hematologic management of obstetric hemorrhage · administer txa to reduce blood loss, bleeding...
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HematologicManagementofObstetricHemorrhage
EvelynLockhart,MDMedicalDirector,UNMHospitalTransfusionService
AssociateProfessor,PathologyandObstetrics/GynecologyUniversityofNewMexicoHealthScienceCenter
FWGBDUterineHemostasisColloquium4/6/2017
Disclosures
Nodisclosuresinprior12months.PreviousDisclosures:Consultant:CSLBehring,Octapharma,Bayer,CerusSpeaker:Octapharma,TEMSystems,Inc.Honoraria:CSLBehring,Octapharma,TEMSystems,Inc.,BayerResearchSupport:TEMSystems,Inc.
ObstetricHemorrhageProtocols
Obstetrichemorrhageprotocolsrecommended:
§ ACOG:PostpartumHemorrhage.PracWceBulleWn#76,2006
§ JointCommission:PrevenWngMaternalDeath.SenWnelEventAlert201044:1-4
§ RCOG:Green-topGuidelines#52,revised2016
§ Nat’lPartnershipforMaternalSafety:Main,etal.ObstetGynecol.2015;126(1):155-62
ImagecourtesyofDr.AndraJames,DukeUniversityMedical
Center
CoagulaWoninPregnancy
Hypercoagulablestate:– LoweredProteinS– Reducedfibrinolysis,increasedPAI-1– Increasedprocoagulantfactors(Fgn,FVII,FVIII,FIX)
• Fibrinogen(non-pregnant):197-400mg/dL
• Fibrinogen(termpregnancy):350-650mg/dL
Szecsi,etal.ThrombHaemost.2010;103(4):718-727
FibrinogenLevelsandSeverePostpartumHemorrhage(PPH)
• ProspecWvemulWcenterstudyinatonicPPH(n=128)
• EnrolledatWmeofsecond-lineuterotonicadministraWon(sulprostone)
• Twogroups:1. SeverePPH:4+pRBCtransfusion,Hgbdrop>4g/dL,procedureintervenWon,ordeath
2. Non-severePPH
• Comparedlaboratoryvaluesbetweengroups:• PT/INR,PTT,plateletcount,fibrinogen,FII,FV,D-dimer,anWthrombin,Protein
C,euglobulinclotlysisWme,thrombin-anWthrombincomplex,plasmin-anWplasmincomplex,thrombomodulin
CharbitJ.ThrombHaemost.2007;5:266-273
LowFibrinogenPredictsSeverePPH
Charbit,etal.J.ThrombHaemost.2007;5(2):266-273
Fibrinogen<200mg/dLatSmeofPPHrecogniSon:predicSveofseverePPH
PITHAGORE6Trial
• Cluster-randomizedcontrolledtrialof106Frenchmaternityunitsover2yearperiod(2004-2006)
• IntervenWon:protocoleducaWonforearlyPPHmanagement
• Primaryoutcome:rateofseverePPHineachunit
• Results:Nosignificantdifferencebetweengroups(1.64%intervenWon,1.65%control)
• SecondaryanalysisperformedcorrelaWngfibrinogenlevelswithPPHfollowingvaginaldelivery
Deneux-Thareux,etal.BJOG.2010;117:1278-1287
PITHAGORE6subanalysis
Subjects:738of6,324paWentswithfibrinogendrawnwithin2hoursofPPHdiagnosis.SeverePPH:n=323Non-severePPH:Meanfibrinogen=420+/-120mg/dL
SeverePPH:Meanfibrinogen=340+/-90mg/dL(p<0.001)
Cortet,etal.BJA.2012;108:984-989
PITHAGORE6subanalysis
LaboratoryvariablesatWmeofdiagnosis:Hgb,platelets,PT,ACTraWoAmermulWvariateanalysis,onlyfibrinogenwaspredicWveofseverePPH.O.R.forfgn<200mg/dL:11.99(2.56-56.06)
