血栓与止血障碍的实验诊断-上交

1、血栓与止血障碍的实验诊断,交通大学 瑞金临床医学院 临床血液教研室 胡翊群,血栓与止血（thrombosis and hemostasis）涉及血管壁、血小板、血液凝固、抗血液凝固、纤溶系统和血液流变学等基础理论，也涉及上述各方面相应的实验检查，为研究和诊断出血性疾病和血栓性疾病所必需。本讲就血栓与止血的基础理论、实验室检查和临床诊断作一简述。,一百年前确定的Virchows血栓模式,导致血栓的各种因素,血管壁受损,血流改变（主要是血流缓慢、涡流）,血液凝固异常,基本理论（1）,出血的概念（BLEEDING） 血栓的概念（THROMBOSE） 出血性疾病（BLEEDING DISORDER，H

2、EMOPHILIA） 血栓性疾病（THROMBOTIC DISORDER） 易栓症（THROMBOPHILIA） 高凝状态（HYPERCOAGULABLE STATE） 低凝状态（HYPOCOAGULABLE STATE）,基本理论（2）,血栓止血理论的适用范围 小血管和微血管 大血管与粥样硬化的问题 血液流变学问题,Laboratory Investigation of Hemostasis,Procoagulant Factors,Coagulant regulative Factors,The Hemostatic Balance,APPROACH TO THROMBOSIS EVENT

3、S,Clinical approach,1.Is the bleeding significant ? 2. Local Vs Systemic ? 3. Platelet Vs Coagulation disorder ? 4. Inherited Vs Acquired ?,1. Demonstration of the defect 2. Identification of the defect(s) 3. Assessment of severity 4. Consequential studies eg. carrier detection 5. Monitoring of trea

4、tment,Laboratory Approach,传统上把直径大于100m的血管称为大血管。在血栓止血机制中，大血管的作用并不明显，但大血管管壁的三层结构界定清楚，并有着与其他血管不同的特殊结构。 1内膜 大血管的内膜(intima) 由内皮层(endothelium) 和内皮下组织(subendothelium)组成。在大血管内皮细胞具有特异性结构的成分是，胞质中都包含一个Weibel -Palade小体。小体的内容物是von Willebrand因子（也叫血管性血友病因子，vWF），外裹的膜上表达了P选择素（P-selectin）。生理情况下，内皮细胞紧密排列在基底膜上，内皮细胞和基底膜

5、共同构建起了双重防止血液外渗的屏障。内皮下组织则由少量平滑肌细胞和零散的巨噬细胞及其中填充的细胞外间质所组成的内皮下基质所构成。,2中膜 大血管的中膜（media）是较厚的一层。往往由一层基本的弹性蛋白质（elastic lamina）来隔离内膜，并最大限度地保持血管壁的形状和维持血管壁的质地。中膜层还具有相当数量的平滑肌细胞及其分泌的糖蛋白(glycoprotein)和蛋白聚糖(proteoglycans)。 3外膜 处在中膜外的一层疏松结缔组织被称为外膜（advertitia）。外膜中有些神经末梢和滋养血管，其主要作用是完整地、连续地将血管与周围组织器官分隔开。,小血管是参与止血作用的主要

6、血管。其中的小动脉、小静脉与大血管的结构基本相同，只是中膜略薄。 最具特殊性的是毛细血管（capillary）和后毛细血管（post- capillary venule）的管壁，是仅有内皮细胞和间质细胞组成的单层细胞结构所围成。这两种细胞根植于基底膜，依赖血管床而排列，细胞间存在大量基质，基质中的不少蛋白都由内皮细胞和间质细胞分泌而来。两种细胞可借助细胞旁小孔完成必要的联系。如果说小血管与大血管的内皮细胞具有类似的作用，那么长型的间质细胞却有着不同的功能。对间质细胞功能比较一致的看法是：具有收缩功能以调节进入组织的血流量；调节毛细血管的生长机制；具有促进脂肪细胞、巨噬细胞、成骨细胞和平滑肌细胞

