Coagulation Tests - AACC

3/31/2015
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APrimeronHemostasisforClinicalChemists
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Author:NeilS.Harris,MBChB,MD,LindsayA.L.Bazydlo,PhD,andWilliamE.Winter,MD
CLNArticles
Boardof
//Date:JAN.1.2012//Source:ClinicalLaboratoryNews
Topics:TestingMethods,Specializations,Coagulation,Thrombosis
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Whendamagetosmallbloodvesselsandcapillariesoccurs,thebodycontrolsbloodloss
viaphysiologicalprocessesreferredtoashemostasis.Invivo,hemostasisdependsonan
interactionbetweentheplasmabasedcoagulationcascade,platelets,andthe
endotheliumofbloodvessels.Intheclinicallaboratory,invitroanalyticalassaysare
capableofmeasuringonlythefirsttwocomponentsofthissystem.Consequently,
laboratorymeasurementsofbloodcoagulationrepresentonlyacloseapproximationofthe
body'shemostaticsystem.
Cliniciansfrequentlyordercoagulationtests,suchastheprothrombintime(PT),activated
partialthromboplastintime(aPTT),andthrombintime(TT),toassessbloodclottingfunction
inpatients.Whiletheselaboratorytestsmaybehelpfulinelucidatingthecauseof
unexplainedbleeding,theyarenothelpfulinpredictingifbleedingwilloccur.Infact,no
singletestcanpredictbleedingintheperioperativeorpostoperativeperiod.Furthermore,
thesecommonlaboratorytestsareoflittlehelpinpredictingbloodclottingorthrombosisin
theabsenceofvesselinjury.Welldescribedassaysareavailabletotestforhereditary
predispositiontothrombosis,butthemajorityofthrombophilicstatescannotbequantified
byanycurrentlaboratorytests.
Clearly,laboratoryassessmentofhemostasispresentsmanychallengesforlaboratorians
andtheclinicianswhointerprettheresults.Thisreviewbrieflyexplainsthecommontests
usedtoassesshemostasis,aswellastheirclinicalcontext,andprovidesaguidefor
https://www.aacc.org/publications/cln/articles/2012/january/coagulationtests
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clinicalchemiststoassessunexplainedbleeding.
TheABCsofCoagulationTests
Laboratorytestsforhemostasistypicallyrequirecitratedplasmaderivedfromwholeblood.
Specimensshouldbecollectedintotubescontaining3.2%sodiumcitrate(109mM)ata
ratioof9partsbloodand1partanticoagulant.Thepurposeofthecitrateistoremove
calciumionsthatareessentialforbloodcoagulationhowever,failuretofillthedrawtube
adequatelycausesthefinalcitrateconcentrationofthepatientsampletobetoohigh.This
isimportantbecausePTandaPTTtestsrequiretheadditionofcalcium.Ifthespecimen
containsexcesscitrate,additionofcalciummaybeinadequate,andthelowplasma
calciumwillleadtoanartificialprolongationofPToraPTT.
Asimilarbutmoresubtleproblemmightariseifthepatient'shematocritisunusuallyhigh,
typically55%.Normally,10mLofbloodwithahematocritof40%contains6mLof
plasma.Ifthehematocritisabnormallyelevated,forexample65%,thespecimenwill
containonly3.5mLofplasma,effectivelyunderfillingthedrawtubewithplasma,leading
toovercitrationoftheplasma.
ForthePTtest,addingathromboplastinreagentcontainingatissuefactor,calcium,and
phospholipidsinitiatescoagulationoftheprewarmedspecimenviatheextrinsic
coagulationpathway(Figure1).Similarly,theaPTTtestisinitiatedbyaddinganegatively
chargedsurfacesuchassilicatotheplasma,aswellasaphospholipidextractthatisfree
oftissuefactor.ThecoagulationpathwaythatoccursintheaPTTtestrepresentsthe
intrinsiccoagulationpathway(Figure1).
Figure1
CoagulationCascade
Thecoagulationcascadeisaseriesofenzymaticreactionsthatturn
inactiveprecursorsintoactivefactors.Theendresultofthecascadeis
theproductionoffibrin,aproteinthatbindsplateletsandothermaterials
inastableclot.Thecascadehastwoinitialpathways:theextrinsic
(tissuefactormediated)andtheintrinsic(contactsysteminitiated).
