Delayed thrombin-induced platelet-fibrin clot generation by clopidogrel: a new dose-related effect demonstrated by thrombelastography in patients undergoing coronary artery stenting

BACKGROUND: We have previously demonstrated that clopidogrel reduces platelet activation and aggregation in patients undergoing stenting. However, the effect of the clopidogrel loading dose on the rate of thrombin-induced platelet-fibrin clot formation is unknown in this patient population. METHODS AND RESULTS: Using thrombelastography (TEG) we measured the time to platelet-fibrin clot formation (R), a marker of the speed of thrombin generation, in 120 patients undergoing elective coronary artery stenting treated with standard and high loading doses of clopidogrel. Platelet reactivity to adenosine diphosphate (ADP) by light transmittance aggregometry (LTA) was determined simultaneously. Measurements were made immediately before and at 24 h after clopidogrel treatment. Clopidogrel produced a prolongation in R (4.4+/-1.4 min pre vs. 5.4+/-1.7 min post, p<0.001) that directly correlated with the change in platelet aggregation (r=0.65, p<0.0001). Prolongation in R was greatest in patients treated with a high loading dose (p=0.004). CONCLUSIONS: Delayed thrombin-induced platelet-fibrin clot formation as measured by TEG is a newly reported dose-related effect of clopidogrel that may contribute to the overall antithrombotic properties of the drug in patients undergoing stenting. This effect was more marked in patients loaded with 600 mg, lending further mechanistic support for this dose of clopidogrel as a more effective antithrombotic regimen than the standard 300 mg dose. Measurement of R may serve as a new indicator of clopidogrel responsiveness.     

抗血小板药物对脑梗死患者血小板-白细胞聚集体的影响

目的观察急性脑梗死患者血小板一白细胞聚集体（PLA）的变化以及阿司匹林和氯吡格雷对其的影响。方法对急性脑梗死和对照组患者血小板聚集率（PAR）、可溶性P选择素（sP—sel）、C-反应蛋白（CRP）和PLA进行检测。同时将急性脑梗死患者随机分为阿司匹林组和氯吡格雷组,观察两组患者治疗前后斯堪的纳维亚神经卒中量表（SNSS）评分、PAR、sP—sel、CRP和PLA的变化。结果急性脑梗死患者血小板单核细胞聚集体（PMA）显著高于对照组（P〈0．001）;PMA水平与PAR、sP-sel、CRP、血糖、胆固醇和纤维蛋白原正相关（P〈0．05）;与SNSS评分负相关（P〈0．05）。脑梗死患者治疗后PMA、PAR明显下降（P≤0．001）,且治疗后氯吡格雷组PMA和PAR（ADP）降低较阿司匹林组更明显（P〈0．05）,但PAR（AA）两组间差异无统计学意义;sP-sel在氯吡格雷组治疗后显著下降（P〈0．001）。结论急性脑梗死患者反映血小板活化的敏感指标PMA明显增高,阿司匹林和氯吡格雷可以降低PMA水平,其中氯吡格雷作用较阿司匹林更为明显。     

Razaxaban,a direct factor Xa inhibitor,in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

