动脉硬化血栓病理生理学课件

AtherothrombosisPathophysiology WhatIsAtherothrombosis TheformationofathrombusonanexistingatheroscleroticplaqueAtherothrombosisisanewtermrecognizingthatatherosclerosis plaquedevelopment andacutethrombosisareintegrallyrelatedtothepresentationofvasculareventsAgeneralizedprogressivediseaseoflarge andmid sizearteriesthataffectsmultiplevascularbeds includingcerebral coronary andperipheralarteriesTheunderlyingdiseaseleadingtomyocardialinfarction MI peripheralarterialdisease PAD ischemiaandmanyformsofstroke MI myocardialinfarction PAD peripheralarterydisease FusterV etal VascMed 1998 3 231 239 RauchU etal AnnInternMed 2001 134 122 238 Atherothrombosis istheLeadingCauseofDeathWorldwide1 Atherothrombosisdefinedasischemicheartdiseaseandcerebrovasculardisease 1TheWorldHealthReport2001 Geneva WHO 2001 22 3 19 3 12 6 9 7 9 6 3 0 5 10 15 20 25 30 Atherothrombosis InfectiousDisease Cancer Injuries PulmonaryDisease AIDS CausesofMortality AtherothrombosisSignificantlyShortensLife AnalysisofdatafromtheFraminghamHeartStudy PeetersA etal EurHeartJ 2002 23 458 466 Atherothrombosisreduceslifeexpectancybyaround8 12yearsinpatientsagedover60years1 AverageRemainingLifeExpectancyatAge60 Men 0 4 8 12 16 20 Healthy Years HistoryofAMI 9 2years HistoryofCardiovascularDisease 7 4years HistoryofStroke 12years 3 2MillionHospitalAdmissions CoronaryAtherosclerosis AcuteMyocardialInfarction 1 153 000Admissions 829 000Admissions HospitalizationsintheUSDuetoVascularDisease CerebrovascularDisease 961 000Admissions VascularDisease OtherIschemicHeartDisease 280 000Admissions PopovicJR HallMJ AdvanceData 2001 319 1 20 PreventableDeaths Approximately57 000deathscouldbeavoidedeachyearintheUSifpatientsweregivenappropriatecare NationalCommitteeforQualityAssurance Washington DC2003 Cervical cancerscreening Prenatalcare blockertreatment Breast cancerscreening Smokingcessation Cholesterolmanagement Diabetescare High bloodpressurecontrol BasedondatafromtheARICstudyoftheNationalHeart Lung andBloodInstitute 1987 1994 IncludesAmericanshospitalizedwithdefiniteorprobableMIorfatalCHD notincludingsilentMIs ACS acutecoronarysyndrome MI myocardialinfarction ARIC AtheroscleroticRiskinCommunities CHD coronaryheartdisease AmericanHeartAssociation HeartDiseaseandStrokeStatistics 2003Update EpidemiologyofACSintheUnitedStates Singlelargestcauseofdeath515 204USdeathsin20001inevery5USdeathsIncidence1 100 000Americanswillhaveaneworrecurrentcoronaryattackeachyearandabout45 willdie 550 000newcasesofanginaperyearPrevalence12 900 000withahistoryofMI angina orboth EpidemiologyofStrokeintheUnitedStates Prevalence4 7millioncasesIncidence700 000neworrecurrentstrokeseachyearMorbidity mortalityThirdleadingcauseofdeath1ofevery14deaths 168 000deaths Stroke aleadingcauseoflong termdisability AmericanHeartAssociation HeartDiseaseandStrokeStatistics 2003Update PeripheralArterialDisease PADaffects12 oftheadultpopulation1 220 ofthepopulationaged 70Associatedwith6 foldincreaseinCVmortality3Underrecognizedandundertreated4Measurementsimple inexpensive andnoninvasiveAppropriateforriskassessmentandscreeningPatientsathighriskneedaggressiverisk factormodificationandantiplateletdrugs4 PAD peripheralarterydisease CV cardiovascular 1NicolaidesAN Symposium Nov 1997 2HiattWR etal Circulation 1995 91 1472 1479 3CriquiMH etal NEnglJMed 1992 326 381 386 4HirschAT etal JAMA 2001 286 1317 1324 Diabetes ImpactinUnitedStates 12millionpeoplewithdiabetes1Diabetesisthe5thleadingcauseofdeath1Halfofdiabeticpatientswillexperiencekidneyfailure1Diabetesistheleadingcauseofnewadultcasesofblindness2Directandindirectdiabetescostswereestimatedat 132billion1in2002 1AmericanDiabetesAssociation