pathophysiologypartdic弥散性血管内凝血课件

1、1 Intravascular Extravascular Normal circulation Hemostasis liquidity solidity ( coagulation) Normal Normal Blood Abnomal Abnomal solidity (coagulation) liqidity Thrombotic disease Hemorrhagic disease Intravascular Extravascular第1页，共57页。2 The function of coagulation system (Extrinsic, Intrinsic path

2、way and platelet) The function of anticoagulation (TFPI, PC system, ATIII and fibrinolytic system) The regulation of balance by VECThe key factors for balance of coagulation-anticoagulation:第2页，共57页。3The chain reaction of blood coagulation FXI FXIa FVII/FVIIa-TF-Ca2+ (on membrane) FIX FIXa TFPI-FXa

3、FVIIIa Ca2+-PL prothrombin (FII) PCI FX Fxa PL-Ca2+ Fva APC (PS) XIII thrombin TM-on-VEC XIIIa ATIII PC Fbn Fbn FM Fbg (FI) (cross-linked) (soluble) TF = tissue factor; TFPI = TF pathway inhibitor; Fbg = fibrinogen; Fbn = fibrin; FM = fibrin monomer; PC = protein C; APC = activated PC; PS = protein

4、S; PCI = PC inhibitor ATIII = antithrombin III; TM = thrombomodulin; VEC = vascular EC第3页，共57页。4The fibrinolysis system Plasminogen (PLg)(Extra-activating pathway) (Intra-activating pathway) tissue-type plasminogen activation of clotting system activator (t-PA) XIa urokinase-type plasminogen thrombi

5、n activator (u-PA) XIIa XII(Exogenous activator) urokinase(UK) kallikrein (KK) streptokinase (SK ) prekallikrein(PK) Plasmin (Pln) Fbg Fbn FDP (fibrinogen) (fibrin) (Fbg/Fbn degradation products) 第4页，共57页。5Inhibit Xa,VIIa,TFInhibit platelet aggregationFibrinolysisPrevent fibrinclot formationTraumaAd

6、renalinThrombinADPNO, PGI2 Xa, IIaPlasminPlasminoginActivatorst-PA, u-PAInactivateVa,VIIIaPSThrombinPC APCTMInhibit Xa, IIaAT III+HeparinTFPIAnticoagulant function of endothelial cells第5页，共57页。6Section 1. Concept and causes of DIC 第6页，共57页。7Todays Question Question 1. What is DIC?第7页，共57页。81. Concep

7、t of DIC Disseminated intravascular coagulation (DIC) A syndrome that results from the disturbance of kinetic balance of coagulation and fibrinolytic processes. Characterized by extensive intravascular microthrombosis and impairment of hemostasia. Its initial link is activation of clotting system in

8、 the body 第8页，共57页。9extensive microthrombin extensive hemorrhage organ dysfunction Shock aneamiaNormal balance of coagulation-anticoagulationHypocoagulable stateHypercoagulable stateUnbalance of coagulation-anticoagulation and DICextensive activation of clotting factors and platelets consumption of

9、clotting factors and plateletssecondary fibrinolysishemorrhageorgan dysfunction Shock aneamia第9页，共57页。10 Therefore DIC usually associated simultaneously with both hemorrhage and thrombosis. Its clinical presentations include: 1) extensive hemorrhage at skin, mucosa and internal organs (viscera); 2)

10、shock; 3) organ dysfunction; 4) aneamia. An extensive activation of coagulation process caused by the entering of coagulation-promoting substances into circulationAn increased consumption of clotting factors and platelets, deposition of fibrin and secondary fibrinolysis.results in第10页，共57页。112. Caus

11、es of DIC including: infectious diseases, extensive tissue injury, obstetric complications, malignant tumors, acute leukemia, shock, hepatic and renal diseases, collagen disease, metabolic diseases, cardiovascular diseases, intravascular hemolysisEtiologic Disease of DIC Diseases or pathologic proce

12、ss which may lead to DICTriggering Factor Any factors which may trigger or promote DIC occur第11页，共57页。12 including: infectious diseases, extensive tissue injury, obstetric complications, malignant tumors, acute leukemia, shock, hepatic and renal diseases, collagen disease, metabolic diseases, cardio

13、vascular diseases, intravascular hemolysis2. Causes of DICTriggering Factor Any factors which may trigger or promote DIC occurEtiologic Disease of DIC Diseases or pathologic process which may lead to DIC1) Tissue injury and release tissue factor (TF) 2) Vascular endothelial cells (VEC) injury3) bact

