妊娠的抗凝治療

妊娠的抗凝治療患者1:QW

主訴:

QW25歲女性機(jī)械性(雙葉)二尖瓣

7周時(shí)至高危妊娠門診就診(2002.4):2021/5/192患者1:QW現(xiàn)病史：8年前行機(jī)械性二尖瓣置換術(shù)

術(shù)后一直口服香豆素類抗凝藥物4年前有過一次成功的懷孕和生產(chǎn)在其第一次懷孕期間,從始至終一直服用香豆素抗凝

剖腹產(chǎn)前改為普通肝素2021/5/193患者1:QWPE示BP:100/60mmHg,HR80次/分妊娠8周是上述指標(biāo)是合適的其他體檢正常2021/5/194患者1:QW實(shí)驗(yàn)室檢查:INR=2.2,其余正常超聲心動(dòng)圖:心房擴(kuò)大,雙葉機(jī)械二尖瓣功能成常,LVEF=65%2021/5/195患者1:QW與患者討論風(fēng)險(xiǎn)和獲益停用香豆素類,開始LMW肝素治療

注射后2,4,6,8小時(shí)監(jiān)測(cè)抗Xa水平調(diào)整LMWH劑量

2021/5/196患者1:QW不幸的是,患者沒有回來進(jìn)行隨訪

2021/5/197患者1:QW患者在妊娠12周末因急性右側(cè)癱瘓至急診室就診

頭部MRI示栓塞性卒中Echo:機(jī)械瓣上血栓形成,機(jī)械瓣膜狹窄2021/5/198患者1:QW治療經(jīng)過:普通肝素開始滴注使用

復(fù)查超聲心動(dòng)圖:機(jī)械性二尖瓣功能正?；颊卟∏榉€(wěn)定但遺留有右側(cè)肢體偏癱和語言障礙2021/5/199患者1:QW治療經(jīng)過:近期成功的剖腹生產(chǎn)出一個(gè)健康男嬰

患者因殘余明顯的右側(cè)癱瘓和語言障礙進(jìn)入護(hù)理病房進(jìn)行康復(fù)治療

患者的孩子由其祖父母照看2021/5/1910妊娠時(shí)的血流動(dòng)力學(xué)改變2021/5/1911血流動(dòng)力學(xué)改變變化百分比妊娠時(shí)間（周）血漿容積RBC容積紅細(xì)胞比積2021/5/1912心輸出量每搏輸出量心率血流動(dòng)力學(xué)改變?nèi)焉飼r(shí)間（周）變化百分比2021/5/1913妊娠期抗凝治療妊娠:高凝狀態(tài) 各種凝血因子水平增加增加血液粘滯度現(xiàn)有的資料尚不足以形成明確的意見和建議沒有隨機(jī)臨床試驗(yàn)2021/5/1914懷孕期間常見的疾病機(jī)械性心臟瓣膜靜脈血栓形成(VTE)

在懷孕期間或在懷孕前不久房顫嚴(yán)重的心衰有癥狀的抗磷脂抗體綜合征Eisenmenger綜合征2021/5/1915目標(biāo)維持有效的抗凝治療避免傷害母親和胎兒

大多都是回顧性資料難以在孕婦中進(jìn)行大規(guī)模前瞻性試驗(yàn)2021/5/1916抗凝藥物常用藥物:華法令普通肝素

低分子肝素LMWH2021/5/1917華法令與VITk依賴的凝血因子相互作用如：II,VII,IX,X及蛋白C和S36－72小時(shí)產(chǎn)生抗凝作用最大抗凝作用需5天2021/5/1918妊娠D類藥物:能自由通過胎盤屏障，對(duì)胎兒產(chǎn)生不良影響對(duì)母乳喂養(yǎng)的胎兒無抗凝作用 華法令2021/5/1919致畸作用:

在孕期6-12周服用華法令(高達(dá)25-30%)骨和軟骨鼻子和肢體發(fā)育不良(扁平鼻)CNS異常報(bào)道較少在妊娠任何時(shí)期使用華法令胎兒或新生兒出血絕大多數(shù)發(fā)生在生產(chǎn)或產(chǎn)后即刻華法令2021/5/1920華法令一般估計(jì)所有的出血風(fēng)險(xiǎn)在5－7％