DiabetesCare 2003 26 917 932 2JuvenileDiabetesResearchFoundationInternational DiabetesFigures http www jdrf org CerebralIschemicstrokeTransientischemicattackCardiacMyocardialinfarctionAnginapectoris stable unstable PeripheralArterialDiseaseCriticallimbischemia claudication ClinicalManifestationsofAtherothrombosis OverlapofVascularDiseaseinPatientsWithAtherothrombosis PAD peripheralarterydisease AdaptedfromTransAtlanticInter SocietyConsensusGroup JVascSurg 2000 31 S16 CoronaryDisease PAD 12 33 15 5 14 13 8 CerebralDisease CoronaryDisease PAD 19 30 25 4 12 7 3 CerebralDisease CAPRIE Aronow Ahn CommonUnderlyingAtherothromboticDiseaseProcess MI myocardialinfarction PAD peripheralarterialdisease CV cardiovascular NessJ etal JAmGeriatrSoc 1999 47 1255 1256 SchaferAI AmJMed 1996 101 199 209 AtherothromboticEvents MI Stroke orCVDeath PlaqueRupture PlateletAdhesion Activation andAggregation ThrombusFormation MI AtherothromboticStroke PAD UnstableAngina RiskofaSecondAtherothromboticEvent Deathdocumentedwithin1hourofaneventattributedtoCHD Note Thischartisbasedonepidemiologicdataandisnotintendedtoprovideadirectbasisforcomparisonofrisksbetweeneventcategories MI myocardialinfarction TIA transientaschemicattack PAD peripheralarterydisease AdultTreatmentPanelII Circulation 1994 89 1333 1363 Kannel WB JCardiovascRisk 1994 1 333 339 Wilterdink JI etal ArchNeurol 1992 49 857 863 Crique MH etal NEnglJMed 1992 326 381 386 UnstableanginaMIIschemicstroke TIACriticallegischemiaIntermitentclaudicationCVdeath ACS Atherosclerosis Stableangina Intermittentclaudication Atherothrombosis AGeneralizedandProgressiveProcess Thrombosis AdaptedfromLibbyP Circulation 2001 104 365 372 Atherothrombosis ThrombusSuperimposedonAtheroscleroticPlaque AdaptedfromFalkE etal Circulation 1995 92 657 671 CharacteristicsofUnstableandStablePlaque Thinfibrouscap Inflammatorycells FewSMCs Erodedendothelium Activatedmacrophages Thickfibrouscap Lackofinflammatorycells Foamcells Intactendothelium MoreSMCs LibbyP Circulation 1995 91 2844 2850 Unstable Stable PlaqueRupture AndrewFarb MDbypermission RiskFactorsforPlaqueRupture ImpairedFibrinolysis Fibrinogen DiabetesMellitus Cholesterol Smoking CapFatigue AtheromatousCore size consistency CapInflammation SystemicFactors LocalFactors Homocysteine PlaqueRupture FusterV etal NEnglJMed 1992 326 310 318 FalkE etal Circulation 1995 92 657 671 CapThickness Consistency MultipleRiskFactorsforAtherothrombosis MI myocardialinfarction AdaptedfromYusufS etal Circulation 2001 104 2746 2753 DrouetL CerebrovascDis 2002 13 suppl1 1 6 LifestyleSmokingDietLackofexercise GeneticTraitsGenderPlA2 GeneralizedDisordersAgeObesity SystemicConditionsHypertensionHyperlipidemiaDiabetesHypercoagulablestatesHomocysteinemia AtherothromboticManifestations MI stroke vasculardeath InflammationElevatedCRPCD40Ligand IL 6Prothromboticfactors FIandII Fibrinogen LocalFactorsBloodflowpatternsShearstressVesseldiameterArterialwallstructure arterialstenosis RiskFactorsforIschemicStroke ModifiableHypertensionAtrialfibrillationCigarettesmokingHyperlipidemiaAlcoholabuseCarotidstenosisPhysicalinactivityObesityDiabetes NonmodifiableAgeSexRace EthnicityHeredity RCAWall LADWall Eccentric lipid rich Concentric fibrotic Ectatic remodeled Black BloodCoronaryPlaqueMR MR magneticresonance LAD leftanteriordescending RCA rightcoronaryartery FayadZA etal Circulation 2000 102 506 510 withpermission LADWall EvidenceofMultiple Vulnerable PlaquesinACS ACS acutecoronarysyndrome AsakuraM etal JAmCollCardiol 2001 37 1284 1288 withpermission Angiographic angioscopicimagesin58 year oldmanwithanteriormyocardialinfarction Multiple vulnerable