14、erial endotoxin4) Ag-Ab complex5) Protein hydrolytic enzymes6) Particle or colloid7) Virus and other microbe第12页，共57页。13Section 2. Pathogenesis of DIC第13页，共57页。14 The mechanism of DIC is very complex and remains unclear up to now. The common pathogenic process include: 1) Triggering clotting activat

15、ion, producing numerous insoluble fibrin (Fbn) and activating platelets; 2) The generated Fbn deposit in microvessels and is more than hydrolytic ability of fibrinolysin; 3) Alteration of fibrinolysis function during the DIC process which is related to the pathologic process of micro-thrombosis and

16、bleeding tendency. 第14页，共57页。151. Activation of clotting system As soon as activation, the clotting response will be magnified by cascade or limited by negative feedback. The clotting system is liable to be activated in the microvessels, leading to micro-thrombus formation. The causes and pathogenes

17、is of clotting system activation including: (1) Tissue injury (2) Vascular endothelial cells injury (3) Other pathway to activate clotting system第15页，共57页。16(1) Tissue injurySevere trauma, burns, surgical operation, obstetric accident, tumor tissue necrosis or metastasis,blood cell injury (radiation

18、 or chemical therapy for leukemia) Excessive destruction of tissue Numerous TF entering the blood Activating clotting reactions Besides, lysozymes released by lysosome of damaged cells may also promote the activation of clotting system. 第16页，共57页。17Infectious, endotoxinemia, Ag-Ab complex, persisten

19、t ischemia and hypoxia, acidosis extensive damage of vascular endothelial cells . activating clotting reactions (activating Mo/Mf, PMN, T-lymphocyte release TNF, IL-1, IFN, PAF, C3a, C5a, O2) (2) Vascular endothelial cells injuryreleasing TF subendothelial exposureplatelets adhesion Aggregation and

20、release第17页，共57页。18 Activation of Mo/Mf, WBC release TF, lysozymes Malignant tumors release TF, cancer procoagulantHemorrhagic pancreatitis, cancer of pancreas release trypsin (may activate prothrombin directly)Exogenous toxin activate FX, prothrombin or transfer Fbg to Fbn directly Extensivehemolys

21、is release ADP activate platelets release erythrin TF-like effect (3) Other pathway to activate clotting system第18页，共57页。192. Change of vasomotorial activity and blood fluidity VEC injury EDRF, PGI2, ETPlatelet activated TXA2Blood flow(vasoconstriction) or stasis (vasodilation) eliminate of coagulan

22、t or activate clotting factors PAF, histamin, BK vascular permeability (BK: bradykinin)Deposit of FbnBlood condense, Viscosity第19页，共57页。203. Disturbance of fibrinolysis (1) Local fibrinolysis clotting VEC injury local anticoagultive and fibrinolytic function deposit of Fbn microthrombus formation (2

23、) Secondary fibrinolysis bleeding FXIa, thrombin, KK, etc. promote transfer PLg to PLn VEC release t-PA, u-PA transfer PLg to PLn Protein C activated by thrombin (via VEC-TM) form activated protein C (APC) anticoagulation and promote fibrinolysis.第20页，共57页。21 Pathological Factors extensive activatio

24、n of clotting factors and platelets intravascular coagulation consumption of clotting secondary factors and platelets fibrinolysis extensive hemorrhage aneamia shock organ dysfunction (Disseminated intravascular coagulation, DIC)Hypercoagulable stateHypocoagulable state第21页，共57页。22Section 3. Primary

25、 clinical presentations of DIC第22页，共57页。23DIC may lead to four consequences as follows: 1. Disturbance of coagulation - Bleeding 2. Disturbance of microcirculation - Shock 3. multiple organs dysfunction - MOD 4. Microangiopathic hemolytic - Anemia第23页，共57页。241. Disturbance of coagulation-BleedingThe

26、 prime and common symptom of DIC is bleeding. The features of bleeding in DIC : (1) High occurrence rate (7080%) (2) Difficult to explain by primary disease (3) Manifold bleeding types (4) Difficult to be cured by regular hemostatics第24页，共57页。25The causes of bleeding in DIC including: (1) Excessive

