弥散性血管内凝血.ppt

1,Chapter 16.,Disseminated intravascular coagulation,2,Intravascular Extravascular Normal circulation Hemostasis liquidity solidity ( coagulation) Normal Normal Blood Abnomal Abnomal solidity (coagulation) liqidity Thrombotic disease Hemorrhagic disease Intravascular Extravascular,3,The function of coagulation system (Extrinsic, Intrinsic pathway and platelet),The function of anticoagulation (TFPI, PC system, ATIII and fibrinolytic system),The regulation of balance by VEC,The key factors for balance of coagulation-anticoagulation:,4,The chain reaction of blood coagulation,FXI FXIa FVII/FVIIa-TF-Ca2+ (on membrane) FIX FIXa 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 ATIII = antithrombin III; TM = thrombomodulin; VEC = vascular EC,5,The 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) urokinase(UK) kallikrein (KK) streptokinase (SK ) prekallikrein(PK) Plasmin (Pln) Fbg Fbn FDP (fibrinogen) (fibrin) (Fbg/Fbn degradation products),6,Inhibit Xa,VIIa,TF,Inhibit platelet aggregation,Fibrinolysis,Prevent fibrin clot formation,Anticoagulant function of endothelial cells,7,Section 1.,Concept and causes of DIC,8,Todays Question Question 1. What is DIC?,9,1. Concept 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 the body,10,extensive microthrombin extensive hemorrhage organ dysfunction Shock aneamia,Normal balance of coagulation-anticoagulation,Hypocoagulable state,Hypercoagulable state,Unbalance of coagulation-anticoagulation and DIC,extensive activation of clotting factors and platelets,consumption of clotting factors and platelets,secondary fibrinolysis,hemorrhage,11,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) shock; 3) organ dysfunction; 4) aneamia.,An extensive activation of coagulation process caused by the entering of coagulation-promoting substances into circulation,An increased consumption of clotting factors and platelets, deposition of fibrin and secondary fibrinolysis.,results in,12,2. Causes 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 hemolysis,Etiologic Disease of DIC Diseases or pathologic process which may lead to DIC,Triggering Factor Any factors which may trigger or promote DIC occur,13,including: infectious diseases, extensive tissue injury, obstetric complications, malignant tumors, acute leukemia, shock, hepatic and renal diseases, collagen disease, metabolic diseases, cardiovascular diseases, intravascular hemolysis,2. Causes of DIC,Triggering Factor Any factors which may trigger or promote DIC occur,Etiologic Disease of DIC Diseases or pathologic process which may lead to DIC,1) Tissue injury and release tissue factor (TF) 2) Vascular endothelial cells (VEC) injury 3) bacterial endotoxin 4) Ag-Ab complex 5) Protein hydrolytic enzymes 6) Particle or colloid 7) Virus and other microbe,14,Section 2.,Pathogenesis of DIC,15,The mechanism of DIC is very complex and remains 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 DIC process which is related to the pathologic process of micro-thrombosis and bleeding tendency.,16,1. 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 pathogenesis of clotting system activation including: (1) Tissue injury (2) Vascular endothelial cells injury (3) Other pathway to activate clotting system,17,(1) Tissue injury,Severe trauma, burns, surgical operation, obstetric accident, tumor tissue necrosis 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.,18,Infectious, endotoxinemia, 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 injury,releasing TF subendothelial exposure,platelets adhesion Aggregation and release,19, 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 hemolysis release ADP activate platelets release erythrin TF-like effect,(3) Other pathway to activate clotting system,20,2. Change of vasomotorial activity and blood fluidity,VEC injury EDRF, PGI2, ET Platelet activated TXA2 Blood flow(vasoconstriction) or stasis (vasodilation) eliminate of coagulant or activate clotting factors PAF, histamin, BK vascular permeability (BK: bradykinin),Deposit of Fbn,Blood condense, Viscosity,21,3. Disturbance of fibrinolysis,(1) Local fibrinolysis clotting VEC injury local anticoagultive and fibrinolytic function deposit of Fbn microthrombus formation (2) 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.,22,Pathological Factors extensive activation 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 state,Hypocoagulable state,23,Section 3.,Primary clinical presentations of DIC,24,DIC 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,25,1. Disturbance of coagulation-Bleeding,The 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,26,The causes of bleeding in DIC including: (1) Excessive 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 cause of DIC and secondary hypoxia, acidosis, cytokines and free radical.,PLn,27,DIC, especially acute DIC, is often associated with shock Shock in sever degree or in late stage can also promote the production of DIC,2. 