可能高達(dá)25-30%可能獨(dú)立于INR可能具有長(zhǎng)期的效果(不確定)2021/5/1921華法令妊娠前期:應(yīng)停用華法令

孕期34－36周后剖腹產(chǎn)VitK并不立即起作用，新鮮冰凍血漿起效更快

母親的皮下肝素應(yīng)不遲于產(chǎn)后6小時(shí)開始使用

可母乳喂養(yǎng)2021/5/1922普通肝素主要作用于Xa因子也作用于XIIa，XIa和IXa因子起效快,停止作用也快需要持續(xù)注入2021/5/1923普通肝素孕期C類藥物:不會(huì)突破胎盤屏障不危害胎兒

2021/5/1924普通肝素長(zhǎng)時(shí)間使用可能有害

難以維持穩(wěn)定的水平靜脈使用不方便肝素誘導(dǎo)的血小板減少癥肝素誘導(dǎo)的骨脫礦物質(zhì)通常在使用7周以上2021/5/1925高劑量的肝素對(duì)于孕期血栓的預(yù)防和治療都是必要的增加肝素結(jié)合蛋白和（肝素？）血漿的容量普通肝素2021/5/1926低分子肝素

(LMWH)FDA孕期B類藥物L(fēng)MWH:較普通肝素出血率低;不太可能導(dǎo)致肝素相關(guān)性血小板減少癥

2021/5/1927低分子肝素

(LMWH)方便皮下注射半衰期長(zhǎng),每天1-2次固定劑量給藥可以進(jìn)行實(shí)驗(yàn)室監(jiān)測(cè)注射4小時(shí)后抗Xa因子水平增加

LMWH逐漸達(dá)到抗Xa因子峰濃度水平

2021/5/1928LMWH:不同情況下的應(yīng)用

靜脈血栓(VTE):

ACOG推薦:在孕婦中,LMWH安全有效

2021/5/1929機(jī)械心臟瓣膜:無一致的意見:可能比肝素和華法令差

不推薦FDA:AmericanCollegeofObstetriciansandGynecologistsTheEuropeanSocietyofCardiology.AmericanCollegeofChestPhysicians推薦作為一種選擇使用:TheAmericanCollegeofChestPhysiciansLMWH:不同情況下的應(yīng)用2021/5/1930FDA:2002年7月，關(guān)于伊諾肝素的警示

“不推薦用于伴有人工瓣膜孕婦的血栓預(yù)防治療

LMWH:不同情況下的應(yīng)用2021/5/1931隨孕期調(diào)整藥物劑量體重增加至抗X因子活性峰濃度時(shí)間隨孕期不同而異

注射后起效較晚低分子肝素

(LMWH)2021/5/1932ACCP:3策略普通肝素

LMWHUHorLMWH+Warfarin+UH+LMWH臨床抗凝策略2021/5/1933臨床抗凝策略策略A:

普通肝素

II

前3月 第二個(gè)3個(gè)月 第3個(gè)3個(gè)月

生產(chǎn)2021/5/1934臨床抗凝策略策略B:

LMWH

II

前3月 第2個(gè)3個(gè)月 第3個(gè)3個(gè)月

生產(chǎn)2021/5/1935臨床抗凝策略策略C:

LMWHorUH 華法令LMWHorUH

II

前3月 第二個(gè)3個(gè)月

第3個(gè)3個(gè)月

生產(chǎn)2021/5/1936機(jī)械瓣膜合并妊娠二尖瓣部位舊的機(jī)械瓣膜主動(dòng)脈瓣部位新的機(jī)械瓣膜aPTT:2.5-3.0xINR:3-4.5抗Xa因子:0.35-0.7U/ml(注射后4小時(shí))aPTT:2.0-3.0xINR:2-3抗Xa因子:0.35-0.7U/ml

(注射后4小時(shí))2021/5/1937常規(guī)推薦不管采取什么治療，長(zhǎng)期的抗凝治療在產(chǎn)后應(yīng)重新開始肝素應(yīng)重新開始使用:剖腹產(chǎn)后12小時(shí)經(jīng)陰道生產(chǎn)后6小時(shí)華法令可以重新開始2021/5/1938從QW的教訓(xùn)中獲得的經(jīng)驗(yàn)

高?；颊?二尖瓣機(jī)械瓣膜

高危時(shí)期:6-12周主訴:QW25歲女性機(jī)械性2葉二尖瓣懷孕7周時(shí)至高危妊娠門診就診(2000.4)2021/5/1939不要再犯傻啦,她上次沒出問題是走運(yùn)現(xiàn)病史8年前行機(jī)械瓣膜置換.術(shù)后行香豆素類抗凝治療4年前有過一次成功的妊娠和分娩第一次妊娠時(shí)從頭至尾服用香豆素類在剖腹產(chǎn)前改為普通肝素從QW的教訓(xùn)中獲得的經(jīng)驗(yàn)