Thesetwopathwaysconvergetobecomethecommonpathwaywith
theactivationoffactorX.Thestepsinthecascadethataremeasuredby
thethreecommoncoagulationassays,PT,aPTT,andTT,areindicated.
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CoagulationCascade
WhenapatienthasanabnormallyprolongedPToraPTT,laboratoriesshouldperforma
mixingstudyofthespecimen(Table1).Toperformthetest,thetechnologistmixesanequal
volumeofthepatient'scitratedplasmawithnormalpooledplasma(NPP)andrepeatsthe
PTand/oraPTT.IftheclottingassaytimenowfallswithinthePTand/oraPTTreference
intervals,theinitialabnormalresultwasduetooneormoreclottingfactordeficiencies.In
contrast,thepresenceofinhibitorsinpatientplasmainterfereswiththeclottingfactorsin
theNPP,butthemixingstudyresultswillnotproducenormalclottingtimes.Another
commonassayusedtoassesshemostasisisTT(Figure1).Thistestmeasurestheabilityof
fibrinogentoformfibrinstrandsinvitro.Toperformthetest,thetechnologistadds
exogenousthrombintoprewarmedplasma.Thisstepensuresthattheresultis
independentofendogenousthrombinoranyoftheotherclottingfactors.TTisparticularly
sensitivetoheparin.
Table1
AssessmentofProlongedaPTT
Thistableshowshowcoagulationassayscanbecombinedtoelucidatethepossiblecausesofa
prolongedaPTT.
No
Clinical Increased Increased Increased Hemostatic Thrombophilia
Features Bleeding Bleeding Bleeding Problems
DVT,PE
1:1Mixing
Study
Corrects
Corrects
Nocorrection
Corrects
Nocorrection
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PT
Pathology
Normal
Prolonged
Deficiencyof
factorsVIII,IX
andsome
casesof
factorXI
deficiency
Deficiencyof
factorsII,V,
X,fibrinogen
Normal
Normal
Autoantibodies Deficiencyof
tofactorVIII
factorXII
(acquired
hemophilia)
Deficiencyof
WarfarinRx
Normal
Antiphospholipid
syndrome
othercontact
factorssuchas
prekallikrein
Somecasesof
factorXI
deficiency
Abbreviations:DVT,deepveinthrombosisPE,pulmonaryembolismRx,treatment.
ThequantitativefibrinogenassayisamodificationoftheTTassay.Thetestrequires
additionofexogenousthrombin,exceptthatinthiscase,thetechnologistdilutesthe
plasmaseveralfoldandaddsgreateramountsofthrombincomparedtotheTTassay.The
results,whicharereportedinmg/dLratherthanseconds,aredeterminedfromastandard
curvegeneratedfromacalibratorplasma.
AnothertestfrequentlyorderedtoassesshemostaticfunctionisDdimer.These
degradationproductsofmaturecrosslinkedfibrinareformedbytheactionoftheenzyme
plasminonfibrin,andelevatedlevelsareanindicatorofthrombosis.Twotypesof
laboratoryassaysmeasureDdimers:noncompetitive,sandwichimmunoassays,and
immunoturbidimetricassays.Ddimerdeterminationisusedforitshighnegativepredictive
valueofthrombosis.Whentheconcentrationiswithinthereferencerange,clinicianscan
excludeasuspecteddeepvenousthrombosis(orpulmonaryembolism).Patientswho
suffertrauma,undergosurgery,orarepregnantcommonlyhaveelevatedlevelsofD
dimers.
Theactivatedclottingtime(ACT)testuseswholeblood,whichismixedwithaclotactivator,
usuallydiatomaceousearthorkaolin.Clottingtypicallytakes70180seconds,andcanbe
measuredmechanicallyorbyanelectrochemicalprocedure.Hospitalsusethetestatthe
bedsidetomonitorhighdoseheparinanticoagulationduringcardiopulmonarybypass
surgeryaswellasduringcardiaccatheterization.
