Diagnosis and treatment of disseminated intravascular coagulation文档格式.docx
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©
2014JohnWiley&
SonsLtd
Keywords:
Disseminatedintravascularcoagulation;
platelets;
coagulationfactors;
fibrindegradationproducts;
tissuefactor;
antithrombin;
activatedproteinC;
thrombomodulin
Summary
Disseminatedintravascularcoagulation(DIC)isaconditioninwhichsystemicactivationofcoagulationwithoutaspecificlocalizationoccurs,resultinginextensiveformationofintravascularfibrin,particularlyinsmallandmidsizevessels.Disseminatedintravascularcoagulationmayleadtoseveralalteredcoagulationparameters,includingalowplateletcount,abnormalglobalclottingassays,lowlevelsofphysiologicalanticoagulantproteases,orincreasedfibrindegradationproducts.Also,morecomplexassaysforactivationofcoagulationfactorsorpathwaysmayindicateinvolvementofthesemoleculesinDIC.Noneofthesetestsalone,however,canaccuratelyascertainorrebuffadiagnosisofDIC.Nonetheless,acombinationofreadilyavailableroutineassaysmaybeinstrumentalinestablishingadiagnosisofDICandcanalsobeusefultopointtoasubsetofpatientswithDICthatmayneeddefinite,oftencostly,interventionsinthehemostaticsystem.CurrentinsightsonrelevantetiologicalpathwaysthatmaycontributetotheoccurrenceofDIChaveledtoinnovativetherapeuticandadjunctiveapproachestopatientwithDIC.Managementoptionsdirectedattheameliorationofhemostaticactivationmaytentativelybeindicatedandwerefoundtobeadvantageousinexperimentalandclinicalinvestigations.Thesetreatmentsencompasseliminationoftissuefactor-mediatedthrombingenerationorrestitutionofnormalanticoagulantfunction.
Introduction
Disseminatedintravascularcoagulation(DIC)isanintensemanifestationofhemostaticactivationthatmayoccurinavarietyofclinicalsettings,mostofwhichimplysomedegreeoflocalorwidespreadinflammation.Activationofcoagulationinthesystemiccirculation,inefficientlycounteractedbycoagulationinhibitorsandamplifiedbydecreasedphysiologicalfibrin-degradingpotential,mayresultinfibrinformationinsmallandmidsizevesselsandmicrovascularthromboticmicroangiopathy[1].Thesubstantialandcontinuingthrombingenerationmayresultinexhaustionofcoagulationproteasesandplatelets,leadingtoanincreasedriskofserioushemorrhagiccomplications,whichsometimesmaybethemostimpressiveclinicalpresentation.Currently,mostetiologicalfactorsinDIChavebeenidentified,whichmayleadtoamoreaccuratediagnosisofthedisorder.Nevertheless,theprecisediagnosisofDICmaybetricky,asmostassaysdemonstrateexhaustionofcoagulationproteasesorindicatethrombocytopenia,whilebiomarkersthatindicatespecificactivationofacoagulationfactororpathwayaremostlyinaccurateandareoftennotaccessibleinmosthospitalsona24hbasis[2,3].Inthisoverview,wewilldiscussbothwidelyavailableandmorecomplexlaboratoryassaysthatmaybehelpfulinthediagnosisofDIC.
Withgrowingunderstandingthatthesimultaneousactivationofsystemicinflammatoryactivityandactivationofhemostasismayleadtoorganfailureincriticallyillpatients,theadjunctivemanagementofDIChasbeenintenselystudiedrecently[4].CurrentthinkingaboutthepathophysiologyofDIChasresultedinnovelstrategiesdirectedatinhibitingtheinitiationorpropagationoffibrinformation.Themostimportanttherapeuticoptionswillbereviewedinthisstudy.
LaboratoryFindingsinDIC
Platelets
LowplateletsorarapidlydevelopingthrombocytopeniaisacentralcharacteristicofDIC(Table1).Asaplateletcountof<
150×
109/Linintensivecarepatientsfrequentlyoccurs[5,6],alowplateletcountisnotaspecificfeatureofDIC.Moderate-to-severethrombocytopenia(platelets<
100×
109/L)isobservedinthemajorityofpatientswithDIC,whereasasmallerproportionofpatients(about10–15%)haveseverethrombocytopenia(<
50×
109/L).IncriticallyillpostoperativepatientswithDIC,thrombocytopenia(<
109/Lplatelets)occursin>
80%[7].TheimportanceofalowplateletcountinDICisassociatedwithanincreasedriskofhemorrhagiccomplications,especiallypatientswithathrombocytopeniaof<
109/Lhaveafourfoldtofivefoldincreasedriskforhemorrhageincomparisonwithpatientswithnormalplateletnumbers,aboveallwhenthepatientusesantithromboticagents[5].TheriskofintracranialhemorrhageinpatientswithDICisrelativelymodest(0.3–0.5%),butmorethan85%ofpatientswithDICwiththisevent,amoderateorseverethrombocytopenia(<
109/L)ispresent.Inspiteoftheorigin,alowplateletcountisanindependentprognosticfactorinICUsurvivalwitharelativeriskof2–4invariousinvestigations[5],especially,asustainedlowplateletcountduringmorethan4daysafteradmissiontoacriticalcaredepartmentoraworseningthrombocytopeniaduringadmissionofacriticallyillpatientisrelatedtoafivefoldincreasedriskofdeath[5,8].
