Useofan)-thrombo)cdrugsinpregnancyandthepostpartum

MarcBlondonmarc.blondon@hcuge.ch

DivisionofAngiologyandHaemostasis

(Prof.MarcRighini&PierreFontana)

GenevaUniversityHospitals

Whichan)coagulantdrugsinpregnancy?Indica)ons(evidence-basedorhope-based)?U)lityofbiologicalmonitoring?Howtomanagean)thrombo)csbeforeandduringdelivery?Inwhomtoprescribepostpartumthromboprophylaxis?

Plan

An)-thrombo)cdrugsinpregnancy

28yoldhealthywoman23rdweekof1stpregnancy(80kg):•  chestpain&shortnessofbreath•  VQscan->lobarpulmonaryembolism

1.  Whichan)thrombo)ctoprescribe?2.  Monitoring?3.  Managementoftheperipartumperiod?

Clinicalcase

An)-thrombo)cdrugsinpregnancy

28yoldhealthywoman23rdweekof1stpregnancy(80kg):•  chestpain&shortnessofbreath•  VQscan->lobarpulmonaryembolism

1.  Whichan)thrombo)ctoprescribe?2.  Monitoring?3.  Managementoftheperipartumperiod?

Clinicalcase

An)-thrombo)cdrugsinpregnancyAn)coagulants&pregnancy

Heparins / Fondaparinux

1

2

34

Mostefficientan)coagulantdrugs(acenocoumarol,warfarin,phenprocoumone)duringpregnancyformechanicalvalves

ChanWS,ArchIntMed2000

An#-vitaminKduringpregnancy

0

5

10

15

20

25

30

Thromboemboliccomplica)ons

VKA

HeparinthenVKA

Heparin

ChanWS,ArchIntMed2000

An#-vitaminKduringpregnancy

An)coagula)oninmother&fetusTeratogeniceffectsin1/16(6-12w)RisksofbleedingatdeliveryBUTremainsanop)onforveryhighthrombo)crisk(mechanicalvalves)

DOACsduringpregnancy

DirectOralAn)coagulants:an)-Xa:rivaroxaban,apixaban,edoxabanan)-IIa:dabigatran

Animalstudiesshowingfetalandplacentaltoxicityabributedtoableedingtendency,at3-4)mesgreaterrivaroxabanconcentra)onsthanusual.

DOACsduringpregnancy

HoeltzenbeinM,ClinResCardiol2016BapatP,AmJObstetGynecol2015

VeryfewreportsofuseofDOACsinpregnantwomen•  Germancase-seriesof37pregnancies–1congenitalcardiacdefectinpolymorbidwomanwithmanymedica)ons

Fondaparinuxduringpregnancy

Synthe)cheparinwithspecifican)-Xaac)vityCrossestheplacentalbarrierlevels1:10infetus

Reportsof~30-40pregnancieswithfondaparinuxnowarningsignalsforhighbleedingorteratogenicriskveryfewdatain1sttrimester

DempfleCEH,NEJM2004ElsaighE,BJH2014

An)-thrombo)cdrugsinpregnancyAn)coagulants&pregnancy

Heparins / Fondaparinux

1

2

34

Heparins

Unfrac#onatedHeparin(UFH)

Low-molecular-weightheparin(LMWH)

Molecularweight[Da] 5000-30000 <9000

An)coagulanteffect Xa=IIa Xa>IIa

Dose-responserela)onship Highlyvariable Predictable

Monitoring Necessary•  aPTT•  an)-Xa(UFH)

Seldomnecessary•  An)-Xa(LMWH)

Elimina)on Hepa)c+re)culoendothelialsystem

Renal

Half-life 1-2h(dose-dependent) 4-6h

Plasmaproteinbinding High Low

Reversal Protamine(full) Protamine(par)al)

H.I.T/OsteoporosisRisk + (+)

Useinpregnancy OK OK

UFH/LMWHduringpregnancy

Meta-analysis:n=2777(94%prophylaxis)

GreerIA,Blood2005

UFH/LMWHduringpregnancy

Meta-analysis:n=981(100%therapeu)cdoses)Antenatalmajorbleeding 1.4%(95%CI0.6-2.4)Postnatalmajorbleeding 1.9%(95%CI0.8-3.6)VTErecurrence 2.0%(95%CI0.6-3.5)Heparininducedthrombocypenia 0%

RomualdiE,JTH2012

UFH/LMWHduringpregnancy

Consistantobserva)onalevidencesugges)ng:-  GoodefficiencyofLMWH(andUFH)-  GoodsecurityofLMWH(andUFH)

-  noteratogenicity-  acceptablebleedingrisk

Prophylac)cdoses

Unfrac)onatedheparin(ACOG)1sttrimester 5000-7500IU b.i.d.2ndtrimester 7500-10000IU b.i.d.3rdtrimester 10000IU b.i.d.

