血栓与止血检测课件

*,本节标题,知识点,小点,具体内容,注释,更细详解,本节标题,知识点,小点,具体内容,注释,更细详解,本节标题,知识点,小点,具体内容,注释,更细详解,*,本节标题,知识点,小点,具体内容,注释,更细详解,*,止血与凝血障碍检查,Disorders of hemostasis and coagulation,止血与凝血障碍检查Disorders of hemostas,血管中流动的血液为什么不凝固,破损的血管为什么能止血,生理状态下,机体内存在着复杂的凝血系统和抗凝系统,凝血,血栓,抗凝,出血,血管中流动的血液为什么不凝固生理状态下机体内存在着复杂的凝血,作为一个临床医生,如何正确选择实验室检查项目,如何正确判断检验结果,首先应弄清正常的凝血与抗凝机制,作为一个临床医生如何正确选择实验室检查项目首先应弄清正常的凝,正常止血机能,两个方面,四个因素,凝血机制,抗凝机制,血管壁,（,vessel wall,）,血小板,（,platelet,）,凝血系统,（,coagulation system,）,抗凝及纤溶系统,（,anticoagulation,and fibrinolytic,）,凝血与抗凝机制的病理生理基础,正常止血机能两个方面四个因素凝血机制抗凝机制血管壁（vess,一、血管壁的止血与抗凝作用,（一）血管壁的止血作用,1.,血管壁的完整性,是防止出血的重要保证,血管内皮细胞之间及内皮下胶原,与,Vit c,有关,血小板参与血管壁的完整性和维持通透性,一、血管壁的止血与抗凝作用（一）血管壁的止血作用 是防止出血,血管壁完整性破坏的出血机制,当,Vit c,缺乏或,plt,减,少时，管壁抵抗力下降,内皮细胞间隙增大,脆性、通透性增加,RBC,及血液成分外溢,出血,血管壁完整性破坏的出血机制当Vit c 缺乏或plt 减内皮,良好的弹力纤维,-,保持血管壁的柔韧性,健全的神经纤维,-,维持血管壁的舒缩性,带负电荷的胶原纤维,-,启动凝血过程,2.,血管内皮下层,良好的弹力纤维-保持血管壁的柔韧性 2. 血管内皮下层,3.,血管内皮细胞产生,Von Willebrand Factor vWF (vW,因子,),Fibronectin Fn (,纤维结合蛋白,),Tissue Factor TF (,组织因子,FIII),Endouthelin ET (,内皮素,),3. 血管内皮细胞产生Von Willebrand Fact,.,神经反射 管腔收缩,血流变慢,出血,/,停止,.,内皮细胞分泌,vWF,、,Fn,促进,plt,粘附,.,释放,FIII,启动外源性凝血途径,.,暴露内皮下胶原,当血管壁受损后,促进血小板粘附,启动内源性凝血途径,.神经反射 管腔收缩 血流变慢当血管壁,当血管壁受损后的一系列变化,.,神经反射,管腔收缩,血流变慢,出血,/,停止,.,内皮细胞分泌,vWF,、,Fn,促进,plt,粘附,.,释放,FIII,启动外源性凝血途径,.,暴露内皮下胶原,促进血小板粘附,启动内源性凝血途径,当血管壁受损后的一系列变化.神经反射管腔收缩血流变慢出血,（二）正常血管壁抗血栓形成能力,血管内皮细胞合成,前列环素,(PGI,2,),扩张血管、抑制,plt,功能,纤溶酶原激活物,(PA),激活纤溶酶、清除小凝块,血栓调节素,(thrombomodulin TM),参与蛋白,C,系统的抗凝作用,肝素或类肝素物质 具有多种抗凝活性,（二）正常血管壁抗血栓形成能力血管内皮细胞合成,创伤、炎症,中毒、缺氧,管壁抗凝作用,病理性血栓形成,创伤、炎症管壁抗凝作用,血小板来自骨髓成熟的巨核细胞,（一）静态下血小板形态,蛋白质,glycoprotein GP,如：,GPI,a,I,b,II,b,a,代谢产生花生四烯酸、血栓烷,A,2,磷脂,(TXA,2,),、血小板 活化因子等,提供催化表面（,PF,3,）,二、血小板在止血机能中的作用,包膜,二、血小板在止血机能中的作用 包膜,（一）静态下血小板形态,膜下：,微管与微丝框架 变形 活化,胞浆：,血栓收缩蛋白 血凝块缩小、加固,三种特殊颗粒：,-,颗粒、致密颗粒、溶酶体,（一）静态下血小板形态膜下：微管与微丝框架 变形,1.,粘附功能（,adhesion function,）,指血小板具有粘附于血管内皮下胶原及其他,异物表面的能力,需要物质,GPIb-,vWF,III,型胶原,纤维结合蛋白（,Fn,）,（二）血小板功能,1.粘附功能（adhesion function） （二）,指活化后的血小板与血小板之间相互连接,的特性,参加因素,GPIIb/IIIa,纤维蛋白原,钙离子,聚集诱导剂,：,ADP,、肾上腺素、,TXA,2,、花生四烯酸,2.,聚集功能（,aggregation function,）,IIb,IIb,指活化后的血小板与血小板之间相互连接2.聚集功能,粘附与聚集的结果,血小板大量聚集、,粘附于血管破损处,形成白色血栓,暂时止血,粘附与聚集的结果血小板大量聚集、形成白色血栓暂时止血,3,释放功能 ：,(release reaction),指血小板在诱导剂的作用下，将胞浆内特殊,颗粒中的内含物释放出血小板的反应,-,颗粒,致密颗粒,溶酶体,与血小板粘附、聚集、炎症反应、创伤修复,动脉粥样硬化等作用有关,3释放功能 ：(release reaction) 指血小,4,血块收缩功能,血凝块,血小板,血栓收缩蛋白,纤维蛋白网 收缩,血清被挤出,血块缩小加固,4血块收缩功能血凝块血小板纤维蛋白网 收缩血清被挤出,PF,3,提供凝血因子催化表面,5,血小板促凝活性,PF3提供凝血因子催化表面5血小板促凝活性,血小板止血功能（小结）,维持血管壁的完整性，毛细血管的通透性,粘附、聚集在血管破损处，形成白色血栓,释放活性物质，促进血小板聚集，增强,血管收缩,促进凝血过程,血块收缩，形成稳固血栓,血小板止血功能（小结） 维持血管壁的完整性，毛细血管的通透,三、凝血因子与凝血过程,血液由流动状态变为凝胶状态称,血液,凝固,。