Coactivation of platelets and the blood coagulation cascade contributes to the pathophysiology of arterial thrombosis. Combination therapy with antiplatelet and anticoagulant drugs may be needed for maximizing the prevention and treatment of arterial thrombosis. Few studies have thoroughly investigated the combined antithrombotic and bleeding effects of these antithrombotic agents. We, therefore, evaluated the antithrombotic and bleeding profiles of dual and triple therapy with razaxaban, a direct factor Xa inhibitor, plus aspirin and/or clopidogrel in rabbit models of electrolytic injury-induced carotid artery thrombosis and cuticle bleeding time, respectively. Compounds were infused either IV or into the portal vein from 1 h before arterial injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. We first evaluated the antithrombotic potency of razaxaban, and examined its ex vivo effects on coagulation parameters to confirm its selectivity. Antithrombotic ED₅₀ of razaxaban averaged 0.22 ± 0.05 mg/kg/h (n = 6). Razaxaban at 3 mg/kg/h IV produced full antithrombotic efficacy, increased significantly ex vivo activated partial thromboplastin time and prothrombin time by 2.2 ± 0.1- and 2.3 ± 0.1-fold, respectively, and inhibited ex vivo factor Xa activity significantly by 91 ± 5% (n = 6, P < 0.05) without affecting ex vivo thrombin activity. Razaxaban at concentrations up to 10 μM did not alter in vitro platelet aggregation responses to ADP, γ-thrombin or collagen. To identify additive or synergistic antithrombotic effects of the various combination therapies, we purposefully used marginally effective doses of razaxaban at 0.1 mg/kg/h, aspirin at 0.3 mg/kg/h and clopidogrel at 1 mg/kg/h. Dual combination of threshold doses of razaxaban and aspirin or clopidogrel produced an enhanced antithrombotic effect without further increases in bleeding time. When compared with dual therapy with aspirin and clopidogrel (38 ± 5% increase in blood flow), addition of razaxaban increased blood flow to 75 ± 5% without additional bleeding time effects (n = 6/group, P < 0.05). In summary, razaxaban was an effective antithrombotic agent in a rabbit model of arterial thrombosis. Low-dose razaxaban was useful in combination with sub-optimal doses of aspirin and/or clopidogrel for the prevention of occlusive arterial thrombosis without excessive bleeding. Presented in part at the 45th Annual Meeting of the American Society of Hematology, December 6–9, 2003, San Diego, California (abstr 3011), and at the XXth Congress of the International Society on Thrombosis and Hemostasis, August 6–12, 2005, Sydney, Australia (abstr P1852).     

Perioperative management of trauma patients admitted on clopidogrel (Plavix). A survey of orthopaedic departments across the United Kingdom

BACKGROUND: Clopidogrel (Plavix) is an anti-platelet drug recommended as lifelong treatment by NICE for all patients following stroke, MI, and peripheral vascular disease. It is also indicated for short-term use following cardiac stent insertion. It irreversibly inhibits platelets for up to 7 days. Current recommendations are to stop treatment 7 days before elective surgery. Current evidence shows that delay to surgery more than 4 days in patients with hip fractures increases postoperative mortality. OBJECTIVES: To determine current practice of orthopaedic surgeons in their management of patients taking clopidogrel admitted following a hip fracture to trauma units in the UK with respect to its peri-operative withdrawal and subsequent timing of surgery. To perform a review of the available literature and produce a suggested protocol for the peri-operative management of this rapidly increasing cohort of patients. DESIGN: National postal survey. PARTICIPANTS: Orthopaedic consultants representing each unit receiving trauma patients in the United Kingdom. RESULTS: There was a 57% response rate (139/244 UK trauma units). 41% (56) stop clopidogrel and operate immediately, 11% (15) stop clopidogrel for between 5 and 10 days pre-operatively, 10% (14) stop clopidogrel for 10 days preoperatively, 19% (26) continue clopidogrel and operate immediately, 19% (26) have another protocol. 15% (20) have written departmental guidelines. 2%(3) quoted published evidence for their practice. CONCLUSIONS: This study demonstrates that there are a wide variety of practices, largely based on anecdotal evidence. Most units (85%) have no formal guidelines. There is evidence in the cardiac literature of increased intra-operative bleeding in patients operated on while taking clopidogrel. There is likely to be an exponential rise in such patients presenting to trauma units and further research is required to guide best practice. Following review of the literature we propose an interim protocol for the withdrawal and resumption of clopidogrel peri-operatively in patients with hip fractures.     

血栓弹力图评价血小板花生四烯酸途径抑制率对血凝块形成的影响

目的了解血小板花生四烯酸途径抑制率对血凝块形成的影响及其与ADP受体途径抑制率的关系。方法联用阿司匹林和氯吡格雷的急性冠脉综合征80例,血栓弹力图测定血小板抑制率和花生四烯酸通道的α角、K时间、MA、TMA。结果花生四烯酸途径抑制率为（81.7±20.7）%,ADP受体抑制率为（65.9±25.3）%,α角为（48.2±15.9）°,MA为（20.8±14.2）mm,TMA为（13.8±7.5）min。随花生四烯酸途径抑制率增高,α角缩小,MA降低,TMA缩短,ADP受体抑制率增高（P〈0.05）,K时间延长并且无K时间病例增多。结论抑制血小板花生四烯酸途径不利于血凝块形成,随抑制率增高,血凝块形成减慢、强度变小;二条途径抑制率呈正相关。     

