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1、妊娠的抗凝治疗,Dali Fan MD PhD FACC FASE,患者1: QW,主诉: QW 25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):,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,患者1: QW,PE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,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%,患者1: QW,与患者
2、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,患者1: QW,不幸的是,患者没有回来进行随访,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,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,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,妊娠时的血流动力学改变,血流动力学改变,变化百
3、分比,妊娠时间（周）,血浆容积,RBC 容积,红细胞比积,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,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,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,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,抗凝药物,常用药物:华法令普通肝素 低分子肝素LMWH,华法令,与VITk依赖的凝血因子相互作用如
4、：II,VII, IX,X及蛋白C和S3672小时产生抗凝作用 最大抗凝作用需5天,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,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,华法令,一般估计所有的出血风险在57 可能高达25-30%可能独立于INR可能具有长期的效果(不确定),华法令,妊娠前期:应停用华法令 孕期3436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
5、小时开始使用 可母乳喂养,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,普通肝素,孕期C类药物: 不会突破胎盘屏障 不危害胎儿,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,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,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,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
6、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,LMWH: 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,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:American College of Obstetricians and Gynecologists The European Society of Cardiology.American College of Chest Physicians推荐作为一种选择使用:The American College of Chest Physicians,LMWH:
7、不同情况下的应用,FDA: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,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),ACCP :3 策略普通肝素 LMWH UH or LMWH + Warfarin + UH + LMWH,临床抗凝策略,临床抗凝策略,策略 A:,临床抗凝策略,策略 B:,临床抗凝策略,策略 C:,LMWH or UH 华法令 LMWH or UHI I 前3月 第二个3个月 第3个3个月,生产,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
8、 新的机械瓣膜,aPTT: 2.5-3.0 x INR: 3-4.5抗Xa因子: 0.35-0.7 U/ml (注射后4小时),aPTT: 2.0-3.0 x INR: 2-3抗Xa因子: 0.35-0.7 U/ml (注射后4小时),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,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: QW 25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),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
9、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,PE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,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,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,不幸的是，患者没有回来进行随访,我
10、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,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,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,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,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
11、关的健康教育是必要的,从QW的教训中获得的经验,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,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,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,Anticoagulation in pregnancy,Dali Fan MD PhD FACC FASE,Patient #1: QW,CC (Chief Complaint): QW is an 25 ye
12、ar-old woman Mechanical (bi-leaflet) mitral valve 7 weeks of pregnancy presented at the high risk pregnancy clinic for consult (April 2002):,Patient #1: QW,HPI (History of Present Illness):Mechanical mitral valve replacement 8 years ago. On coumadin sinceHad one successful pregnancy and delivery 4 y
13、ears agoHad been on coumadin throughout her first pregnancy until the endSwitched to unfractionated heparin before C-section,Patient #1: QW,PE (Physical Exam): BP: 100/60 mmHg, HR 80sAppropriate for 8 weeks pregnancyThe rest of the physical exam is normal,Patient #1: QW,Laboratory tests: Normal exce
14、pt INR = 2.2Echocardiogram: Dilated left atrium, normal functioning bi-leaflet mechanical mitral valve, LVEF = 65%,Patient #1: QW,Risk and benefit discussed with the patientCoumadin was stopped, LMW heparin startedPost injection Anti-Xa level monitored at 2, 4, 6, 8 hoursLMW heparin dose was adjuste
15、d,Patient #1: QW,Unfortunately, patient did not come back to clinic for follow-up,Patient #1: QW,Patient presented to the ER for acute onset of left-sided paralysis at the end of the 12th week.Head MRI suggest embolic strokeEcho: thrombus on the mechanical mitral valve, mechanical mitral stenosis,Pa