是由一系列凝血因子参加的、复杂,的酶促反应和分子聚合过程,三、凝血因子与凝血过程 血液由流动状态变为凝胶,分为三个阶段，两个途径（内源性、外源性）,第一阶段：凝血酶原激活物形成,第二阶段：凝血酶形成,第三阶段：纤维蛋白形成,分为三个阶段，两个途径（内源性、外源性）第一阶段：凝,目前公认的凝血因子共,14,个，按罗马字命名的有,12,个，尚有高分子量激肽原,(HMWK),，激肽释放酶原,(PK),大多数由肝脏产生，其中,II,、,VII,、,IX,、,X,合成依赖于,Vitk,，称,Vitk,依赖因子,正常情况下，所有因子都处于无活性状态,目前公认的凝血因子共14个，按罗马字命名的有12个，尚有高分,IIa Ca,2+,VIII- VIIIa III,Plt- PF,3,Ca,2+,IIa Xa,V,Va,Ca,2+,正常凝血过程（瀑布学说）,PF,3,磷脂,凝血酶原,(II),凝血酶,(IIa),纤维蛋白原,(I),可溶性纤维蛋白 稳固性纤维蛋白,内源性途径,胶原等带负电荷表面,PK,a,PK,XII,XIIa HMWK,外源性途径,组织损伤释放,组织因子（,III,）,XI XIa,IIa,IX IXa,VIIa VII,XIII,XIIIa,参加因子：,所需时间：,X,Xa,（凝血旁路）,VIII,、,IX,、,XI,、,XII V,、,X,、,II,、,I III,、,VII,Ca,2+,、,PF,3,、,磷脂,38min,正常凝血过程（瀑布学说）,四 、正常抗凝及纤溶系统,（一）细胞抗凝机制,单核,-,巨噬细胞,吞 噬,清 除,凝血过程有关 物质和产物,四 、正常抗凝及纤溶系统（一）细胞抗凝机制单核-巨噬细胞吞,（二）体液抗凝机制,血液中存在多种抗凝物质及抗凝系统,1,抗凝血酶,III,（,antithrombin III,，,AT-III,）,AT-III,灭活,IIa,、,IXa,、,Xa,、,a,、,XIIa,、激肽释放酶,肝素,（二）体液抗凝机制 血液中存在多种抗凝物质,2.,组织因子途径抑制物,(tissue factor pathway inhibitor TFPI),TF,a,a,TFPI,灭活,a,、,TF,、,a,TF,a,2. 组织因子途径抑制物(tissue factor,3.,蛋白,C,系统,蛋白,C,（,Protein C, PC,）,蛋白,S,（,Protein S, PS),血栓调节素（,thrombomodulin, TM,）,活化蛋白,C,抑制物,(activated protein C inhibitor, APCI ),3. 蛋白C系统蛋白C（Protein C, PC）,血管内皮细胞,蛋白,C,蛋白,C,a,凝血酶,血栓,调节素,APCI,灭活,Va,、,a,激活纤溶系统,血管内皮细胞,蛋白,S,蛋白,C,系统抗凝机制,血管内皮细胞蛋白C蛋白Ca 凝血酶血栓APCI灭活Va、a,4,其它,肝素辅因子,-,（,HC-,）,抗凝谱同,AT-,活性仅,AT-,的,1/3,在肝素协同下作用可扩大,1000,倍,肝素（,heparin,）,生理状态下血液中含量甚微,最重要的抗凝作用是增强,AT-,和,HC-,效应,4其它 肝素辅因子-（HC-）,（三）纤维蛋白溶解系,（,fibrinolysis,，纤溶系统）,主要作用：分解纤维蛋白（原），清除血管,内由于纤维蛋白沉积引起的阻塞，保持血流通畅,最重要的生理性抗凝系统,XIIa PK,纤溶酶原,纤溶酶,u-PA t-PA,（三）纤维蛋白溶解系（fibrinolysis，纤溶系统）,纤维蛋白原 纤维蛋白单体 稳固纤维蛋白,纤溶酶 纤溶酶 纤溶酶,B,1-42,B,15-42,D,二聚体、多聚体,A,、,B,、,C,、,H A,、,B,、,C,、,H,X,、,Y,、,D,、,E X,、,Y,、,D,、,E X,、,Y,、,D,、,E,被降解的纤维蛋白（原）产物统称为,FDP,纤维蛋白原 纤维蛋白单体 稳固纤维蛋白,凝血因子,纤溶系统,血小板,抗凝系统,血管内皮细胞,血栓与止血检测课件,止凝血障碍性疾病的发病机制,血管壁结构与功能异常,血小板质与量异常,凝血因子质与量异常,抗凝及纤溶系统异常,循环中凝血及抗凝物质增加,综合因素,止凝血障碍性疾病的发病机制血管壁结构与功能异常,止凝血障碍的实验检查,止凝血障碍的实验检查,一、毛细血管抵抗力试验,(capillary resistance Test, CRT),又称毛细血管脆性试验或束臂试验,毛细血管壁完整性,内皮结构与功能,血小板质与量,异常,脆 性,通透性,压力,易出血,原 理,一、毛细血管抵抗力试验(capillary,方 法,血压计袖带,上臂加压,8min,在前臂直径,5cm,圆圈内计数出血点,(,收缩压,+,舒张压,)2,方 法(收缩压+舒张压)2,参考值,男性,0-5,个 女性,0-10,个,10,个为异常,意 义,本实验观察血管壁、血小板的综合止血作用,1.,异常提示：毛细血管脆性、通透性,2.,常见于：,血管壁结构与功能异常,血小板质与量异常,参考值,二、出血时间,（,bleeding time,BT,）,原 理,测定毛细血管被刺破后至自然止血所需,时间主要反映血管壁和血小板相互作用,二、出血时间（bleeding time,BT）原 理,方 法,用标准弹簧针或刀片刺破皮肤,2-3mm,深，观察出血自然停止的时间,参考值,Duke,法,1-3 min 4min,为延长,Ivy,法,2-6min 7min,为延长,BT,测定器法,6.92.1min 9min,为延长,方 法 用标准弹簧针或刀片刺破皮肤2-3mm,意 义,1.,BT,长短主要受血小板因素和血管壁,因素的影响,意 义1. BT长短主要受血小板因素和血管壁,意 