Disseminated Intravascular Coagulation

1. Disseminated Intravascular Coagulation

2. Introduction of DIC • An acquired syndrome characterized by systemicintravascular coagulation and secondary bleeding • Coagulation is always the initial event. • Morbidity: 0.2‰-0.5 ‰ Mortality: 50%-60% • Multiple causes

3. Hemostasis Review • Coagulation cascade • Vascular Endothelium • Anticlotting Mechanisms • Fibrinolytic System • Blood Flow Dynamics

4. 1.Coagulation • Intrinsic Pathway • Extrinsic Pathway • Common Pathway • Contact Pathway • Tissue Factor Pathway • Primary factor in DIC

5. Tissue Factor （TF） • TF is a transmembrane glycoprotein which contains abundant phosphatide. • When TF enters blood, the calcium ions combine FⅦ to the phosphatide of TF to form a complex which can activate FⅩ to FⅩa. • FⅩa , calcium , FⅤa and phosphatide of PL act together to produce an activator of prothrombin. Finally thrombin can be produced. • VEC is not express TF in normal state. But endotoxin stimulation of VEC also produces TF. • Normal tissues and malignant tumors contain a large amount of TF. Different tissue contain different amount of TF

6. Activity of TF tissue Activity of TF（/mg） • Liver 10 • Muscle 20 • brain 50 • Lung 50 • Placenta 2000

7. 2.Vascular Endothelium • Vascular endothelium expresses: • Tissue Plasminogen Activator (t-pA)， t-PAI • Tissue factor pathway inhibitor (TFPI) • Tissue factor (TF) • NO，PGI2 / ET • Thrombomodulin (TM, 凝血酶调节素▽):

8. Inactivates Ⅴa、Ⅷa; Inhibits Ⅹa binding to PL; Leads to release of t-PA thrombomodulin (TM) Surface of VEC prothrombin coagulation activity Activated PC （APC） thrombin Protein C, PC Protein S thrombomodulin (TM ): A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation.

9. 3.Anticlotting Mechanisms • 1) Antithrombin III (A-TIII): • The major inhibitor of the coagulation cascade. • Inhibits Thrombin (70%-80%) • Inhibits activated Factors IX, X, XI, and XII. • Activity is enhanced by heparin. • Produced mainly by liver • 2) Tissue factor pathway inhibitor （TFPI）: Ⅶa, Xa Produced by EC • 3) Protein C sytem: VEC (Ⅴa,Ⅷa, Ⅹa )

10. 4. The fibrinolytic system PAI-1 Plasminogen Tissue Plasminogen Activator (t-PA) Urokinase (uPA) Thrombin, FⅫa, FⅪa Plasmin Inhibitor Fibrin, fibrinogen Plasmin Fibrin/ fibrinogen degradation products (FgDP / FDP▽)

11. 概念： 纤维蛋白（原）降解产物，指纤维蛋白（原）被纤溶酶分解后形成的多肽碎片 作用： 1 抑制纤维蛋白单体聚合 2 抗凝血酶 3 抑制Plt粘附、聚集、释放 FgDP/ FDP

12. 5. Phagocytosis of mononuclear phagocyte system (MPS): Most of the products of intravascular coagulation (fibrin monomer, prothrombin etc.), as well as various initiators of the process (endotoxin, tissue fragments, antigen-antibody complexes etc.) are removed from the circulation by MPS through unselective phagocytosis.

13. summary anticoagulation coagulation 1. Intact VEC 1.Intrinsiccoagulation pathway （Ⅻ→ Ⅻ a） 2.Extrinsic coagulation pathway（TF enters into blood） 2.quite rapid blood flow velocity 3. Phagocytosis of MPS 4.physiological anticoagulation substances:AT-Ⅲ、PC、TFPI 5. Fibrinolyticsystem

15. The Concept of DIC • The Causes and Accelerating factors of DIC • The Pathophysiology of DIC • Clinical Manifestations of DIC • The Stages and Types of DIC • The Diagnosis and Treatment of DC

16. DIC 是一种继发性的、以广泛微血栓形成并相继出现止、凝血功能障碍为病理特征的临床综合征。 一.Concept of DIC SYSTEMIC ACTIVATION OF COAGULATION Intravascular deposition of fibrin Depletion of platelets and coagulation factors Thrombosis of small and midsize vessels Bleeding DEATH Organ failure

17. 二、Causes and accelerating factors factors of DIC • The causes and triggering factors of DIC Causes：引起DIC的基础疾病或病理过程（病因性疾病）

