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org/category/hematology/) / Venousthromboembolism(VTE)
CONTENTS
Definition
Etiology
PathophysiologyofDVT
Eric Wong (http://www.pathophys.org/author/wongeric/) and Sultan Chaudhry (http://www.pathophys.org/author/sultan/)
PathophysiologyofPE
Faculty reviewer: Dr. Peter L. Gross, Associate Professor, Division of Hematology and Thromboembolism, Department of Medicine (McMaster University)
ClinicalfeaturesofDVT
ClinicalfeaturesofPE
Denition
DiagnosisofDVT
DiagnosisofPE
Deepveinthrombosis(DVT)andpulmonaryembolism(PE)aremanifestationsofthesamepathologicalentity,calledvenousthromboembolism(VTE).
Treatment
Anembolusisanyintravascularmaterialthatmigratesfromitsoriginallocationtooccludeadistalvessel.Althoughtheemboluscanbeabloodclot(thrombus),fat,air,
amnioticfluid,ortumour,aPEisusuallycausedbyathrombusoriginatingfromthedeepveinsinthelegs(deepvenousthrombosis,DVT).
Thecoagulationcascadeisanessentialpartofhemostasis.However,thesamecoagulationfactorscangiverisetoclotformationinthecirculationthatisinappropriate(i.e.notforhemostasis).
Thrombicanforminboththearteriesandveins,buttheyhavedifferentpathophysiologyandleadtodifferentoutcomes.Thischapterisaboutvenousthrombosis.
Arterialthrombosis Venousthrombosis(VTE)
Feedback
Treatment Mainlyantiplateletagents(ASA,clopidogrel) Mainlyanticoagulants(heparins,warfarin)
Etiology
NEnglJMed.(http://www.ncbi.nlm.nih.gov/pubmed/18322285#)2008Mar6358(10):103752.
JCardiovascNurs.(http://www.ncbi.nlm.nih.gov/pubmed/16000912#)2005JulAug20(4):2549.
VenousthromboembolismisassociatedwithVirchowstriad:threeconditionsthatpredisposetothrombusformation.
1.Hypercoagulability
2.Stasis
3.Endothelialdamage
(http://www.pathophys.org/vte/pevirchow2/)
VTEoftenarisefromthesynergisticeffectsofmultipleriskfactors,forexample,whenapatientwithinheritedfactorVLeidenmutationusesoralcontraceptives(acquiredriskongeneticrisk
background).
Feedback
Triadcomponent Associatedriskfactors
Hypercoagulability Hereditaryfactors(inheritedthrombophilia)
Changesinblood FactorVLeiden*:ActivatedfactorV(FVa)isacofactorforactivatedfactorX,andtogether,theyleadtothrombingenerationfromitszymogen,
coagulation prothrombin.Thrombinisaserineproteasethatcleavessolublefibrinogenintoinsolublefibrinandactivatesotherfactorsthatamplifythe
pathway,shifting coagulationcascade.Toregulatecoagulationandprotectagainstclotformation,activatedproteinC(aPC)cleavesandinactivatesFVa.Factor
balancetoward VLeidenisamutationatoneoftheaPCcleavagesites,renderingfactorVaresistanttoinactivation,thuspredisposingtoclotformationand
coagulation VTE.Individualswiththismutationareata5foldincreasedriskfordevelopingafirstVTE.
ProthrombinG20210A*:Mutationatnucleotide20210fromguaninetoadenine.Themutationisinthe3untranslatedregionofthe
prothrombinandthereforedoesnotalterthestructureoftheprotein,butcausesincreasedproductionofprothrombin(factorII).Individualswith
thismutationareata24foldincreasedriskfordevelopingafirstVTE.
Deficienciesinantithrombin(AT),proteinC(PC)andproteinS(PS),plasminogen(Pg):
AT,PSandPCarethemajoranticoagulationproteinsandgeneticdefectscanleadtoqualitativeorquantitativedefectsintheirstructure
predisposingpatientstodevelopingVTE.