义,2.,BT,延长,血小板明显,50,10,9,/L,血小板功能异常：血小板无力症或药物,影响（如阿斯匹林、潘生丁）,血管壁异常：遗传性毛细血管扩张症,综合：血管性假性血友病（,VWD,）、,DIC,意 义 2. BT延长,意 义,3,BT,缩短,某些严重高凝状态或血栓性疾病,心梗、脑梗、,DIC,高凝期,意 义3BT缩短,三、血小板计数,（,Platelet count,）,参考值,100-300,10,9,/L,400,10,9,/L,为增加,三、血小板计数（Platelet count）参考值,意 义,1,血小板减少,生成障碍：再障、白血病、骨纤、放射病,破坏过多：,ITP,、,SLE,、脾亢,消耗过多：,DIC,、,TTP,意 义1血小板减少,2,血小板增多,一过性增多：,急性大出血、溶血或脾切除术后,持续性增多：,骨髓增生性疾病：慢粒、真红、,原发性血小板增多症,意 义,2血小板增多意 义,血凝块,血小板,血栓收缩蛋白,纤维蛋白网 收缩,血清被挤出,血块缩小加固,原理,四、血块退缩试验,（,clot retraction test, CRT,）,血凝块血小板纤维蛋白网 收缩血清被挤出原理,方法,全血标本注入试管中，静置，观察,析出的血清占原有全血量的 百分比,表示血块退缩的程度,方法 全血标本注入试管中，静置，观察 表示血块退缩,参考值,30min-1h,开始退缩,18h-24h,完全退缩,退缩完全：,析出的血清,全血量,40-50%,参考值 40-50%,意义,1,主要用于血小板功能测定的初筛试验,2,退缩不良见于：,a),血小板功能异常或量,（尤其,正常对照,10s,以上者 延长,正常对照,5s,以上者 缩短,六、活化部分凝血活酶时间,（,activated partial thromboplastin time,APTT,）,原 理 XII 因子活化剂六、活化部分,与,CT,意义相同,延长：,1.,主要检测内源性途径的凝血因子缺陷,（如,、,、,/,血友病甲、乙、丙）,2.,其次检测第二、三阶段因子，如凝血,酶原、纤维蛋白原,3.,严重肝病、,DIC.,4.,循环中抗凝物质增多,5,普通肝素应用的首选监测指标,意 义,与CT意义相同 意 义,缩短,：,高凝状态,(hypercoagulation state),（脑血栓、心梗、,DIC,高凝期）,缩短：高凝状态(hypercoagulation stat,七、血浆凝血酶原,（,Prothrombin time, PT,）,原 理,组织因子,(,兔脑、胎盘、肺组织浸液,),Ca,2+,血浆,参考值,QUIK,法：,11-13s,七、血浆凝血酶原（Prothrombin ti,意 义,为外源性途径的筛选试验,延长：,1,因子,II,、,V,、,VII,、,X,单独或联合缺乏,2,严重纤维蛋白原降低（尤其,1g/L,时）,3,Vitk,缺乏症、严重肝病,4,纤溶亢进（如,DIC,后期）,5,循环中抗凝物质增加，如,SLE,6,口服抗凝剂的首选监测指标：,INR 2-3,意 义 为外源性途径的筛选试验,缩短：,高凝状态,（,hypercoagulation state,）,缩短： 高凝状态（hypercoagulation,八、凝血酶凝固时间,（,thrombin clotting time, TT,）,原 理,标准凝血酶,血浆,参考值,16-18s,超过正常对照,3s,为延长,八、凝血酶凝固时间（thrombin clo,意 义,主要检测凝血过程第三阶段,1,纤维蛋白原质与量异常,2,FDP,增多，如纤溶亢进,3,循环中抗凝物质增多，如,AT-,、肝素,样物质,4,异常球蛋白增多，如多发性骨髓瘤,意 义 主要检测凝血过程第三阶段,九、血浆纤维蛋白原定量,参考值,双缩脲法：,2-4g/L,4g/L,为异常,意 义,减少：,1,先天性纤维蛋白原缺乏症,2,DIC,（消耗过多）,3,严重肝病,增高：,1,高凝状态：血栓性疾病，急性炎症,手术创伤、恶性肿瘤等,2,生理性：部分正常老人，妊娠晚期,九、血浆纤维蛋白原定量参考值 双缩脲法：2-4g/L,十、血浆鱼精蛋白副凝试验,原 理,纤溶过程中,FDP,鱼精蛋白,十 游离,纤维蛋白单体 凝集,参考值,正常人阴性,（,plasma protamine paracoagulation test PPPT, 3P,试验）,十、血浆鱼精蛋白副凝试验原 理 （plasma pro,意 义,阳性：,1,提示血中,FDP,增多，见于,DIC/,纤溶亢进,2,溶栓治疗后,3,假阳性：大出血（创伤、手术、咯,血、呕血），恶性肿瘤、人工流产等,阴性：,1,正常人,2,原发性纤溶,3,DIC,晚期,意 义阳性：,初筛试验 筛选试验,确诊试验,实验项目的选择,N N N N,凝血因子异常可能,+,延长,N,不良 血小板功能异,常、,vWD,+ N/ N N,血管因素,+,延长,不良 血小板量减少,束臂,Plt,血块收缩 结 果,试验,BT,计数 试验 判断,初筛试验 筛选试验 确诊试验实验项目的选择 N,APTT,、,PT,、,TT,、纤维蛋白原定量检测,进一步做以下筛选试验,：,APTT、PT、TT、纤维蛋白原定量检测进一步做以下筛选试验,APTT,、,PT,、,TT,、纤维蛋白原定量,1.,仅有,APTT,延长,提示内源性途径因子异常：尤其是,、,IX,、,XI,不能用正常血浆纠正：提示抗,、,抗,IX,抗体存在,APTT、PT、TT、纤维蛋白原定量1.仅有APTT延长,2.,仅有,PT,延长,提示外源性因子异常,(FII,、,V,、,VII,、,X,）,Vitk,缺乏（,II,、,VII,、,IX,、,X,为,Vitk,依赖因子）,严重肝病,延长不被正常血浆纠正：循环中抗凝物质增多,APTT,、,PT,、,TT,、纤维蛋白原定量,2.