelet activation, there was a positive correlation between platelet aggregation and surface CD40L expression (rho = 0.5, p = 0.02) and between platelet expression of CD40L and P-selectin (rho = 0.4, p = 0.05) in unstable CVD. There was no correlation between CD40L and platelet count or C-reactive protein. Only surface expression of CD40L compared with platelet-derived (plasma) or total (serum) CD40L level proved a reliable marker of platelet function in patients who had stable CVD and those who had unstable CVD. In conclusion, our data demonstrate the complex nature of CD40L and highlight the distinct processes of expression, shedding, and clearance of this ligand in patient populations.     

高负荷剂量氯吡格雷对急性冠脉综合征患者介入治疗后血清sCD40L和hs-CRP浓度的影响

目的探讨高负荷剂量氯吡格雷对急性冠脉综合征(acute coronary syndrome,ACS)患者介入治疗后血清sCD40L和高敏C反应蛋白(high-sensitivity C-reactive protein,hs-CRP)水平的影响。方法选择ACS患者190例分为高负荷剂量组94例(首剂负荷剂量600 mg,以后每天氯吡格雷150 mg,共用7 d,而后以每天氯吡格雷75 mg维持治疗)和标准剂量组96例(首剂负荷剂量300 mg,以后每天氯吡格雷75 mg维持治疗)。于服氯吡格雷前,经皮冠状动脉介入(percutaneous coronary intervention,PCI)治疗前,术后第1天,术后第7天,术后第30天血清sCD40L和hs-CRP的浓度,并记录患者术后1、3、6个月发生主要心血管事件、出血事件的情况。结果高负荷剂量组PCI治疗后不同时间点血清可溶性CD40配体(sCD40L)、hs-CRP浓度均低于标准剂量组,差异有统计学意义(P<0.05)。sCD40L与hs-CRP的变化趋势的相关性检验结果显示两者呈正相关(皮尔森相关系数r=0.128,P<0.001)。结论高剂量氯吡格雷比标准剂量氯吡格雷对sCD40L、hs-CRP的抑制作用更强;当氯吡格雷抑制炎症反应产物hs-CRP产生的同时也会抑制炎症产物sCD40L的产生。     

Thromboxane-dependent CD40 ligand release in type 2 diabetes mellitus.

OBJECTIVES: The goals of this study were to characterize the platelet contribution to soluble CD40 ligand (sCD40L), to correlate its formation with the extent of oxidative stress and platelet activation, and to investigate the effects of improved metabolic control and low-dose aspirin on these processes. BACKGROUND: Inflammation, oxidative stress, and platelet activation are involved in the pathogenesis of type 2 diabetes (T2DM) and its complications. The CD40-CD40L interactions result in inflammatory and pro-thrombotic responses. METHODS: Urinary 8-iso-prostaglandin (PG)F2alpha and 11-dehydro-thromboxane (TX)B2, in vivo markers of oxidative stress and platelet activation, respectively, plasma CD40L, and C-reactive protein (CRP) were measured in 114 T2DM patients and 114 control patients. A randomized, parallel group, 17-day study of aspirin (30, 100, or 325 mg/day) was performed in 18 T2DM patients. A similar study was performed in six healthy volunteers (aspirin, 100 mg/day). Twenty poorly controlled T2DM patients were studied before and after improved metabolic control. RESULTS: Compared with control patients, diabetic patients showed significantly higher levels of 8-iso-PGF2alpha, 11-dehydro-TXB2, sCD40L, and CRP. On multiple regression analysis, 11-dehydro-TXB2 and 8-iso-PGF2alpha excretion rates predicted sCD40L levels. Soluble CD40L linearly correlated with 11-dehydro-TXB2 (rho = 0.67, p < 0.0001), and both were reduced after one week of aspirin (p < 0.0026), with slow recovery over 10 days after aspirin withdrawal. Improved metabolic control was associated with a reduction in sCD40L, 8-iso-PGF2alpha, and 11-dehydro-TXB2. CONCLUSIONS: This study provides several lines of evidence for the dependence of sCD40L release on TXA(2)-dependent platelet activation in T2DM and provides novel mechanistic insight into the amplification loops of persistent platelet activation in this setting.     