7、分化的潜能。,血管止血功能,1.促血栓形成 血管收缩：自主神经能力增强、内皮素-1。 血管性血友病因子（von Willebrand factor，vWF）：参与血小板粘附。 胶原暴露：诱导血小板聚集。 组织因子（tissuefactor，TF）：激活凝血系统。 纤溶酶原激活抑制物-1（plasminogen activated inhibitor-1，PAI-1）：抑制组织纤溶酶原激活物（t-PA）和（u-PA）。,抗血栓形成,血管扩张：前列环素（prostacyclin，PGI2）、一氧化氮（nitric oxide，NO）和自主神经能力减低。 血栓调节蛋白（thrombomodulin，

8、TM）：与凝血酶结合形成复合物，激活蛋白C系统。 肝素类似物：硫酸乙酰肝素软骨素、抗凝血酶等。,VWF,VWF,VWF,VWF,VWF,VWF,collagen,collagen,collagen,collagen,Shear Flow,VWF,VWF,VWF,VWF,VWF,VWF,collagen,collagen,collagen,collagen,VWF,VWF,VWF,VWF,VWF,VWF,collagen,collagen,collagen,collagen,Blood Flow,Dense Granule,Platelet Aggregation,2凝血机制,1）经典凝血机制：

9、分内源、外源和共同三条途径。图10 2）修正凝血机制：TF/FVIIa复合物激活FIXa；Mg2+参与凝血反应；组织因子途径抑制物（TFPI）抑制TF/FVIIa和FXa；凝血酶激活FXI。图11,Amplification effect,Positive and negative feedback,Circulating inactive precursors,Surface localized clotting,Benefits of the Coagulation Cascade,抗凝血机制,1抗凝血酶（antithrombin，AT） 与肝素结合形成复合物，该复合物灭活凝血酶、FXa、

10、FIXa、FXIa、FXIIa等。 2蛋白C系统 包括蛋白C（PC）、蛋白S（PS）、血栓调节蛋白（TM）和内皮细胞蛋白C受体（EPCR）。 图12,Antithrombine,Thrombine,Endotheliocyte,Protine C,Thr,PC,EPRC,Thrombomoduline,Endotheliocyte,XII XIIa,XI XIa,IX IXa,X Xa,II IIa,Fibrinogen Fibrin,VIIIa+Ca+Pl,Va+Ca+Pl,纤维蛋白溶解（纤溶）系统,1纤溶成分 1）激活纤溶成分：组织纤溶酶原激活物（t-PA）、尿激酶型纤溶酶原激活物（u-P

11、A）、因子XIIa、激肽释放酶（K）、纤溶酶原（PLG）等。 2）抑制纤溶成分：纤溶酶原激活抑制物（PAI）和2-抗纤溶酶（2-AP）等。,2纤溶激活,在激活物（t-PA、u-PA）的作用下，PLG转变为纤溶酶（PL）。PL降解纤维蛋白（原）和其他凝血因子的过程。图13、图14 3纤溶降解 纤维蛋白原的降解产物（FgDP）有碎片X、Y、D和E等；纤维蛋白降解产物有碎片X、Y、ED等。纤维蛋白（原）的降解产物为FDPs。 图15,Fibrinogen Fibrin,Fibrin Polymerization and Cross Linking,FXIIIa,Plasminogen Plasmin

12、,IIa (thrombin),Fibrinolysis,XII XIIa,XI XIa,IX IXa,X Xa,II IIa,Fibrinogen Fibrin,VIIIa+Ca+Pl,Va+Ca+Pl,Fibrinogen Fibrin,Fibrin Polymerization and Cross Linking,FXIIIa,Plasminogen Plasmin,IIa (thrombin),Fibrinolysis,Secondary Hemostasis-Session Focus,Hypocoagulation disorders Inherited, e.g., hemoph