Thecoagulationfactoractivityassaydeterminesthelevelofvariouscoagulationfactors.An
essentialcomponentoftheassayisafactordeficientplasmathatlacksthespecificfactor
beingtested.Toperformtheassay,thetechnologistdilutesthepatient'scitratedplasmain
abufferandmixesthedilutedspecimenonetoonewiththefactordeficientplasma.The
patient'sspecimensuppliesthemissingfactortotheassay,whichiscompletedby
performingastandardPToraPTT,dependingonthefactorbeingtested.Asanexamplefor
factorsVIIIandIX,whichparticipateintheintrinsiccoagulationpathway,thelabshouldrun
theaPTTtest.Incontrast,aPTassaywouldbeusedtodeterminefactorVII,whichis
involvedintheextrinsiccoagulationpathway.Calibrationoftheassaysinvolvesastandard
referenceplasmawithaknownconcentrationofthefactorbeingtested.
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PlateletFunction
Anothercomponentoflaboratoryassessmentofhemostasisisplateletfunctiontesting.
Plateletaggregometryisconsideredtheclassictestofplateletfunction.Thistestincludesa
plateletactivatingagonistsuchasADP,epinephrine,orcollagen.Thetechnologistadds
theagonisttoplateletrichplasmaandmonitorsplateletaggregationinaphotometer
cuvette.Opticaldensitychangesareplottedtoviewtheaggregationcurve.
Otherdevicesmeasureplateletadhesionunderhighshearconditions.Inthismethod,the
instrumentfirstdrawsanaliquotofthespecimenthroughacapillaryunderconditionsof
highshearstressandthenthroughaverysmallapertureinadisposablecartridge.The
latteriscoatedwithcollagenandepinephrineorcollagenandADP.Innormalindividuals,
thisproducesplateletadhesionandactivationthateventuallyplugstheapertureandstops
theflow.Theassayendpointiscalledtheclosuretime.
TheAntiXaAssay
CliniciansoccasionallyordertheantiXatesttomonitorandadjustpatients'levelsof
unfractionatedheparin,awidelyusedanticoagulant.Thischromogenicmethodgenerally
containsexogenousfactorXaandantithrombin(AT),bothinexcess,aswellasa
chromogenicsubstrateforfactorXa.Someversionsoftheassayusethepatient'sownAT,
aserineproteaseinhibitorthatisthemajorinhibitorofcoagulationproteases,insteadof
addingexogenousAT.Ineitherapproach,heparinpresentinthespecimencomplexeswith
ATandthiscomplexinhibitsfactorXa.AnyresidualfactorXacleavesthechromogenic
substrate,therebyreleasingayellowcoloredchromophore.Labsreporttheseresultsas
unitspermLofantiXaactivity.
ClinicalProblemsAssociatedwithBleeding
Manyclinicalconditionscanleadtounexplainedbleeding.Propertestingcanhelp
cliniciansdiscernthecause.Thissectionpresentssomeofthemorecommoncausesand
whichtestsshouldbeused(Table2).
Table2
SequentialUseofCoagulationAssaystoAssessBleeding
Thistableshowshowcoagulationassayscanbecombinedtoelucidatethe
possiblecausesofunexplainedbleeding.
Step
Test
Indicationfor
PerformingTest
PurposeofTest
Goto
Step
assessextrinsic,
intrinsicandcommon
pathwaysand
adequacyofplatelet
numbers
3or4or
5
PT,aPTT,
fibrinogen,
platelet
count
unexplained
bleeding
1:1mixing
study
prolongedPT,
aPTT
assess
deficiency/dysfunction
vsinhibitor
specific
mixingstudies
assessfactor
iffactor
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factor
activity
assays
showcorrection
TT
mixingstudydoes
notcorrect
deficiencyorwarfarin
Rx
ruleoutheparin
contamination
antiXa
assay
mixingstudydoes
notcorrect
assayfor
specific
factor
inhibitors
mixingstudydoes
notcorrectand
heparinis
excluded
ruleoutacquired
hemophiliaandother
factorinhibitors
reducedfactorVIII
activity
ruleoutvWD
von
Willebrand
antigenand
activity
platelet
function
screen
reducedfactorVIII ruleoutvWDand
activityornormal
plateletdysfunction
plasmabased
coagulationtests
withnormalplatelet
counts
factorXIII
allprevioustesting
screen,tests iswithinnormal
fordisorders limits
of
fibrinolysis
(e.g.,TEG)
VIIIis
low,
proceed
to7and
8
ifheparin
is
excluded,
proceed
to6
ruleoutfibrinolytic
problems
Congenitalhemophilia.Theclassicbleedingdisorder,congenitalhemophilia,isanX
linked,recessivegeneticabnormality.Maleswithonecopyofthedefectareaffected
however,femalesareasymptomaticcarriers.Thediseaseoriginatesfromoneoftwo
alteredproteinsinthecoagulationcascade,factorVIII(hemophiliaA)orfactorIX
(hemophiliaB),whichareindistinguishableclinically.TheincidenceofhemophiliaAis1in
5,000malelivebirths,andthatofhemophiliaBis1in30,000.
