1、1Disseminated intravascular coagulation2 Intravascular Extravascular Normal circulation Hemostasis liquidity solidity (coagulation)Normal Normal Blood Abnomal Abnomal solidity (coagulation)liqidity Thrombotic disease Hemorrhagic disease Intravascular Extravascular3 The function of coagulation system
2、 (Extrinsic,Intrinsic pathway 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:4The chain reaction of blood coagulation FXI FXIa FVII/FVIIa-TF-Ca2+(on membrane)FIX FIX
3、a TFPI-FXa 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 S;PCI=PC inhibitor A
4、TIII=antithrombin III;TM=thrombomodulin;VEC=vascular EC5The fibrinolysis system Plasminogen(PLg)(Extra-activating pathway)(Intra-activating pathway)tissue-type plasminogen activation of clotting system activator(t-PA)XIa urokinase-type plasminogen thrombin activator(u-PA)XIIa XII(Exogenous activator
5、)urokinase(UK)kallikrein(KK)streptokinase(SK)prekallikrein(PK)Plasmin(Pln)Fbg Fbn FDP (fibrinogen)(fibrin)(Fbg/Fbn degradation products)6Inhibit Xa,VIIa,TFInhibit platelet aggregationFibrinolysisPrevent fibrinclot formationTraumaAdrenalinThrombinADPNO,PGI2 Xa,IIaPlasminPlasminoginActivatorst-PA,u-PA
6、InactivateVa,VIIIaPSThrombinPC APCTMInhibit Xa,IIaAT III+HeparinTFPIAnticoagulant function of endothelial cells7Section 1.Concept and causes of DIC 8Todays Question Question 1.What is DIC?91.Concept of DIC Disseminated intravascular coagulation(DIC)A syndrome that results from the disturbance of kin
7、etic balance of coagulation and fibrinolytic processes.Characterized by extensive intravascular microthrombosis and impairment of hemostasia.Its initial link is activation of clotting system in the body 10extensive microthrombin extensive hemorrhage organ dysfunction Shock aneamiaNormal balance of c
8、oagulation-anticoagulationHypocoagulable stateHypercoagulable stateUnbalance of coagulation-anticoagulation and DICextensive activation of clotting factors and platelets consumption of clotting factors and plateletssecondary fibrinolysishemorrhageorgan dysfunction Shock aneamia11 Therefore DIC usual
9、ly associated simultaneously with both hemorrhage and thrombosis.Its clinical presentations include:1)extensive hemorrhage at skin,mucosa and internal organs (viscera);2)shock;3)organ dysfunction;4)aneamia.An extensive activation of coagulation process caused by the entering of coagulation-promoting
10、 substances into circulationAn increased consumption of clotting factors and platelets,deposition of fibrin and secondary fibrinolysis.results in122.Causes of DIC including:infectious diseases,extensive tissue injury,obstetric complications,malignant tumors,acute leukemia,shock,hepatic and renal dis
11、eases,collagen disease,metabolic diseases,cardiovascular diseases,intravascular hemolysisEtiologic Disease of DIC Diseases or pathologic process which may lead to DICTriggering Factor Any factors which may trigger or promote DIC occur13 including:infectious diseases,extensive tissue injury,obstetric
12、 complications,malignant tumors,acute leukemia,shock,hepatic and renal diseases,collagen disease,metabolic diseases,cardiovascular diseases,intravascular hemolysis2.Causes of DICTriggering Factor Any factors which may trigger or promote DIC occurEtiologic Disease of DIC Diseases or pathologic proces
13、s which may lead to DIC1)Tissue injury and release tissue factor(TF)2)Vascular endothelial cells(VEC)injury3)bacterial endotoxin4)Ag-Ab complex5)Protein hydrolytic enzymes6)Particle or colloid7)Virus and other microbe14Section 2.Pathogenesis of DIC15 The mechanism of DIC is very complex and remains
14、unclear up to now.The common pathogenic process include:1)Triggering clotting activation,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 D
15、IC process which is related to the pathologic process of micro-thrombosis and bleeding tendency.161.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
16、,leading to micro-thrombus formation.The causes and pathogenesis of clotting system activation including:(1)Tissue injury (2)Vascular endothelial cells injury (3)Other pathway to activate clotting system17(1)Tissue injurySevere trauma,burns,surgical operation,obstetric accident,tumor tissue necrosis