2021/5/1940PE示BP:100/60mmHg,HR80次/分對(duì)于妊娠8周來說上述指標(biāo)是合適的其他的體檢正常從QW的教訓(xùn)中獲得的經(jīng)驗(yàn)

2021/5/1941實(shí)驗(yàn)室檢查:除INR=2.2外，其余正常Echo:左房擴(kuò)大，雙葉機(jī)械性二尖瓣功能正常，LVEF=65%從QW的教訓(xùn)中獲得的經(jīng)驗(yàn)

2021/5/1942和患者討論可能的風(fēng)險(xiǎn)和獲益停止香豆素類,開始使用LMWH注射后2,4,6,8小時(shí)監(jiān)測(cè)抗Xa水平調(diào)整LMWH劑量她在門診呆了一天從QW的教訓(xùn)中獲得的經(jīng)驗(yàn)

2021/5/1943不幸的是，患者沒有回來進(jìn)行隨訪我們給她打電話并留下信息,隨訪極端重要從QW的教訓(xùn)中獲得的經(jīng)驗(yàn)2021/5/1944她又賭博了，但這次她輸了患者在妊娠12周末因突發(fā)右側(cè)癱瘓至急診室就診

頭部MRI提示栓塞性卒中Echo:二尖瓣機(jī)械瓣血栓,機(jī)械瓣狹窄從QW的教訓(xùn)中獲得的經(jīng)驗(yàn)2021/5/1945治療經(jīng)過:開始肝素治療并滴注肝素復(fù)查echo:機(jī)械性二尖瓣膜功能正常患者病情穩(wěn)定，但遺留了明顯的左側(cè)癱瘓和語言障礙從QW的教訓(xùn)中獲得的經(jīng)驗(yàn)2021/5/1946治療經(jīng)過:近期成功的進(jìn)行了剖腹產(chǎn)生下一個(gè)健康的男嬰患者遺留了明顯的右側(cè)癱瘓和語言障礙，進(jìn)入護(hù)理病房進(jìn)行康復(fù)治療她的孩子由孩子的祖父母照看

從QW的教訓(xùn)中獲得的經(jīng)驗(yàn)2021/5/1947應(yīng)牢記:植入機(jī)械瓣膜的年輕女性患者，與其進(jìn)行嚴(yán)肅的討論并對(duì)其進(jìn)行相關(guān)的健康教育是必要的

從QW的教訓(xùn)中獲得的經(jīng)驗(yàn)2021/5/1948應(yīng)牢記:懷孕是一場(chǎng)賭博拿自己的生命

拿孩子的健康

從QW的教訓(xùn)中獲得的經(jīng)驗(yàn)2021/5/1949應(yīng)深刻理解并牢記:認(rèn)真的高標(biāo)準(zhǔn)的臨床隨訪是絕對(duì)必要的和患者討論血液監(jiān)測(cè)的時(shí)間表電話隨訪從QW的教訓(xùn)中獲得的經(jīng)驗(yàn)2021/5/1950如果單身，不要結(jié)婚

如果有生育能力，不要懷孕

如果懷孕,不要生產(chǎn)

如果生產(chǎn)，不能哺乳伴有機(jī)械瓣膜的年輕女性21世紀(jì)合并有心臟病的婦女的產(chǎn)科格言2021/5/19512021/5/1952AnticoagulationinpregnancyDaliFan

MDPhDFACCFASE2021/5/1953Patient#1:QWCC(ChiefComplaint):