PatientswithhemophiliahavereducedfactorVIIIorfactorIXactivityinfresh,citrated
plasma,andthediseaseisclassifiedassevere(<1%),moderate(15%),ormild(630%)
dependingontheamountoffactoractivity.Inthesevereform,patientshavespontaneous,
deepbleedingintomusclesandjoints,aswellasseverebleedingafterinjury.These
individualspresentininfancy.Incontrast,themildformmaybediagnosedinadulthood
andevenaslateasmiddleage.Affectedindividualsbleedaftersurgeryortraumabutnot
spontaneously.
Thefollowinglabresultsareconsistentfindingsforhemophilia:1)significantlyprolonged
aPTTthatcorrectsina1:1mixingstudy2)PTwithinthereferencerange3)fibrinogenand
TTwithinthereferencerange3)normalplateletfunctionand4)normalvonWillebrand
testresults(seebelow).
vonWillebrandDisease.DefectivesynthesisorreleaseoffunctionalvonWillebrandfactor
(vWF)causesdefectiveplateletadhesionandleadstoaspectrumofconditions,suchas
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epistaxis,heavymenstrualbleeding,andeasybruising.
LabsuseanimmunoturbidimetrictechniquetomeasuretheplasmaconcentrationofvWF,
andtheymeasurevWFactivityusingthepatient'splasmaincombinationwithformalin
fixed,normaldonorplateletsandristocetin,whichservesasacofactorintheassay.
AnotherinformativetestexaminesthestructureofvWFmultimers.Anancillarytestisfactor
VIIIactivity,sincelowvWFisfrequentlyassociatedwithlowfactorVIIIactivity.Ifthefactor
VIIIactivityissufficientlydecreased,aPTTmaybeprolonged.Inmostformsofvon
Willebranddisease,bleedingisaconsequenceofplateletdysfunctionthatresultsfromthe
insufficiencyofactivevWFandnotfromreducedfactorVIIIactivity.
Acquiredhemophilia.Althoughrare,acquiredhemophiliaresultsfromspontaneous
formationofautoantibodiestofactorVIIIinapreviouslyhealthyindividual,eithermaleor
female.Asthenamesuggests,thereisnoovertgeneticcomponent.FactorVIIIactivityis
significantlydecreasedasaresultoftheautoantibodies,andsevereanduncontrolled
bleedingresults.
LaboratorystudiesrevealamarkedlyprolongedaPTT,anormalPT,andalowFVIIIactivity.
Forthesepatients,a1:1mixingstudydoesnotcorrecttheabnormalaPTT.
AcquiredvonWillebrandSyndrome.Alsouncommon,acquiredvonWillebrandsyndrome
(AVWS)referstothedevelopmentofvonWillebranddeficiencyrelativelylateinlifeina
previouslyhealthyindividual.AVWSmaybeseeninavarietyoflymphoproliferative
disorders,monoclonalplasmacelldisorders,autoimmunedisease,andcardiacvalvular
diseaseorseptaldefects.vWFactivityintheseindividualsmaybereducedbyinhibitory
antibodies,adsorptiontocellsurfaces,orareasofelevatedshearstressthatoccurviaa
stenoticheartvalveorseptaldefect.
LabstudiesshowdecreasedfactorVIIIactivity,prolongedaPTTiffactorVIIIis<40%,
impairedplateletresponsetoristocetin,andprolongedclosuretimes.
