Current Role of Platelet Glycoprotein Ⅱ b/Ⅲ a Receptor Inhibitors in Clinical Trials of Cardiovascular Diseases

Thrombosis formation on disrupted atherosclerotic plaque is the most common acuse of cardiovascular diseases, in the pathophysiology, increased platelet reactivity is a descriptor of the risk of cardiovascular events in healthy persons and in patients with overt coronary artery disease. Regardless of the stimulus for activation platelet-platelet interation and thrombus formation is ultimately regulated through the GP Ⅱ b/Ⅲ a receptor

OBSERVATION OF MEGAKARYOCYTOPOIESIS IN HUMAN FETUS BY IMMUNOCYTOCHEMICAL STAINING WITH ANTI-PLATELET GLYCOPROTEIN ⅡB /ⅢA MONOCLONAL ANTIBODY

Fetal liver tissues obtained from 28 human fetuses with gestation age from 3 to 6 months and fetal bone marrow from 35 human fetuses from 3 to 7 months were observed by immunochemical staining with anti-platelet GPⅡ b / Ⅲa monoclonal antibody and ABC technique. In the fetal liver, megakaryocytes were wholly located among growing fetal liver cells and near foci of hemopoiesis. Some megakaryocytes in the fetal liver were small7890- lymphoid-like megakaryocytes. The size of megakaryocytes both in the fetal liver (14.79 ± 4.52μm) and in the fetal bone marrow (16.08±7.39 μm) was small, which did not vary significantly over the gestation age ranging from 3 to 6 or 7 months. However, the maturation stage of megakaryocytes in the fetal liver shifted to more mature stage with the advancement of gestation, although the maturation stage of megakaryocytes in the fetal bone marrow did not change with the advancement of gestation from 4 to 7 months, the megakaryocyte in the fetal bone marrow was less mature

人源性抗血小板膜糖蛋白Ⅱb/Ⅲa Fab噬菌体抗体库的筛选与鉴定

目的从已构建的人源性抗血小板膜糖蛋白(glycoprotein,GP)Ⅱb/ⅢaFab噬菌体抗体库中筛选人源性抗血小板膜GPⅡb/ⅢaFab抗体,并对特异性阳性克隆进行鉴定。方法以表达GPⅡb/Ⅲa的CHO123细胞包板,对人源性抗血小板膜GPⅡb/ⅢaFab噬菌体抗体库进行富集筛选,采用细胞ELISA法筛选特异性阳性克隆,用Western blot法鉴定表达蛋白与GPⅡb/Ⅲa结合的特异性,将阳性克隆进行扩增、测序。结果以CHO123细胞富集淘筛3轮,并用ELISA法检测到2个高亲合力的特异性识别血小板膜GPⅡb/Ⅲa的克隆,Westernblot鉴定结果显示在阳性克隆的培养上清和细菌冻融上清均有特异性条带出现。对核苷酸序列进行同源性分析,证实这两个克隆轻链基因与人免疫球蛋白κ轻链的同源性分别高达97%和98%,重链基因与人免疫球蛋白Fd段的同源性分别高达94%和93%。结论利用噬菌体抗体库技术,成功地从人源性抗血小板膜GPⅡb/ⅢaFab抗体库中筛选出抗血小板膜GPⅡb/Ⅲa的特异性阳性克隆,该克隆具有较高的特异性,其克隆基因符合抗体可变区结构特点。

GpⅡb/Ⅲa基因多态性与冠心病关系的研究

目的探讨血小板膜糖蛋白(Gp)Ⅱb/Ⅲa基因多态性与冠心病的关系。方法选择冠心病患者86例(A组)和健康体检者80例(B组),运用聚合酶链—序列特异性引物技术进行GpⅡb人类血小板抗原3(HPA-3)及GpⅢa HPA-1多态性检测。结果A组和B组中GpⅡb HPA-3 aa、ab、bb基因型分布有统计学差异,A组ab、bb基因型的分布较B组高,A组b等位基因频率高于B组。GpⅡb HPA-3 ab和bb基因型在心肌梗死组中的分布、b等位基因频率高于非心肌梗死组。结论GpⅡb HPA-3b等位基因可能是冠心病的遗传易患因子,GpⅡb HPA-3可能为心肌梗死发生的遗传易感性标志,GpⅢa HPA-1基因可能与冠心病发生无关联。

