1、REGULATION OF COAGULATION/DISSEMINATED INTRAVASCULAR COAGULATION2020年10月2日1REGULATION OF COAGULATIONIntroduction Coagulation necessary for maintenanceof vascular integrity Enough fibrinogen to clot all vessels What controls clotting process?2020年10月2日2COAGULATION CASCADEorFXIIFXIIaTFFVIIFGFHMWKFXIFX
2、IaorFVIIaCa+2FIXFIXaCa+2Ca+2Ca+2VIIIVIIIaTVVaTCa+2FXFXaCa+2Ca+2PTTCommon PathwayMiddle ComponentsSurface Active ComponentsINTRINSIC PATHWAYEXTRINSIC PATHWAY2020年10月2日3COAGULATION INHIBITORS Tissue Factor Pathway Inhibitor(TFPI)Lipoprotein Associated Coagulation Inhibitor(LACI)Extrinsic Pathway Inhib
3、itor(EPI)Complexes with Factors VIIa/TF/Xa;inactivates Xa Antithrombin III/Heparin Cofactor II/Heparin Binds and Inactivates Enzymes Protein C/Protein S/Thrombomodulin Cleaves&Inactivates Cofactors(Va&VIIIa)Plasminogen-3 hemostasis Cleaves Fibrin2020年10月2日4ATIII+ThrombinATIII.ThrombinHeparinANTITHRO
4、MBIN III-MECHANISM OF ACTION2020年10月2日5PROTEIN C ACTIVATIONProtein C+ThrombinActivatedProtein CTTTMProtein CActivatedProtein CThrombinThrombomodulin+*Ca2020年10月2日6PROTEIN C-MECHANISM OF ACTIONAPCFactor Va/Factor VIIIaPro SPLiFVa/FVIIIa2020年10月2日7COAGULATION INHIBITORS Tissue Factor Pathway Inhibitor
5、(TFPI)Lipoprotein Associated Coagulation Inhibitor(LACI)Extrinsic Pathway Inhibitor(EPI)Complexes with Factors VIIa/TF/Xa;inactivates Xa Antithrombin III/Heparin Cofactor II/Heparin Binds and Inactivates Enzymes Protein C/Protein S/Thrombomodulin Cleaves&Inactivates Cofactors(Va&VIIIa)Plasminogen-3
6、hemostasis Cleaves Fibrin2020年10月2日8ANTICOAGULANT PROTEIN DEFICIENCYDisease entities Heterozygous Protein Deficiency Increased Venous Thrombosis Occasional Increased Arterial Thrombosis Warfarin Induced Skin Necrosis Homozygous Protein Deficiency Neonatal Purpura Fulminans Fibrinogenolysis Chronic D
7、IC2020年10月2日9ANTICOAGULANT PROTEIN DEFICIENCY Dominant Increased Venous Thrombosis Young Age of Thrombosis No Predisposing Factors to Thrombosis Increased Thrombin Generation Positive Family History Recessive No history of thrombosis No family history Neonatal Purpura Fulminans Increased Thrombin Ge
8、neration2020年10月2日10ACTIVATED PROTEIN C RESISTANCE 1st described by Dahlback,1994 Hallmark:Failure of activated Protein C to prolong aPTT First noted in screening of plasma samples of patients with increased clotting Functional defect described before protein defect noted2020年10月2日11ACTIVATED PROTEI
9、N C RESISTANCE Bertina et al described genetic defect Mutation of Arg 506 Gln Named Factor V Leiden Found in 98%of patients with APC Resistance2020年10月2日12ACTIVATED PROTEIN C RESISTANCE Extremely common(5-20%of Caucasian population with mutation)Increases risk of venous thromboembolism(VTE)c.4x in h
10、eterozygous form,more in homozygous Can exist in combination with other defects(protein C,protein S,ATIII,plasminogen)In combination,has synergistic effect on other anticoagulant protein deficiencies2020年10月2日13FACTOR Va INACTIVATIONFactor VaiFVaAPCPro SPLPROTEIN C-MECHANISM OF ACTION2020年10月2日14FAC
11、TOR VIIIa INACTIVATIONFactor VIIIaiFVIIIaAPCPro SPLFactor VPROTEIN C-MECHANISM OF ACTION2020年10月2日15HYPERCOAGULABLE STATESAcquired Anticardiolipin Syndrome Malignancy Immobilization TTP DIC Oral Contraceptive Therapy Prosthetic Valves PNH Myeloproliferative diseases Nephrotic Syndrome Inflammatory D
12、iseases Atherosclerosis Surgery Diabetes mellitus2020年10月2日16ACQUIRED HYPERCOAGULABLE STATESMechanisms C4b Binding Protein-Acute Phase Reactant Increases in inflammatory diseases Binds to Protein S Bound Protein S inactive as cofactor Inflammation Increased IL-1&TNF Both downregulate thrombomodulin
13、Thrombin becomes procoagulant instead of anticoagulant protein2020年10月2日17ANTITHROMBOTIC THERAPY Preventive-Stop further clot formation Heparin/Low molecular weight heparin Warfarin Aspirin Hirudin/Argatroban Thrombolytic-Lyse clot already formed Streptokinase Urokinase Tissue plasminogen activator2
