1、止血、凝血机制,正常止血机制,初期止血血管内皮细胞损伤，内皮下组织成分暴露（主要为胶原），血小板发生黏附、聚集和释放反应，形成血小板血栓 二期止血凝血、抗凝和纤溶诸系统相互协调、有序完成的过程，血浆中一系列凝血因子经级联酶促反应依次被活化,最终形成纤维蛋白凝块,Normal hemostasis（止血）,adhesion粘附,aggregation聚集,coagulation pathway 凝血途径,初期止血机制,TXA2,ADP,纤维蛋白原,凝血酶,PF4-TG PDGF,纤维蛋白,PGI2,聚集,白色血栓,释放,粘附,v WF,EC SE,+,+,Fibrin,Fibrinogen,Pr
2、othrombin,Thrombin,FVa,FX,FXa,FVIIIa,FIXa,TF/FVIIa,Generation of thrombin,TF/FVIIa,Platelets adhere to VWF bound to sub-endothelium collagen,The platelet is activated and fibrinogen and other adhesive proteins engage with GpIIb/IIIa,Tissue factor initiates thrombin generation. Thrombin activates fac
3、tors V and VIII,Thrombin converts fibrinogen to fibrin,Fibrin acts as a cofactor for thrombin-dependent FXIII activation.,+,+,FVIII,FV,Procoagulant,Fibrin,Fibrinogen,Prothrombin,Thrombin,FVa,FX,FXa,FVIIIa,FIXa,Procoagulant roles for thrombin,TF/FVIIa,1,2,3,4,TF/FVIIa,Thrombin binds to GpIba, cleaves
4、 PAR and GpV (not shown) and further activates platelets,Platelet,Activated Platelet,exposure/engagement,GpIIb + GpIIIa GpIba + GpIb + GpIX + GpV GpIa + GpIIa,Procoagulant,+,+,Fibrin,Fibrinogen,Prothrombin,Thrombin,FVa,FX,FXa,FVIIIa,FIXa,TF/FVIIa,5,PARs activated,Procoagulant roles for thrombin,6,Gp
5、V cleaved,TF/FVIIa,Thrombin bound to GpIba activates FXI, leading to further thrombin generation,+,+,Procoagulant,Fibrin,Fibrinogen,Prothrombin,Thrombin,FVa,FX,FXa,FVIIIa,FIXa,Procoagulant roles for thrombin,TF/FVIIa,FXIa,7,TF/FVIIa,Thrombin proteolytically inactivates ADAMTS13, preventing destabili
6、sation of the platelet plug,+,+,Fibrin,Fibrinogen,Prothrombin,Thrombin,FVa,FX,FXa,FVIIIa,FIXa,Platelet-plug enhancing role of thrombin,TF/FVIIa,High MW vWF multimers,Lower MW vWF multimers,ADAMTS13,8,TF/FVIIa,The haemostatic plug expands in an unregulated manner,Cofactor competition between TM and f
7、ibrin abruptly halts plug expansion,+,+,Thrombomodulin,Fibrin,Fibrinogen,Prothrombin,Thrombin,FVa,FX,FXa,FVIIIa,FIXa,Anti-fibrinolytic role of thrombin,TF/FVIIa,TAFI,TAFIa,Inhibition of fibrinolysis,9,TF/FVIIa,Fibrin monomer,Endothelial cell surface,VWF前体的结构,VWF前体是2813个氨基酸的多肽，包括22个氨基酸的信号肽，741个 氨基酸的前
8、导肽和2050个氨基酸的成熟肽（单体）；, VWF主要是由内皮细胞和巨核细胞合成，血浆中的VWF 主要来源于内皮细胞； VWF前体在分泌前经历一系列化学修饰，如内质网中 proVWF二聚体化、N-糖基化；高尔基体中O-糖基化、 N-侧链碳水化，蛋白水解、 proVWF二聚体多聚体化及 vWF多聚体形成等； 成熟的VWF多聚体或者直接分泌入血浆或储存在内皮细 胞Weibel-Palade小体或血小板颗粒中； 分泌到血浆中的VWF多聚体或被肝脏清除或在足够剪切 力时被vWF切割酶ADAMTS13在VWFA2区Y1605-M1606处切割；,VWF的代谢,VWF的生理作用,血浆VWF水平的影响因素,
9、 遗传因素（75%）vWF部分基因多态性影响VWF血浆水平ABO血型系统：VWF血浆水平在O型人群中最低而 在AB血型的人群中最高，且O型人 群冠心病的发病率也明显低于非O 型人群； 非遗传因素: 年龄；炎症；高血糖;压力等；, 分为1型、2型（2A、2B、2N、2M）、3型； 多为常染色体显性遗传，3型和2N型为常染色体隐形遗传； 皮肤紫癜、粘膜出血，特别是牙龈和鼻出血最常见，女性患 者表现为月经增多； 发病机制： VWF质或量的异常；,血管性血友病概述,血栓性血小板减少性紫癜(TTP),五联征 发热; 血小板减少性紫癜； 微血管性溶血性贫血； 精神、神经系统异常； 肾脏损害；,ADAMTS
10、-13 consist of a signal peptide (S), a short propeptide (P), a metalloprotease domain, a disintegrin-like domain (Dis), 8 thrombospondin-1 repeats (numbered 18), a Cys-rich (Cys) and spacer domain ， two CUB domains and metalloprotease domain (M). The M domain cleaves the Tyr1605Met1606 bond within V
11、WF domain A2; the Cys-rich and spacer domains interact with additional features of VWF domain A2.,ADAMTS-13的结构,TTP发病机制模式图,ADAMTS13,vWF,antibody,获得性TTP,遗传性TTP,血浆vWF水平的正常分布范围较宽，95%的可信区间：50IU/dL-200IU/dL；低的血浆vWF水平易导致出血，而高水平的血浆vWF有血栓倾向，但在正常血浆vWF水平与病理状态之间并无明显界限,Deficiency of factor VIII or IX results in
12、recurrent joint and soft tissue bleeding.,The genes for factor VIII and IX are on the long arm of the X-chromosome. Monogenic defects resulting in hemophilia consist of point mutations, deletions, and inversions.,FVIII,FIX,Bleeding symptoms correlate with deficiency: severe bleeding with severe (5%)
13、 deficiency.,x-chromosome,Hemophilia A and B,carrier,affected,X-linked Inheritance,50%,50%,100%,0%,Techniques for carrier testing, prenatal diagnosis, and, with gene transfer methods, preimplantation genetic modification,SPANISH ROYALTY,GERMAN ROYALTY,BRITISH ROYALTY,RUSSIAN ROYALTY,Alexei,Alexandra,Alice,Elizabeth II,George VI,George V,Edward VII,Queen Victoria,Prince Edward,Leopold,Beatrice,Waldemar,Irene,Henry,Rupert,Alphonso,Gonzalo,Leopold,Maurice,Alice,Victoria,. . . X-linked recessive pattern of inheritance,carrier,affected,The Royal Disease,