QWisan25year-oldwomanMechanical(bi-leaflet)mitralvalve7weeksofpregnancypresentedatthehighriskpregnancyclinicforconsult(April2002):2021/5/1954Patient#1:QWHPI(HistoryofPresentIllness):Mechanicalmitralvalvereplacement8yearsago.OncoumadinsinceHadonesuccessfulpregnancyanddelivery4yearsagoHadbeenoncoumadinthroughoutherfirstpregnancyuntiltheendSwitchedtounfractionatedheparinbeforeC-section2021/5/1955Patient#1:QWPE(PhysicalExam):BP:100/60mmHg,HR80sAppropriatefor8weekspregnancyTherestofthephysicalexamisnormal2021/5/1956Patient#1:QWLaboratorytests:NormalexceptINR=2.2Echocardiogram:Dilatedleftatrium,normalfunctioningbi-leafletmechanicalmitralvalve,LVEF=65%2021/5/1957Patient#1:QWRiskandbenefitdiscussedwiththepatientCoumadinwasstopped,LMWheparinstartedPostinjectionAnti-Xalevelmonitoredat2,4,6,8hoursLMWheparindosewasadjusted2021/5/1958Patient#1:QWUnfortunately,patientdidnotcomebacktoclinicforfollow-up2021/5/1959Patient#1:QWPatientpresentedtotheERforacuteonsetofleft-sidedparalysisattheendofthe12thweek.HeadMRIsuggestembolicstrokeEcho:thrombusonthemechanicalmitralvalve,mechanicalmitralstenosis2021/5/1960Patient#1:QWTreatment:Un-fractionatedheparinstartedandtitratedRepeatechocardiogram:mechanicalmitralfunctionnormalizedPatientstabilizedbutremainwithsignificantright-sidedparalysisanddysphasia2021/5/1961Patient#1:QWTreatment:Successfullyc-sectionforahealthyboyatnear-termPatientwenttonursinghomeforrehabilitationwithsignificantresidueright-sidedparalysisanddysphasiaHerchildrenweretakencareofbythegrandparents.2021/5/1962HemodynamicChangesinPregnancy2021/5/1963HemodynamicChangesPercentChangePregnancyWeeksPlasmaVolumeRBCVolumeHematocrit2021/5/1964HemodynamicChangesPercentChangePregnancyWeeksCardiacOutputStrokeVolumeHeartRate2021/5/1965AnticoagulationDuringPregnancyPregnancy:astateofhypercoagulability IncreasedlevelsofvariousclottingfactorsIncreasedbloodviscosity.InsufficientdatafordefinitiverecommendationsNorandomizedclinicaltrials2021/5/1966CommonDiseasesduringPregnancyInvolvedMechanicalheartvalvesVenousthromboembolism(VTE)immediatelypriortoorduringpregnancyAtrialfibrillationSevereheartfailureSymptomaticantiphospholipidantibodysyndrome.Eisenmengersyndrome2021/5/1967GoalsTomaintaintherapeuticanticoagulationToavoidingmaternalorfetalharmretrospectivedatamostlylargeprospectivetrialsamongpregnantwomendifficulttoconduct.2021/5/1968AnticoagulantsCommonDrugs:WarfarinUnfractionatedheparin(UFH)Low-molecular-weightheparin(LMWH)2021/5/1969WarfrinInterferencewiththevitaminKdependentcoagulationfactorsII,VII,IX,andX,andproteinsCandSTheeffectisdelayedfor36to72hoursFulleffecttakesfivedays2021/5/1970WarfrinPregnancycategoryDdrug:

FreelycrossestheplacentalbarrierandcanharmthefetusNoanticoagulanteffectonthebreast-fedinfants

2021/5/1971WarfrinTeratogeniceffects:Takenbetween6th-12thweeksofgestation(ashighas25-30%)BoneandcartilageNasalandlimbhypoplasia(flatnose)Centralnervoussystem(CNS)abnormalitiesislesswell-documentedwarfarinuseatanystageduringpregnancyFetalorneonatalhemorrhageGreatestduringandimmediatelyafterdelivery2021/5/1972WarfrinBestoverallestimateoftheriskisapproximately5to7percent.Canbeashighas25-30%MaybeindependentoftheINRMayhavelongtermeffect(uncertain)2021/5/1973WarfrinPre-term:Warfarinshouldbediscontinuedafter34to36weeksofgestationcesareandeliveryVitaminKdoesnotworkimmediately.FreshfrozenplasmaworksquickerMaternalsubcutaneousheparingenerallyshouldberesumednolaterthan6hoursBreastfeedingisOK2021/5/1974UnfractionatedheparinMostlyonfactorXa,alsoonfactorsXIIa,XIa,andIXaWorksquickly,stopsworkingquicklyRequirecontinuousinfusion2021/5/1975UnfractionatedheparinPregnancycategoryCdrug:DoesNOTcrossestheplacentalbarrierDoesNOTharmthefetus2021/5/1976UnfractionatedheparinProlongedusecanbeharmful:DifficultyofmaintainingastablelevelInconvenienceofIVadministrationHeparin-inducedthrombocytopeniaHeparin-inducedbonedemineralizationUsuallymorethansevenweeksofuse2021/5/1977UnfractionatedheparinHigherdosesofheparinarenecessaryforpregnantwomenforbothprophylaxisandtherapy.Increasedinheparin-bindingproteinsandplasmavolume2021/5/1978Low-molecular-weightheparin

(LMWheparin)FDAinpregnancycategoryBLMWheparin:lessbleedingthanwithunfractionatedheparin;Lesslikelytoprecipitateheparin-associatedthrombocytopenia