*The2mostcommonhereditaryfactorsautosomaldominantriskinheritance
Acquiredfactors
Cancer:Cancercellsinduceaprothromboticstatethroughavarietyofmechanisms.Somecancercellsexpress(i)procoagulantproteinsand
(ii)causethereleaseofmicroparticles(solublefragmentsoftumourcellmembranes)leadingtoasystemichypercoagulablestate.Two
commonprocoagulantproteinsaretissuefactor,whichindirectlyactivatesfactorXbycomplexingwithfactorVII,andcancerprocoagulant,
whichdirectlyactivatesfactorX.Tumourinducedhypoxiaandreleaseofinflammatorycytokineshavealsobeenspeculatedtocausea
prothromboticstate.
PathophysiolHaemostThromb.(http://www.ncbi.nlm.nih.gov/pubmed/16855354#)200635(12):10310.
BestPractResClinHaematol.(http://www.ncbi.nlm.nih.gov/pubmed/19285272#)2009Mar22(1):4960.
Chemotherapy:ChemotherapydrugshavebeenshowntoinduceTFintumorcellsaswellasmonocytes,downregulationofproteinCandS
(naturalanticoagulationmechanism),directdamagetothevascularendothelium,andplateletactivation.Antiangiogenicagents
(bevacizumab)haveplateletandendothelialactivationpropertiesleadingtoaprothromboticstate.
ArteriosclerThrombVascBiol.(http://www.ncbi.nlm.nih.gov/pubmed/19228604#)2009Mar29(3):31620.
Oralcontraceptivesandhormonereplacementtherapy:Hyperestrogenemiacausesincreasedhepaticsynthesisofprocoagulantproteins
anddecreasedsynthesisofanticoagulantandfibrinolyticproteins.
ThrombRes.(http://www.ncbi.nlm.nih.gov/pubmed/20163835#)2010Jul126(1):511.
Pregnancyandpostpartumperiod:HighestrogenlikeOCP/HRTandstasisduetoobstructionofinferiorvenacavabyfetus.
Centralobesity:Mechanismsincludeprocoagulanteffectsofadipocytokines(leptinandadiponectin),increasedactivityofcoagulation
cascade,increasedinflammation,oxidativestress,andendothelialdysfunction.
EurJVascEndovascSurg.(http://www.ncbi.nlm.nih.gov/pubmed/17185009#)2007Feb33(2):22333.
Heparininducedthrombocytopenia(HIT):Heparinbindsplateletfactor4(PF4)andexposesapreviouslymaskedepitope,leadingtothe
productionofIgGantibodyinsomeheparintreatedpatients.IgGbindstotheheparinPF4complex,formingimmunecomplexesthatbindand
activateplatelets.Thisleadstoahypercoagulablestateandthrombocytopenia.Plateletactivationalsoinducesendothelialcellinjury.
Blood.(http://www.ncbi.nlm.nih.gov/pubmed?term=Determinants%20of%20PF4%2Fheparin%20immunogenicity#)2007Dec15110(13):425360.
Stasis Reducedmobility:Increaseslengthofcontactofcoagulationfactorswithendothelium.
Theslowingor Examples:Longhaulairtravel,hospitalization
stoppingofblood Polycythemia:Hyperviscosity,duetoexcessiveoverproductionofredbloodcells,leadstostasisofbloodintheveins.
flow Endothelialinjury:Stasisdirectlydamagestheendotheliumaswellasreducesthenaturalfibrinolysis.
Congestiveheartfailure:Failuretopumpbloodforwardresultsinvenousstasisandelevatedcentralvenouspressure.
Endothelial Endothelialdysfunction:Shiftsthebalancebetweenclotgenerationandbreakdowntowardsthrombosisduetodecreasedsynthesisofnitric
damage oxideandprostacyclinandincreasedendothelin1.
Normalendothelium Hypertension
isantithrombotic. Cigarettesmoking
Endothelialdamage:Exposureofsubendothelialtissuefactorandcollagen,whichofferasubstrateforplateletbinding,activationand
aggregationleadingtoclotformation.
Chronicindwellingcentralvenouscatheter(cathetersalsodirectlyactivatetheintrinsicpathway)
Majorsurgery
Trauma
Pathophysiology of DVT
SeminNuclMed.(http://www.ncbi.nlm.nih.gov/pubmed/11330789)2001Apr31(2):90101.
