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08 dic
该文档讨论了止血失调的各个方面，包括凝血和抗凝血系统的功能、弥散性血管内凝血（DIC）的概念及其病因、临床表现和治疗原则。DIC是一种以广泛的血管内凝血为特征的病理过程，可能引发微血栓的形成、凝血因子和血小板的减少，以及后续的出血和器官功能障碍。治疗策略包括使用抗凝药物（如肝素）和支持性治疗以恢复凝血与抗凝血的平衡。
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- 1. Dept. of PathologyDept.of Pathology Medical CollegeMedical College Hunan Normal UniversityHunan Normal University (( 湖南 范大学医学院病理学教研室师湖南 范大学医学院病理学教研室师 )) 1 Chapter 8Chapter 8 Disturbance of HemostasisDisturbance of Hemostasis （凝血与抗凝血平衡紊乱）（凝血与抗凝血平衡紊乱）
- 2. 22 Disturbance of HemostasisDisturbanceof Hemostasis a.a. Coagulation and anticoagulationCoagulation and anticoagulation homeostasishomeostasis b.b. Disseminated intravascularDisseminated intravascular coagulation (DIC)coagulation (DIC)
- 3. Apoptosis Oxygen SocietyEducation Program Tome & Briehl 3 a.a. Coagulation SystemCoagulation System b.b. Anticoagulation SystemAnticoagulation System c.c. Fibrinolytic SystemFibrinolytic System The Three Hemostasis Systems
- 4. The ”Classic” CoagulationSystem XII XIIa XI XIa IX IXa II IIa I Ia (Fibrin) Phospholipid, Ca++ , VIII Phospholipid, Ca++ , V 4 Prothrombin activator formation Thrombin formation Fibrin formation X Xa Intrinsic Fibrin net XIIIa VIIa VII Tissue factor (III) Ca++TF Extrinsic X II: Prothrombin I: Fibrinogen
- 5. a.a. Coagulation SystemCoagulationSystem b.b. Anticoagulation SystemAnticoagulation System c.c. Fibrinolytic SystemFibrinolytic System The Three Hemostasis Systems
- 6. 1.1. FromFrombody fluid (plasma)body fluid (plasma) (1)(1) Antithrombin (AT- )Ⅲ ⅢAntithrombin (AT- )Ⅲ Ⅲ (2)(2) Thrombomodulin (TM) - protein C systemThrombomodulin (TM) - protein C system (3)(3) Tissue factor pathway inhibitor (TFPI)Tissue factor pathway inhibitor (TFPI) (4) Heparin(4) Heparin 2. From Cells2. From Cells (1) Vascular endothelial cells (VEC)(1) Vascular endothelial cells (VEC) (2) Monocyte-macrophage system(2) Monocyte-macrophage system (3) Liver cells(3) Liver cells Anticoagulation System 6
- 7. The Effect ofAntithrombin III 7 Tissue factor XII XIIa XI XIa IX IXa X Xa X II IIa I Ia (fibrin) Phospholipid, Ca++ , VIII Phospholipid, Ca++ , V VIIa VII Ca++TF Extrinsic Intrinsic AT-III × × ×
- 8. The Effect ofProtein C 8 Tissue factor XII XIIa XI XIa IX IXa X Xa X II IIa I Ia (fibrin) Phospholipid, Ca++ , VIII Phospholipid, Ca++ , V VIIa VII Ca++TF Extrinsic Intrinsic aPC × ×
- 9. Protein S FVIIIa FVa Endothelial cell TheEffect of Protein C Thrombomodulin Protein C Activated protein C Thrombin EPCR 9 EPCR: Endothelial protein C receptor ↑ Release of tPA, uPA
- 10. A glycoprotein synthesizedby vascular endothelial cells (VECs). Also called extrinsic pathway inhibitor (EPI). Inactivate VIIa & Xa. Tissue factor pathway inhibitor （ TFPI ）
- 11. The Effect ofTFPI 11 Tissue factor XII XIIa XI XIa IX IXa X Xa X II IIa I Ia (fibrin) Phospholipid, Ca++ , VIII Phospholipid, Ca++ , V VIIa VII Ca++TF Extrinsic Intrinsic TFPI × ×
- 12. Produced in mastcells & basophils. Acts as cofactor for AT-III. - promoting anticoagulant effect of AT-III. Heparin
- 13. a.a. Coagulation SystemCoagulationSystem b.b. Anticoagulation SystemAnticoagulation System c.c. Fibrinolytic SystemFibrinolytic System The Three Hemostasis Systems