血小板GPⅡb/Ⅲa受体拮抗剂在神经介入治疗中的应用

血小板糖蛋白(GP)Ⅱb/Ⅲa受体拮抗剂可以有效抑制血小板聚集。作为抗血小板新药,Ⅱb/Ⅲa受体拮抗剂在作用机制、用法、用量等方面都不同于阿司匹林、氯吡格雷等传统药物。认识Ⅱb/Ⅲa受体拮抗剂的药理作用和临床应用状况,对血管内介入放射学,尤其是对于抗血小板要求比较严格的神经血管内支架成形术围手术期的应用具有重要意义。

冠心病患者与健康老年人血小板表面蛋白酪氨酸磷酸酶、P-选择素及膜糖蛋白Ⅱb/Ⅲa的变化

目的探讨冠心病患者血小板膜上蛋白酪氨酸磷酸酶(CD148)的变化。方法采用流式细胞仪三色免疫荧光分析检测健康老年人和冠心病患者血小板膜上蛋白酪氨酸磷酸酶(CD148)的阳性百分率、蛋白酪氨酸磷酸酶(CD148)的几何荧光强度、P-选择素(CD62P)的阳性百分率、P-选择素(CD62P)的几何荧光强度及膜糖蛋白Ⅱb/Ⅲa复合物(PAC-1)的阳性百分率、膜糖蛋白Ⅱb/Ⅲa复合物(PAC-1)的几何荧光强度的表达水平。结果冠心病患者和健康老年人的血小板膜CD62P、CD62P几何荧光强度表达量相比较(6.24 vs 0.89,P<0.01;45.64 vs 25.38,P<0.05),差异有统计学意义;CD148、CD148几何荧光强度表达量相比较(7.12 vs 0.45,P<0.01;41.35 vs 20.12,P<0.01),差异有统计学意义;PAC-1及PAC-1几何荧光强度的表达量(22.64 vs 1.84,P<0.01;43.46 vs 22.45,P<0.01),差异有统计学意义,但与当日血压、血糖及血脂无相关关系。结论 CD62P及PAC-1、CD148是血小板活化的敏感指标,冠心病患者有血小板活化现象,为冠心病患者提供了理论检测指标。

vWF与GPⅡb/Ⅲa在血小板黏附、聚集中的作用及与PCI术并发症的关系

遗传性假血友病因子(vWF)是一种黏附、多聚糖蛋白,分布在血浆、血小板和内皮下,在血小板黏附到内皮下的过程中起着重要作用。GPⅡb/Ⅲa在凝血过程中的血小板黏附和聚集中也起关键作用,血小板激活导致GPⅡb/Ⅲa构型发生变化,继而使GPⅡb/Ⅲa受体与配体纤维蛋白原的结合加强,纤维蛋白原在相邻血小板分子间形成桥梁,导致血小板聚集的加速。经皮冠状动脉介入治疗术后并发症的发生与血小板的激活、血栓形成有关,本文旨在简述vWF和Ⅱb/Ⅲ在血小板黏附和聚集中的作用及其与经皮冠状动脉介入治疗(PCI)术后并发症发生的关系。

国产血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂替罗非班在急性心肌梗死支架置入术中的应用

目的 探讨国产血小板糖蛋白（GP）Ⅱb/Ⅲa受体拮抗剂替罗非班（欣维宁）在急性心肌梗死支架置入中的应用效果.方法 64例急性心肌梗死患者按入院先后顺序分成两组：冠状动脉内置入支架加用国产替罗非班组34例,冠状动脉内置入支架加用普通肝素组30例,观察两组患者用药后对冠状动脉再灌注的影响,并随访主要心脑血管事件和出血并发症.结果 用国产替罗非班组达到TIMI 2～3级血流的患者为97.1%（33/34）,达到3级血流的患者为91.2%（31/34）;用普通肝素组达到2～3级血流的患者为76.7%（23/30）,达到3级血流的患者为70.0%（21/30）,两组差异有统计学意义.国产替罗非班组的患者住院期间无主要心血管事件发生.结论 特异性血小板GPⅡb/Ⅲa受体拮抗剂国产替罗非班对改善急性心肌梗死后血流再灌注及临床预后具有积极作用.

血小板糖蛋白Ⅱb的基因多态性与脑梗死的相关性研究

目的从分子病因学的角度探索血小板糖蛋白(Glycoprotein,GpⅡb)的基因多态性是否与脑梗死的发生相关,为缺血性卒中的预防及进一步治疗提供理论基础.方法选取病例组122例,对照组99例,提取空腹静脉血白细胞中DNA,经聚合酶链反应(PCR)后,用限制性内切酶Fok I酶切,2.2%琼脂糖凝胶电泳,紫外分析仪观察.结果 GpⅡb组中≤70岁的人GpⅡbSer843等位基因的纯合子型与增加脑梗死的危险相关(P=0.029);将病例组和对照组中的男性,按照基因型bb组和(aa+ab)组进行分析,结果显示两组之间有显著差异(P=0.01,OR=2.194,95%CI=1.177～4.091).结论 GpⅡb Ⅱe/Ser843的基因多态性与脑梗死的发生相关.