CritCareClin.(http://www.ncbi.nlm.nih.gov/pubmed/22082518)2011Oct27(4):86984,vi.
Circulation.(http://www.ncbi.nlm.nih.gov/pubmed/12814982)2003Jun17107(23Suppl1):I2230.
Deepvenousthrombosisusuallyarisesinthelowerextremities.MostDVTsforminthecalfveins,particularlyinthesoleussinusoidsandcuspsofthevalves.
Venousvalvesareavascular,which,inconjunctionwithreducedflowofoxygenatedbloodinveins,predisposestheendotheliumtobehypoxemic.Theendothelium
aroundvalvesrespondsbyexpressingadhesionmoleculesthatattractleukocytes.Thesecellstransfertissuefactortotheendothelium,whichcancomplexwith
activatedfactorVIItobeginthecoagulationcascadeviatheextrinsicpathway.Themaincomponentofthesevenousthrombiisfibrin(asproductofcoagulation
cascade)andredbloodcells,whichgettrappedintheclot.Plateletsalsocontribute,buttoalesserextent.
TheskeletalmusclepumphelpspreventDVTbymovingbloodpastthevalves(i.e.reducingvenousstasis),whichwashesawayactivatedclottingfactorsthatcan
otherwisepropagatetheinitialthrombus.
Ifaclotformsanddoesnotresolve(seebelow),itwillextendproximallyintothepoplitealandfemoralveins(proximalveins).25%ofcalfDVTswillextendproximally
within7days.WhilecalfDVTsareusuallyasymptomaticanddonotgiverisetosignificantPEs,proximalDVTsaremorelikelysymptomaticandcanembolizetoform
dangerousPEs.
Bythenumbers
96%ariseinthelowerextremities4%ariseintheupperextremities.
Chest.(http://www.ncbi.nlm.nih.gov/pubmed/17925416)2008Jan133(1):1438.
OfsymptomaticlowerextremityDVTs,88%involvetheproximalveinstherestonlyinvolvethecalfveins.AlmostalllowerextremityDVTsarisefromthecalfveins
andextendproximally.
ArchInternMed.(http://www.ncbi.nlm.nih.gov/pubmed/8257253)1993Dec27153(24):277780.
Feedback
90%ofPEsarisefromDVTs.
50%ofsymptomaticproximallowerextremityDVTshaveasymptomaticPEs.
70%ofPEshaveasymptomaticDVTs.
28%ofsymptomaticDVTswillhavepostthromboticsyndromeafter5years.
Resolutionandconsequences
Theinitialthrombuscanleadtocompleteresolution,clotextension/embolization,ororganization.
Completeresolution:Fibrinolysisisadynamicprocesswhereplasminogenisconvertedintoplasmin,anenzymethatdegradesfibrinintosolublepeptides.
Fibrinolysisstartswithinhours,anditcanleadtocompleteorpartialresolutionofthethrombus.Partialresolutionmayleadtoanyoneofthese3consequences.
Clotextensionandembolization:Proximalflowofthevenousbloodsweepsthethrombusinthesamedirection,extendingitintotheproximalveins.
Organization:Thrombithatdonotresolvebegintoretractwithindays.Atthesametime,inflammatorycellsinfiltratethethrombiandcauseremodeling.Theresidualclot
isincorporatedintothevesselwallandalayerofendothelialcellsformsontop(reendothelialization).Thisprocess,calledorganization,allowssomebloodflowto
resume,butitdestroysvalvesalongthelengthoftheclotandcausesscarringoftheveins.Thehemodynamicchangestotheveincausespostthromboticsyndrome.
PostthromboticsyndromeisaconsequenceofDVTs,andtheclinicalfeaturesincludepain,legedema,andothersignsofvenousinsufficiency.Itoccursin
approximately1/3ofDVTcases.Thecauseisacombinationofvenousobstructionbyresidualclotsorvenousscarringandvenousrefluxduetovalvedestruction.
PreventionofthissequelaincludesadequateanticoagulationtopreventVTErecurrenceandcompressionstockingstoimprovevenousreturn.