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) (5) Microthrombus coronary perfusion pulmonary hypertension cardiac load Ischemia, hypoxia& acidosis,returned blood to heart,effective circulation blood volume ,peripheral resistance,heart function and cardiac output,29,3. Multiple organs dysfunction (MOD),Perfusion impairment / ischemia-reperfusion injury activation 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 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 respiration s,e.g. Lung ARDS; 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 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) Pathologic alteration and symptoms of primary diseases (which should be rule out from MOD). inflammation of the lungs dysfunction of respiration s,32,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 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,33,4. 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 hemolysis can provide more triggering material (ADP and membrane phospholipid) for continued intravascular coagulation.,34,Section 4.,Factors influencing the development of DIC,35,Mononuclear phagocyte system dysfunction Severe dysfunction of the liver Hypercoagulable state Disorder of microcirculation Fibrinolytic system dysfunction,36,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) Mononuclear phagocyte system dysfunction,37,(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 anticoagulative factors.,38,Primary: 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 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, misuse of fibrinolytic inhibitor,etc.,(4) Disorder of microcirculation,40,Section 5,Stages and types of DIC,41,1. 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 microthrombin,Increased consumption of clotting factors and platelet,Considerable formation of plasmin and FDP,42,1. Stages of DIC,Pathophysiology Clinical Laboratory findings (1)Hypercoagulable stage (2)Consuming hypocoagulable stage (3)Secondary fibrinolytic Stage,Hypercoagulable,Bleeding,Bleeding markedly,43,1. 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 platelet,Prolonged clotting and recalcification time Reduction of platelet count and Fbg narkedly,Shortened CLT, ELT; Prolonged TT 3P test (+), Increased FDP,CLT = clot-lysis time ELT = euglobulin-lysis time TT = thrombin time,44,Production of FDP and 3p test (plasma protamine paracoagulation test),Fibrinogen Thrombin Fibrin monomer (FM) Fibrin polymer Plasmin XIIIa FDP-X,Y,D,E Stabilized fibrin ( blood clotting ) X + FM soluble fibrin monomer complex (SFMC) Protamin SFMC X + FM blood clotting,45,Develop time Common causes Clinic feature,2. Types of DIC According to the rate of development, divide into 3 types,Acute Subacute Chronic,a few hours to days,within days to weeks,months,46,Develop time Common causes Clinic feature,2. Types of DIC According to the rate of development, divide into 3 types,Acute Subacute Chronic,malignant tumors collagenosis,metastasis of malignant tumors; retained dead fetus,severe infection or trauma ammiotic fluid embolism,47,Develop time Common causes Clinic feature,2. Types of DIC According to the rate of development, divide into 3 types,Acute Subacute Chronic,mild or concealed,microthrombin formation bleeding,shock, blooding exacerbate rapidly,48,: According to compensatory state, divide into 3 types Clotting factors and platelet Clinical situations compensatory Consumption = production discompensatory Consumption production over compensatory Consumption production,49,: 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 recovery,50,Section 6.,Principles of prevention and treatment of DIC,51,1. Pathophysiology bases of diagnosis 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,52,2. Pathophysiology bases of prevention and treatment of DIC,(1) Earlier diagnosis and treatment (2) Treatment of the causative 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 treatment,Back to cover next chapter,53,A syndrome resulting from the disturbance balance of coagulation and fibrinolytic processes, characterized by extensive intravascular microthrombosis and impairment o