17、 or metastasis,blood cell injury(radiation 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.18Infectious,endotoxinem
18、ia,Ag-Ab complex,persistent 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 Ag
19、gregation and release19 Activation of Mo/Mf,WBC release TF,lysozymes Malignant tumors release TF,cancer procoagulant Hemorrhagic pancreatitis,cancer of pancreas release trypsin(may activate prothrombin directly)Exogenous toxin activate FX,prothrombin or transfer Fbg to Fbn directly Extensive hemolys
20、is release ADP activate platelets release erythrin TF-like effect(3)Other pathway to activate clotting system202.Change of vasomotorial activity and blood fluidity VEC injury EDRF,PGI2,ETPlatelet activated TXA2Blood flow(vasoconstriction)or stasis(vasodilation)eliminate of coagulant or activate clot
21、ting factors PAF,histamin,BK vascular permeability (BK:bradykinin)Deposit of FbnBlood condense,Viscosity213.Disturbance of fibrinolysis (1)Local fibrinolysis clotting VEC injury local anticoagultive and fibrinolytic function deposit of Fbn microthrombus formation (2)Secondary fibrinolysis bleeding F
22、XIa,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.22 Pathological Factors extensive activation of clotting factors and platelets intravascular coag
23、ulation consumption of clotting secondary factors and platelets fibrinolysis extensive hemorrhage aneamia shock organ dysfunction (Disseminated intravascular coagulation,DIC)Hypercoagulable stateHypocoagulable state23Section 3.Primary clinical presentations of DIC24DIC may lead to four consequences
24、as follows:1.Disturbance of coagulation -Bleeding 2.Disturbance of microcirculation-Shock 3.multiple organs dysfunction-MOD 4.Microangiopathic hemolytic-Anemia251.Disturbance of coagulation-BleedingThe prime and common symptom of DIC is bleeding.The features of bleeding in DIC:(1)High occurrence rat
25、e(7080%)(2)Difficult to explain by primary disease (3)Manifold bleeding types (4)Difficult to be cured by regular hemostatics26The causes of bleeding in DIC including:(1)Excessive consumption of coagulation substances (clotting factors and platelets);(2)Secondary enhance of fibrinolysis (3)Anticoagu
26、lative 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 cause of DIC and secondary hypoxia,acidosis,cytokines and free radical.PLn Thrombin Fbg(FI)FM sFbn Fbn 27 DIC,especially acute DIC,is of
27、ten associated with shock Shock in sever degree or in late stage can also promote the production of DIC2.Dsturbance of microcirculation-shock 28(1)Extensive microthrombus formation(2)Extensive bleeding permeability plasma exudation(3)Activating kinin,histamin shock microvessel dilation(4)FDP(A,B,C)(
28、5)Microthrombus coronary perfusion pulmonary hypertension cardiac load Ischemia,hypoxia&acidosis returned bloodto hearteffective circulation blood volume peripheral resistanceheart function andcardiac output293.Multiple organs dysfunction(MOD)Perfusion impairment/ischemia-reperfusion injuryactivatio
29、n of WBC/inflammatory mediator Ischemic tissue damage MOD MOD is usually the most important cause of death in DIC.30 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 f
30、ailure.(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 should be rule out from MOD).inflammation of the lungs dysfunction of respiration s e.g.Lung ARDS
31、;kidney ARF;Digestive system nausea,vomiting,diarrhea,hemorrhage;Liver jaundice and hepatic failure;Heart CO,PAWP;Pituitary necrosis Sheehans syndrome;Adrenal cortex hemorrhagic necrosis Waterhouse-friderchsens syndrome;CNS bleeding,edema(somnolence,coma,convulsion)31 Occurrence of MOD is related to
32、 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 circulation Heart hypoxia,acidosis Other organs (3)Pathol
33、ogic alteration and symptoms of primary diseases(which should be rule out from MOD).inflammation of the lungs dysfunction of respiration s32 Occurrence of MOD is related to following factors:(1)Extensive microthrombi formation in the organs ischemia,hypoxia,impairment of metabolism and function,or e