Subcutaneousinjec)ons:Ø  localskinallergiesØ  nodules

An)-thrombo)cdrugsinpregnancy

28yoldhealthywoman23rdweekof1stpregnancy(80kg):•  chestpain&shortnessofbreath•  VQscan->lobarpulmonaryembolism

1.  Whichan)thrombo)ctoprescribe?Enoxaparin80mg/kgb.i.d.(Clexane®)Nadroparin0.8ml=15’200IUo.d.(Fraxiforte®)

Clinicalcase

INDICATIONSFORHEPARININPREGNANTWOMEN

An)-thrombo)cdrugsinpregnancy

Long-terman)coagula)onü mechanicalcardiacvalvesü  atrialfibrilla)onü  recurrentvenousthromboembolism(VTE)ü  thrombo)can)phospholipidsyndrome(APS)

Pregnancy-relatedan)coagula)onü  treatmentofacuteVTEü preven)onofVTEü obstetricalan)phospholipidsyndromeü preven)onofpregnancycomplica)ons??

Indica)onsforan)coagula)oninpregnancy

LMWH–pregnancycomplica)ons

BatesSM,ACCPGuidelines,Chest2012

An)-thrombo)cdrugsinpregnancyLong-termtherapeu)can)coagula)on

Pre-pregnancy Pregnancy Post-partum

VKA*DOAC*

StopVKAorDOACSwitchtoLMWHenoxaparin(Clexane)biddalteparine(Fragmin)odnadroparine(Fraxiforte)odnadroparine(Fraxiparine)bid

VKALMWH?DOAC

VKADOAC

*todiscuss:switchtoacenocoumarol

An)-thrombo)cdrugsinpregnancyPregnancy-relatedan)coagula)on

Pre-pregnancy Pregnancy Post-partum

---

Preven)onofVTEstartprophylac)cLMWHObstetricalAPSstartprophylac)cLMWH+low-doseaspirinAcuteVTEstarttherapeu)cLMWH

LMWHLMWHaspirinLMWHVKA

stop?aspirin±stop

MONITORINGOFLMWHINPREGNANCY

Pharmacokine)csofLMWH-prophylac)c

ErikssonBI,ThrombHaemost1995

Healthysubjects

•  Clexane40mg(0.4ml)

•  Fragmin5000IU(0.2ml)

•  UFH5000IU

Pharmacokine)csofLMWH-therapeu)c

FrydmanAM,JClinPharmacol1988

Healthysubjects

•  Clexane20mg(0.2ml)

•  Clexane40mg(0.4ml)

•  Clexane60mg(0.6ml)

•  Clexane80mg(0.8ml)

Monitoringusuallyunnecessary

Predictablean)coagulanteffectwithweight-basedregimensClinicalstudies(VTE)withoutmonitoringPerhapsusefulinspecificpopula)ons:•  RenalFailure•  Extremeweights•  Pregnancy?

Pregnancy-specificmetabolism

é GFR(15thweek)é volumeofdistribu)on

prolongaRonofT1/2

PatelJP,CirculaRon2013

Supportstheuseofonce-dailyLMWHinpregnancyQues)onsthevalidityofincreasingLMWHdosetomaintainpeakan)-Xaac)vity

Antenatalmonitoring-recommanda)ons

BatesSM,ACCPguidelines,Chest2012

An)-thrombo)cdrugsinpregnancy

28yoldhealthywoman23rdweekof1stpregnancy(80kg):•  chestpain&shortnessofbreath•  VQscan->lobarpulmonaryembolism•  Fraxiforte®0.8ml