三联疗法治疗急性ST段抬高型心肌梗死的疗效观察

目的:观察氯吡格雷联合阿司匹林和尿激酶治疗急性ST段抬高型心肌梗死的临床疗效。方法:将2009年6月-2010年6月我院60例确诊的急性ST段抬高型心肌梗死患者随机均分为观察组(氯吡格雷联合阿司匹林和尿激酶治疗)和对照组(阿司匹林和尿激酶治疗),比较2组治疗急性ST段抬高型心肌梗死的临床疗效。结果:观察组总有效率为93.33%,对照组为63.33%,观察组疗效明显高于对照组,2组比较差异有统计学意义(P<0.01)。对照组不良反应发生率(33.33%)高于观察组(3.33%),2组比较差异有统计学意义(P<0.05)。结论:氯吡格雷联合阿司匹林和尿激酶治疗急性ST段抬高型心肌梗死疗效确切,不良反应少。     

Beneficial effects of clopidogrel on glycemic indices and oxidative stress in patients with type 2 diabetes

Objective of present study is to evaluate the possible role of clopidogrel in improving glycemic indices and oxidative stress in patients with type 2 diabetes.This study was performed on 42 uncontrolled type 2 diabetic patients at the specialized center for Endocrinology and Diabetes, Al-Rasafa Directorate of Health, Baghdad. All of the patients were treated with (glibenclamide 5 mg at morning) and randomized into two groups: the first group includes 22 patients treated with clopidogrel tablets (75 mg/day) for 2 months; the second group includes 20 patients treated with a placebo formula (sodium bicarbonate 200 mg/day) for the same period. Treatment with clopidogrel produced significant improvement (P < 0.05) in fasting serum glucose (FSG), fasting serum insulin level, quantitative insulin sensitivity check index (QUICKI); and oxidative stress markers: serum malondialdehyde (MDA) and serum reduced glutathione (GSH) compared to their baseline levels. There was significant elevation (P < 0.05) in both FSG and fasting serum insulin and the MDA level with significant reduction (P < 0.05) in QUICKI of placebo group compared to their baseline levels. However, clopidogrel produced significant elevation (P < 0.05) in AST and ALT levels but placebo formula caused no significant alteration (P > 0.05) in the serum levels of these two enzymes.In conclusion the treatment with clopidogrel improved glycemic indices and reduced oxidative stress in patients with type 2 diabetes.     

不同负荷剂量氯吡格雷治疗急性冠脉综合征的临床应用研究

目的比较不同负荷剂量氯吡格雷在经皮冠脉介入治疗(PCI)术前应用对治疗急性冠脉综合征(ACS)的有效性和安全性,对更高负荷剂量的氯吡格雷安全性进行评估。方法120例诊断为ACS的患者随机分为A、B、C三组(na=nb=nc=40),三组患者临床基本资料差异无统计学意义(p>0.05)。A、B、C三组分别于术前6h给予600mg、450mg和300mg负荷剂量氯吡格雷,观察服药前?服药后2h、4h、6h血小板聚集率,30天主要终点事件(住院期间休克、死亡、靶血管重建、再发心梗、心绞痛、脑卒中)及术后30天出血事件和不良反应发生情况。结果与标准的300mg方案相比,氯吡格雷600mg比氯吡格雷450mg前6h内对血小板激活的抑制程度更大。氯吡格雷负荷剂量的增加可减少30天主要心血管事件的发生率。三组30天出血事件和不良事件发生情况差异无统计学意义(p>0.05)。结论与300mg氯吡格雷负荷剂量相比,较高的氯吡格雷负荷剂量能够产生更快、更强的血小板抑制,且安全性相似。     

LC-MS/MS法测定人血浆中氯吡格雷的浓度及其药动学研究

目的:建立以高效液相色谱串联质谱电喷雾检测(LC-MS/MS)法测定人血浆中氯吡格雷浓度的方法,并研究其在健康人体内的药动学。方法:以噻氯匹定为内标,血浆样品经液-液萃取后,采用汉邦-C18柱进行分离,通过三重四极杆串联质谱仪,以多反应监测(MRM)方式进行测定。结果:氯吡格雷血药浓度在10～10000pg.mL-1范围内线性关系良好(r=0.9992);平均相对回收率在98.7%～100.8%之间,日内、日间RSD均≤13.01%。结论:本方法快速、简便、准确、灵敏,适用于氯吡格雷的人体药动学研究。