- 14. Involved in dissolvingthe clot that has already formedInvolved in dissolving the clot that has already formed in vessels.in vessels. As soon as the clot is formed, its breakdownAs soon as the clot is formed, its breakdown (fibrinolysis) begins immediately.(fibrinolysis) begins immediately. Fibrinolytic System
- 15. Fibrinolytic Pathway Plasminogen Plasmin Fibrin/Fibrinogen Fibrin/Fibrinogen degradation products(FDP) 15 Plasminogen Activator Inhibitor (PAI) Antiplasmin Plasminogen Activator Tissue-type (tPA) Urokinase-type (uPA) Thrombin, F a, F aⅫ Ⅺ Kallikrei n
- 16. Apoptosis Oxygen SocietyEducation Program Tome & Briehl 17 Regulation of Hemostasis
- 17. Regulation of Hemostasis VascularEndothelial Cells (VECs)Vascular Endothelial Cells (VECs) 11 、、 Anti-coagulationAnti-coagulation ：： - Physical barrier, inhibiting aggregation of platelets- Physical barrier, inhibiting aggregation of platelets - Produce or absorb anticoagulants- Produce or absorb anticoagulants ：： TFPI, AT-TFPI, AT- , TMⅢ, TMⅢ 22 、、 Pro-coagulationPro-coagulation ：： - Produce or absorb coagulants- Produce or absorb coagulants ：： TF, a, a, aⅨ Ⅹ ⅪTF, a, a, aⅨ Ⅹ Ⅺ - Secrete adhesion molecules: FN, ICAM-1- Secrete adhesion molecules: FN, ICAM-1 33 、、 Fibrinolysis:Fibrinolysis: - Promotion of tPA- Promotion of tPA - Inhibition of PAI- Inhibition of PAI 44 、、 Vascular toneVascular tone ：： Dilation or constrictionDilation or constriction
- 18. Damaged VECsDamaged VECsNormalVECsNormal VECs 19
- 19. 2121 Disturbance of HemostasisDisturbanceof Hemostasis a.a. Coagulation and anticoagulationCoagulation and anticoagulation homeostasishomeostasis b.b. Disseminated intravascularDisseminated intravascular coagulation (DIC)coagulation (DIC)
- 20.
- 21. Apoptosis Oxygen SocietyEducation Program Tome & Briehl 23 Disseminated intravascular coagulation (DIC) a.a. ConceptConcept b.b. CausesCauses c.c. PathogenesisPathogenesis d.d. Precipitating factorsPrecipitating factors e.e. Clinic manifestationsClinic manifestations f.f. Pathophysiological basis of prevention andPathophysiological basis of prevention and treatment of DIC (3P, DD)treatment of DIC (3P, DD)
- 22. A pathological processcharacterized byA pathological process characterized by widespread intravascular coagulationwidespread intravascular coagulation that resultsthat results in the formation of microthrombi throughout thein the formation of microthrombi throughout the body, followed by depletion of coagulation factorsbody, followed by depletion of coagulation factors and platelets, andand platelets, and subsequent fibrinolysis andsubsequent fibrinolysis and hemorrhagehemorrhage.. Concept of DIC Hypercoagulable state Hypocoagulable state
- 23. 25 SYSTEMIC ACTIVATION OF COAGULATION Intravascular deposition of fibrin Depletionof platelets and coagulation factors Thrombosis of blood vessels Bleeding Organ failure DEATHDEATH Hypercoagulable state Hypocoagulable state
- 24. Apoptosis Oxygen SocietyEducation Program Tome & Briehl 26 Disseminated intravascular coagulation (DIC) a.a. ConceptConcept b.b. CausesCauses c.c. PathogenesisPathogenesis d.d. Precipitating factorsPrecipitating factors e.e. Clinic manifestationsClinic manifestations f.f. Pathophysiological basis of prevention andPathophysiological basis of prevention and treatment of DIC (3P, DD)treatment of DIC (3P, DD)
- 25. Causes of DIC •Infectious diseasesInfectious diseases • MalignancyMalignancy • TraumaTrauma • Obstetrical emergencyObstetrical emergency • OthersOthers 27
- 26.