34、ven 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 should be rule out from MOD).inflammation of the lungs dysfunction of res
35、piration334.Microangiopathic 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
36、 hemolysis can provide more triggering material(ADP and membrane phospholipid)for continued intravascular coagulation.34Section 4.Factors influencing the development of DIC35 Mononuclear phagocyte system dysfunction Severe dysfunction of the liver Hypercoagulable state Disorder of microcirculation F
37、ibrinolytic system dysfunction36 Prolonged and excessive Repeated infection administration of glucocorticoid hormones Severe hepatic disease Impairing Mo/Mf f system function Disable to clean clot-promoting substances (Fbg,Fbn,FM and FDP,etc.)Generalized Shwartzman reaction,GSR(1)Mononuclear phagocy
38、te system dysfunction37(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 elimination of clotting and anticoagulat
39、ive factors.38Primary:genetic ATIII,PC,PS deficiency,etc.Secondary:nephrotic syndrome,malignant tumors,leukemia,toxemia of pregnancy,etc.(3)Hypercoagulable state 39 1)VEC injury Activation of clotting system;2)Blood flowor stasis accumulation of activated clot factors;3)Dysfunction of liver,kidney a
40、bility 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,misuse of fibrinolytic inhibitor,etc.(4)Disorder of microcirculation40Secti
41、on 5Stages and types of DIC411.Stages of DIC Pathophysiology Clinical Laboratory findings(1)Hypercoagulable stage(2)Consuming hypocoagulable stage(3)Secondary fibrinolytic Stage Exessive activation of clotting factors and formation of microthrombinIncreased consumption of clotting factors and platel
42、etConsiderable formation of plasmin and FDP 421.Stages of DIC Pathophysiology Clinical Laboratory findings(1)Hypercoagulable stage(2)Consuming hypocoagulable stage(3)Secondary fibrinolytic Stage Hypercoagulable Bleeding Bleeding markedly 431.Stages of DIC Pathophysiology Clinical Laboratory findings
43、(1)Hypercoagulable stage(2)Consuming hypocoagulable stage(3)Secondary fibrinolytic Stage Shortened clotting and recalcification time;Increased adherence of plateletProlonged clotting and recalcification time Reduction of platelet count and Fbg narkedlyShortened CLT,ELT;Prolonged TT 3P test(+),Increa
44、sed FDP CLT=clot-lysis timeELT=euglobulin-lysis timeTT=thrombin time44Production of FDP and 3p test(plasma protamine paracoagulation test)FibrinogenThrombin Fibrin monomer(FM)Fibrin polymer PlasminXIIIa FDP-X,Y,D,E Stabilized fibrin (blood clotting)X+FM soluble fibrin monomer complex(SFMC)Protamin S
45、FMC X+FM blood clotting45 Develop time Common causes Clinic feature 2.Types of DIC According to the rate of development,divide into 3 types Acute Subacute Chronica few hours to dayswithin days to weeks months46 Develop time Common causes Clinic feature 2.Types of DIC According to the rate of develop
46、ment,divide into 3 types Acute Subacute Chronicmalignant tumors collagenosismetastasis of malignanttumors;retained dead fetussevere infection or trauma ammiotic fluid embolism47 Develop time Common causes Clinic feature 2.Types of DIC According to the rate of development,divide into 3 types Acute Su
47、bacute Chronicmild or concealedmicrothrombin formation bleeding shock,blooding exacerbate rapidly48:According to compensatory state,divide into 3 types Clotting factors and platelet Clinical situations compensatory Consumption=production discompensatory Consumption production over compensatory Consu
48、mption production49:According to compensatory state,divide into 3 types Clotting factors and platelet Clinical situations compensatory Mild DIC discompensatory Acute DIC over compensatory Chronic DIC or recovery50Section 6.Principles of prevention and treatment of DIC51 1.Pathophysiology bases of di
49、agnosis of DIC (1)Existence of causative diseases;(2)Existence of characteristic symptoms and signs of DIC (3)Positive laboratory findings:platelet count,Fbg,PT&TT,3P test(+),CLT&ELT 522.Pathophysiology bases of prevention and treatment of DIC (1)Earlier diagnosis and treatment (2)Treatment of the c
50、ausative disease (3)Anticoagulation 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 nex