Noneofthestandardlaboratorytestsdescribedaboveprovidediagnosticinformationfor
identifyingthrombophilicstates.Inthemajorityofcases,hypercoaguabledisordersare
acquired,and,exceptforantiphospholipidsyndromeandthehereditarythrombophilias,
therearenoinformativelaboratorytests(Table3).
Table3
LaboratoryAssessmentofHypercoaguableStates
Hypercoaguable
State
Inflammation
Trauma
Clinical
Scenario
Mechanisms
Laboratory
Tests
Commonin
almostevery
postoperative
surgicaland
traumapatient
ElevatedfactorVIII,
vWF,fibrinogen,
inflammatory
cytokinescombined
withvenousstasis
None
Apparentor
Inflammation,
None
Surgery
Immobilization
Malignancy
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(Trousseau
Syndrome)
occultneoplasm
cytokines,proteases.
Productionoftissue
factorbytumor
Hormonal
Oral
Estrogenis
associatedwith
elevatedfactorII,VII,
VIII,Xandfibrinogen,
decreased
antithrombin,
decreasedproteinS
None
Antibodiesto
phospholipidand
phospholipidbinding
proteins.
Inflammationand
endothelialdamage.
glycoproteinI
Lupus
anticoagulant
testing
antibodiesto
cardiolipin
andbeta2
Heparininduced Acquired
thrombocytopenia antibodyto
(HIT)
heparin/platelet
factor4complex
Plateletactivation
andreleaseof
microparticles
Testfor
antibodiesto
heparin/PF4
byELISA
Hereditary
Thrombophilia
Multiple(seetext)
PCRbased
contraceptives
Pregnancy
Antiphospholipid
Syndrome
Acquired
autoimmune
disorder
Unexplained
thrombosisatan
earlyageor
thrombosisat
unusualsitesor
recurrent
thrombosis
DNAanalysis
Functional
activity
assays
Antiphospholipidsyndrome.Anautoimmuneprothromboticacquiredcondition,
antiphospholipidsyndrome(APLS)isfrequentlyassociatedwithamarkedlyprolonged
aPTT,leadingtoaconcernthattheaffectedindividualmightbeatriskforamajor
hemorrhage.Notonlyisthishighlyunlikely,butasaprothromboticstate,APLSistypically
associatedwithvenousthromboembolismand/orarterialthrombosis.Theconditionmay
alsopresentwithfetallossorstillbirth,whichlikelyoccursasaresultofplacental
inflammationorthrombosis.
IndividualswithAPLShaveantibodiesknownaslupusanticoagulants(LA).These
antibodiesaredirectedtocomplexesofbeta2glycoproteinI/phospholipidor
prothrombin/phospholipid,andtheyinterferewithandprolonginvitroclottingassays.Inthe
body'svascularsystem,however,thepresenceofendothelialcellsandleukocytes,aswell
asmanyothercomponentsthatareabsentfromthesimplifiedinvitroclottingassay,
increasethelikelihoodofclotting.
TheclassiclaboratoryfindingsinAPLSpatientsareprolongedaPTT,normalPT,andno
correctionoftheaPTT1:1mixingstudy.AddingexcessphospholipidtotheaPTTassay,
however,reducestheclottingtime.ThisisthebasisforthesocalledLAassay.Oneversion
oftheLAassayisthediluteRussell'svipervenomtime(dRVVT).Theassaycomponents
activateonlythecommoncoagulationpathwayviafactorX,andtheyareindependentof
factorVIIIorantibodiestofactorVIII.LaboratoriesalsocanconfirmAPLSbydetectingIgG
orIgMantibodiestocardiolipinortobeta2glycoproteinIinanELISAtypeassay.
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FactorVLeiden.AvariantoffactorV,factorVLeidencausesahereditary
hypercoagulabilitydisorder.Individualswiththedisorderhaveapointmutationinthefactor
Vgenethatproducesasingleaminoacidswitch(argininetoglutamine,R506Q)that
makestheproteinresistanttoinactivationbyactivatedproteinC.HeterozygosityforfactorV
Leidenincreasestheriskforvenousthromboembolismabouttwoorthreefold.