- 27. Activity of TFin Human Tissues Tissue Activity of TF （ /mg ） • Liver 10 • Muscle 20 • Brain 50 • Lung 50 • Placenta 2000 29
- 28. Apoptosis Oxygen SocietyEducation Program Tome & Briehl 32 Disseminated intravascular coagulation (DIC) a.a. ConceptConcept b.b. CausesCauses c.c. PathogenesisPathogenesis d.d. Precipitating factorsPrecipitating factors e.e. Clinic manifestationsClinic manifestations f.f. Pathophysiological basis of prevention andPathophysiological basis of prevention and treatment of DIC (3P, DD)treatment of DIC (3P, DD)
- 29. Stage ofStage of hypercoagulabilityhypercoagulability StageofStage of hypocoagulabilityhypocoagulability Stage ofStage of secondary fibrinolysissecondary fibrinolysis 33
- 30. Apoptosis Oxygen SocietyEducation Program Tome & Briehl 34 Disseminated intravascular coagulation (DIC) a.a. ConceptConcept b.b. CausesCauses c.c. PathogenesisPathogenesis d.d. Precipitating factorsPrecipitating factors e.e. Clinic manifestationsClinic manifestations f.f. Pathophysiological basis of prevention andPathophysiological basis of prevention and treatment of DIC (3P, DD)treatment of DIC (3P, DD)
- 31. Precipitating FactorsPrecipitating Factors •Impairment of clearance mechanismImpairment of clearance mechanism - Mononuclear phagocyte system dysfunction- Mononuclear phagocyte system dysfunction • Liver DiseaseLiver Disease - Synthesis of coagulation factors- Synthesis of coagulation factors ↓↓ • Hypercoagulable state of bloodHypercoagulable state of blood - Pregnancy- Pregnancy • Microcirculation dysfunctionMicrocirculation dysfunction - Acidosis, plasma viscosity- Acidosis, plasma viscosity ↑↑, platelet aggregation, platelet aggregation
- 32. Generalized Shwartzman Reaction （GSR ） 36 Thorium dioxide destroys the mononuclear phagocyte function. ↓ Endotoxin ↓ DIC Thorium dioxide ( 二 化氧 钍 )
- 33. Why More DICin Pregnant Women? Hypercoagulable State Platelets ↑ Coagulation factors ↑ I, II, III, V, VII, IX, X, XII PAI-1 (produced from placenta) ↑ Anticoagulation factors ↓ AT-III, tPA, uPA 孙慧兰
- 34. Apoptosis Oxygen SocietyEducation Program Tome & Briehl 39 Disseminated intravascular coagulation (DIC) a.a. ConceptConcept b.b. CausesCauses c.c. PathogenesisPathogenesis d.d. Precipitating factorsPrecipitating factors e.e. Clinic manifestationsClinic manifestations f.f. Pathophysiological basis of prevention andPathophysiological basis of prevention and treatment of DIC (3P, DD)treatment of DIC (3P, DD)
- 35. Clinical Manifestations • BleedingBleeding •Circulatory disturbance - shockCirculatory disturbance - shock • Multiple organ dysfunction syndromeMultiple organ dysfunction syndrome • Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia 40
- 36.
- 37.
- 38.
- 39.
- 40.
- 41.
- 42. Anemia During DIC 47 Microangiopathichemolytic anemia (MAHA) Formation of Schistocytes
- 43. Schistocyte Formation force Fibrin strands RBC RBCRBC fragments
- 44. RBCs trapped onfibrin nets in DIC (scanning electron microscope ）
- 45.
- 46. Apoptosis Oxygen SocietyEducation Program Tome & Briehl 51 Disseminated intravascular coagulation (DIC) a.a. ConceptConcept b.b. CausesCauses c.c. PathogenesisPathogenesis d.d. Precipitating factorsPrecipitating factors e.e. Clinic manifestationsClinic manifestations f.f. Pathophysiological basis of prevention andPathophysiological basis of prevention and treatment of DIC (3P, DD)treatment of DIC (3P, DD)
- 47. Laboratory Tests forDIC • Basic blood examinationsBasic blood examinations • Platelet count: Blood Platelet Count (BPC) ↓Platelet count: Blood Platelet Count (BPC) ↓ • Peripheral blood smear:Peripheral blood smear: - Schistocytes (in approximately 50% of cases)- Schistocytes (in approximately 50% of cases) 53