仅有PT延长APTT、PT、TT、纤维蛋白原定量,3.,全部异常,纤维蛋白原缺乏症,FDP,增多,血中抗凝物质增多,肝功能衰竭,进一步做有关因子的测定,(,确诊试验,),APTT,、,PT,、,TT,、纤维蛋白原定量,3.全部异常APTT、PT、TT、纤维蛋白原定量,思 考 题,试简述凝血过程？,简述出血的临床诊断步骤？,思 考 题试简述凝血过程？,参 考 书 目,欧阳钦主编,.,临床诊断学（年制规划教材）人民卫生出版社,叶任高主编,.,内科学,.,第,5,版,.,人民卫生出版社,陈灏珠主编,.,实用内科学,.,第,11,版,.,人民卫生出版社,孙荣武等主编,.,临床实验诊断学,.,上海科学技术出版社,参 考 书 目欧阳钦主编.临床诊断学（年制规划教材）,参 考 书 目,Charles C J. Carpenter, M.D.,M.A.C.P. Cecil Essentials of Medicine (fifith edition). Health Sciences Asia, Elsevier Science.,HARRISONS PRINCIPLES OF INTERNAL MEDICINE 15th edition,参 考 书 目Charles C J. Carpent,73,The Examination of,Hemostasis and Coagulation,73 The Examination of,74,Question 1,When one was wounded or cut,why the bleeding can stop?,74Question 1When one was wound,75,Question 2,Why the normal person not have a thrombosis in his blood vessels, and why the clot in some wounded vessel can dissolved and the vessel can open again?,75Question 2Why the normal per,76,Qustion 3,When a patient with excessive bleeding,the doctor how to do clinical assessment?,76Qustion 3When a patient with,77,Question 4,After the clinical assessment , how to evaluate the function of hemostasis and coagulation in laboratory?,77Question 4After the clinical,78,Normal hemostasis (1),Normal hemostasis involves the physiologic,balance,of,procoagulation,and,anticoagulation,factors that maintains liquid blood flow and the structural integrity of the vasculature.,78Normal hemostasis (1) Norm,79,Normal hemostasis (2),Vascular damage,results in initiation of the clotting with the goal of producing a localized platelet/fibrin plug to prevent blood loss; this followed by processes that lead to clot containment ,wound healing, clot dissolution and tissue regeneration and remodeling.,The blood vessels remain patent and deliver adequate organ blood flow.,79Normal hemostasis (2) Vasc,80,Normal hemostasis (3),Procoagulation,Anticoagulation,Vascular wall Fibrinolytic system,Platelets Antithrombin III,Coagulation factors APC and protein S,TFPI,80Normal hemostasis (3)Procoag,81,What will happen? hamorrhage,Normal hemostasis,Procoagulation,Anticoagulation,Vascular wall Fibrinolytic system,Platelets Antithrombin III,Coagulation factors APC and protein S,TFPI,81What will happen? hamorr,82,What will happen? Thrombosis,Normal hemostasis,Procoagulation,Anticoagulation,Vascular wall Fibrinolytic system,Platelets Antithrombin III,Coagulation factors APC and protein S,TFPI,82What will happen? Thromb,83,Normal hemostasis_ vascular wall physiology (1),Vascular endothelial cells (ECs) function as :,(1)A barrier to