LaboratoryresultsforthisgeneticconditionincludePTandaPTTwithinthenormalrange.
Inaddition,aPTTwillberesistanttoactivatedproteinC,andinnormalindividuals,adding
activatedproteinCtoafreshplasmaspecimenwillcauseprolongationofaPTT.Thiseffect
isbluntedforindividualswithfactorVLeiden.DNAstudiesdefinitivelyconfirmtheG1691A
nucleotideswitch.
ProthrombinG20210A.Anotherhereditarythrombophilia,theG20210Apolymorphismin
theprothrombingeneelevatestheplasmaconcentrationsofprothrombin(FII)without
changingtheaminoacidsequenceoftheprotein.
PatientswiththismutationhavePTandaPTTresultsthatfallwithinthenormalrange,as
wellasnormalfunctionalclotbasedstudies.DNAstudieswillshowaGtoAsubstitutionin
the3'untranslatedregionofprothrombingeneatnucleotide20,210.
ProteinCandSdeficiency.ThesetwovitaminKdependentfactorsinterrupttheactivityof
clottingfactorsVandVIII.ActivatedproteinCisaproteolyticenzyme,whileproteinSisan
essentialcofactor.
Antithrombindeficiency.AT,formerlycalledATIII,isavitaminKindependentglycoprotein
thatisamajorinhibitorofthrombinandothercoagulationserineproteases,including
factorsXaandIXa.ATformsacompetitive1:1complexwithitstargetbutonlyinthe
presenceofanegativelychargedglycosaminoglycan,suchasheparinorheparinsulfate.
PatientswithATdeficiencywillhavelittletonoATIIIactivityasmeasuredinachromogenic
assay.
InterpretationofCoagulationTests
Aswithanylaboratorytest,ourgoalaslaboratoriansistoassistclinicianswithutilization
andinterpretationofteststhatassesshemostasis.Unlikeanelevatedserumcreatinineora
highthyroidstimulatinghormonethatindicateimpairedrenalfunctionandhypothyroidism
respectively,testsofhemostasishavetobeinterpretedinthecontextofclinicalfindingsas
wellasotherlaboratoryfindings.Giventhedireconsequencesofunexplainedbleeding,
clinicallaboratoriansshouldactivelyadvisecliniciansonuseandinterpretationof
coagulationtests.Ashotgunapproachtohemostaticdisordersisrarelysuccessfulandcan
resultindelayeddiagnosisandtreatmentforpatients.
SUGGESTEDREADING
EbyCS.WarfarinDosing.ShouldLabsOfferPharmacogeneticTesting?CLN200935(6).
HarrisNS,WinterWE.TheInternationalNormalizedRatioAToolforMonitoringWarfarin
Therapy.CLN201036(11).
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HarrisNS,WinterWE,LedfordKraemerMR.Hemostasis:AReview&Methodsof
AssessmentintheClinicalLaboratory.Chapter21,pp265283.IN:ContemporaryPractice
inClinicalChemistry2ndEdition,Clarke,W.2011(AACCPress,WashingtonDC).
HoffbrandAV,MossPAH.EssentialHaematology.6thEdition.Chapters26(Coagulation
Disorders)and27(ThrombosisandAntithromboticTherapy).WileyBlackwell2011.
HoffmanM,MonroeDM.Coagulation2006:Amodernviewofhemostasis.HematolOncol
ClinNAm200721:111.
KrollMH.ThromboelastographyTheoryandPracticeinMeasuringHemostasis.CLN
201036(12).
NeilS.Harris,MBChB,MD,isclinicalassociateprofessorandcodirectoroftheCoreDiagnostic
LaboratoryintheDepartmentofPathology,Immunology,andLaboratoryMedicineattheUniversityof
FloridaCollegeofMedicineinGainesville.Email
LindsayA.L.Bazydlo,PhD,isclinicalassistantprofessoranddirectorofclinicalchemistryinthe
DepartmentofPathology,ImmunologyandLaboratoryMedicineattheUniversityofFloridaCollegeof
MedicineinGainesville.Email
WilliamE.Winter,MD,isprofessorofpathologyandpediatricsattheUniversityofFloridain
Gainesville.Email
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