27、consumption of coagulation substances (clotting factors and platelets); (2) Secondary enhance of fibrinolysis (3) Anticoagulative effects of fibrin degradation products; Fbg / Fbn FDP(fragment X,Y,E,D) X,Y + FM soluble fibrin monomer complex (SFMC) (4) Injury of capillary wall caused by primary caus

28、e of DIC and secondary hypoxia, acidosis, cytokines and free radical. PLn Thrombin Fbg (FI) FM sFbn Fbn 第25页，共57页。26 DIC, especially acute DIC, is often associated with shock Shock in sever degree or in late stage can also promote the production of DIC2. Dsturbance of microcirculation - shock 第26页，共

29、57页。27(1) Extensive microthrombus formation(2) Extensive bleeding permeability plasma exudation(3) Activating kinin, histamin shock microvessel dilation(4) FDP (A,B,C)(5) Microthrombus coronary perfusion pulmonary hypertension cardiac load Ischemia, hypoxia& acidosis returned bloodto hearteffective

30、circulation blood volume peripheral resistanceheart function andcardiac output第27页，共57页。283. Multiple organs dysfunction (MOD)Perfusion impairment / ischemia-reperfusion injuryactivation of WBC / inflammatory mediator Ischemic tissue damage MOD MOD is usually the most important cause of death in DIC

31、.第28页，共57页。29 Occurrence of MOD is related to following factors: (1)Extensive microthrombi formation in the organs ischemia, hypoxia, impairment of metabolism and function, or even necrosis and organ failure. (2) Pathologic alteration caused by effects of organs each other DIC Lungs pulmonary circul

32、ation Heart hypoxia, acidosis Other organs (3) Pathologic alteration and symptoms of primary diseases (which should be rule out from MOD). inflammation of the lungs dysfunction of respiration s e.g. Lung ARDS; kidney ARF; Digestive system nausea, vomiting, diarrhea, hemorrhage; Liver jaundice and he

33、patic failure; Heart CO, PAWP; Pituitary necrosis Sheehans syndrome; Adrenal cortex hemorrhagic necrosis Waterhouse-friderchsens syndrome; CNS bleeding, edema (somnolence, coma, convulsion) 第29页，共57页。30 Occurrence of MOD is related to following factors: (1)Extensive microthrombi formation in the org

34、ans ischemia, hypoxia, impairment of metabolism and function, or even necrosis and organ failure. (2) Pathologic alteration caused by effects of organs each other DIC Lungs pulmonary circulation Heart hypoxia, acidosis Other organs (3) Pathologic alteration and symptoms of primary diseases (which sh

35、ould be rule out from MOD). inflammation of the lungs dysfunction of respiration s第30页，共57页。31 Occurrence of MOD is related to following factors: (1)Extensive microthrombi formation in the organs ischemia, hypoxia, impairment of metabolism and function, or even necrosis and organ failure. (2) Pathol

36、ogic alteration caused by effects of organs each other DIC Lungs pulmonary circulation Heart hypoxia, acidosis Other organs (3) Pathologic alteration and symptoms of primary diseases (which should be rule out from MOD). inflammation of the lungs dysfunction of respiration第31页，共57页。324. Microangiopat

37、hic hemolytic anemia RBC may damaged as they move through the fibrin net and result in a striking hemolytic anemia, with a special morphologic abnormality of the RBC called schistocyte. (Twisted cells, crenated cells, triangular cells, helmet-shaped cells, and microspherocytes ) The hemolysis can pr

38、ovide more triggering material (ADP and membrane phospholipid) for continued intravascular coagulation.第32页，共57页。33Section 4.Factors influencing the development of DIC第33页，共57页。34Mononuclear phagocyte system dysfunctionSevere dysfunction of the liverHypercoagulable stateDisorder of microcirculationF

39、ibrinolytic system dysfunction第34页，共57页。35 Prolonged and excessive Repeated infection administration of glucocorticoid hormones Severe hepatic disease Impairing Mo/Mf system function Disable to clean clot-promoting substances (Fbg, Fbn, FM and FDP, etc.) Generalized Shwartzman reaction, GSR (1) Mono

40、nuclear phagocyte system dysfunction第35页，共57页。36(2)Severe dysfunction of the liver 1) Pathogenic factors of liver disease such as virus, Ag-Ab complex and some drugs may activate clotting system. 2) Acute hepatic necrosis may release TF and lysozymes 3) Decreased ability of production and eliminatio