Pathophysiology of PE
HellenicJCardiol.(http://www.ncbi.nlm.nih.gov/pubmed/17489347#)2007MarApr48(2):94107.
Circulation.(http://www.ncbi.nlm.nih.gov/pubmed?term=Circulation.%202003%20Dec%202%3B108(22)%3A27269.#)2003Dec2108(22):27269.
Hemodynamic consequences
Increasedrightventricularafterload:fromincreasedpulmonaryvascularresistance.
Rightventriculardilatationandhypertrophy:parasternalheave,loudP2
RVischemia
Rightsided(backward)heartfailure:increasedjugularvenouspressure(JVP)
Decreasedleftventricularfilling:becauseofbowingofinterventricularseptumtoleftsidefromRVhypertrophy
Leftsided(forward)heartfailure:hypotension,syncope,cardiogenicshock
Resolution
Intrinsicthrombolyticmechanisms(plasmin)starttolyseclots:Ddimer(breakdownproductoffibrin)levelsincreaseinserum.
SymptomaticPEistreatedwithanticoagulationtherapy(oralorparenteral),thrombolytictherapy(formassivePEcausingcardiogenicshock),orinferiorvenacava
filter(ifanticoagulationiscontraindicated).SeeTreatmentsectionfordetails.
UntreatedlargePEcausesdeathbyacuteincreaseinrightventricularpressure,leadingtoRVfailure.
Feedback
Feedback
(http://www.pathophys.org/vte/pepathophys/)
CliniciansaccuratelydiagnoseDVTusingclinicalfeaturesinapproximately25%ofcasesbecausethesignsandsymptomsareneithersensitivenorspecific.Therefore,itisimportanttoconfirm
clinicalfindingsusingadditionaltesting,suchascompressionultrasonography.ThesignsandsymptomsofDVTarisefrom(i)venousobstructionand(ii)inflammationoftheveins.Patients
mayalsopresentwithfeaturesofpulmonaryembolism.
Symptoms Signs Mechanism
Homanssign FirstobservedbysurgeonDr.JohnHomans,thesigniselicitedbypassivedorsiflexionoftheankle.Positivefindingsincludeincreased
resistancetodorsiflexionorkneeflexion,bothinresponsetoirritationoftheposteriorcalfmuscles.Thissignisneithersensitivenorspecific.
NEnglJMed.(http://www.ncbi.nlm.nih.gov/pubmed/20993045)1946Aug1235(5):1637.
Clinical features of PE
HellenicJCardiol.(http://www.ncbi.nlm.nih.gov/pubmed/17489347#)2007MarApr48(2):94107.
JAMA.(http://www.ncbi.nlm.nih.gov/pubmed/14657070)2003Dec3290(21):284958.
PEsarefrequentlyasymptomatic.Symptomaticpatientsmostcommonlypresentwithdyspnea.SignsofDVTareonlyfoundinabout1/3ofPEpatients.
Parasternalheave,loudP2, Increasedpulmonarypressure(fromvasoconstriction)causesrightventricularoverload(loudP2)andrightventricular
increasedJVP dilatation(parasternalheave).RightsidedbackwardheartfailurecausesincreasedJVP,andeventuallyleftsided
heartfailure(tachycardia).
Hemoptysis PEcausesdamagetothepulmonaryvasculature,whichleadstobleedingintotheairways.Coughisusually
Feedback
andcough nonproductive,andmaybetriggeredbyirritationofthepleuraortheairways.
AmJMed.(http://www.ncbi.nlm.nih.gov/pubmed?term=Am%20J%20Med.%202007%20Oct%3B120(10)%3A871
9.#)2007Oct120(10):8719.
Diagnosis of DVT
JAMA.(http://www.ncbi.nlm.nih.gov/pubmed/16403932)2006Jan11295(2):199207.(DiscussionofWellsDVTscorehere)
Chest.(http://www.ncbi.nlm.nih.gov/pubmed/22315267)2012Feb141(2Suppl):e351S418S.(2012ChestGuidelines)
Diagnosisstartswithhistory(riskfactors)andphysical,whichcanbeusedtogenerateapretestprobabilityusingavalidatedclinicalpredictionrule,suchastheWellsDVTscore(see
JAMAreferenceabove).PatientswithhighlikelihoodofDVTcanbefurthertestedwithcompressionultrasonography,wherethelengthoftheproximalveins(poplitealandfemoral)is
sequentiallycompressedwiththeultrasoundprobe.Normalveinsareeasilyoccludedwithmoderateexternalcompression,butaDVTwillpreventocclusionoftheveinlumen.Ultrasonography
isbothsensitiveandspecificforDVTs.
