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1、Disorders of Hemostasis:ThrombosisJohn Lazarchick,M.D.Director,Hematopathology/HemostasisAugust 30,2001HypercoagulabilityDefinition:Alteration in the hemostatic balance between blood fluidity and clot formation.This is due to genetic and acquired disorders which shift this balance toward excessive o
2、r inappropriate platelet aggregation and fibrin formation and predispose to thrombosis.Prethrombotic States10-inherited abnormalities resulting from mutations affecting the function of coagulant proteins and natural inhibitors20-acquired defects that either affect the endothelium,fluid flow or blood
3、 components.These defects are often superimposed on 10 defectsHypercoagulability:Prethrombotic StatesVirchow (1856)Abnormalities of blood vesselsAbnormalities of fluid flowAbnormalities of blood componentsBlood Vessel AbnormalitiesEndothelial cell antithrombotic properties-PGI2,NO2,TFPI,PAI-1,hepara
4、ns,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 atherosclerosisAtherosclerosisEndothelial injury and dysfunctionLDL choles
5、terol oxidized LDL-foam cellsDiabetes mellitus glycated LDL cholesterolSmoking free radical productionHypertension smooth muscle proliferationGenetic alterations MTHFR mutationsR.Ross.Atherosclerosis.NEJM 340:115-126,1999AtherosclerosisSite specific:BifurcationsBranching vesselsCurvaturesDecreased s
6、hear stress and increased turbulencePlaque formation and ruptureUnstable plaque.R.Ross NEJM 340:115-126,1999.Blood Flow AbnormalitiesStasis is the underlying mechanism as the cause of venous or arterial thrombosisConditions-immobilization,surgery,congestive heart failure,pregnancy,obesity.Increased
7、blood viscosity RBCs-polycythemias,sickle cellsWBCs myeloproliferative disorders especially CMLPlatelets-primary thrombocytosisParaproteins-Myeloma,Waldenstroms MacroglobulinemiaHypercoagualbility:Hereditary/AcquiredFactor V LeidenProthrombin 20210Protein CProtein SAnti-thrombin IIIDysfibrinogenemia
8、HyperhomocysteinemiaPAI-IPlatelet glycoprotein IIb/IIIaFactor V LeidenMutation at position 506 rendering FV insensitive to degradation by activated protein C.Autosomal dominant;5%Caucasian population.Heterozygote-7x increased risk for venous thrombosisHomozygote-80 x increased riskOften found in ass
9、ociation with other risk factors-protein C and S deficienciesProthrombin 20210 MutationMutation results in increased synthesis of prothrombin resulting in elevated plasma levels of biochemically normal prothrombinAutosomal dominant;1-2%of populationIncreased risk of venous thrombosis-2xProtein C Def
10、iciencyAutosomal dominant Mutation results in mild to severe deficiency;increase risk for venous thrombosis homozygote=purpura fulminans0.2%of US populationAcquired-DIC,liver disease,oral contraceptives,oral anticoagulant useProtein S DeficiencyAutosomal dominantIncreased risk of venous thrombosisAc
11、quired deficiencies-DIC,liver disease.coumarin therapy,pregnancy(2nd and 3rd trimesters),estrogen replacement therapy,L-asparginase chemotherapyHyperhomocysteinemiaIncreased levels are associated with increased risk of arterial and venous thrombosis.Multiple effects on endothelial cells-decreased th
12、rombomodulin,increased TF activity,inhibition of NO and TPAHyperhomocysteinemiaPrimary-mutation of MTHFR geneAcquired-vitamin B12,B6 or folic acid deficiency,hypothyroidism,isoniazid,methotrexate,theophylline Hereditary ThrombophiliaConsider if:family history of thrombosishistory of recurrent thromb
13、osisthrombosis at a young ageno acquired predisposing factors for thrombosisMalignancyRisk for thrombosis is multifactorial.Predominantly venous thrombosis-stasis,tumor invasion of vessels,chemotherapy effects superimposed on acquired or primary defects in hemostasis.Distinct procoagulant(cysteine p
14、rotease)found in many patients which can activate FX directly.Antiphospholipid Antibody SyndromeAutoimmune disorder,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
15、 platelet phospholipids in patients with lupus anticoagulants(aPTT and/or PT).ThrombusSize,shape and morphologyMural thrombusInfected thrombus bacterial endocarditisVerrucous thrombus Libman-Sacks endocarditisThrombusNatural history:ResolutionPropagationFragmentation/embolizationOrganization Resolut
16、ionPropagation complete occlusionFFragmentation and EmbolizationOrganization Fibroblast proliferationOrganization Endothelial cell differentiationResolutionOrganization-RethrombosisThrombusClinical presentation:Arterial coronary,carotid and femoralAcute MI,AnginaCVA,TIAClaudicationVenous superficial veins,deep veinsThrombophlebitis,swollen,painful extremityPulmonary embolus