氯吡格雷抑制急性冠状动脉综合征患者血小板释放可溶性CD40配体

目的 探讨在非ST段抬高急性冠状动脉综合征(non-ST-segment elevation acute coronary syndromes,NSTEACS)患者短期应用氯吡格雷是否有抑制ADP诱导血小板释放可溶性CD40配体(sCD40L)的作用.方法 NSTEACS 42例,患者服用氯吡格雷6～8 d,治疗前后采静脉血,提取富含血小板血浆(platelet rich plasma,PRP)并用二磷腺苷诱导血小板聚集和释放sCD40L,在不同时间点终止反应,用酶联免疫法测量sCD40L浓度,进行自身前后对照.结果 治疗前后血浆sCD40L分别为(0.20±0.16)μg/L和(0.19±0.18)μg/L(P＞0.05);治疗前后PRP受ADP诱导后20 min释放的sCDdOL浓度分别为(4.3±2.5)μg/L和(2.8±1.9)μg/L(P＜0.001),诱导后40 min释放的sCD40L浓度分别为(5.3±3.1)μg/L和(2.9±1.6)μg/L(P＜0.001).结论 短期应用氯吡格雷可能对非ST段抬高急性冠状动脉综合征患者血小板炎症凶子sCD40L释放具有抑制作用,提示氯吡格雷很可能具有抗炎效应.     

国产和进口氯吡格雷对经皮冠状动脉介入术后血小板功能的影响

目的观察国产氯吡格雷和进口氯吡格雷对冠心病患者经皮冠状动脉介入治疗(PCI)术后血小板功能的影响。方法将450例冠心病患者随机分为2组,其中国产氯吡格雷组230例,进口氯吡格雷组220例。另选健康对照组220例。两治疗组分别于PCI术前3天开始服用氯吡格雷,服用氯吡格雷前、PCI术前、术后10min及PCI术后1周检查血小板聚集率及血小板活化指标。结果冠心病患者血小板聚集率及血小板活化状态较健康对照组明显增高。治疗前国产和进口氯吡格雷组的血小板聚集率及血小板活化指标差异无统计学意义。两治疗组PCI术后10min血小板聚集率及血小板活化状态均较术前明显增高,PCI术后1周两治疗组之间差异无统计学意义。结论PCI术后血小板聚集率及血小板活化状态明显增高,国产和进口氯吡格雷均有良好的抗血小板作用,两者抗血小板聚集和活化的作用相似。     

Inflammatory response to percutaneous coronary intervention in stable coronary artery disease

Percutaneous coronary intervention (PCI) can be regarded as a model for mechanical induced plaque rupture. The objective of this study was to evaluate the inflammatory response to PCI in stable coronary artery disease (CAD) by analysing plasma levels of a wide range of inflammatory mediators. Consecutively, we included 36 patients with stable angina pectoris after successful revascularization by PCI with implantation of a bare metal stent (BMS) or a drug eluting stent (DES). Patients were followed for 7 days with serial measurements of inflammatory mediators in plasma. C-reactive protein (CRP) and Pentraxin 3 showed a statistical significant early increase after PCI peaking at 3 days and 3 h, respectively. Vascular cell adhesion molecule-1 (VCAM-1) increased significantly with a peak at 3 days, while E-selectin showed a statistical significant gradual decrease. Markers of platelet mediated inflammation showed increasing (CD40 ligand) and decreasing (P-selectin) levels after PCI. While monocyte chemoattractant protein, CCL21 and CXCL16 increased rapidly in response to PCI, Interleukin-8, CCL19 and RANTES decreased. Patients with DES had significantly lower levels of VCAM-1 and RANTES compared to those with BMS. A femoral access site was associated with higher CRP levels than a radial access site. The use of glycoprotein-IIb/IIIa-inhibitors was associated with significantly higher CD40L and RANTES levels. Our findings underscore the complex nature of the inflammatory responses during PCI in stable CAD, and suggest that simultaneous measurements of several markers may be needed to characterize these PCI-related responses. The responses were only in a minor degree influenced by stent type, access site and the use of glycoprotein-IIb/IIIa-inhibitors.     