2.  Monitoring?Usuallynomonitoring.Adjustmentofdoseaccordingtoweightgain(?)

Clinicalcase

PERIPARTUMMANAGEMENT

Peripartummanagement

Toreducetheriskofathrombo)ccomplica)onü minimizethedura)onofnon-an)coagula)on

Toreducetheriskofanobstetricalbleedingcomplica)on

ü  minimizean)coagula)onduringlabour

Toreducetheriskofspinalhematomaü  avoidan)coagula)onatthe)meofneuraxial

anesthesia

Peripartummanagement

Needforindividualassessmentofthrombo)c/bleedingriskandwillingnessofaneuraxialanesthesia

low-grade(expert)basedevidence

Riskofperipartumthrombo)ccomplica)on

•  AxeracuteVTEinpregnancy:2%ofantenatalrecurrentVTEwithLMWH

•  HalfofVTErecurrencein1stweekoftreatment

•  Systema)creviewofpregnancy-relatedmassivePE:16%duringorwithin24hofdelivery

AbsoluteriskislowbutNOTif:

recentdiagnosisofacuteVTEsevereAPLmechanicalvalve

RiskofobstetricalbleedingwithLMWH

Meta-analysisoffull-doseLMWHSeverePostpartumHemorrhage2%(95%CI0.8-3.6,n=981)

Case-controlstudiesHigh-dosenadroparinvs.none:6.8%vs.4.6%(ns)LMWH(67%high-dose)vs.none:10.9%vs.8.2%(ns)

Obstetricalbleedingmainlyrelatedtoobstetricalcauses(placentalretenRon,uterineatony)

RomualdiE,JTH2013KnolHM,ThrombRes2012

KominiarekMA,JPerinat2007

Noclinicallyrelevantincreaseinriskofpost-partumhemorrhagewhenLMWHisstoppedatthestartofspontaneouslabourorbeforeinduc)onoflabour

Riskofspinalhematoma

Study2 Popula#on Nspinal/epidural

SpinalBlockade

EpiduralBlockade

MoenV(2004)

SwedishSurvey1990-1999

50’000/205’000 1:50’000 1:205’000

RuppenW(2006)

Systema)creview1966-2005 1’100’299 1:183’000

BatemanBT(2013)

USretrospec)veregistry1999-2010

79’837 0

RoseroEB(2016)

USadministra)veretrospec)vecohort1998-2010

2’320’950 1:155’000

Riskofspinalhematoma

«Contribu)ng»factors:•  Non-obstetricalse{ng•  Epidural>spinalanesthesia•  difficult/trauma)cplacement•  Coagula)ondefects•  An)coagulants•  Comorbidi)es•  Olderage•  Pregnancy:HELLP,thrombocytopenia

MoenV,Anesthesiology2004VandermeulenEP,AnesthAnalg1994

Presumedneedfornoan)coagulanteffectofheparinatthe)meofspinaltap/epiduralcatheterinser)onorremoval

Spinalhematoma&an)thrombo)cs

Spinalhematoma&an)thrombo)cs

Dose Placement/Removal HeparinaSerremoval

LMWH Prophylac)c 12haxerlastdose wait2(6-8)h

Therapeu)c 24haxerlastdose wait2(24)h

UFH Prophylac)c* beforenexts.c.injec)on

wait1h

Therapeu)c 2-4haxerstoppingiv wait1h

*notestablishedfor>10’000IU/day

Likelysafe–noreportofspinalhematomaassociatedwithanRthromboRctherapyinparRurents.

ASRArecommendaRons,2010

Spinalhematoma&an)thrombo)cs

amorecau)ousapproachNeuraxialanesthesiaifan)-Xa(HBPM)<0.1IU/ml*Prophylac)cLMWH(enoxaparin40mg):an)-Xaat12hofinjec)onaround37thweekadvisetowithholdfrominjec)oniflaborstartsnorecommendaRontoinducedeliveryTherapeu)cLMWH(enoxaparin1mg/kgb.i.d.)switchtob.i.d.dosingaround36thweekinsomecases:switchtoUFHi.v.priortodeliveryan)-Xabeforeneuraxialanesthesiaadvisetowithholdfrominjec)oniflaborstartsrecommendaRontoinducedelivery(~38thweek)*detectablethreshold OrRgueiraM,AnesthIntensCare2014

Spinalhematoma&aspirin

SmallprevalenceofNSAID/aspirinuseincase-seriesofspinalhematomaRetrospec)ve/prospec)vecohortsofneuraxialanesthesiawithaspirin