41、n of clotting and anticoagulative factors.第36页，共57页。37Primary: genetic ATIII, PC, PS deficiency, etc. Secondary: nephrotic syndrome, malignant tumors, leukemia, toxemia of pregnancy, etc.(3) Hypercoagulable state 第37页，共57页。38 1) VEC injury Activation of clotting system; 2) Blood flowor stasis accumu

42、lation of activated clot factors; 3) Dysfunction of liver, kidney ability of eliminate clot factors and fibrinolytic products 4) Vasomotorial impairment feasible to Fbn deposit and microthrombi formation. (5) Fibrinolytic system dysfunction e.g. senility, smoking, late stage of pregnancy, diabetes,

43、misuse of fibrinolytic inhibitor,etc.(4) Disorder of microcirculation第38页，共57页。39Section 5Stages and types of DIC第39页，共57页。401. Stages of DIC Pathophysiology Clinical Laboratory findings (1)Hypercoagulable stage(2)Consuming hypocoagulable stage(3)Secondary fibrinolytic Stage Exessive activation of c

44、lotting factors and formation of microthrombinIncreased consumption of clotting factors and plateletConsiderable formation of plasmin and FDP 第40页，共57页。411. Stages of DIC Pathophysiology Clinical Laboratory findings (1)Hypercoagulable stage(2)Consuming hypocoagulable stage(3)Secondary fibrinolytic S

45、tage Hypercoagulable Bleeding Bleeding markedly 第41页，共57页。421. Stages of DIC Pathophysiology Clinical Laboratory findings (1)Hypercoagulable stage(2)Consuming hypocoagulable stage(3)Secondary fibrinolytic Stage Shortened clotting and recalcification time; Increased adherence of plateletProlonged clo

46、tting and recalcification time Reduction of platelet count and Fbg narkedlyShortened CLT, ELT; Prolonged TT 3P test (+), Increased FDP CLT = clot-lysis timeELT = euglobulin-lysis timeTT = thrombin time第42页，共57页。43Production of FDP and 3p test (plasma protamine paracoagulation test) FibrinogenThrombi

47、n Fibrin monomer (FM) Fibrin polymer PlasminXIIIa FDP-X,Y,D,E Stabilized fibrin ( blood clotting ) X + FM soluble fibrin monomer complex (SFMC) Protamin SFMC X + FM blood clotting第43页，共57页。44 Develop time Common causes Clinic feature 2. Types of DIC According to the rate of development, divide into

48、3 types Acute Subacute Chronica few hours to dayswithin days to weeks months第44页，共57页。45 Develop time Common causes Clinic feature 2. Types of DIC According to the rate of development, divide into 3 types Acute Subacute Chronicmalignant tumors collagenosismetastasis of malignanttumors; retained dead

49、 fetussevere infection or trauma ammiotic fluid embolism第45页，共57页。46 Develop time Common causes Clinic feature 2. Types of DIC According to the rate of development, divide into 3 types Acute Subacute Chronicmild or concealedmicrothrombin formation bleeding shock, blooding exacerbate rapidly第46页，共57页

50、。47: According to compensatory state, divide into 3 types Clotting factors and platelet Clinical situations compensatory Consumption = production discompensatory Consumption production over compensatory Consumption production第47页，共57页。48: According to compensatory state, divide into 3 types Clotting

51、 factors and platelet Clinical situations compensatory Mild DIC discompensatory Acute DIC over compensatory Chronic DIC or recovery第48页，共57页。49Section 6.Principles of prevention and treatment of DIC第49页，共57页。50 1. Pathophysiology bases of diagnosis of DIC (1) Existence of causative diseases; (2) Exi

52、stence of characteristic symptoms and signs of DIC (3) Positive laboratory findings: platelet count, Fbg , PT & TT, 3P test (+), CLT & ELT 第50页，共57页。512. Pathophysiology bases of prevention and treatment of DIC (1)Earlier diagnosis and treatment (2) Treatment of the causative disease (3) Anticoagula

53、tion treatment (to block the vicious cycle of clotting response) (4) Protection of organ function (5) Supplement of fresh blood or plasma, concentrated platelet or clotting factors (to recover coagulation- anticoagulation balance) (6) Antifibrinolysis treatmentBack to cover next chapter第51页，共57页。52 A syndrome resulting from the disturbance balance ofcoagulation and fibrinolytic processes, characterized byextensive intravascular microthro