Cortet,etal.BJA.2012;108:984-989
MajorObstetricHemorrhagewithHypofibrinogenemia
Green,etal.BritJHaematol.2016;172:616-624
UKObstetricSurveillanceSystem:July2012–June2013Subjects:8+RBCtransfusionwithin24hoursofdeliveryN=181casesMediannadirfgnlevel:<200mg/dLforallcauses
Platelet-fibrinstrands
ViscoelasWcClot-basedTesWng
Wholebloodsample
OscillaWngcuporpin
TwoplapormsintheU.S.:1. TEG:thromboelastography
2. ROTEM:rotaWonalthromboelastometry
ROTEMtracing
ImagefromWhiWngandDiNardo.AmJHematol.2013;89:228-232
MaximumClotFirmness(MCF):Measuresclot“toughness”;
ReflectsplateletsandfibrinogenacSvity
A5andA10Clotfirmnessat5or10minutes;
PredictsMCF
ROTEM:BiomarkerforPPHProgression
• ProspecWve,observaWonalstudy• N=356womanwithPPH>1,000mL
• Primaryoutcome:ROTEM(FibtemA5)orClaussfgnlevelaspredictorforPPHprogressionto>2,500mL
• InfinalmulWvariatemodel:
– FibtemA5independentpredictor(O.R.0.85[0.77-0.95])
– LowerFgn(<2g/L)andFibtemMCF(<10mm)associatedwithlongerbleeds,invasiveprocedures,andearliertransfusion
Collins,etal.Blood.2014;124(11):1727-1736
Fibrinogenconcentrate(FC)
• FDAapprovedin2009fortreatmentofcongenitalfibrinogendeficiency(afibrinogenemiaandhypofibrinogenemia).
• NotapprovedinUSforacquiredhypofibrinogenemia.
• Lyophilizedpowdermadefromcryoprecipitatedpooledhumanplasma.
• Pathogenreducedforbothenvelopedandnon-envelopedviruses.
• Pharmacovigilancedata:riskofthrombosis3.48per105dosesused.1
1. Dickneite,etal.BloodCoagFibrinolysis.2009;20(7):535-540
FIB-PPHtrial
• MulWcenter,doubleblindedRCTinDenmark
• n=249randomized
• Subjects:primaryPPH(regardlessofdeliverymode)
• Treatment:earlypreempWve2gfibrinogenconcentrate(FC)vs.salineplacebo
• Primaryoutcome:RBCtransfusion6weeksfollowingdelivery
WikkelsøAJ,etal.BrJAnaesth.2015Apr;114(4):623-33.
FIB-PPHTrialResults
• AllsubjectshadEBL>1L(meanEBL=1.5L)• Baselinefgnlevelmean:4.5g/Lforbotharms– Only2.2%hadfgnlevels<2.0g/Latbaseline
• Primaryoutcome:nodifference– FCgroupRBCtransfusion:20.3%– PlacebogroupRBCtransfusion:21.5%(P=0.88)
• Conclusions:empiricearlyFCnothelpfulinnormofibrinogenemicwomenwithPPH
WikkelsøAJ,etal.,BrJAnaesth2015Apr;114(4):623-33.
FibrinogeninPPH:GuidelineRecommendaWons
1. Kozek-Langnecker,etal.,EurJAnaesthesiol.2013;30(6):270–3822. MavridesE,etal.,BJOG.2016;124:e106-e1493. Lyndon,etal.CMQCCOBHemorrhagetoolkit.FromURL:cmqcc.org/ob_hemorrhage,lastaccessed12/2/20154. CollinsP,etal.JThrombHaemost.2015;14:205-210
OrganizaSon/Group RecommendaSonEuropeanSocietyofAnaesthesia(2013)1
• Fgnlessthan2g/LmayindicateincreasedriskforPPH(Grade2C)
• Fgn<1.5–2.0g/LdeficitshouldbetriggersforFgnsubsWtuWon
(Grade1C)RoyalCollegeofObstetriciansandGynaecologists(2016)2
• Fgnlevelgreaterthan2g/LshouldbemaintainedduringongoingPPH(GradeC).