Effect of clopidogrel pretreatment on inflammatory marker expression in patients undergoing percutaneous coronary intervention

Platelets play an important role in the inflammatory response. In a nonrandomized comparison, we examined the effect of clopidogrel pretreatment on platelet inflammatory marker expression in patients undergoing percutaneous coronary intervention (PCI). Platelet expression of the inflammatory markers CD40 ligand (L) and CD62 P-selectin (P) and serum levels of interleukin-6 and CD40L were compared in patients pretreated (>24 hours before PCI) or not pretreated with clopidogrel. Blood samples were obtained before and after the procedure, and from 18 to 24 hours later. Marker expression in resting and adenosine diphosphate (ADP) (50 micromol/L) and thrombin receptor activating peptide (TRAP) (10 micromol/L) activated samples was quantified by flow cytometry. Serum CD40L and interleukin (IL)-6 levels were determined by enzyme-linked immunosorbent assay. Seventy-nine patients were recruited into the study. Forty-two percent were pretreated with clopidogrel for a median of 5 days (range 1 to 1,325). Clopidogrel pretreatment was associated with lower ADP-activated platelet CD40L expression in baseline and postprocedural samples. Similarly, platelet CD62P expression at all time points in ADP-activated and in baseline and postprocedural TRAP-activated samples was lower in patients pretreated with clopidogrel. These differences remained after multivariate adjustment between the groups. Serum CD40L levels increased from 2.13 +/- 2.37 ng/ml at baseline to 4.77 +/- 3.86 ng/ml at 18 to 24 hours after the procedure (p <0.0001). Similarly, serum IL-6 levels increased at 18 to 24 hours after the procedure (14.8 +/- 42.0 pg/ml before vs 25.5 +/- 36.0 pg/ml at 18 to 24 hours after the procedure, p <0.0001). Clopidogrel pretreatment did not affect serum IL-6 or CD40L levels. Thus, clopidogrel pretreatment reduces platelet inflammatory marker expression in patients undergoing PCI.     

Phase I study of eptifibatide in patients with sickle cell anaemia

The α IIb β 3 antagonist eptifibatide is an effective treatment for patients with acute coronary syndromes (ACS). Platelet reactivity and CD40 ligand (CD40L) may play a role in the pathophysiology of sickle cell anaemia (SCA) similar to that in ACS, suggesting that inhibition of platelet aggregation and CD40L release by eptifibatide may benefit patients with SCA. Following eptifibatide infusion, safety and pharmacodynamic data were obtained from four SCA patients in their non-crisis, steady states. Eptifibatide was well tolerated, with no adverse changes in the haematological, biochemical or coagulation parameters studied. Eptifibatide did not increase plasma levels of platelet factor 4 or beta-thromboglobulin, P-selectin exposure or platelet:leucocyte aggregate formation. Moreover, decreases in platelet aggregation and soluble CD40L (sCD40L) levels achieved in SCA patients were comparable to those observed in the treatment of ACS. Finally, indicators of inflammation, macrophage inflammatory protein-1 α , tumour necrosis factor- α and myoglobin were reduced following eptifibatide infusion, while vasodilation correlatives, matrix metalloproteinases (MMP-2 and MMP-9) and leptin were increased. Based on these phase I results, eptifibatide may benefit SCA patients by inhibiting platelet aggregation, decreasing sCD40L levels and favourably altering plasma levels of inflammatory mediators.     

Platelet function in clopidogrel-treated patients with acute coronary syndrome.

Percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS) is associated with increased risk of thrombotic complications. ACS enhances platelet activation; whether pretreatment with clopidogrel is sufficient to suppress platelet function in patients with ACS is not known. This study assessed platelet function in patients with and without ACS prior to PCI and after pretreatment with a single dose of 600 mg clopidogrel. Blood samples of 402 patients prior to PCI with (n = 119) or without (n = 283) ACS were collected at least 2 h after 600 mg clopidogrel administration. Maximal platelet aggregation in response to ADP (5 and 20 micromol/l), collagen (4 microg/ml) and TRAP (25 micromol/l) was measured with optical aggregometry. Surface expression of glycoprotein IIb/IIIa and P-selectin was assessed with flow cytometry at baseline and after stimulation with 5 and 20 micromol/l ADP. Agonist-induced platelet aggregation did not differ significantly between patients with and without ACS (P > or = 0.15). Parameters of platelet activation (glycoprotein IIb/IIIa and P-selectin surface expression) were significantly higher in ACS patients at baseline and after 5 and 20 micromol/l ADP stimulation (P < 0.0001). Patients with ACS continue to exhibit increased platelet activation after pretreatment with 600 mg clopidogrel. This finding supports the need for additional platelet function inhibition during PCI in patients with ACS.