14、020年10月2日18HEPARIN THERAPY Enhances activity of AT III Parenteral administration required Onset of action immediate Monitor aPTT Lower dose may work in patients without active thrombosis2020年10月2日19HEPARIN THERAPYComplications Bleeding Causes mild platelet dysfunction Thrombocytopenia common Osteopo
15、rosis common with long-term use Heterogeneous mixture;therefore dosing problematic2020年10月2日20HEPARIN THERAPYLow Molecular Weight Heparin-Advantages Less heterogeneous than heparin Less inhibition of platelet function Longer half life-Can give 1-2x/day Much less thrombocytopenia?safer,equally effect
16、ive2020年10月2日21HEPARINLow Molecular Weight Heparin-Disadvantages Bleeding-?Less than with heparin(probably not)Most cross react with heparin RE:thrombocytopenia Each preparation is different Less overall experience with the drug2020年10月2日22LEPIRUDIN/ARGATROBAN Specific thrombin inhibitors Inhibit th
17、rombin bound to fibrin Inhibits platelet activation by thrombin Both currently approved for heparin-induced thrombocytopenia2020年10月2日23COUMADIN(warfarin)Mechanism of Action Inhibits Vitamin K dependent carboxylase activity Prevents reduction of Vitamin K Humans secrete des-carboxyglutamic acid,an i
18、nactive protein DOES NOT AFFECT PROTEINS ALREADY SYNTHESIZED Monitor using prothrombin time Multiple interactions with other drugs Antidote-Vitamin K2020年10月2日24THROMBOLYTIC THERAPY Streptokinase Purified from bacteria(Streptococcus)Binds to plasminogen,&complex activates a second plasminogen molecu
19、le to plasmin High incidence of allergic reactions Urokinase Purified from urine initially Recombinant form now available Activates plasminogen directly Tissue plasminogen activator Made by endothelial cells Increased affinity for fibrin-bound plasminogen relative fibrin specificity Recombinant form
20、 available Activates plasminogen directly2020年10月2日25THROMBOLYTIC THERAPYActions Used in myocardial infarction Lyses coronary thrombi Improves/preserves LV function Decreases mortality High rate of reocclusion-esp with TPA Lyses hemostatic plugs everywhere Increased incidence of bleeding-esp CNS Low
21、ers plasma fibrinogen?which drug is superior2020年10月2日26DIC Acute Shock Sepsis Allergic reactions Mismatched transfusion Obstetrical problems Trauma Burns Extracorporeal circulation Acidosis Purpura fulminans Subacute/Chronic Acute leukemia Carcinomas Hemangiomata Aortic aneurysms?liver disease2020年
22、10月2日27ACUTE DIC Almost always secondary Consumptive coagulopathy Decreases in both coagulants&anticoagulants Severity may relate to levels of anticoagulants2020年10月2日28DICPlasminogen ActivationF XIIF XIIaPrekallikreinKallikreinPlasminogenPlasminUrokinaseTPA2020年10月2日29FIBRINOGEN SPLIT PRODUCTSFibri
23、nogen,340,000Fragment X,250,000Fragment Y,150,000Fragment D,90,000Fragment D,90,000Fragment E,50,0002020年10月2日30DEFIBRINATIONMechanisms Release of Tissue Procoagulants Tumor Fetal/Placental/Amniotic Prostatic Pancreatic WBC RBC Shock Damage to Vascular Tree Septicemia Aortic aneurysm Hemangioma Tumo
24、r emboli?Shock Decreased Clearance Liver disease?Shock2020年10月2日31DICTesting(Acute)TestResultProthrombin TimeSlightly to grossly prolongedaPTTVariableFibrinogenUsually lowThrombin timeUsually prolongedFactor levelsVariablePlatelet CountUsually lowRBC fragmentationSometimes presentFibrin split produc
25、tsUsually present2020年10月2日32DICTherapy Depends on primary manifestation Thrombosis-Anticoagulant therapy Bleeding-Replacement therapy Primary treatment Replacement Cryoprecipitate-Fibrinogen Fresh frozen plasma-Other factors Platelets Heparin Rarely indicated2020年10月2日33演讲完毕，谢谢观看！Thank you for reading!In order to facilitate learning and use,the content of this document can be modified,adjusted and printed at will after downloading.Welcome to download!汇报人：XXX 汇报日期：20XX年10月10日34