Effects of glycoprotein Ⅱb/Ⅲa antagonists and chloride channel blockers on platelet cytoplasmic free calcium

Platelet activation plays an important role in thrombosis. Platelet glycoprotein Ⅱ b/Ⅲ a （ GPⅡ b/Ⅲ a ） is the receptor of fibrinogen. Platelet cross-linking with fibrinogen through GP Ⅱ b/Ⅲ a is the process of thrombosis. Ca^2＋ is an important intracellular second messenger in platelet activation. It has been reported that GP Ⅱ b/Ⅲ a receptors were involved in the calcium influx of activated platelet, and GP Ⅱ b/Ⅲ a receptor had characteristics of calcium channel or an adjacent calcium channel.

汉族人血小板膜糖蛋白Ⅲa PLA基因多态性与冠心病血瘀证的相关性

目的:观察血小板膜糖蛋白Ⅲa(glycoproteinⅢa,GPⅢa)PLA1/PLA2基因多态性和北京、河北地区汉族人中各基因型的分布频率,分析该基因多态性与冠心病、冠心病血瘀证易感性的相关性。方法:采用病例对照设计,筛选符合入选标准的110例冠心病血瘀证患者和102例冠心病非血瘀证患者为研究对象,另收集39例健康志愿者作为对照人群。所有入选病例均进行中医辨证分型,提取全血DNA,采用TaqMan探针技术检测PLA1/PLA2基因多态性。结果:TaqMan探针检测图谱表明,健康对照组、冠心病血瘀证组和冠心病非血瘀证组rs5918多态位点分型皆为纯合子TT型,即PLA1/PLA2型,而PLA1/PLA1(TC)型和PLA2/PLA2(CC)型缺如,未再进一步作统计学分析。结论:GPⅢaPLA1/PLA2多态位点不是汉族人冠心病和冠心病血瘀证的危险因素,相关的易感基因可能存在于其他多态位点中。

Safety, Pharmacokinetic and Pharmacodynamic Studies of Batifiban Injection Following Single-and Multiple-Dose Administration to Healthy Chinese Subjects

Batifiban, a synthetic cyclic peptide, is a potent platelet glycoprotein GPⅡb/Ⅲa antagonist which may be useful in the treatment and prevention of acute coronary syndromes. The pharmacokinetics and pharmacodymanic （inhibition of platelet aggregation） effects, and tolerability of batifiban were investigated in healthy subjects following single bolus injection with doses of 55, 110, or 220 μg/kg, or multiple doses of an bolus followed intravenous infusion for 24 h （180 μg/kg plus 2.0 μg/minokg, and 220 μg/kg plus 2.5μg/minokg） in this phase I clinical trial. Plasma levels of batifiban and areas under the curve were found to be proportional to doses. Batifiban was rapidly eliminated with a half-life of approximately 2.5 h. Significant differences were noted for plasma levels of batifiban and areas under the curve between males and females. No significant differences in the terminal half-life were found between males and females. Batifiban reversibly inhibited ex vivo platelet aggregation in a dose- and concentration-dependent manner, consistent with its mechanism as a GPⅡ b/Ⅲa antagonist. Single and multiple intravenous doses of batifiban were found to be safe and well tolerated in healthy subjects. These results support a bolus injection plus intravenous infusion regimen of batifiban for the treatment and prevention of acute coronary syndromes.

Comparison of efficacy and safety of native eptifibatide vs. tirofiban in patients with acute coronary syndrome undergoing percutaneous coronary intervention

To compare clinical outcomes and safety of eptifibatide or tirofiban in patients with acute coronary syndrome（ACS） undergoing percutaneous coronary intervention（PCI）. Methods：Thirty-six patients with ACS（unstable angina/non-ST-segment elevation myocardial infarction, UA/NSTEMI） who underwent PCI were randomly divided into two groups to receive eptifibatide or tirofiban treatment. Eptifibatide or tirofiban was predominantly initiated in the catheter laboratory before the intervention. In-hospital and 30-day MACE outcomes; bleeding as well as platelet counting were investigated in those two groups. Results：No in-hospital and 30-day MACE event occurred in the two groups. The number of ischemia leads after treatment reduced compared to that before PCI in the two groups. There was improvement in the number of ischemia leads for 24 h after administration in the tirofiban group than those in eptifibatide group（4.21 ± 2.46 vs. 3.89 ± 3.31, P =0.03）. The two groups showed no incidence of massive bleeding. Minor bleeding rates were 16.7% and 22.2% in the two groups respectively. Conclusion：Eptifibatide as an adjunct to PCI may further decrease the incidence of ischemia event in patients with ACS and improve the safety, but its long-term efficacy and side effects need further observation.

