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MPR(http://www.pathophys.org) / Hematology(http://www.pathophys.

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).

Arterial vs. venous thrombosis


ThrombHaemost.(http://www.ncbi.nlm.nih.gov/pubmed/21225099)2011Apr105(4):58696.

Thecoagulationcascadeisanessentialpartofhemostasis.However,thesamecoagulationfactorscangiverisetoclotformationinthecirculationthatisinappropriate(i.e.notforhemostasis).
Thrombicanforminboththearteriesandveins,buttheyhavedifferentpathophysiologyandleadtodifferentoutcomes.Thischapterisaboutvenousthrombosis.

Arterialthrombosis Venousthrombosis(VTE)

Mechanism Typicallyfromruptureofatheroscleroticplaques. TypicallyfromacombinationoffactorsfromVirchowstriad.

Location Leftheartchambers,arteries Venoussinusoidsofmusclesandvalvesinveins

Diseases Acutecoronarysyndrome Deepvenousthrombosis


Ischemicstroke Pulmonaryembolism
Limbclaudication/ischemia

Composition Mainlyplatelets Mainlyfibrin

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.

Eects of mechanical occlusion


Increasedalveolar(physiologic)deadspace:decreasedperfusionofalveolidistaltothrombuscausesthealveolitobeventilatedbutnotperfused,resultinginV/Q
mismatch(highV/Q)andincreaseddeadspace
Increasedminuteventilation:patientcompensatesfordeadspaceandrespondstochemicalirritationbyhyperventilation.
Hypocapnia:increasedminuteventilationcausesdecreasedbloodCO2andrespiratoryalkalosis.Hypocapniaexacerbatesalveolarhypoxemiabycausing
secondarybronchoconstriction.
Increasedpulmonaryvascularresistance:duetovascularobstructionbythrombusandchemicalmediatorsfromplatelets(seebelow)
Decreasedsurfactantandatelectasis:vascularcompromisebeyondthrombusreducessurfactantproductionandthuspredisposesdistalregiontoatelectasis

Eects of chemical mediators


Plateletsfromthethrombussecretechemicalmediatorssuchashistamineandserotonin,whichcausespulmonaryvasoconstrictionandbronchoconstriction.
Bronchoconstrictionleadstoalveolarhypoxemia,whichinturncausesmorevasoconstrictionandincreasedvascularresistance.

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.

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Feedback

(http://www.pathophys.org/vte/pepathophys/)

Clinical features of DVT


SeminNuclMed.(http://www.ncbi.nlm.nih.gov/pubmed/11330789)2001Apr31(2):90101.
JAMA.(http://www.ncbi.nlm.nih.gov.libaccess.lib.mcmaster.ca/pubmed/9546569)1998Apr8279(14):10949.

CliniciansaccuratelydiagnoseDVTusingclinicalfeaturesinapproximately25%ofcasesbecausethesignsandsymptomsareneithersensitivenorspecific.Therefore,itisimportanttoconfirm
clinicalfindingsusingadditionaltesting,suchascompressionultrasonography.ThesignsandsymptomsofDVTarisefrom(i)venousobstructionand(ii)inflammationoftheveins.Patients
mayalsopresentwithfeaturesofpulmonaryembolism.
Symptoms Signs Mechanism

Asymmetric Pittingedemaon Swellingandpittingedemaarecausedbyvenousobstruction.Calfcircumferenceismeasured10cmbelowthetibialtuberosity.Normal


leg/calfswelling affectside differencebetweenthetwolegsshouldbelessthan1cmgreaterthan3cmdifferenceisconsideredsignificant.

Pain,erythema Localizedtenderness Pain,erythema,andtendernessarecausedbyvascularinflammation.Recruitmentofinflammatorycellstothrombusandvenousstasiscauses


alongdeepvenous phlebitis.
system

Homanssign FirstobservedbysurgeonDr.JohnHomans,thesigniselicitedbypassivedorsiflexionoftheankle.Positivefindingsincludeincreased
resistancetodorsiflexionorkneeflexion,bothinresponsetoirritationoftheposteriorcalfmuscles.Thissignisneithersensitivenorspecific.
NEnglJMed.(http://www.ncbi.nlm.nih.gov/pubmed/20993045)1946Aug1235(5):1637.

Dilatedsuperficial Palpablecord Dilatedsuperficialveinsarecausedbyobstructionofthedeepvenoussystem.Palpablecordreferstopalpablesuperficialveins,whichisa


veins(non signofsuperficialphlebitis.
varicose)

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.

Symptoms Correspondingsign(s) Mechanism

Dyspnea* Tachypnea*,decreasedairentry, Hyperventilationtocompensateforincreaseddeadspaceandinresponsetochemicalmediatorsfrom


localizedrales,wheezing platelets.Dyspneaisasymptomofcentral,whichcausesmoreseverehemodynamicconsequencesbecauseof
occlusionoflargervessels.*Mostcommonsymptomandsign,respectively.

Parasternalheave,loudP2, Increasedpulmonarypressure(fromvasoconstriction)causesrightventricularoverload(loudP2)andrightventricular
increasedJVP dilatation(parasternalheave).RightsidedbackwardheartfailurecausesincreasedJVP,andeventuallyleftsided
heartfailure(tachycardia).

Palpitations Hemodynamicsigns:Tachycardia Seeabove.Tachycardiaisasympatheticresponsetodecreasedcardiacoutput.

Pleuritic Pleuralfrictionrub,signsofpleural PEnearthepleura(peripheralPE)causesischemiatotheregion,resultingininflammation.Sincethepleurais


chestpain effusion(stonydullnesson innervated,inflammationwillproducelocalizedpleuriticchestpain.Inflammationalsoincreasesthepermeabilityofthe
percussion,decreasedfremitus) pleuralsurface,leadingtoaccumulationofexudativepleuralfluid(pleuraleffusion).

Hemoptysis PEcausesdamagetothepulmonaryvasculature,whichleadstobleedingintotheairways.Coughisusually

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andcough nonproductive,andmaybetriggeredbyirritationofthepleuraortheairways.
AmJMed.(http://www.ncbi.nlm.nih.gov/pubmed?term=Am%20J%20Med.%202007%20Oct%3B120(10)%3A871
9.#)2007Oct120(10):8719.

Syncope Hypotension,cyanosis Decreasedleftventricularfilling,causingforwardheartfailure.

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.
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(http://www.pathophys.org/vte/vteanticoagulation/)

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