- 48. • The coagulationdefect •Partial thromboplastin time (PTT) •Prothrombin time •Thrombin time •Fibrinogen concentration 54 Laboratory Tests for DIC
- 49. THE ”CLASSIC” COAGULATIONSYSTEM Surface contact Tissue factor XII XIIa XI XIa IX IXa X Xa X II IIa I Ia (fibrin) Phospholipid, Ca++ , VIII Phospholipid, Ca++ , V VIIa VII Ca++ PTT Prothrombin time 55
- 50. • Tests forfibrinolysis •Fibrinogen degradation products (FDP) •D-dimer •Plasma protamine paracoagulation test (3P) 56 Laboratory Tests for DIC
- 51. Fbg: Fibrinogen FM: Fibrinmonomer Fbn: Fibrin Pln: Plasmin 3P Test: Plasma Protamine Paracoagulation Test Purpose:Purpose: Examining the existence of FDPExamining the existence of FDP protamine Dissociating FM Fibrin multimer (Clot) Fbg FM Fbn Ⅱa XⅢa FDP Pln Pln FM—X (Soluble complex) (A, B, C X,Y)
- 52. Fbg FM Fbn ⅡaXⅢa Pln Primary fibrinolysis A,B,C,X,Y + D-Monomer A,B,C,X,Y + D-Dimer Secondary Pln fibrinolysis D-Dimer Test Purpose:Purpose: Examining the existence of secondary fibrinolysisExamining the existence of secondary fibrinolysis
- 53. Treat primary diseasesandTreat primary diseases and eliminate predisposing factors.eliminate predisposing factors. Improving microcirculation.Improving microcirculation. Restore balance betweenRestore balance between coagulation and anti-coagulation.coagulation and anti-coagulation. Protect organ function.Protect organ function. Principles of Treatment
- 54. Treatment: Anticoagulation 1.Heparin • IndicationsIndications –forms manifested by thrombosis orforms manifested by thrombosis or acrocyanosisacrocyanosis – forms that accompanyforms that accompany • cancercancer • vascular malformationsvascular malformations • retained dead fetusretained dead fetus • acute promyelocytic leukemiaacute promyelocytic leukemia 63
- 55. Treatment: anticoagulation 1.heparin • Dosage –Theoptimaldosageof heparinis thesourceof somedisagreement; – 50u/kg, intravenous infusion, Q6h – 5000-10000u, subcutaneously,Q12-24h 64
- 56. Treatment: anticoagulation 1.heparin • Laboratorymonitoring –aPTT: aprolongationof between1.5and2times normal; – CT; • Reversalof heparineffect – 1mgprotaminesulfate: 100uheparin – infusedintravenously – rateof infusion< 5mg/min 65
- 57.
- 58. Treatment: anticoagulation 1.heparin • LMWH –Characteristics • Posses higheranti- aactivitythananti-thrombinⅩ activity; • Longerhalf-timeandahigher, morereliable bioavailability • Alowerincidenceof bleedingcomplications. – Usage • 75-150IUA a/Kg.d, subcutaneously, ×3-5days.Ⅹ 67
- 59. Treatment: anticoagulation 2. others •AT-Ⅲ – Decreasethedoseof heparin; – Improvetheresponse. – Dose: 1500-3000uBid-Tid, intravenous infusion×5-7days; 68
- 60. Treatment: Antiplateletdrugs • Indications – inhypercoagulabilitystate; –thediagnosis of DIC is stillnotcertain; – inmildcases. • Usage – compounddansheninfusion 20-40mlBid-Tid×3-5days – Lowmolecularweightdextran 500-1000ml/d ×3-5days – Ticlopidine250mgBidp.o. ×5-7days – Dipyridamole 500mg/d×3-5days; 69
- 61. Treatment: Haemostatic support • plateletconcentrates –plateletcount<20×109 /Lorhaveseverelife-threatening bleeding; • freshfrozenplasma(FFP) – 10-15ml/kgbodyweightwhentheINRof PTis greaterthan1.5; • cryoprecipitate – 1-4unit/10kgbodyweightwhenthefibrinogenconcentrationis 0.8g/lorless. • Fibrinogen – 1st dose: 2-4g(1-1.5g 50mg/L)→↑ • PPSB – 200u=200mlFFP 70
- 62. Treatment: Fibrinolytic inhibitors • Indications –theunderlyingdisorders havealready controlledorcured; – excessivefibrinolysis is observed; – Latestageof DIC; • Contraindications – patients withearlystageof DIC. 71
- 63. Treatment: Fibrinolytic inhibitors • Usage –PAMBA(氨甲苯酸 ) 600- 800mg/d – tranexamic acid(氨甲环酸 ) 500- 700mg/d – -aminocaproic acid(ε 氨基已酸 )4-10g/d Attention – Theseagents shouldbeprecededby replacementof depletedbloodcomponents and continuous heparininfusion. 72
- 64.