Efficacy and Safety of Tirofiban in Thrombolytic Therapyfor Ischemic Stroke

Objective:To evaluate the efficacy and safety of tirofiban hydrochloride in the treatment of ischemic stroke with thrombolytic therapy.Method:Two hundred patients with acute ischemic stroke thrombolysis were randomly divided into the experimental group and the control group.The experimental group was given tirofiban with the addition of rtpa in the control group and the therapeutic effects of the two groups were compared.Results:In comparison with the control group,the NIHSS improvement rate was 98%in the experimental group within 14 days.The platelet aggregation rate and efficacy in the experimental group were significantly reduced than the control group(P<0.01).The major adverse reaction in the two groups was hemorrhage with an incidence rate of 3%.Conclusion:Tirofiban hydrochloride is a highly effective and selective platelet glycoprotein Ⅱb/Ⅲa receptor inhibitor,which is safe and effective in combination with heparin and aspirin.

Gene Big Data-A Research for Monogenic Hypertension Diagnosis

This paper designed a detailed procedure for monogenic hypertension diagnosis by Whole Exome Sequencing(WES)and provided reliable precise medication guidance.Identification of mutated points provides the clinician valuable information for effective individualized therapeutic option.Therapeutic options that specifically restore the pathway disturbed by these point mutations can be selected to give a precise medicinal guidance.

血栓抽吸联合血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂在急性STEMI患者直接PCI中临床疗效的Meta分析

目的：评价血栓抽吸联合血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂（GPI）在急性STEMI患者直接PCI中的临床疗效。方法：计算机检索The Cochrane Library、PubMed、CNKI、万方数据库等关于急性STEMI患者直接PCI中应用血栓抽吸联合GPI的随机对照试验,按纳入与排除标准独立选择试验、资料提取和质量评价,对同质研究采用RevMan 5.2软件进行Meta分析。结果：最终纳入10项研究,共1 223例患者,分为试验组与对照组。Meta分析结果显示：与对照组相比,试验组主要心血管不良事件发生率（OR=0.55,95%CI：0.35~0.88,P=0.01）明显降低;TIMI 3级血流（OR=4.01,95%CI：2.55~6.32,P〈0.01）及ST段回落情况（OR=2.55,95%CI：1.89~3.44,P〈0.01）得到明显改善;试验组左室射血分数（OR=7.22,95%CI：6.03~8.42,P〈0.01）优于对照组。结论：血栓抽吸联合GPI的应用可以明显降低急性STEMI患者MACE发生率,增加TIMI 3级血流,改善术后ST段回落情况及左室射血分数。

不同血管分型的进展性缺血性脑卒中的基线特征及应用替罗非班的疗效

目的观察不同血管分型的进展性缺血性脑卒中(PIS)的基线特征及应用替罗非班的临床效果。方法回顾性选取2020年3月—2022年3月湘潭市中心医院收治的PIS患者89例,根据治疗方法不同分为观察组42例和对照组47例。对照组患者予以常规治疗及阿司匹林100 mg联合氢氯吡格雷75 mg抗血小板聚集,观察组患者在对照组基础上加用替罗非班治疗,根据责任血管(小动脉闭塞型和大动脉粥样硬化型)进一步亚组分析,比较各组NIHSS评分、住院时间,随访90 d,比较各组mRS评分、焦虑、抑郁及胃肠道出血发生率。结果观察组与对照组及各亚组基线特征、入院时NIHSS评分、加重时NIHSS评分比较差异均无统计学意义(P>0.05);观察组治疗7 d后NIHSS评分低于对照组,ΔNIHSS评分及随访90 d mRS评分良好率高于对照组,住院时间短于对照组(P<0.05)。根据责任血管分型的亚组分析显示,在小动脉闭塞亚组中,观察亚组加重7 d后的NIHSS评分低于对照亚组,ΔNIHSS评分及随访90 d mRS评分良好率高于对照亚组,住院时间短于对照亚组(P<0.05);而在大动脉粥样硬化亚组中,2亚组患者基线特征、入院时NIHSS评分、加重时NIHSS评分、治疗7 d后NIHSS评分、ΔNIHSS评分、住院时间及随访90 d mRS评分良好率比较差异均无统计学意义(P>0.05)。随访90 d,观察组与对照组及各亚组焦虑、抑郁、胃肠道出血发生率比较差异均无统计学意义(P>0.05)。结论与口服抗血小板药物比较,替罗非班对不同责任血管导致的PIS疗效可能存在差异,替罗非班可显著改善小动脉闭塞型PIS的神经功能缺损,疗效确切,且安全性高,值得推广应用。