13、ilia Acquired, e.g., liver disease Hypercoagulation/Thrombosis Defects of Fibrinolysis Acquired disorders,Fibrinolysis-Plasminogen Activation,Intrinisic: factor XIIa, kallikrein, HMWK and plasma protein proactivator Extrinsic: tissue plasminogen activators (TPAs) Body fluids: secretory duct activato

14、rs Exogenous: urokinase, streptokinase and tissue plasminogen activator (tPA),Fibrin Degradation,FDP (FSP) fibrin degradation products (fibrin split products) Molecular fragments of fibrin clot Plasmin degrades both fibrin and fibrinogen FDP removed by reticuloendothelial system Final cleavage forms

15、 D (D-D dimer) and E fragments,Fibrin Degradation,D-D dimer test Indicative of in vivo fibrinolysis Specific for fibrin degradation (other tests also detect fibrinogen degradation) Effects of fibrin degradation products Inhibit coagulation Inhibit platelet aggregation May have life threatening conse

16、quences,Coagulation and Fibrinolytic Inhibitors,Coagulation, naturally occurring Antithrombin (AT) Synthesized in the liver Inhibits thrombin, XIIa, XIa, Xa, IXa, plasmin and kallikrein Forms enzyme inhibitor complexes Enhanced by heparin Naturally occurring heparin contained in mast cells (tissue b

17、asophils) and basophils,Coagulation and Fibrinolytic Inhibitors,Alpha-2-macroglobulin Alpha-1-antitrypsin C1 inactivator Protein C and S Fibrinolysis Alpha-2-antiplasmin Alpha-2-macroglobulin Alpha-1-antitrypsin Other: AT, C1,一）常用筛选试验 1一期止血缺陷 指血管壁和血小板的缺陷。常用筛选试验如下： 1）毛细血管脆性试验（capillary resistance tes

18、t,CRP） 2）出血时间（bleeding time, BT） (3)血小板计数（platelet count, Plt） (4)血块收缩试验(clot retraction test, CRT) 目的 结果判断 临床意义 评价,Bleeding Time Test,Timer is started upon incision,BT = Time to complete cessation of free blood flow,2二期止血缺陷,指凝血机制和抗凝机制缺陷。常用筛选试验如下： （1）活化的部分凝血活酶时间（activated partial thromboplastin time

19、, APTT） 2）凝血酶原时间（prothrombin time, PT） 3）纤维蛋白原含量测定（fibrinogen, Fg) 4）凝血酶时间（thrombin time, TT） 目的 结果判断 临床意义 评价,3纤溶系统,观察纤溶活性变化，常用筛选试验有： 1）纤维蛋白（原）降解产物测定（fibrin(ogen) degradation products, FDPs） 2）D-二聚体测定（D-dimer, DD） 目的 结果判断 临床意义 评价,三、临床诊断,一）临床特征 1一期止血缺陷特征 1）皮肤、粘膜出血为主，内脏出血少见。 2）创口即刻出血难止，持续时间不长。 3）压迫止血有

20、效，止血后不易复发。 4）有遗传性和获得性。,2二期止血缺陷特征,（1）深部组织出血为主，内脏出血常见。 （2）创口延迟性出血难止，持续时间较长。 3）输血制品有效，但易复发。 4）有遗传性和获得性。 3纤溶活性亢进特征 1）皮肤大片状瘀斑，粘膜、内脏出血。 2）创口以渗血为特征，尤其在损伤部位。 3）对抗纤溶药有效。 4）多为获得性。,（二）筛选试验诊断思路,1一期止血缺陷的思路 图21 （1）BT 和Plt （2）BT 和Plt 3）BT（N）和Plt（N） 4）BT 和Plt （N/ ）,2二期止血缺陷的思路,（1）APTT（N）和PT（N） 2）APTT 和PT （N） 3）APTT（