- 65. 治疗：总结 • DIC 各期治疗原则 –早期 • 首选肝素加血小板聚集抑制药； • 禁用纤溶抑制药； • 不需输血及补充凝血因子； 74
- 66. 治疗：总结 • DIC 各期治疗原则 –中期 • 肝素治疗为主； • 适当输血及补充凝血因子； • 在应用肝素基础上慎重使用小剂 量抗纤溶药； 75
- 67. 治疗：总结 • DIC 各期治疗原则 –晚期 • 抗纤溶药以及输血补充凝血因子为 主； • 如不能确定血管内凝血是否终止可 同时使用小剂量肝素； 76
- 68. A 56-year-old manwas admitted to the emergency department after a car accident. He had several bone fractures, a cerebral contusion, and hemodynamic instability caused by a ruptured spleen. Emergency splenectomy and aggressive administration of fluids restored hemodynamic stability, and the patient was transferred to the intensive care unit (ICU). A few hours later, profuse extravasation was noted from the abdominal drains, endotracheal tube, and puncture sites of all intravascular lines. Clinical Case 77
- 69. Laboratory tests showeda rapidly falling hemoglobin level and a platelet count of 25,000/µL (normal>150 ， 000/µL). The prothrombin time (PT) was 29 sec (normal, <12.5). The level of fibrinogen degradation products was 360-520 g/L (normal, <40) and the plasma antithrombin III level was 28% (normal, 80-120). Clinical Case 78
- 70. Based on thesefindings, the diagnosis was DIC secondary to severe trauma. Surgical exploration revealed diffuse oozing of blood at the site of the operation, but only partial surgical hemostasis could be achieved. The patient was given supportive treatment with large infusions of fresh plasma and platelet concentrates. The bleeding stopped 48 hours later. Coagulation parameters eventually returned to normal and the subsequent clinical course was uneventful. Clinical Case 79
- 71.
Editor's Notes
- #2 Disorders are big problems in clinic. http://v.qihuang99.com/player/1777.html?1777-0-2
- #5 Three stages and three complexes. Ca++ also called factor IV.
- #7 AT-III is serine protease inhibitor produced by the liver.
- #8 Serine protease inhibitors (AT-Ⅲ, HC-Ⅱ, PN-1,α1-AT) Antithrombin III: synthesized by hepatic cells & VEC inhibits: mainly factors Xa, IXa, and IIa also factors VIIa and III. Activity enhanced by heparin binding.
- #10 Protein S (also known as S-Protein) is a vitamin K-dependent plasma glycoprotein synthesized in the endothelium. The best characterized function of Protein S is its role in the anti coagulation pathway, where it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. Thrombomodulin functions as a cofactor in the thrombin-induced activation of protein C in the anticoagulant pathway by forming a 1:1 stoichiometric complex with thrombin.
- #15 Clot: thrombus.
- #16 Kallikrein: 激肽释放酶
- #20 内毒素可直接损伤VEC，或通过TNF、IL-1、PAF、C5a介导VEC的损伤
- #25 shock, and multiple organ dysfunction and microangiopathic hemolytic anemia can occur.
- #26 shock, and multiple organ dysfunction and microangiopathic hemolytic anemia can occur.
- #29 Figure 41-2. Pathogenetic pathways that may lead to disseminated intravascular coagulation (DIC). Simultaneously occurring tissue factor-driven activation of coagulation is facilitated by disruption of physiologic anticoagulant pathways, and the resulting fibrin is inadequately removed by an impaired fibrinolytic system. Ag-Ab, antigen-antibody; IL-1, interleukin-1; PMN, polymorphonuclear neutrophils; TNF, tumor necrosis factor. Traditionally, DIC was thought to be the result of activation of the combined coagulation pathways (i.e., the extrinsic and intrinsic routes) (47,48). In the classic concept of the coagulation cascade, the extrinsic route was started by a tissue-derived component, which activated plasma factor VII, leading to direct conversion of prothrombin (49). This process could proceed as long as tissue damage existed, such as during systemic infections, trauma, solutio placentae, and malignancies. Alternatively, the contact route of coagulation could be started by the contact-mediated activation of factor XII, which by the action of the cofactors kallikrein and kininogen, could convert factor XI and the further intrinsic route of coagulation (50). In the conceptual contact pathway, it has been uncertain which factors other than, perhaps, collagen and artificial surfaces would actually mediate the &quot;contact&quot; element. In recent years, the molecular mechanisms of both coagulation pathways have been explored and the cofactors further identified (51). In general, the current concept is that for actual thrombin and fibrin formation, the extrinsic pathway is predominant (Fig. 41-2) (52). The role, if any, of the contact system in the fibrin-forming process is currently uncertain, but several questions remain, which are addressed in the following sections.
- #34 The mechanisms that activate or &quot;trigger&quot; DIC act on processes that are involved in normal hemostasis; namely, the processes of platelet adhesion and aggregation and the contact-activated (intrinsic) and tissue-activated (extrinsic) pathways of coagulation. 1. Activation of the extrinsic coagulation system by tissue factor expressed on cell surfaces: trauma, cancer, obstetric events, ascites (shunt) etc; 2. Activation of intrinsic coagulation system by causing injury to endothelial cells: hypotension, endotoxin, heat stroke, vasculitis, aneurysm, hemangioma etc; 3. Activation of coagulation factors, e.g., factor Ⅹ by cancers, factor Ⅱ by snake venoms; All of these lead to thrombin generation that in the presence of failure of the control mechanisms results in intravascular coagulation. This in turn, can lead to thrombosis and consumption of platelets, fibrinogen, and other coagulation factors. Bleeding can be caused by depletion of these essential hemostatic components; by the anticoagulant effects of fibrinogen/fibrin degradation products; and by further depletion of fibrinogen, factor Ⅴ, and factor Ⅷ by plasmin if generated in excess by the secondary fibrinolysis or if uninhibited due to diminished antiplasmin levels.