ADdimerlevelcanbedonetoruleoutDVTinindividualswithlowpretestprobability(seediscussioninDiagnosisofPE).
ContrastvenographyisconsideredthegoldstandardfordiagnosisofDVT,althoughthisisrarelydonebecauseitisinvasive,expensive,andnotreadilyavailable.
Contrastisinjectedintothedorsalfootvein,andthelegisimagedwithCTscanorMRI.
Diagnosis of PE
JAMA.(http://www.ncbi.nlm.nih.gov/pubmed/14657070)2003Dec3290(21):284958.
Diagnosisisbasedonhistoryandphysical,andconfirmedwithCTorV:Qscaniftheclinicalsuspicionishigh.TheWellscriteriacanbeusedtodeterminerisk(pretestprobability)of
PE.
Criteria Points
1 Clinicalsigns/symptomsofDVT 3
2 NootherdiagnosismorelikelythanPE 3
3 Tachycardia:heartrate>100 1.5
4 Immobilizationfor>3days(e.g.strictbedrest) 1.5
OR
Surgeryintheprevious4weeks
5 PreviousDVTorPE 1.5
6 Hemoptysis 1
7 Malignancy 1
Lowrisk(<2):3%pretestprobability
Moderate(26):20%
High(>6):63%
ThrombHaemost.(http://www.ncbi.nlm.nih.gov.libaccess.lib.mcmaster.ca/pubmed?term=Thromb%20Haemost.2000%3B83%3A416420.)2000Mar83(3):41620.
NoteonDdimer:InlowriskpatientswithsymptomsthatsuggestPE,aDdimercanbeusedtoruleoutPEifnegative(highsensitivity,lowspecificity).Ddimerlevelismeasuredinthe
blood.Asexplainedabove,itisadegradationproductoffibrin,whichiselevatedifacoagulationandfibrinolysisreactionhappensinthebody.InPE,endogenousfibrinolyticmechanismstry
todissolvetheclot,whichisthebasisofanelevatedDdimer.However,theDdimerlevelnotspecificandiselevatedinanytypeofinflammatoryprocess.Itsclinicalutilityislimitedtoruling
outPEinthosewithalowpretestprobability.
Treatment
Chest.(http://www.ncbi.nlm.nih.gov/pubmed/22315268)2012Feb141(2Suppl):e419S94S.
ThegoalsoftreatmentforVTEare(i)anticoagulationtopreventfurtherclotgenerationand(ii)thrombolysisifthethrombusislargeenoughtocausehemodynamiccompromise.
Anticoagulation:Reducesfurtherclotformation
Anticoagulationwithparenteral(intravenousorsubcutaneous)andoralanticoagulantsisthemainstayofVTEtherapy.Typically,oneoftheparenteralagents(e.g.heparin,LMWH,or
fondaparinux)oraneworalanticoagulant(e.g.rivaroxaban)isstartedfirst.Thepatientmaybetransitionedtoatraditionaloralanticoagulant(e.g.warfarin)forchronicanticoagulation.
Unfractionatedheparin(UFH):InhibitsthefunctionofthrombinaswellasXabyinducingconformationalchangesinantithrombin,allowingittobindtheenzymes
better.
Lowmolecularweightheparin(LMWH):FunctionssimilartoUFH,butduetothesmalleraverageheparinchainlength,acceleratesthebridgingofATwithXaonly,
andnotthrombin.
Fondaparinux:ApentasaccharidesequencethatdirectlybindstoAT(atanallostericsite)andinducesaconformationalchangeallowingittobindandinhibitfactorXa
only.
Rivaroxaban:AneworalanticoagulantthatinhibitsfactorXabybindingtoitsactivesite.
