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1、1,Disorders of Hemostasis: Thrombosis,John Lazarchick, M.D.Director, Hematopathology/HemostasisAugust 30, 2001,2,3,Hypercoagulability,Definition: Alteration in the hemostatic balance between blood fluidity and clot formation. This is due to genetic and acquired disorders which shift this balance tow
2、ard excessive or inappropriate platelet aggregation and fibrin formation and predispose to thrombosis.,4,Prethrombotic States,10 - inherited abnormalities resulting from mutations affecting the function of coagulant proteins and natural inhibitors20 - acquired defects that either affect the endothel
3、ium, fluid flow or blood components. These defects are often superimposed on 10 defects,5,Hypercoagulability:Prethrombotic States,Virchow (1856)Abnormalities of blood vesselsAbnormalities of fluid flowAbnormalities of blood components,6,Blood Vessel Abnormalities,Endothelial cell antithrombotic prop
4、erties- PGI2, NO2, TFPI, PAI-1, heparans, thrombomodulinGenetic predisposition and acquired defects in these functions increase the risk of arterial and venous thrombosisRole of dietary excesses, hypertension, diabetes mellitus, obesity, smoking, lipid abnormalities in atherosclerosis,7,Atherosclero
5、sis,Endothelial injury and dysfunctionLDL cholesterol oxidized LDL- foam cellsDiabetes mellitus glycated LDL cholesterolSmoking free radical productionHypertension smooth muscle proliferationGenetic alterations MTHFR mutations,8,R. Ross. Atherosclerosis. NEJM 340:115-126, 1999,9,Atherosclerosis,Site
6、 specific:BifurcationsBranching vesselsCurvaturesDecreased shear stress and increased turbulencePlaque formation and rupture,10,Unstable plaque. R.Ross NEJM 340:115-126, 1999.,11,Blood Flow Abnormalities,Stasis is the underlying mechanism as the cause of venous or arterial thrombosisConditions - imm
7、obilization, surgery, congestive heart failure, pregnancy, obesity.Increased blood viscosity RBCs - polycythemias, sickle cellsWBCs myeloproliferative disorders especially CMLPlatelets - primary thrombocytosisParaproteins - Myeloma, Waldenstroms Macroglobulinemia,12,Hypercoagualbility:Hereditary/Acq
8、uired,Factor V LeidenProthrombin 20210Protein CProtein SAnti-thrombin IIIDysfibrinogenemia,HyperhomocysteinemiaPAI-IPlatelet glycoprotein IIb/IIIa,13,14,Factor V Leiden,Mutation at position 506 rendering FV insensitive to degradation by activated protein C.Autosomal dominant; 5% Caucasian population
9、.Heterozygote - 7x increased risk for venous thrombosisHomozygote - 80 x increased riskOften found in association with other risk factors - protein C and S deficiencies,15,Prothrombin 20210 Mutation,Mutation results in increased synthesis of prothrombin resulting in elevated plasma levels of biochem
10、ically normal prothrombinAutosomal dominant; 1-2% of populationIncreased risk of venous thrombosis - 2x,16,Protein C Deficiency,Autosomal dominant Mutation results in mild to severe deficiency; increase risk for venous thrombosis homozygote = purpura fulminans0.2% of US populationAcquired - DIC, liv
11、er disease, oral contraceptives, oral anticoagulant use,17,Protein S Deficiency,Autosomal dominantIncreased risk of venous thrombosisAcquired deficiencies - DIC, liver disease. coumarin therapy, pregnancy (2nd and 3rd trimesters), estrogen replacement therapy, L-asparginase chemotherapy,18,Hyperhomo
12、cysteinemia,Increased levels are associated with increased risk of arterial and venous thrombosis.Multiple effects on endothelial cells - decreased thrombomodulin, increased TF activity, inhibition of NO and TPA,19,Hyperhomocysteinemia,Primary - mutation of MTHFR geneAcquired - vitamin B12, B6 or fo
13、lic acid deficiency, hypothyroidism, isoniazid, methotrexate, theophylline,20,Hereditary Thrombophilia,Consider if :family history of thrombosishistory of recurrent thrombosisthrombosis at a young ageno acquired predisposing factors for thrombosis,21,Malignancy,Risk for thrombosis is multifactorial.
14、Predominantly venous thrombosis - stasis, tumor invasion of vessels, chemotherapy effects superimposed on acquired or primary defects in hemostasis.Distinct procoagulant (cysteine protease) found in many patients which can activate FX directly.,22,Antiphospholipid Antibody Syndrome,Autoimmune disord
15、er, either primary or secondary, associated with an increased risk for arterial and venous thrombosis.Antibody is to cardiolipin in APA (ELISA assay); antibody is to beta 2 glycoprotein 1 and platelet phospholipids in patients with lupus anticoagulants (aPTT and/or PT).,23,Thrombus,Size, shape and m
16、orphologyMural thrombusInfected thrombus bacterial endocarditisVerrucous thrombus Libman-Sacks endocarditis,24,25,26,27,Thrombus,Natural history:ResolutionPropagationFragmentation/embolizationOrganization,28,Resolution,29,Propagation complete occlusion,30,F,Fragmentation and Embolization,31,Organiza
17、tion Fibroblast proliferation,32,Organization Endothelial cell differentiation,33,Resolution,34,Organization - Rethrombosis,35,Thrombus,Clinical presentation:Arterial coronary, carotid and femoralAcute MI, AnginaCVA, TIAClaudicationVenous superficial veins, deep veinsThrombophlebitis, swollen, painful extremityPulmonary embolus,36,37,