- #36 Mononuclear phagocyte system clears activated coagulation factors.
- #39 三多一少。
- #47 Bleeding of the
- #49 裂体碎片
- #54 由于DIC的症状、体征缺乏特异性，其中许多又与基础疾病的临床表现重叠，因此大多数DIC的诊断需有实验指标作依据。 Platelet count: thrombocytopenia is an early and consistent sign of DIC. Peripheral blood smear: Examination of the blood smear reveals schistocytes in approximately 50% of cases.
- #55 (1)Partial thromboplastin time (PTT), Prothrombin time, and thrombin time: The PTT, PT, TT are prolonged in most patients with acute DIC. Early in the course of the disorder, and in chronic DIC, the PTT may be normal, or even shorter than normal, which may be the result of the procoagulant effects of activated coagulation factors. (2) Fibrinogen concentration: The plasma levels of fibrinogen usually are significantly depressed. But the fibrinogen concentration may remain within normal limits despite consumption because of its elevation as an acute-phase reactant.It may be markedly elevated initially in patients with sepsis, neoplasia, or otherinflammatory disorders, the concentration of fibrinogen may not fall below the reference range, at least early during the course of DIC.
- #57 3. Tests for fibrinolysis (1) Fibrinogen degradation products (FDP): There is usually an increased level of FDP. (2) D-dimer: Assay of plasma D-dimer is very useful for evaluation of patients with DIC. Increased levels indicate that cross-linked fibrin generated by thrombin has been digested by plasmin. (3) Plasma protamine paracoagulation test (3P) (4) Euglobulin lysis time
- #64 Indications: Administration of heparin is beneficial in some categories of acute and chronic DIC, including purpura fulminant, acute promyelocytic leukemia, dead fetus syndrome (at time of removal), and aortic aneurysm (prior to resection). Heparin is also indicated for treating thromboembolic complications in large vessels and before surgery in patients with metastatic carcinoma. Heparin administration may also be helpful when intensive blood component replacement fails to improve excessive bleeding and fails to increase the level of hemostatic factors.
- #65 Dosage: heparin may be administered by continuous intravenous infusion or intermittent intravenous. The optimal dosage of heparin, however, is the source of some disagreement. 静脉注射标准肝素后，10分钟即可产生抗凝作用，约2小时可达作用高峰，6小时内大部位在单核-巨噬系统内经去硫酸而被降解，亦可以原型由肾脏排出。注入体内肝素的半减期为30～360分钟，平均约90分钟。
- #66 The activated PTT is the preferred laboratory test for monitoring heparin. For the first 48 hours, aPTT should be measured at 6-12 hour intervals. When the drugs is given an an intermittent schedule, to monitor therapy, the PTT should be obtained the hour prior to the next scheduled infection the heparin dosage and the rate of infusion adjusted to achieve a prolongation of between 1.5 and 2 times normal. Heparin anticoagulation can be reversed by the intravenous infusion of protamine sulfate. One milligram of protamine neutralizes approximately 100 units of heparin. The calculated dose of protamine sulfate is then infused intravenously at a rate no greater than 5mg per minute.Rapid infusion can reslut in marked hypotension, dyspnea, bradycardia, and even anaphylaxis.
- #67 Heparin molecules with fewer than 18 saccharides(LMWH) can be prepared chemically or enzymatically from natural heparin. Because of the smaller molecular size, LWMH is less able to bind to AT3 and thrombin simultaneously but does retain its ability to inhibit factor 10a.
- #68 Given in a dose of 2500u subcutaneously twice a day No laboratory monitoring is required for subcutaneous LWMH therapy at doses of 2500u twice a day.