Chronicanticoagulation:ForprophylaxisagainstfutureVTE
Anyoftheagentsforacuteanticoagulationcanbeusedforchronicanticoagulation,buttheyarelessconvenientforoutpatientsduetotheneedfordailyinjections.Oralanticoagulationdrugs
arethemainstayforoutpatientanticoagulation.VitaminKantagonists(e.g.warfarin)weretraditionallyused,butneweragents,suchasdabigatranandrivaroxaban,canalsobeused.In
addition,aspirinisanantiplateletagentthathasbeenshowntoreduceVTEeventsinrecenttrials.
VitaminKantagonists(e.g.warfarin):WarfarininhibitsthevitaminKdependentsynthesisofcalciumdependentclottingfactors(II,VII,IXandX).Furthermore,
warfarinalsoinhibitsPSandPC(partoftheendogenousanticoagulationpathway).
TheinhibitionofPCandPSoccursfasterthantheotherclottingfactors,makingwarfarinacutelyaprocoagulant.Therefore,warfarinmustbegivenconcomitantly
withacuteanticoagulantsatfirst(aprocessknownasoverlapping)to(i)preventacuteprocoagulanteffectand(ii)allowtimeforinhibitionofvitaminKdependent
factors.Oncethepatientsinternationalnormalizedratio(INR)istherapeutic(23),acuteanticoagulantscanbediscontinued.
WarfarinhasbeenthemainstayofchronicVTEtherapyforover50years,butthereareseveralissueswithitsuse:(i)increasedbleedingrisk,(ii)teratogenicityin
pregnancy,(iii)interactionwithmanyfoodsanddrugs,and(iii)closemonitoringrequiredbecauseanticoagulationeffectisnotreliablypredictablebydosage.New
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antithromboticmedicationshavebeendevelopedthatarepotentiallysaferthanwarfarin.
Directthrombininhibitors(e.g.dabigatran):Directlyblockthrombinfunctionbyblockingtheactivesite.Dabigatranisequivalenttowarfarininbothpreventionof
recurrentclotsandbleedingriskinpatientswithacuteVTE,butitdoesnotrequiremonitoringduetoitspredictabletherapeuticeffect(RECOVERtrial).
NEnglJMed.(http://www.ncbi.nlm.nih.gov/pubmed/19966341#)2009Dec10361(24):234252.
DirectXainhibitors(e.g.rivaroxaban):DirectlyinhibitthefunctionofXabyblockingtheactivesite.Unlikewarfarinanddabigatran,rivaroxabandoesnotrequire
overlappingwithheparins.RivaroxabanisequivalenttowarfarininshortandlongtermpreventionofPEinsymptomaticpatients,butitdoesnotrequiremonitoring
oroverlapping,andhassignificantlylowerbleedingriskcomparedtowarfarin(EINSTEINPEtrial).
NEnglJMed.(http://www.ncbi.nlm.nih.gov/pubmed/22449293#)2012Apr5366(14):128797.
Aspirin:Althoughthisantiplateletagentisclassicallyusedtopreventarterialthrombosis,newevidencesuggeststhatitcanalsobeusedforrecurrentVTEprevention.
Dailyaspirin(100mg/dayusedintrials)canreduceVTErecurrencebyapproximately1/3.Aspirin,althoughnotaseffectiveasotheranticoagulants,maybeusedifthe
patientisintolerantofanticoagulants.
NEnglJMed.(http://www.ncbi.nlm.nih.gov/pubmed/23121404)2012Nov22367(21):203941.
Thrombolysis:Breaksdownthethrombus
Tissueplasminogenactivator(tPA):activatesplasminogen(Pg)toplasmin(Pn),whichcleavesthethrombus,generatingsolubleDdimerproducts.
Contraindicationstoanticoagulation
Thrombectomy:Ifalargethrombuscreateshemodynamiccompromise,andtherearecontraindicationstothrombolysis,theclotcanbesurgicallyremovedorby
interventionalradiology.
Inferiorvenacava(IVC)filter:TemporaryIVCfilterscanbeplacedtostopthemovementofclotsfromthedeepveinsofthelowerextremityfromtravellingtothe
pulmonaryvasculature.
Feedback
(http://www.pathophys.org/vte/vteanticoagulation/)
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