妊娠的抗凝治疗

妊娠的抗凝治疗患者1:QW

主诉:

QW25岁女性机械性(双叶)二尖瓣

7周时至高危妊娠门诊就诊(2002.4):2021/5/192患者1:QW现病史：8年前行机械性二尖瓣置换术

术后一直口服香豆素类抗凝药物4年前有过一次成功的怀孕和生产在其第一次怀孕期间,从始至终一直服用香豆素抗凝

剖腹产前改为普通肝素2021/5/193患者1:QWPE示BP:100/60mmHg,HR80次/分妊娠8周是上述指标是合适的其他体检正常2021/5/194患者1:QW实验室检查:INR=2.2,其余正常超声心动图:心房扩大,双叶机械二尖瓣功能成常,LVEF=65%2021/5/195患者1:QW与患者讨论风险和获益停用香豆素类,开始LMW肝素治疗

注射后2,4,6,8小时监测抗Xa水平调整LMWH剂量

2021/5/196患者1:QW不幸的是,患者没有回来进行随访

2021/5/197患者1:QW患者在妊娠12周末因急性右侧瘫痪至急诊室就诊

头部MRI示栓塞性卒中Echo:机械瓣上血栓形成,机械瓣膜狭窄2021/5/198患者1:QW治疗经过:普通肝素开始滴注使用

复查超声心动图:机械性二尖瓣功能正常患者病情稳定但遗留有右侧肢体偏瘫和语言障碍2021/5/199患者1:QW治疗经过:近期成功的剖腹生产出一个健康男婴

患者因残余明显的右侧瘫痪和语言障碍进入护理病房进行康复治疗

患者的孩子由其祖父母照看2021/5/1910妊娠时的血流动力学改变2021/5/1911血流动力学改变变化百分比妊娠时间（周）血浆容积RBC容积红细胞比积2021/5/1912心输出量每搏输出量心率血流动力学改变妊娠时间（周）变化百分比2021/5/1913妊娠期抗凝治疗妊娠:高凝状态 各种凝血因子水平增加增加血液粘滞度现有的资料尚不足以形成明确的意见和建议没有随机临床试验2021/5/1914怀孕期间常见的疾病机械性心脏瓣膜静脉血栓形成(VTE)

在怀孕期间或在怀孕前不久房颤严重的心衰有症状的抗磷脂抗体综合征Eisenmenger综合征2021/5/1915目标维持有效的抗凝治疗避免伤害母亲和胎儿

大多都是回顾性资料难以在孕妇中进行大规模前瞻性试验2021/5/1916抗凝药物常用药物:华法令普通肝素

低分子肝素LMWH2021/5/1917华法令与VITk依赖的凝血因子相互作用如：II,VII,IX,X及蛋白C和S36－72小时产生抗凝作用最大抗凝作用需5天2021/5/1918妊娠D类药物:能自由通过胎盘屏障，对胎儿产生不良影响对母乳喂养的胎儿无抗凝作用 华法令2021/5/1919致畸作用:

在孕期6-12周服用华法令(高达25-30%)骨和软骨鼻子和肢体发育不良(扁平鼻)CNS异常报道较少在妊娠任何时期使用华法令胎儿或新生儿出血绝大多数发生在生产或产后即刻华法令2021/5/1920华法令一般估计所有的出血风险在5－7％

可能高达25-30%可能独立于INR可能具有长期的效果(不确定)2021/5/1921华法令妊娠前期:应停用华法令

孕期34－36周后剖腹产VitK并不立即起作用，新鲜冰冻血浆起效更快

母亲的皮下肝素应不迟于产后6小时开始使用

可母乳喂养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续注入2021/5/1923普通肝素孕期C类药物:不会突破胎盘屏障不危害胎儿

2021/5/1924普通肝素长时间使用可能有害

难以维持稳定的水平静脉使用不方便肝素诱导的血小板减少症肝素诱导的骨脱矿物质通常在使用7周以上2021/5/1925高剂量的肝素对于孕期血栓的预防和治疗都是必要的增加肝素结合蛋白和（肝素？）血浆的容量普通肝素2021/5/1926低分子肝素

(LMWH)FDA孕期B类药物LMWH:较普通肝素出血率低;不太可能导致肝素相关性血小板减少症

2021/5/1927低分子肝素

(LMWH)方便皮下注射半衰期长,每天1-2次固定剂量给药可以进行实验室监测注射4小时后抗Xa因子水平增加

LMWH逐渐达到抗Xa因子峰浓度水平

2021/5/1928LMWH:不同情况下的应用

静脉血栓(VTE):