CaliforniaMaternalQualityCareCollaboraWve(2015)3
• IniWalorderforcryoprecipitatewhenFgn<100mg/dLorifpaWent
hassevereabrupWonoramnioWcfluidembolism
• MaintainFgn>100-125mg/dLISTH(2015)4 • SuggestmaintainingFgn>2g/Lwithcryoorfibrinogen
concentrates
TranexamicAcid(TXA)andPPH
• CochranereviewonTXAforprevenWonofPPH1
– 12trials,3285subjects– Bloodloss>400-500mLandbloodtransfusionlesscommoninwomenreceivingTXA(moderatequalityevidence)
– Effectonmaternalmortalityandseveremorbidityuncertain
• CRASH-22:RCTofTXAintrauma– >20,000adultsubjects– 1gIVTXA+1gIVTXAinfusionvs.salineplacebo– SignificantreducWoninall-causemortalityandbleedingdeaths– NoincreaseinthromboemboliccomplicaWons
1. NovikovaandHofmeyer.CochraneDatabaseSystRev.2015;(6):CD007872
2.CRASH-2trialcollaborators,Lancet.2010;376:23-32
TXAforTreatmentofPPH• FrenchmulWcenterRCTateightobstetriccenters
• Subjects:vaginaldeliverieswithEBL>800mL– N=72pergroup
• IntervenWon:4gTXA,followedby1g/hourfor6hours.– AddiWonalprocoagulanttreatments(plasma,fgnconcentrates,platelets)allowedamerEBL=2,500mL
• Primaryoutcome:reducWonofbloodlossinPPH
• Note:notblindedorplacebo-controlled
Ducloy-Bouthors,etal.CritCare.2011;15:R117
TXAforTreatmentofPPH
UseofprocoagulantbloodproductssignificantlylessinTXAgroup:7%versus20%(p=0.013)Bloodlossfrom30minto6hourssignificantlylowerinTXAgroup:p=0.042Notaclinicallysignificantbloodlossdifference:173mLvs.221mL
Ducloy-Bouthors,etal.CritCare.2011;15:R117
• Randomizedtrialenrolling20,000women;completedenrollmentin2016
• Subjects:PPHamervaginalorC-secWondelivery• IntervenWon:1gI.V.TXAvs.placebo(2gTXAmaxdose)
• Primaryoutcome:maternaldeathorhysterectomy
• Endpoint:death,discharge,or42dayspost-intervenWon• Secondaryendpointsincludethromboemboliceventsinbothmotherandinfant Shakur,etal.Trials.2010;11:40
TXAinPPH:GuidelineRecommendaWons
1. Kozek-Langnecker,etal.EurJAnaesthesio.2013;30(6):270–3822. MavridesE,etal.BJOG.2016;124:e106-e149
3.WHOrecommendaWonsfortheprevenWonandtreatmentofpostpartumhemorrhage,20124.CollinsP,etal.JThrombHaemost.2015;14:205-210
OrganizaSon/Group RecommendaSonEuropeanSocietyofAnaesthesia(2013)1
AdministerTXAtoreducebloodloss,bleedingduraWon,andtransfusionrequirements(Grade1B)
RoyalCollegeofObstetriciansandGynaecologists(2016)2
ConsideraWonshouldbegiventotheuseofTXAinthemanagementofPPH(GradeB).
WHO(2012)3 Forrefractoryatonicandtrauma-relatedbleeding(weakrecommendaWon,moderateevidence)
ISTH(2015)4 SuggestthatwomenwithongoingPPHbeconsideredtoreceive1gTXA
Conclusions
• Fibrinogenlevels<2g/LareassociatedwithseverePPH
• UncertaintyregardingtherapeuWcfibrinogentargets;manyguidelinessuggesWngmaintainingfibrinogen>2g/L
• TranexamicacidrecommendedinmanyguidelinesforPPHmanagement;safetyandefficacytobedeterminedinlargeRCTs