Obstetrics(2RCTPreven)onofpre-eclampsia) N=1873epiduralwithaspirin60mg Prevalence0%(95%CI0-0.2%)

VelaVasquezRS,BrJAnesth2015ButwickAJ,IntJObstetAnesth2010

Spinalhematoma&combinedan)thrombo)cs

Prophylac)cLMWH+low-doseaspirin(indica)on–APS)ASRAguidelines:NOneuraxialanesthesia

OKforcombina)onofLMWH+aspirinifan)-Xa<0.1

Peripartuminfluenceofan)thrombo)cs

BoilotT,GynecolObstetFerRl2015

203womenwithproph/therLMWH(cases)vs.812womenwithoutLMWHNoinfluenceonprevalenceofanesthesia(90%vs.90%)But–  éspinal(23%vs.2%)–  égeneralanesthesia(5%vs.1%)

Influenceonmodeofdelivery–  éprovoca)onoflabour(52%vs.21%)–  éelec)veCS(26%vs.1%)

An)-thrombo)cdrugsinpregnancy

28yoldhealthywoman23rdweekof1stpregnancy(80kg):•  chestpain&shortnessofbreath•  VQscan->lobarpulmonaryembolism•  Fraxiforte®0.8ml•  Nomonitoring,nodoseadjustment(90kg)

3.Managementofperipartum?36thweek–changetoClexane®80mgb.i.d.Proposeddeliveryat38thweek

Clinicalcase

Day-1Labour

Post-partum

StopClexane(lastdosethepriorday)MaternityWardAdmission(Switchtoi.v.UFH)(An)-Xamonitoringpriortoneuraxialanalgesia)NeuraxialanalgesiaInduc)onoflabourNoan)coagula)onduringlabour(inmost)DeliveryAbla)onofneuraxialcatheterStarti.v.UFHorLMWH4-6haxerdeliveryAn)coagula)onwithLMWHorVKAfor6weeks

Clinicalcase

POSTPARTUMPREVENTIONOFVENOUSTHROMBOEMBOLIM(VTE)

ChablozP,BJH2001MacklonNS,BJOG1997

0

500

1000

1500

2000

2500

3000

3500

4000

4500

10-14 15-19 20-24 25-29 30-34 35-39

Weeks

D-dimer(ng/ml)

p<0.005

p<0.005

n.s.

p<0.001

p<0.001

0

500

1000

1500

2000

2500

3000

3500

4000

4500

10-14 15-19 20-24 25-29 30-34 35-39

Weeks

10-14 15-19 20-24 25-29 30-34 35-39

Weeks

D-dimer(ng/ml)

p<0.005

p<0.005

n.s.

p<0.001

p<0.001

p<0.005

p<0.005

n.s.

p<0.001

p<0.001

p<0.005

p<0.005

n.s.

p<0.001

p<0.001

PostpartumVTE

1-4VTE/1000pregnancies80’000birthsperyear

à 150-300VTE(150postpartum)

PostpartumVTE

HighRisk

ModerateRisk

Lowrisk Earlymobiliza)on

Earlymobiliza)on+

short-termLMWH

Earlymobiliza)on+

LMWH6weeks

NoorfewminorRF

MajorRFCombina)onofminorRF

SevereRFCombina)onofmajorRF

RCOGguidelineNo.37a,2015BlondonM,CirculaRon2015

BlondonM,JThrombHaemost2015

BlackraceAsian-1

IUGR

① 28y,Vaginaldelivery40w.

② 23y,BMI31,emergencyCSat38w.

③ 34y,Blackrace,VagD30w.

④ 38y,IUGR,VagD39w,endometri)s.

⑤ 32y,Asianrace,elec)veCS.

Postpartumprophylaxis?

NO

YES

YES

YES(long)

NO

An)-thrombo)cdrugsinpregnancy

LMWH–mainlyVTEpreven)onandtreatment.EfficientandsafeNorecommendedmonitoringNeedtoan)cipateperipartummanagement

InterdisciplinarymanagementWomen’spreferences(analgesia)

PostpartumVTEprophylaxis–RCOGguidelines

Take-homemessages

Marc.blondon@hcuge.chDivisionofAngiology&Haemostasis(022)372.92.92SpecialthankstoFrançoiseBoehlen