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