21、N）和PT 4）APTT 和PT 图22 3纤溶活性亢进的思路 1）FDP（-）和DD（-）： 纤溶活性正常，见于正常人。 2）FDP（+）和DD（+）：纤溶活性亢进，见于DIC、溶栓治疗。 3）FDP（+）和DD（-）：FDP假阳性，见于肝病等；原发性纤溶活性亢进。 4）FDP（-）和DD（+）：FDP假阴性，见于DIC等；DD假阳性。,四、临床应用,（一）血小板功能异常性疾病 表6 （二）血友病类出血性疾病 1.血友病（hemophilia） 表7 2血管性血友病（von Willebrand disease, vWD） 表8 三）肝脏疾病出血 凝血因子和抗凝蛋白的合成减少 凝血因子和抗凝

22、蛋白的消耗增多 循环抗凝物质和血FDP增多,I. Pathophysiology of Coagulation,NORMAL HEMOSTASIS System of interactions between: 1.BLOOD VESSEL WALL 2.PLATELETS 3.COAGULATION FACTORS Assures integrity of circulatory system after vessel injury,NORMAL AND PATHOLOGIC CLOT FORMATION _ _ Vessel Wall,NORMAL AND PATHOLOGIC CLOT

23、FORMATION _ _ Vessel Wall Endothelial Cells,NORMAL AND PATHOLOGIC CLOT FORMATION _ _ Vessel Wall Endothelial Cells,NORMAL AND PATHOLOGIC CLOT FORMATION _ _ / / _ Vessel Injury,NORMAL AND PATHOLOGIC CLOT FORMATION _ vv v _ / / _ Von Willebrand factor = v,NORMAL AND PATHOLOGIC CLOT FORMATION _ vv v _

24、vvvvvv_ Von Willebrand factor = v,NORMAL AND PATHOLOGIC CLOT FORMATION _ vv v _ vvvvvv_ Von Willebrand factor = vplatelet =,VII/TFNORMAL AND PATHOLOGIC CLOT FORMATION _ vv v _ vvvvvv_ Von Willebrand factor = vplatelet =,VII/TFNORMAL AND PATHOLOGIC CLOT FORMATION _ vv v _ vvvvvv_ Von Willebrand facto

25、r = vplatelet =,VII/TFNORMAL AND PATHOLOGIC CLOT FORMATION X_ vv v _ vvvvvv_ Von Willebrand factor = vplatelet =,VII/TFNORMAL AND PATHOLOGIC CLOT FORMATION X_ Vvv v II_ vvvvvv_ IIa (Fibrin) Von Willebrand factor = vplatelet =,VII/TFXIINORMAL AND PATHOLOGIC CLOT FORMATION XI IX VIII (v) X_ Vvv v II_

26、vvvvvv_ IIa (Fibrin) Von Willebrand factor = vplatelet =,VII/TFXIINORMAL AND PATHOLOGIC CLOT FORMATION XI IX VIII (v) X_ Vvv v II_ vvvvvv_ IIa (Fibrin) Von Willebrand factor = vplatelet =,VII/TFXIINORMAL AND PATHOLOGIC CLOT FORMATION XI IX VIII (v) X_ Vvv v II_ vvvvvv_ IIa (Fibrin) Von Willebrand fa

27、ctor = vplatelet = fibrin clot =,VII/TFXIIBLEEDING DISORDERS 1. Hemophilia XI IX VIII (v) X_ Vvv v II_ vvvvvv_ IIa (Fibrin) Von Willebrand factor = vplatelet = fibrin clot =,VII/TFXIIBLEEDING DISORDERS 1. Hemophilia XI2. Von Willebrand Disease IX VIII (VWF) X_ Vvv v II_ vvvvvv_ IIa (Fibrin) Von Will

28、ebrand factor = vplatelet = fibrin clot =,VII/TFXIITHROMBOPHILIA: 1. Deficiency of Clot Inhibitors XI IX VIII (v) X_ Vvv v II_ vvvvvv_ IIa (Fibrin) Von Willebrand factor = vplatelet = Clot Inhibitors,Protein C, S,AT-III,VII/TFXIITHROMBOPHILIA: 1. Deficiency of Clot Inhibitors XI2. Factor Mutations I

