DisordersofHemostasis:ThrombosisHypercoagulabilityDefinition:Alterationinthehemostaticbalancebetweenbloodfluidityandclotformation.Thisisduetogeneticandacquireddisorderswhichshiftthisbalancetowardexcessiveorinappropriateplateletaggregationandfibrinformationandpredisposetothrombosis.PrethromboticStates10-inheritedabnormalitiesresultingfrommutationsaffectingthefunctionofcoagulantproteinsandnaturalinhibitors20-acquireddefectsthateitheraffecttheendothelium,fluidfloworbloodcomponents.Thesedefectsareoftensuperimposedon10defectsHypercoagulability:

PrethromboticStatesVirchow(1856)AbnormalitiesofbloodvesselsAbnormalitiesoffluidflowAbnormalitiesofbloodcomponentsBloodVesselAbnormalitiesEndothelialcellantithromboticproperties-PGI2,NO2,TFPI,PAI-1,heparans,thrombomodulinGeneticpredispositionandacquireddefectsinthesefunctionsincreasetheriskofarterialandvenousthrombosisRoleofdietaryexcesses,hypertension,diabetesmellitus,obesity,smoking,lipidabnormalitiesinatherosclerosisAtherosclerosisEndothelialinjuryanddysfunctionLDLcholesterol–oxidizedLDL---foamcellsDiabetesmellitus–glycatedLDLcholesterolSmoking–freeradicalproductionHypertension–smoothmuscleproliferationGeneticalterations–MTHFRmutationsR.Ross.Atherosclerosis.NEJM340:115-126,1999AtherosclerosisSitespecific:BifurcationsBranchingvesselsCurvaturesDecreasedshearstressandincreasedturbulencePlaqueformationandruptureUnstableplaque.R.RossNEJM340:115-126,1999.BloodFlowAbnormalitiesStasisistheunderlyingmechanismasthecauseofvenousorarterialthrombosisConditions-immobilization,surgery,congestiveheartfailure,pregnancy,obesity.IncreasedbloodviscosityRBCs-polycythemias,sicklecellsWBCs–myeloproliferativedisordersespeciallyCMLPlatelets-primarythrombocytosisParaproteins-Myeloma,Waldenstrom’sMacroglobulinemiaHypercoagualbility:

Hereditary/AcquiredFactorVLeidenProthrombin20210ProteinCProteinSAnti-thrombinIIIDysfibrinogenemiaHyperhomocysteinemiaPAI-IPlateletglycoproteinIIb/IIIaFactorVLeidenMutationatposition506renderingFVinsensitivetodegradationbyactivatedproteinC.Autosomaldominant;5%Caucasianpopulation.Heterozygote-7xincreasedriskforvenousthrombosisHomozygote-80xincreasedriskOftenfoundinassociationwithotherriskfactors-proteinCandSdeficienciesProthrombin20210MutationMutationresultsinincreasedsynthesisofprothrombinresultinginelevatedplasmalevelsofbiochemicallynormalprothrombinAutosomaldominant;1-2%ofpopulationIncreasedriskofvenousthrombosis-2xProteinCDeficiencyAutosomaldominantMutationresultsinmildtoseveredeficiency;increaseriskforvenousthrombosishomozygote=purpurafulminans0.2%ofUSpopulationAcquired-DIC,liverdisease,oralcontraceptives,oralanticoagulantuseProteinSDeficiencyAutosomaldominantIncreasedriskofvenousthrombosisAcquireddeficiencies-DIC,liverdisease.coumarintherapy,pregnancy(2ndand3rdtrimesters),estrogenreplacementtherapy,L-asparginasechemotherapyHyperhomocysteinemiaIncreasedlevelsareassociatedwithincreasedriskofarterialandvenousthrombosis.Multipleeffectsonendothelialcells-decreasedthrombomodulin,increasedTFactivity,inhibitionofNOandTPAHyperhomocysteinemiaPrimary-mutationofMTHFRgeneAcquired-vitaminB12,B6orfolicaciddeficiency,hypothyroidism,isoniazid,methotrexate,theophyllineHereditaryThrombophiliaConsiderif:familyhistoryofthrombosishistoryofrecurrentthrombosisthrombosisatayoungagenoacquiredpredisposingfactorsforthrombosisMalignancyRiskforthrombosisismultifactorial.Predominantlyvenousthrombosis-stasis,tumorinvasionofvessels,chemotherapyeffectssuperimposedonacquiredorprimarydefectsinhemostasis.Distinctprocoagulant(cysteineprotease)foundinmanypatientswhichcanactivateFXdirectly.AntiphospholipidAntibodySyndromeAutoimmunedisorder,eitherprimaryorsecondary,associatedwithanincreasedriskforarterialandvenousthrombosis.AntibodyistocardiolipininAPA(ELISAassay);antibodyistobeta2glycoprotein1andplateletphospholipidsinpatientswithlupusanticoagulants(aPTTand/orPT).ThrombusSize,shapeandmorphology

Muralthrombus Infectedthrombus–bacterialendocarditis Verrucousthrombus–Libman-Sacks endocarditisThrombusNaturalhistory:ResolutionPropagationFragmentation/embolizationOrganizationResolutionPropagation–completeocclusionFFragmentationandEmbolization Organization–FibroblastproliferationOrganization–EndothelialcelldifferentiationResol