contain and prevent blood from contacting the highly thrombogenic subendothelial contents;,(2)Coagulant properties:collagen, FVIII, fibrinectin, integrins, PLT-EC adhesion molecule-1, selectins(E- and -P), vWF.,(3)Vasoconstriction,83Normal hemostasis_ vascular,84,Normal hemostasis_ vascular wall physiology (2),(4)Anticoagulant:,Vasodilation Thrombomodulin,ADPase Tissue factor pathway,Heparan sulfates inhibitor (TFPI),Nitric oxide Tissue plasminogen,Prostacyclin activator (t-PA),84Normal hemostasis_ vascular,85,Normal hemostasis_ vascular wall physiology (3),ECs procoagulant ECs anticoagulant,85Normal hemostasis_ vascular,86,Normal hemostasis_ vascular wall physiology (4),When ECs are demaged or activated:,ECs procoagulant ECs anticoagulant,86Normal hemostasis_ vascular,87,Normal hemostasis_ vascular wall physiology (5),The procoagulation of ECs is mediated by both the ECs themselves and by the subendothelial matrix,which is exposed by vascular injury.,Activated ECs express on their surface adhesion ligands, including selectins, -integrins, platelet-EC adhesion molecule-1, and von Willebrand factor.,87Normal hemostasis_ vascular,88,Normal hemostasis_ vascular wall physiology (6),On the EC surface, these proteins localized and promote,platelet adhesion,and also mediate migration of leukocytes into tissues.,Exposed subendothelial matrix binds vWF and contains other procoagulant adhesive moieties, including thrombospondin, fibronectin, and collagen.,88Normal hemostasis_ vascular,89,Normal hemostasis_ vascular wall physiology (7),These functions both as ligands to capture platelets and as activators of adherent platelets.,Collagen in particular is a strong platelet agonist causing platelets to underg dense granule release and to express conformationally active ligands, such as GPIIb/IIIa.,89Normal hemostasis_ vascular,90,Normal hemostasis_ vascular wall physiology (8),Another critical procoagulant mediator exposed by EC damage is,tissue factor(TF),which is constutively expressed by subenthelial smooth muscle cells and fibroblasts.,TF is the major initiator of the soluble coagulation system that results in the formation of a definitive fibrin clot.,90Normal hemostasis_ vascular,91,Normal hemostasis_ vascular wall physiology (10),The normal ECs that surround the site of injury exert,anticoagulant properties,that prevent propagation of clot beyond the injury, thereby avoiding thrombosis of the entire vessel.,91Normal hemostasis_ vascular,92,Platelet