29、X VIII (v) X_ Vvv v II_ vvvvvv_ IIa (Fibrin) Von Willebrand factor = vplatelet =,Protein C, S,AT-III,Factor V Leiden,Prothrombin 20210,VII/TFXIITHROMBOPHILIA: 1. Deficiency of Clot Inhibitors XI2. Factor Mutations 3. Vessel Damage Inducers IX VIII (v) HomocysteineLAC X_ Vvv v II_ vvvvvv_ IIa (Fibrin

30、) Von Willebrand factor = vplatelet =,Protein C, S,AT-III,Factor V Leiden,Prothrombin 20210,I. NORMAL HEMOSTASIS A.Blood Vessel Wall B. Platelets C. Coagulation System II. DISORDERS OF PRIMARY HEMOSTASIS A. Von Willebrand Disease B.Thrombocytopenia C.Disorders of Platelet Function III. DISORDERS OF

31、SECONDARY HEMOSTASIS A.Hemophilia B.Vitamin K Deficiency C. Liver Disease D.Disseminated Intravascular Coagulation (DIC) E.Inhibitors IV.DISORDERS OF THROMBOSIS A.Factor V Leiden B.Prothrombin 20210 C.Homocysteine C677T, Hyperhomocysteinemia D.Protein C, S, Antithrombin III Deficiency,II. Disorders

32、of Primary Hemostasis,Primary HemostasisSecondary Hemostasis Defects: Platelet Plug FormationFibrin Clot Formation Disorders: Von Willebrand DiseaseHemophilia A, B Platelet DisordersVitamin K Deficiency QuantitativeLiver Disease Qualitative DIC Bleeding Sx: Mild, early, mucosalMod, severe, late, bod

33、y cavity,VON WILLEBRAND DISEASE Type 1 VWDType 2 VWDType 3 VWD 65-70%30-35%5% Autosomal dominantAutosomal dominantAutosomal recessive Defect: Low VWFDefect: Abnl VWFDefect: absent VWF Clinically mildClinically moderateClinically severe Menorrhagia Epistaxis, bruiseEpistaxis, bruise Dx: DelayedDx: Ea

34、rlyDx: Early Rx: DDAVPRx: VWF concentrateRx: VWF concentrate,Von Willebrand Disease Hemophilia Test FVIII:CLowLow RCoFLowNormal VWF:AgLowNormal Closure TimeProlongedNormal,III. Disorders of Secondary Hemostasis,DISORDERS OF SECONDARY HEMOSTASIS Congenital Coagulation DeficiencyAcquired Coagulation D

35、eficiency RareCommon Involves single coagulation factorInvolves multiple coagulation factors Severe bleedingMild to moderate bleeding Chronic disabilityMinor, no disability Specialized care, treatmentNo specialized care, treatment,CONGENITAL PLASMA COAGULOPATHIES FACTOR NAMEINCIDENCEBLEEDING INHERIT

36、ANCE GENETICS TENDENCY Ia Fibrinogen1:1,000,000+AR4q23-32 hypo0/+AD,AR4q23-32 dys0/+AD,AR4q23-32 II Thrombin 1:1,000,000+AR11p11-q12 V1:1,000,000+AR1q21-q25 VII1:500,000+AR13q34 VIII Anti-Hemophilic1:10,000+ to +XXq28 VWF Von Willebrand1:100+ to +AD,AR12pter-p12 IX Christmas 1:30,000+ to +XXq27 X St

37、uart1:500,000+ to +AR13q34 XI 1:500,0000/+AD4q32-q35 XII Hageman?0AD5q33-qter XIII-A 1:1,000,000 +AR6p24-p25 XIII-S 1:1,000,000 +AR1q31-q32,HEMOPHILIA X-Linked Bleeding Disorder Deficiency of Factor VIII, IX Bleeding Joints Hemarthroses Muscles Hematomas Infancy Circumcision Bleeding Severity (FVIII