18. 感染性疾病: 细菌感染败血症、内毒素血症、病毒性肝炎、流行性出血热 广泛组织损伤: 大面积挫伤或烧伤、挤压综合症、大手术、器官移植 产科意外: 胎盘早剥、羊水栓塞、宫内死胎、妊娠中毒症、流产术 恶性肿瘤: 肺、消化系及泌尿系癌、转移癌、恶性葡萄胎、绒毛膜上皮癌 急性白血病: 急性早幼粒白血病 其他疾病: 内毒素休克、严重出血或过敏性休克、大面积心肌梗死、异型输血、巨大海棉状血管瘤、肾小球肾炎、类风湿关节炎、系统性红斑狼疮、肾移植排斥反应 Common Causes of DIC

19. Triggering factors of DIC • Tissue injury: TF enters into blood • VEC injury: • Endotoxin • Ag-Ab complex • Protease • Others:particles, virus, hypoxia

20. 2. Precipitating factor(accelerating factors ) of DIC （1) Impairment of the MPS （2） Liver Disease （3） Hypercoagulable state of blood （4） Microcirculation dysfunction （5） Others

21. (1)Impairment of the mononuclear phagocyte system • The mononuclear phagocyte system (MPS) is composed of mononuclear cell and phagocyte. • Most of the products of intravascular coagulation (free fibrin, prothrombin activator), as well as various initiators of the process (endotoxin, tissue fragments, antigen-antibody complex, thromboplastins) are removed from the circulation by the unspecific phagocytosis of MPS

22. Kupffer cell in liver are very important in the clearance of activated clotting factors (Ⅸa, Ⅹa and Ⅻa) • Any factors that decrease or impair MPS will accelerate the occurrence of DIC in a manner comparable to that produced experimentally in the general Shwarzman reaction (GSR) in animals

23. GeneralizedShwartzmanreaction（GSR） 1924, Sanarelli: 亚致死量霍乱菌滤液i.v. Rat24h i.v. 大肠杆菌或变形杆菌滤液 Ratdied of shock DIC and shock haemorrhagic infarct Mechanism: 长期大量应用糖皮质激素,反复感染或严重肝疾病 ↓the function of MPS ↑DIC

24. (2) Severe Liver Disease • Some causes (Ag-Ab complex, drugs) of the disease may directly activate coagulation • Acute severe hepatitis release TF and lysosome enzyme; there is gutdrived endotoxemia at the late stage of hepatocirrhosis • Impaired synthesis of some clotting factors such as FII, FVII, FV, FIX and FX also Antithrombin ,Proteins C (PC) and S (PS) • Impaired synthesis anti-clotting factors such as of PC, PS and antithrombin can lead to susceptibility to DIC • The damaged liver reduces the clearance of activated clotting factors such as FⅩa and FⅡa. • Often associated with bleeding

25. (3) Hypercoagulable state of blood Primary: inherited lack of AT-Ⅲ, PC and PS or PC-resisting syndrome Secondary:

26. 1) Pregnancy: the blood in pregnancy after 3 months begins to increase coagulability, which is most marked in the terminal stage of pregnancy a) PL and clotting factors (FⅠ, FⅡ,F Ⅴ, F Ⅶ, F Ⅸ, FⅩ, FⅫ) are increased b) the substances with the action of anticoagulation (AT-Ⅲ) and with the activity of fibrinolysis (t-PA, u-PA)are decreased c) fibrinolysis inhibitors are increased → form the hypercoagulable state of blood in pregnancy Therefore, obstetrical suddenness (such as amniotic fluid embolism, early separation of placenta, died fetus) is very easy to induce DIC

27. 2) Acidosis: acidosis causes the reducing of pH of the blood → a) VEC can be damaged by increased [H+] d) The activity of heparin is decreased. c) activity of clotting factors and platelets is increased d) disturbance the vessel movement activity and hemorheology:↑vessel permeability, blood oozing , → high blood viscosity, vasodilation, slow blood flow velocity. → hypercoagulable state of blood

28. (4)Microcirculation dysfunction Local: vessel movement, blood, acidosis, VEC, WBC Systemic: shock→ Vessel’s movement and reaction↓ disorders of hemorheology VEC was damaged Tissue was damaged Inflammation and inflammatory media Multiple Organs dysfunction → formation of DIC

29. (5) Others stress → impaired movement of vessel Old age, smoking, late stage of pregnancy, diabetes , unapt using of inhibitor→decreased activity of fibrinolysissystem Experiment: alive animalEndotoxin or thrombin i.v. →microthrombosis is temporal, about 1hPlus fibrinolytic inhibitor or NE → the reservation of microthrombosis

30. 三、Pathophysiology of DIC The course of DIC occurrence :To trigger coagulation →the deposit and reserve of Fbn • Activation of Blood Coagulation • The changes of vessel’s movement and hemodynamics （血液动力学） • Impaired Fibrinolysis

31. （一）Activation of Blood Coagulation • 1、Tissue injury • 2、VEC injury • 3、Other pathways