physiology : morphology (1),Small anucleate cell fragments,1.5-3.0m,Granules,92Platelet physiology : morph,93,Platelet physiology platelet formation (2),Megakaryocyte,Platelets,formation of demarcation membranes,93Platelet physiology platele,94,Platelet physiology ,Platelet function (3),Platelet adhesion,Platelet activation, releases reaction,Platelet aggregation,Support of local coagulation,94Platelet physiology Platel,95,Platelet physiology (4),Receptor-ligand interactions promoting adhesion,(1) GPIb/IX:vWF,(2) GPIIb/IIIa : fibrinogen and,GPIIb/ IIIA :vWF,(3) GPIa/IIa : collagen,(4) P-selectin:P-selectin glycoprotein,ligand-1,95Platelet physiology (4)Recep,96,Platelet physiology (5),Receptor-ligand interactions mediating activation:,(1) GPV: thrombin,(2) GPVI: collagen,96Platelet physiology (5) Re,97,Secreted -granule proteins:,(1) Ligands (fibrinogen, fibronection thrombomodulin, vWF),(2) Enzymes (,2,-antiplasmin,FV,FVIII, and FXI),(3) Antiheparin (PF4),97Secreted -granule proteins:,98,Platelet physiology (7),Secreted dense granule agonists:,ADP,serotonin,Secreted cytosolic FXIII,Thromoxane A2 formation,Phosphatidylserine expreession,98Platelet physiology (7) Sec,99,Coagulation cascade(1),Coagulation factors:,(1) The liver is the major site of synthesis of most of the coagulation factors,(2) The factor VIII is produced not only by the liver but also by ECs and cells of the reticuloendothelial system,99Coagulation cascade(1)Coagul,100,Coagulation cascade (2),(3),Vitamin K dependent factors, including FII, FVII, FIX, FX ( procoaglants), protein C, protein S (anticoagulants), post their translation modification are added 10 to 12 -carboxyglutamate residues;These residues is critical for calcium binding and for determining the function structure of the proteins and their proper binding to membrane surface.,100Coagulation cascade (2) (,101,For the perspective of laboratory testing, the,coagulation cascade,can be divided into what are traditionally termed the,extrinsic,and,intrinsic,pathways,which converge on the common pathway and lead to thrombin and fibrin formation.,101 For the perspective of l,102,Coagulation cascade (4),In the physiological condition, the extrinsic pathway is,main pathway,and the,tissue factor,is a,initiator,. Tissue factor is constitutively expressed on subendothelial fibrobalats and smooth muscle cells that are only exposed to blood by EC damage. TF is also expressed on peripheral monocytes and vascular endothelial cells, after