38、, IX level) Severe 0.05 U/ml - Rare, traumatic bleeds Clotting Factor Treatment Reactive, not Preventive Costly Complications More disabling than the disease (HIV, AIDS, Hepatitis, Inhibitor),BLEEDING SYMPTOMS IN HEMOPHILIA HemarthrosisHematuria HematomasRetroperitoneal Hematoma EpistaxisCompartment

39、 Syndrome Oral BleedingPsoas Muscle Hematoma Circumcision BleedingIntracranial Hemorrhage Postoperative Bleeding,HEMOPHILIA: IDEAL TARGET FOR GENE THERAPY Hemophilia is not a lethal disease. Treatment is suboptimal. Complications of current therapy continue: infectious, orthopedic. The factor level

40、to be achieved is not crucial. The site of production of factor is not crucial, as long as secreted into circulation. The duration of treatment is not crucial.,Treatment of Congenital Factor Deficiencies Factor DeficiencyTreatmentComment I, XIIICryoprecipitateNo viral inactivation II, V, VII, X, XIF

41、resh frozen plasmaNo viral inactivation Retested plasma Recombinant Factor VIIaCostly, frequent dosing VIIIRecombinant Factor VIII Mild: DDAVPTachyphylaxis, flushing VWFMild: DDAVPTachyphylaxis, flushing Other: VWF ConcentrateLipid-enveloped viruses IXRecombinant Factor IX XIINoneNo bleeding,Vitamin

42、 K Deficiency Fat soluble vitamin absorbed in ileum Required for synthesis of clotting proteins II, VII, IX, X, protein C, protein S Cofactor: glutamic acid -carboxyglutamic acid Site of action of oral anticoagulant (coumadin),Vitamin K Metabolism VITAMIN K Glutamic acid -Carboxyglutamic Acid Factor

43、 II IIa Factor VII VIIa Factor IX IXa Factor X Xa Protein C APC Protein S APS,Causes of Vitamin K Deficiency 1. Dietary Deficiency Green leafy vegetables: daily reqt 100-200 g/day 2. Hemorrhagic Disease of the Newborn Day 2-7: bleeding in skin, mucosa Third trimester deficiency, infant lack of gut b

44、acteria 3. Lack of Synthesis in Gastrointestinal Tract Antibiotic Therapy 4. Poor Gastrointestinal Absorption Lack of bile salts Obstructive jaundice Rapid Transit Diarrhea, sprue 5. Inhibitor of Synthesis Coumadin Pesticides,Vitamin K Deficiency Diagnosis PT Early deficiency: F VII t = 4-6 hours PT

45、, APTT Late deficiency: F II t = 72 hours Treatment Depends on clinical setting, bleeding severity Vitamin K: 2.5 mg po, SQ to 10-15 mg IV Withhold anticoagulant Fresh frozen plasma: if bleeding severe,据报道,诊断肝病时，对观察病情和判断预后有价值的指标是：因子VII：C和II：C减低，先于肝功能异常，可作为肝病早期诊断的指标之一；Fg和因子V：C减低，反映肝病严重，或进入肝硬化；异常凝血酶原增

46、高是诊断原发性肝癌参考指标之一；因子VIII：C和vWF：Ag水平越高，反映肝病越严重，因子VIII：C降低提示并发DIC；因子XIIIa：Ag、ATIII 水平低于35%或PLG的水平低于20%时提示预后不佳；肝病时常呈多个因子的联合变化，故需综合分析。,Mechanism of Coagulopathy of Liver Disease 1.Decreased Synthesis of Coagulation Factors Decreased factors: BLEEDING 2.Decreased Degradation of Activated Coagulation Factor

47、s Increased activated factors: DIC 3.Synthesis of Abnormal Coagulation Factors Fibrinogen missing sialic acid: DYSFIBRINOGEN 4.Platelet Sequestration Hypersplenism: THROMBOCYTOPENIA,Laboratory Features of Liver Disease Prolonged PT and APTT Deficiency of factors Prolonged TT and RT Dysfibrinogen, hy