Table1.RoutinelaboratoryvalueabnormalitiesinDIC
TestAbnormalityCausesotherthanDICcontributingtotestresult
a
e.g.,proteinC,AT,proteinS.
PlateletcountDecreasedSepsis,impairedproduction,majorbloodloss,hypersplenism
ProthrombintimeProlongedVitaminKdeficiency,liverfailure,majorbloodloss
aPTTProlongedLiverfailure,heparintreatment,majorbloodloss
FibrindegradationproductsIncreasedHematoma
ProteaseinhibitorsaDecreasedLiverfailure,capillaryleakage
Coagulationfactorsandglobalclottingtimes
OngoingactivationandsubsequentexhaustionofcoagulationproteasesresultsindecreasedconcentrationsofthesefactorsinpatientswithDIC(Table1).Also,reducedproductionofclottingfactors,causedbyattenuatedliverfunctionand/orshortageofvitaminK,andsimultaneouscoagulationfactorreductions,duetosubstantialhemorrhage,maybeimportantinDIC(Table2)[9].Despitethefactthattheprecisenessofone-stageclottingmeasurementsinconsumptioncoagulopathieshasbeendebated(duetointerferencewithactivatedcoagulationfactorsintheassay),theconcentrationofclottingfactorsseemstoshowafairlygoodrelationshipwiththeintensityofDIC.Thereducedlevelofclottingfactorsisreadilydetectedbyabnormalcoagulationscreeningtests,includingtheprothrombintime(PT)ortheactivatedpartialthromboplastintime(aPTT).AnabnormalPToraPTTcanbefoundin15–30%ofcriticallyillpatientsandoccursinthevastmajorityofpatientswithDIC[10].However,itshouldbementionedthatoverallclottingassays,suchasthePTandaPTT,notverywellmirrorinvivocoagulation.Nevertheless,theseassaysareareadilyavailablemeanstoswiftlyassessthelevelofoneormoreclottingfactors[11].Usually,globalclottingassayswillbecomeabnormaliftheconcentrationofclottingproteinsis<
50%andforsomereagentsonly<
30–40%.Thisisimportantbecausetheconcentrationsofclottingfactors,thatarerequiredforcorrectfunctioningofcoagulation,areapproximatelyintherangeof25–50%.Variousreagentsmayproducehighlyvariablenormalvaluesandabnormallevels.Becauseofthis,agrowingnumberoflaboratoriesareemployingtheinternationalnormalizedratio(INR)asasubstituteofthePT.Theadvantageofenhancedcomparabilitybetweencenters,however,shouldbeoffsetagainstthefactthattheINRhasnotbeendevelopedasascreeningtestforclottingabnormalities[12,13].
Table2.DifferentialdiagnosisofsuspectedDIC
DifferentialdiagnosisAdditionaldiagnosticclues
DICProlongedaPTTandPT,increasedfibrinsplitproducts,lowlevelsofphysiologicalanticoagulantfactors(antithrombin,proteinC)
MassivebloodlossMajorbleeding,lowhemoglobin,prolongedaPTTandPT,
ThromboticmicroangiopathySchistocytesinbloodsmear,Coombs-negativehemolysis,fever,neurologicsymptoms,renalinsufficiency,coagulationtimesusuallynormal,ADAMTS13levelsdecreased;
PTandaPTTnormal
Heparin-inducedthrombocytopeniaUseofheparin,venousorarterialthrombosis,positiveHITtest(usuallyELISAforheparin-plateletfactorIVantibodies),reboundofplateletsaftercessationofheparin;
coagulationtimesusuallynormal;
PTnormal(aPTTmaybeprolongedduetoheparin)
VitaminKdeficiencyPTprolonged,aPTTnormalorslightlyprolonged,normalplateletcount
LiverinsufficiencyPTandaPTTprolonged,platelets(moderately)low,livertestabnormalities,hypersplenism,jaundice
Incontradictiontomostothercoagulationfactors,plasmaconcentrationsoffactorVIIIaremarkedlyincreasedinmostpatientswithDIC,presumablycausedbysubstantialreleaseofvonWillebrandfactorfromvascularendothelialcellsandacutephasepropertiesoffactorVIII.PreviousinvestigationshavedirectedatarelativedeficiencyofthevonWillebrandfactorcleavingproteaseADAMTS-13,whichmayresultinincreasedlevelsofverylargevonWillebrandmultimersinplasma,promotingplatelet-vesselwallbindingandtheensuingoccurrenceofathromboticmicroangiopathiccondition,whichmayalsobeafactorinorganfailure[14].
Inolderliterature,assessmentoffibrinogenisoftenmentionedasavaluableassaytoascertainthepresenceofDIC;
however,thismarkerisnotusefultoestablishDICinthevastmajorityofpatients.Fibrinogenbehavesasanacutephaseprotein,andtherefore,itsconcentrationcanbecompletelynormalforalongtimedespitemassiveconsumptionlevels.TheaccuracyofalowfibrinogenconcentrationincaseofDICwas<
30%,andlowlevelsoffibrinogenwereonlyestablishedinpatients