exposure to activating or inflammatory stimuli.,102Coagulation cascade (4) I,103,Coagulation cascade (5),The coagulation in vivo is propagated by enzyme complexes that function effectively only on phospholipid membrane surfaces.,The appropriate phopholipid surface appears to be predominantly supplied by the platelets.,103Coagulation cascade (5) Th,104,Coagulation cascade (6),Platelet-expressed phophotidylserine accelerates procoagulant enzymatic reactions and simultaneously protects activated factors from circulating inhibitors.,TF-FVIIa converts FX to Fxa and FIX to FIXa, both of which are bound to platelet receptors.This process culminates in accelerated thrombin generation.,104Coagulation cascade (6)Plat,105,Coagulation cascade in vivo(8),TF-bearing cell,Prothrombin Thrombin aPLTs,TF FVIIa,FX FXa,Fribrinogen Fibrin,FXI,FXIa,FIX FIXa,FVIII FVIIIa,A-PLTs,FV FVa,FX FXa,XIIa,A-PLTs,FVa,Kallikrein,HMWK,Contact,TFPI,FXIII FXIIIa,105Coagulation cascade in vivo,106,Coagulation cascade (9),Intrinsic,XII,XI XIa,XIIa,Kallikrein,HMWK,Contact,PK,IX,Ixa+,VIIIa,VIII,X,Xa V,Xa.Va.II,Thrombin,Fibrinogen Fibrin monomer Fibrin polymers,TF,TF.VIIa,VII,XIII XIIIa,Extrinsic,106Coagulation cascade (9)Intr,107,Endogeneous anticoagulant pathway,X,Va.Xa.II,Thrombin,TFPI,TF.VIIa,ATIII,IX IXa,VIIIa,APC,PS,Thrombomodulin,Fibrinogen Fibrin clot,PC,PS,107Endogeneous anticoagulant p,108,Endothelial-associated fibrinolysis (1),(1),Intravascular fibrinolytic activity results from a balance between plaminogen activators (t-PA,u-PA) and inhibitors (PAI-1,2,-antiplasmin).,(2) Regulation of fibrinolysis occurs at the endothelial surface.,108Endothelial-associated fibr,109,Endothelial-associated fibrinolysis (2),(3),Vascular endothelial cells synthesize and secrete t-PA and PAI-1.Plasminogen activation to plasmin is boosted by cell surface-associated t-PA, especially in the presence of fibrin clot, and to a lesser extent by the relatively small circulating amounts of u-PA.,(4) Inhibition of plasmin is mediated by ,2,-antiplasmin and ,2,-macroglobin.,109Endothelial-associated fibr,110,Endothelial-associated fibrinolysis (3),Plasminogen,Plasmin,Fibrin clot polymer,Fibrin degradation,Products (X,Y,D-dimer),t-PA,PAI-1,-Antiplasmin,EC,u-PA,XIII,110Endothelial-associated fibr,111,Clinical assessment of excessive bleeding (1),(1),Is there a bleeding disorder?,No:,No bleeding on previous challenge,Local cause identified,Family history negative,Laboratory investigation not required,Yes or