48、pofibrinogenemia Thrombocytopenia Platelet sequestration, consumption, production Platelet Functional Defects Nonspecific platelet aggregation defects Fibrinolysis Decreased fibrinogen, presence of FDP Decreased plasmin inhibitor (2-antiplasmin),DYSFIBRINOGEN OF LIVER DISEASE THROMBIN TIME (TT) Time

49、 for clot to form after thrombin conversion of fibrinogen to fibrin REPTILASE TIME (RT) Time for clot to form after reptilase conversion of fibrinogen to fibrin NORMALDYSFIBRINOGEN TT = 18 secondsTT = 26 seconds RT = 16 seconds RT = 25 seconds IIa (THROMBIN, REPTILASE) I Ia (FIBRINOGEN) (FIBRIN) (DY

50、SFIBRINOGEN),LIVER DISEASE TREATMENT OF BLEEDING BLOOD LOSSRBCs + 2x FFP FACTOR DEFICIENCIESFFP THROMBOCYTOPENIAPlatelet Concentrates PLATELET DYSFUNCTIONDDAVP VITAMIN K DEFICIENCYVitamin K HYPOFIBRINOGENEMIACryoprecipitate FIBRINOLYSISAprotonin,（四）血栓前状态和血栓性疾病的实验诊断,血栓前状态（prethrombotic state）也称血栓前期（p

51、rethrombotic phase），是指血液有形成分和无形成分的生化和流变学发生某些变化。在这一病理状态下，血液有可能形成血栓或血栓栓塞性疾病。诊断血栓前状态和血栓性疾病的实验可从以下三方面进行。,1筛选试验,APTT可能缩短；PT可能缩短；Fg测定可能增高；PagT的聚集率可能增高；血液粘度测定一般增高。 2常用诊断试验 测定血浆中的vWF：Ag增高反映血管内皮细胞损伤；-TG增高反映血小板被激活；可溶性纤维蛋白复合物单体（SFMC）增高反映凝血酶活性增强或形成增多；AT：A减低反映凝血酶活性增强；FDP和D-D增高反映纤溶酶活性增强。,3特异诊断试验,测定血浆中TM和（或）ET-1增高

52、反映血管内皮细胞受损；P-selectin 和（或）11-去氢-血栓烷B2（11-DH-TXB2）增高反映血小板被激活；F1+2和（或）FPA增高反映凝血酶活性增强或其形成增多；TF增高反映外源凝血途径活性增强；TAT增高反映凝血酶活性增强和（或）PC被凝血酶和TM所激活；PAP反映纤溶酶活性增强或形成增多。,（五）纤溶活性亢进,1原发性纤溶症（primary fibrinolysis） 原发性纤溶亢进症，简称原发性纤溶，是由于纤溶酶原激活物（t-PA，u-PA）增多导致纤溶酶活性增强，后者降解血浆纤维蛋白原和多种凝血因子。,2继发性纤溶症 (second fibrinolysis),主要见于

53、弥散性血管内凝血（DIC）。DIC时，由于因子XIIa、激肽释放酶（K）、凝血酶等增多导致纤溶酶增多或活性增强，后者降解血浆纤维蛋白（原）和多个凝血因子。DIC的实验室诊断，同时有下列三项以上异常者：Plt低于100109/L或进行性下降；血浆Fg低于1.5g/L；PT缩短或延长3s以上或呈动态变化；3P试验阳性或FDP超过20mg/L。此外，PLG含量或活性降低、AT含量或活性降低、血浆因子VIII：C低于50%都有助于疑难病例的诊断。 表9 近年来，DIC前期（pre-DIC）提出的指标是：F1+2、TAT、PAP、D-D等四项，其中二项或二项以上阳性便可诊断。,DIC的分型,1.按发生速度： 临床上可分急、慢性和亚急性三种。急性患者有：广泛性出血、注射部位和手术创面渗血难止，大片状皮肤瘀斑和血肿，以及广泛性粘