急性心肌梗死患者经靶向灌注导管行梗死相关血管远端逆向用药球囊预扩张对冠状动脉血流的影响

目的探讨急性ST段抬高心肌梗死患者急诊直接经皮冠状动脉介入治疗(percutaneous coronary intervention,PCI)应用靶向灌注导管行梗死相关血管(infarct-related artery,IRA)逆向用药防治冠状动脉慢/无复流研究中小球囊低压力预扩张对其疗效的影响。方法回顾性分析46例急性ST段抬高心肌梗死患者在直接PCI前均应用靶向灌注导管行IRA靶病变远端逆向注射血小板糖蛋白Ⅱb/Ⅲa抑制剂替罗非班、硝酸甘油,根据在IRA逆向用药前靶病变处是否行球囊预扩张分为预扩张组(21例)和未行预扩张组(25例),比较两组的临床资料、术中慢/无复流现象发生率,并观察住院期间主要心血管事件。结果预扩张组患者慢/无复流的发生率9.5%,主要心脏事件发生率9.5%;未行预扩张组患者慢/无复流发生率8%,主要心脏事件发生率12%。结论两组患者慢/无复流和不良心血管事件发生率无明显差别,急性ST段抬高心肌梗死患者经靶向灌注导管行IRA远端逆向用药前IRA靶病变处小球囊低压力预扩张不增加慢/无复流的发生,不影响直接PCI治疗结果。

半量替罗非班在老年急性心肌梗死急诊经皮冠状动脉介入治疗的疗效和安全性

目的 探讨半量替罗非班对老年急性ST段抬高心肌梗死（STEMI）患者急诊PCI的疗效及安全性.方法 入选STEMI行急诊PCI老年患者114例,随机分为标准剂量组56例和半量组58例.标准剂量组给予替罗非班0.10~0.15 μg/（kg·min）静脉滴注48 h,半量组给予0.05~0.075 μg/（kg·min）静脉滴注24 h.比较2组TIMI及心肌染色分级（MBG）2~3级血流率,术后90 min的ST段回落百分比（sumSTR）、LVEF、左心室舒张末和收缩末内径变化及主要心脏不良事件、出血、消化道不良反应的发生率.结果 标准剂量组TIMI及MBG 2~3级血流率较半量组虽有升高趋势,但差异无统计学意义（P〉0.05）;2组术后90 min的sumSTR〉50%比例及患者住院期间不良事件发生率比较,差异无统计学意义（P〉0.05）;半量组出血发生率低于标准剂量组（3.45% vs 16.07%,P〈0.05）.结论 半量替罗非班在预防缺血方面的疗效与标准剂量相当,但在出血风险方面的安全性明显升高.

冠状动脉内注射替罗非班对急诊介入治疗中慢血流现象的临床疗效

目的探讨冠状动脉内注射血小板膜糖蛋白Ⅱb/Ⅲa受体拮抗剂治疗急诊PCI中出现冠状动脉慢血流现象(CSF)患者的临床疗效及安全性。方法入选99例急诊PCI中出现CSF的患者,根据是否冠状动脉内注射替罗非班,分为替罗非班组44例和对照组55例;比较2组PCI术后即刻TIMI血流,术后90min完全ST段回落率、住院期间以及3个月随访LVEF、主要不良心血管事件(MACE)和出血事件。结果与对照组比较,替罗非班组术后ST段回落率明显增加(84.1%vs 65.5%,P=0.036),LVEF改善情况明显提高[(7.74±4.21)%vs(5.17±3.63)%,P=0.002],2组术后3个月MACE发生率无明显差异(P=0.466);出血事件差异无统计学意义(P=0.302)。结论急诊PCI中出现CSF情况时,冠状动脉内注射替罗非班可改善心肌灌注,加快LVEF的恢复。