32. 1.Severe tissue injury →to activate extrinsic coagulation system causes：sever trauma, burn, major operation, malignant necrosis mechanism：tissue factor enters into blood lysosome enzyme (may activate clotting factors)

33. 2. Extensive damage of VEC→loss of balance between coagulation and anticoagulation causes：infection, hypoxia, acidosis,antigen-antibody complex Fbn

34. Mechanism: • Damaged VEC (micro-V. and Capi) express TF→to trigger extrinsic coagulation system • VEC was damaged→blood contacts with exposed collagen to activate FⅫ to form FⅫa → intrinsic clotting cascade is triggered. • WBC :TNF, IL-1, PAF, superoxide, C3a C5a →↑the injury of VEC • Anticoagulation and fibrinolysis activity are decreased: anticoagulants(TFPI , TM, AT-Ⅲ) ↓, PAI↑ • ET ↑, / NO ↓, PGI2 ↓ • Platelet activation.

35. PLadhesion to damaged VEC Nomal VEC（scanning electron microscope ）

36. 3. Other pathways to induce coagulation • Activated mononuclear phagocyte：TF, lysosome enzyme • Malignant tumors:TF,cancer procoagulant（★FⅩ) • Trypsin (胰蛋白酶): hemorrhagic acute pancreatitis, pancreas malignant tumor→ Trypsin → ★FⅡ • Exogenous toxin ：snake venom , bee venom → ★FⅩ, FⅡ, FⅠ • Severe haemolysis: ADP （★PL), 红细胞素具TF样作用

37. (二) The changes of vessel’s movement and hemodynamics • sympatho-adrenomedullary system (SAS) • Damaged VEC: NO↓, PGI2↓/ ET ↑ activated platelet:TXA2↑ • PAF, histamine, Bradykinin→ ↑ capillary permeability →blood viscosity ↑

38. (三) Impaired Fibrinolysis • 1、Decreased fibriolysis: Damaged VEC: negative charge ↓, the expression and absorbing of TFPI↓, AT-Ⅲ↓, TM↓, t-PA↓, PAI-1↑ • 2、Secondary increased fibriolysis: coagulation→ FⅡa Fbn →VEC release t-PA the activation of fibriolysis → FgDP/ FDP: ↑anticlotting →bleeding

39. 四、 Clinical Manifestations of DIC • Bleeding • Shock • MODS • Microangiopathic hemolytic anemia

40. 1、bleeding：is the most obvious clinical finding, is seen in 70~80% of DIC case, is life threatening.

41. Mechanism of bleeding in DIC (1) Consumption of coagulative factors ( Ⅰ、Ⅱ、Ⅴ、Ⅷ、Ⅹ) and platelet (2) Secondary activation of fibrinolysis system: plasminogen → plasmin: fibrin 、 fibrinogenFDP Ⅱa、Ⅴ、Ⅷ、Ⅻa consumption

42. (3) Formation of FDP→ anticoagulation fibrinogen plasmin X、A、B Y、D FgDP/FDP D、E fibrin plasmin X′、Y′、D、E′ X、Y、D：inhibit fibrin monomer aggregation Y、E： have anti-thrombin action Most of them： inhibit platelet aggregation and release Water-soluble Small peptide

43. (4) Vessel was damaged: • primary factors • secondary factors: hypoxia, acidosis, free radical

44. 2. Microcirculation disturbance -shock (1) microthrombi → the blood return ↓ (2) excess bleeding → blood volume ↓ (3) Cardiac output ↓:heart or lung thrombi, acidosis (4) Vasodilation and permeability of capillary↑ (a) activation of complement and kinin system→histamine, kinin release peripheral resistance ↓ permeability of capillary ↑ A,B,C → ↑ histamine, kinin (b)FDP vasodilation permeability of capillary ↑

45. 3. Multiple organ dysfunction syndrome (MODS) (1) primary disease →cause organ dysfunction (2) extensive microthrombi in organs → serious ischemic tissue damage (3) interaction between organs : e.g. pulmonary infection →DIC, pulm. dysfunction → PaO2↓, PaCO2↑ pulmonary artery pressure ↑ → heart dysfunction →aggravate microcirculation disturbance

46. 4. microangiopathic hemolytic anemia (微血管病性溶血性贫血)

47. Microscopic findings in DIC • Fragments • Schistocytes （裂体细胞） • Paucity of platelets

48. RBC hanging on fibrin strands （scan electron microscope ，left2000，right5200）

49. 五、 The Stages and Types of DIC 1、 Stages of DIC 1.Hypercoagulable stage: clotting system is activated, thrombin in blood, microthrombi 2.Hypocoagulable stage: clotting factors and PL↓, bleeding 3.Secondary fibrinolytic stage FgDP/FDP→inhibit PL aggregation and fibrin formation → bleeding↑, shock ,MODS 2、types of DIC

50. 六、 Diagnosis and Treatment of DIC