plaquesdetectedinnon culpritsegments10 12 Culpritlesion 8 detectedwiththrombus red Multiple vulnerable plaquesdetectedinnon culpritsegments1 7 MultipleComplexCoronaryPlaquesinPatientsWithAcuteMI MI myocardialinfarction GoldsteinJA etal NEngJMed 2000 343 915 922 withpermission Culpritlesion Multipleplaquesdetected Multipleplaquesdetected ACS acutecoronarysyndrome RioufolG etal Circulation2002 106 804 808 withpermission Frequencyofmultipleactiveplaquerupturesbeyondtheculpritlesion Patients 80 ofPatientsWith 2Plaques N 24 FrequencyofMultiple Active PlaquesinPatientsWithACS ACS TipoftheAtherothrombotic Iceberg ACS acutecoronarysyndrome UA unstableangina NSTEMI non ST segmentelevationmyocardialinfarction STEMI ST segmentelevationmyocardialinfarction AdaptedfromGoldsteinJA JAmCollCardiol 2002 39 1464 1467 PresenceofMultipleCoronaryPlaques VascularInflammation PersistentHyperreactivePlatelets Clinical Subclinical AcutePlaqueRuptureACS UA NSTEMI STEMI HemostaticPlugFormation Thrombin AGGREGATION Fibrin HemostaticClot Clotting PlateletAggregation 0min 10min 5min SECONDARY PRIMARY COAGULATION AdaptedfromFergusonJJ etal AntiplateletTherapyinClinicalPractice 2000 15 35 Adhesion TheRoleofPlateletsinAtherothrombosis Aggregation 1 Activation 2 3 GPIIb IIIaInhibitors 1 PlateletAdhesion 2 PlateletActivation Platelet GPIb Plaquerupture 3 PlateletAggregation ASA Clopidogrel Ticlopidine ASA acetylsalicyclicacid CannonandBraunwald HeartDisease 2001 TxA2 PlateletsRoleinThrombosis Fibrin Platelets RBCs WhiteThrombus Fibrin Platelets RBCs CoagulationThrombus HighFlowSlowFlow Platelets RoleinThrombosis RBCs redbloodcells ThrombinSerotoninEpinephrineCollagen Activation ActivatedPlatelet COX Degranulation GpIIb IIIafibrinogenreceptor Toneighboringplatelet ClopidogrelTiclopidine TXA thromboxane PDGF platelet derivedgrowthfactor PlateletHyperreactivityFollowingACSPredicts5 YearOutcomes PlateletAggregabilityStatus 0 10 20 30 40 50 Death CardiacEvents 10 3 6 4 14 9 24 1 46 2 34 6 Patients RR 1 6 CI0 5 5 5 Negative n 94 RR 1 6 CI0 7 3 5 RR 5 4 CI2 2 13 4 RR 3 1 CI1 6 5 8 Intermediate n 29 Positive n 26 ACS acutecoronarysyndrome Relativeriskcomparedtogroupwithnegativeaggregation AdaptedfromTripMD etal NEnglJMed 1990 322 1549 1554 PlateletsReleaseInflammatoryMediatorsandLeadtoVascularInflammationandPlaqueInstability RANTES RegulatedonActivation NormalT cell ExpressedandSecreted LibbyP etal Circulation 2001 103 1718 1720 InflammatoryModulatorsCD40ligandPlateletfactor4RANTES UnstablePlaque ActivatedPlatelets PlaqueRupture Thrombosis ThrombospondinPlatelet derivedgrowthfactorNitricoxide CD40LisactivatedbyagonistssuchasADP thrombin orcollagen ThetranslocationofCD40Lseemstocoincidewiththepresenceofrelease granulecontents includingplatelet derivedgrowthfactor PDGF transforminggrowthfactorbeta plateletfactor4 andthrombospondin GPIIb IIIaantagonistsblockthehydrolysisandsubsequentreleaseofSCD40Lfromplatelets TheSheddingofSolubleSCD40LDuringPlateletStimulation SCD40L SCD40ligand PDGF platelet derivedgrowthfactor TGF transforminggrowthfactor beta PF4 plateletfactor4 TSP thrombospondin AndreP etal Circulation 2002 106 896 899 withpermission InflammatoryModulatorsProducedbyPlatelets TGF 5Stimulatesmoothmusclecellbiosynthesis Nitricoxide3Effectsonmonocyte leucocyte endothelium andsmoothmusclecells CD154 CD40ligand 1 4Regulatesmacrophageandsmoothmusclecellfunctions RANTES2Influencesmacrophageadhesiontoendothelialcell PF41Mediatesshear resistantarrestofmonocytestoendothelium Platelet PDGF1Inducesproliferationofsmoothmusclecells Thrombospondin1Interactswithcellsurfacereceptors 1LibbyP etal Circulation 2001 103 1718 1720 2vonHundelshaus