- #69 AT-Ⅲ是人体内最为重要的生理性抗凝物质。主要作用是灭活凝血过程启动后形成的凝血酶，同时还有抑制因子Ⅻ、Ⅺ、Ⅹa及Ⅸa的作用，其机制是上述激活凝血因子的丝氨酸活性中心以1∶1与AT－Ⅲ的精氨酸反应中心结合，形成复合物，致其凝血活性丧失。肝素通过与AT-Ⅲ中赖氨酸结合，增强其抗凝作用。当AT-Ⅲ活性降至50%以下时，即可出现血栓形成。DIC时，AT-Ⅲ有消耗性降低，肝素治疗又可加剧AT-Ⅲ的减少，这不仅有利于DIC的发展，而且也降低了肝素治疗的疗效。因此，在DIC抗凝治疗中，适时、适量补充AT-Ⅲ，是极为重要的一环。 药用AT-Ⅲ目前主要来自血浆浓缩物及基因重组制剂等。DIC时用量为首剂40～80 IU/kg·d，静脉注射，以后逐日递减，以维持AT-Ⅲ活性至80～160%为度。由于AT-Ⅲ血中半寿期长达50小时以上，因此一般每日用药一次即已足够。疗程5～7天。 由于国内纯品及浓缩AT-Ⅲ尚难普遍推广应用，故通常以新鲜血浆替代。输注时按1ml血浆含AT-Ⅲ 1IU计算，可在2～3日内按需要情况分次补充，至少维持AT-Ⅲ活性在50%上。
- #70 Drugs which inhibit platelet function include the following: Dipyridamole 200-400mg/d intravenous drip; ( a phosphodiesterase inhibitor with vasodilator effects) Aspirin 0.9-1.2g/d;(1.inhibits prostaglandin synthesis, thereby blocking the formation of TXA2; 2.inhibits platelet aggregation;3.inhibits the synthesis of the anticoagulant prostaglandin, PGI2) Low molecular weight dextran 500-1500ml/d
- #71 Haemostatic support In DIC the concentration of both procoagulant factors and their control protein may be reduced. It is conventional offer haemostatic replacement therapy after massive blood transfusion with: platelet concentrates, 1 donor unit/10kg body weight when the platelet count is below 50×109/L; (2) fresh frozen plasma (FFP) 10-15ml/kg body weight when the PTR is greater than 1.5; (3) additional cryoprecipitate when the fibrinogen concentration is 0.8g/l or less. Attention:Replacement therapy may be need to be repeated Q8h, with adjustment of doses according to the platelet count, PT, APTT, fibrinogen level, and volume load. Infusions should be stopped as soon as normal or neat-normal values of hemostatic factors are attained. 新鲜冰冻血浆(fresh frozen plasma，FFP)：是用ACD和CPD抗凝采血，于6小时内将血浆分出并迅速在-30℃以下冰冻和保存的血浆。这种血浆内凝血因子的含量基本上保持正常，并可保存12个月。FFP可用于补充体内多种凝血因子缺乏，但由于其凝血因子未浓缩，输注过多有造成循环超负荷的危险 冷沉淀是新鲜冰冻血浆(FFP)在l-5℃条件下不溶解的白色沉淀物主要含因子Ⅷ、因子ⅩⅢ、vWF和纤维蛋白原等 凝血酶原复合物浓缩剂(prothrombin complex Concerntrate，PCC)是一种混合人血浆制成的冻干制剂。它含有维生素K依赖性凝血因子Ⅱ、Ⅶ、Ⅸ和Ⅹ。
- #72 In these conditions the use of fibrinolytic inhibitors can be considered, provided that: (1) the patient is bleeding profusely and has not responded to replacement therapy; (2)excessive fibrinolysis is observed, i.e., a very short euglobulin lysis time. Patients with early stage of DIC should not be treated by antifibrinolytic agents like ε-aminocaproic acid and tranecamic acid. These drugs block the secondary compensatory fibrinolysis that accompanies DIC and partially preserves tissue perfusion.it may provoke increased thrombosis and microvascular occulsion.
- #73 In such circumstances the use of antifibrinolytic agents should be preceded by replacement of depleted blood components and continuous heparin infusion.