2021/5/1979Low-molecular-weightheparin

(LMWheparin)Convenient,SubcutaneousinjectionLongerhalf-life.FixeddosesonceortwicedailyLaboratorymonitoringcanbeperformedAnti-factorXalevels4hoursafterinjectionLMWheparinistitratedforpeakanti-Xalevel.2021/5/1980LMWheparin:differentsituationsVenousthromboembolism(VTE):AmericanCollegeofObstetriciansandGynecologists(ACOG)recommendation:LMWHissafeandeffectivetopreventortreatVTEinpregnancy.2021/5/1981LMWheparin:differentsituationsMechanicalheartvalves:Concerning,conflictingrecommendation:MaybeworsethanheparinandwarfarinNotrecommendedFDA:AmericanCollegeofObstetriciansandGynecologistsTheEuropeanSocietyofCardiology.AmericanCollegeofChestPhysiciansRecommendedtouseasanoption:TheAmericanCollegeofChestPhysicians2021/5/1982LMWheparin:differentsituationsFDA:InJuly2002,awarningforenoxaparin:“notrecommendedforthromboprophylaxisinpregnantwomenwithprostheticheartvalves”2021/5/1983NeeddoseadjustmentsasthepregnancycontinuesWeightgainTimingofpeakanti-XactivitylevelsduringpregnancyvaryOccurredlaterafterinjectionLow-molecular-weightheparin

(LMWheparin)2021/5/1984ACCP(AmericanCollegeofChestPhysicians:3StrategiesUH(Un-fractionatedHeparin)LMWH(LowMolecularWeightHeparin)UHorLMWH+Warfarin+UH+LMWHPracticalAnticoagulationStrategies2021/5/1985PracticalAnticoagulationStrategiesStrategyA:

UnfractionatedHeparin

II

1stTrimester 2ndTrimester 3rdTrimester

Delivery2021/5/1986PracticalAnticoagulationStrategiesStrategyB:

LowMolecularWeightHeparin

II

1stTrimester 2ndTrimester 3rdTrimester

Delivery2021/5/1987PracticalAnticoagulationStrategiesStrategyC:

LMWHorUH WarfarinLMWHorUH

II

1stTrimester 2ndTrimester 3rdTrimester

Delivery2021/5/1988PregnancywithMechanicalValveMitralpositionOlderMechanicalValveAorticpositionNewerMechanicalValveaPTT:2.5-3.0xINR:3-4.5Anti-Xa:0.35-0.7U/ml

(4hoursafterinjection)aPTT:2.0-3.0xINR:2-3Anti-Xa:0.35-0.7U/ml

(4hoursafterinjection)2021/5/1989GeneralrecommendationsLong-termanticoagulationshouldberesumedpostpartumregardlessofwhichregimenisused.Heparincanberestarted:12hourspost-cesareandelivery6hourspost-vaginalbirthWarfarincanrestart2021/5/1990PatientQW–LesionLearnedHighriskpatient:(mitralmechanical)

Highriskperiod:6-12weeksCC(ChiefComplaint):QWisan25year-oldwomanMechanical(bi-leaflet)mitralvalve7weeksofpregnancypresentedatthehighriskpregnancyclinicforconsult(April2002):2021/5/1991Donotbefooled,shetookachancelasttime.PatientQW–LesionLearnedHPI(HistoryofPresentIllness):Mechanicalmitralvalvereplacement8yearsago.OncoumadinsinceHadonesuccessfulpregnancyanddelivery4yearsagoHadbeenoncoumadinthroughoutherfirstpregnancyuntiltheendSwitchedtounfractionatedheparinbeforeC-section2021/5/1992PatientQW–LesionLearnedPE(PhysicalExam):BP:100/60mmHg,HR80sAppropriatefor8weekspregnancyTherestofthephysicalexamisnormal2021/5/1993PatientQW–LesionLearnedLaboratorytests:NormalexceptINR=2.2Echocardiogram:Dilatedleftatrium,normalfunctioningbi-leafletmechanicalmitralvalve,LVEF=65%2021/5/1994RiskandbenefitdiscussedwiththepatientCoumadinwasstopped,LMWheparinstartedPostinjectionAnti-Xalevelmonitoredat2,4,6,8hoursLMWheparindosewasadjustedShespentthewholedayintheclinicPatientQW–LesionLearned2021/5/1995Unfortunately,patientdidnotcomebacktoclinicforfollow-upCallher,wedidandleftmessages,follow-upiscriticallyimportantPatientQW–LesionLearned2021/5/1996Shegambledagain,thistimeshelostPatientQW–LesionLearnedP