ACOG推荐:在孕妇中,LMWH安全有效

2021/5/1929机械心脏瓣膜:无一致的意见:可能比肝素和华法令差

不推荐FDA:AmericanCollegeofObstetriciansandGynecologistsTheEuropeanSocietyofCardiology.AmericanCollegeofChestPhysicians推荐作为一种选择使用:TheAmericanCollegeofChestPhysiciansLMWH:不同情况下的应用2021/5/1930FDA:2002年7月，关于伊诺肝素的警示

“不推荐用于伴有人工瓣膜孕妇的血栓预防治疗

LMWH:不同情况下的应用2021/5/1931随孕期调整药物剂量体重增加至抗X因子活性峰浓度时间随孕期不同而异

注射后起效较晚低分子肝素

(LMWH)2021/5/1932ACCP:3策略普通肝素

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

普通肝素

II

前3月 第二个3个月 第3个3个月

生产2021/5/1934临床抗凝策略策略B:

LMWH

II

前3月 第2个3个月 第3个3个月

生产2021/5/1935临床抗凝策略策略C:

LMWHorUH 华法令LMWHorUH

II

前3月 第二个3个月

第3个3个月

生产2021/5/1936机械瓣膜合并妊娠二尖瓣部位旧的机械瓣膜主动脉瓣部位新的机械瓣膜aPTT:2.5-3.0xINR:3-4.5抗Xa因子:0.35-0.7U/ml(注射后4小时)aPTT:2.0-3.0xINR:2-3抗Xa因子:0.35-0.7U/ml

(注射后4小时)2021/5/1937常规推荐不管采取什么治疗，长期的抗凝治疗在产后应重新开始肝素应重新开始使用:剖腹产后12小时经阴道生产后6小时华法令可以重新开始2021/5/1938从QW的教训中获得的经验

高危患者:二尖瓣机械瓣膜

高危时期:6-12周主诉:QW25岁女性机械性2叶二尖瓣怀孕7周时至高危妊娠门诊就诊(2000.4)2021/5/1939不要再犯傻啦,她上次没出问题是走运现病史8年前行机械瓣膜置换.术后行香豆素类抗凝治疗4年前有过一次成功的妊娠和分娩第一次妊娠时从头至尾服用香豆素类在剖腹产前改为普通肝素从QW的教训中获得的经验

2021/5/1940PE示BP:100/60mmHg,HR80次/分对于妊娠8周来说上述指标是合适的其他的体检正常从QW的教训中获得的经验

2021/5/1941实验室检查:除INR=2.2外，其余正常Echo:左房扩大，双叶机械性二尖瓣功能正常，LVEF=65%从QW的教训中获得的经验

2021/5/1942和患者讨论可能的风险和获益停止香豆素类,开始使用LMWH注射后2,4,6,8小时监测抗Xa水平调整LMWH剂量她在门诊呆了一天从QW的教训中获得的经验

2021/5/1943不幸的是，患者没有回来进行随访我们给她打电话并留下信息,随访极端重要从QW的教训中获得的经验2021/5/1944她又赌博了，但这次她输了患者在妊娠12周末因突发右侧瘫痪至急诊室就诊

头部MRI提示栓塞性卒中Echo:二尖瓣机械瓣血栓,机械瓣狭窄从QW的教训中获得的经验2021/5/1945治疗经过:开始肝素治疗并滴注肝素复查echo:机械性二尖瓣膜功能正常患者病情稳定，但遗留了明显的左侧瘫痪和语言障碍从QW的教训中获得的经验2021/5/1946治疗经过:近期成功的进行了剖腹产生下一个健康的男婴患者遗留了明显的右侧瘫痪和语言障碍，进入护理病房进行康复治疗她的孩子由孩子的祖父母照看

从QW的教训中获得的经验2021/5/1947应牢记:植入机械瓣膜的年轻女性患者，与其进行严肃的讨论并对其进行相关的健康教育是必要的

从QW的教训中获得的经验2021/5/1948应牢记:怀孕是一场赌博拿自己的生命

拿孩子的健康

从QW的教训中获得的经验2021/5/1949应深刻理解并牢记:认真的高标准的临床随访是绝对必要的和患者讨论血液监测的时间表电话随访从QW的教训中获得的经验2021/5/1950如果单身，不要结婚

如果有生育能力，不要怀孕

如果怀孕,不要生产

如果生产，不能哺乳伴有机械瓣膜的年轻女性21世纪合并有心脏病的妇女的产科格言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