- #78 Contusion 挫伤 Extravasation 溢出物
- #79 thromboplastin: 促凝血酶原激酶，tissue factor
- #80 Ooze渗出 Hemostasis 止血 The cornerstone of the management of disseminated intravascular coagulation is the treatment of the underlying disorder. Treatment of disseminated intravascular coagulation without treatment of the underlying cause is predestined to fail. Supportive measures may be necessary, although firm evidence on which to base management is scarce, and there is no consensus regarding the optimal treatment or supportive strategy. A patient with disseminated intravascular coagulation who has diffuse bleeding from various sites at presentation will need different supportive treatment from what is appropriate for a patient with thrombotic obstruction of the vasculature and subsequent multiorgan failure. Anticoagulants Theoretically, interruption of coagulation should be of benefit in patients with disseminated intravascular coagulation. Indeed, experimental studies have shown that heparin can partially inhibit the activation of coagulation in cases that are related to sepsis or other causes. Adequate prophylaxis is also needed to eliminate the risk of venous thromboembolism. Heparin has been shown to have a beneficial effect in small, uncontrolled studies of patients with disseminated intravascular coagulation, but not in controlled clinical trials. Although the safety of heparin in patients with disseminated intravascular coagulation who are prone to bleeding has often been debated, clinical studies have not shown that treatment with heparin significantly increased the incidence of bleeding complications. Taken together, these findings suggest that treatment with heparin is probably useful in patients with disseminated intravascular coagulation, particularly those with clinically overt thromboembolism or extensive deposition of fibrin, as occurs with purpura fulminans or acral ischemia. Patients with disseminated intravascular coagulation are usually given relatively low doses of heparin (300 to 500 U per hour) as a continuous infusion. Low-molecularweight heparin may also be used as an alternative to unfractionated heparin. Novel, antithrombin III–independent inhibitors of thrombin, such as desirudin and related compounds, might be more effective than heparin, and experimental studies have had promising results. However, there have not yet been any controlled clinical trials of these drugs in patients with disseminated intravascular coagulation, and the relatively high risk of bleeding associated with the use of these compounds may be a limiting factor. Platelets and Plasma Low levels of platelets and coagulation factors may cause serious bleeding or may increase the risk of bleeding in patients who require an invasive procedure. In such patients, the efficacy of treatment with platelet concentrate and plasma has clearly been shown. There is no evidence to support the use of prophylactic administration of platelets or plasma to patients with disseminated intravascular coagulation who are not bleeding and who are not at high risk for bleeding. It may be necessary to administer large volumes of plasma (up to 6 units per 24 hours) to ameliorate or correct the coagulation defect. Treatment with coagulation-factor concentrates may overcome the need for large infusions of plasma, but their use in patients with disseminated intravascular coagulation is generally not advocated because the concentrates may be contaminated with traces of activated coagulation factors, which could exacerbate the coagulation disorder. Also, these concentrates contain only selected coagulation factors, whereas patients with disseminated intravascular coagulation usually have a deficiency of all coagulation factors. Concentrates of Coagulation Inhibitors Restoration of physiologic pathways of anticoagulation might be an appropriate aim of therapy. Antithrombin III is one of the most important natural inhibitors of coagulation, and patients with disseminated intravascular coagulation almost invariably have an acquired deficiency of antithrombin. The administration of this inhibitor in supraphysiologic concentrations reduced sepsis-related mortality in animals. Several controlled clinical trials, mostly in patients with sepsis or with septic shock, have shown beneficial effects in terms of improvement of disseminated intravascular coagulation and sometimes improvement in organ function. In the more recent trials, very high doses of antithrombin III concentrate were used (up to 150 percent of normal), and the favorable effect in these trials seems to be more distinct. Some trials showed a modest reduction in mortality in patients treated with antithrombin III, but this effect did not reach statistical significance. A meta-analysis of the trials with adequate study methods showed a reduction in mortality from percent to 44 percent (odds ratio for death, 0.63; 95 percent confidence interval, 0.39 to 1.0). At present, a large randomized, controlled multicenter trial with supraphysiological dosing of antithrombin III in patients with sepsis is being conducted and the outcome of this trial will help determine the place of antithrombin III treatment in sepsis and disseminated intravascular coagulation. In the meantime, antithrombin III treatment may be considered as a supportive therapeutic option in patients with severe disseminated intravascular coagulation, although the substantial costs of this treatment may be a limiting factor. Antifibrinolytic Agents Antifibrinolytic treatment is effective in patients with bleeding, but the use of these agents in patients with disseminated intravascular coagulation is generally not recommended. Since the deposition of fibrin in this disorder appears to be due in part to insufficient fibrinolysis, further inhibition of the fibrinolytic system would not seem to be appropriate. A clear exception might be made in the case of patients with primary or secondary hyperfibrinolysis, such as those with the coagulopathy associated with acute promyelocytic leukemia and some patients with disseminated intravascular coagulation in association with cancer. In such patients, antifibrinolytic treatment has controlled the coagulopathy. FUTURE THERAPEUTIC OPTIONS A logical therapeutic intervention would be directed against tissue-factor activity. One such inhibitor, recombinant nematode anticoagulant protein c2, a potent and specific inhibitor of the complex formed by tissue factor and factor VIIa with factor Xa, has recently been developed and is currently being evaluated in a clinical study. Administration of recombinant tissue factor–pathway inhibitor may also block tissue-factor activity in endotoxin-induced activation of coagulation (de Jonge E, et al.: unpublished data). This possibility is now being evaluated in clinical trials. In view of the impairment of the protein-C system in patients with disseminated intravascular coagulation, supplementation with (activated) protein C may be beneficial, as was true in an animal model of the disorder. Adequately controlled clinical trials of protein-C concentrates are currently being initiated or are under way.