16、tient #1: QW,Treatment:Un-fractionated heparin started and titratedRepeat echocardiogram: mechanical mitral function normalizedPatient stabilized but remain with significant right-sided paralysis and dysphasia,Patient #1: QW,Treatment:Successfully c-section for a healthy boy at near-termPatient went
17、 to nursing home for rehabilitation with significant residue right-sided paralysis and dysphasiaHer children were taken care of by the grand parents.,Hemodynamic Changes in Pregnancy,Hemodynamic Changes,Percent Change,Pregnancy Weeks,Plasma Volume,RBC Volume,Hematocrit,Hemodynamic Changes,Percent Ch
18、ange,Pregnancy Weeks,Cardiac Output,Stroke Volume,Heart Rate,Anticoagulation During Pregnancy,Pregnancy: a state of hypercoagulability Increased levels of various clotting factors Increased blood viscosity. Insufficient data for definitive recommendationsNo randomized clinical trials,Common Diseases
19、 during Pregnancy Involved,Mechanical heart valvesVenous thromboembolism (VTE) immediately prior to or during pregnancyAtrial fibrillationSevere heart failureSymptomatic antiphospholipid antibody syndrome.Eisenmenger syndrome,Goals,To maintain therapeutic anticoagulationTo avoiding maternal or fetal
20、 harm retrospective data mostlylarge prospective trials among pregnant women difficult to conduct.,Anticoagulants,Common Drugs:WarfarinUnfractionated heparin (UFH)Low-molecular-weight heparin (LMWH),Warfrin,Interference with the vitamin K dependent coagulation factorsII, VII, IX, and X, and proteins
21、 C and SThe effect is delayed for 36 to 72 hoursFull effect takes five days,Warfrin,Pregnancy category D drug: Freely crosses the placental barrier and can harm the fetus No anticoagulant effect on the breast-fed infants,Warfrin,Teratogenic effects: Taken between 6th-12th weeks of gestation (as high
22、 as 25-30%)Bone and cartilageNasal and limb hypoplasia (flat nose)Central nervous system (CNS) abnormalities is less well-documented warfarin use at any stage during pregnancyFetal or neonatal hemorrhageGreatest during and immediately after delivery,Warfrin,Best overall estimate of the risk is appro
23、ximately 5 to 7 percent.Can be as high as 25-30%May be independent of the INRMay have long term effect (uncertain),Warfrin,Pre-term:Warfarin should be discontinued after 34 to 36 weeks of gestation cesarean deliveryVitamin K does not work immediately. Fresh frozen plasma works quickerMaternal subcut
24、aneous heparin generally should be resumed no later than 6 hoursBreast feeding is OK,Unfractionated heparin,Mostly on factor Xa, also on factors XIIa, XIa, and IXaWorks quickly, stops working quicklyRequire continuous infusion,Unfractionated heparin,Pregnancy category C drug: Does NOT crosses the pl
25、acental barrier Does NOT harm the fetus,Unfractionated heparin,Prolonged use can be harmful:Difficulty of maintaining a stable levelInconvenience of IV administrationHeparin-induced thrombocytopeniaHeparin-induced bone demineralization Usually more than seven weeks of use,Unfractionated heparin,High
26、er doses of heparin are necessary for pregnant women for both prophylaxis and therapy. Increased in heparin-binding proteins and plasma volume,Low-molecular-weight heparin (LMW heparin),FDA in pregnancy category BLMW heparin: less bleeding than with unfractionated heparin; Less likely to precipitate
27、 heparin-associated thrombocytopenia,Low-molecular-weight heparin (LMW heparin),Convenient, Subcutaneous injectionLonger half-life. Fixed doses once or twice dailyLaboratory monitoring can be performed Anti-factor Xa levels 4 hours after injection LMW heparin is titrated for peak anti-Xa level.,LMW
28、heparin: different situations,Venous thromboembolism (VTE):American College of Obstetricians and Gynecologists (ACOG) recommendation: LMWH is safe and effective to prevent or treat VTE in pregnancy.,LMW heparin: different situations,Mechanical heart valves: Concerning, conflicting recommendation: Ma
29、y be worse than heparin and warfarinNot recommended FDA:American College of Obstetricians and Gynecologists The European Society of Cardiology.American College of Chest PhysiciansRecommended to use as an option:The American College of Chest Physicians,LMW heparin: different situations,FDA:In July 20
30、02, a warning for enoxaparin: “not recommended for thromboprophylaxis in pregnant women with prosthetic heart valves”,Need dose adjustments as the pregnancy continues Weight gain Timing of peak anti-X activity levels during pregnancy vary Occurred later after injection,Low-molecular-weight heparin (
31、LMW heparin),ACCP (American College of Chest Physicians:3 StrategiesUH (Un-fractionated Heparin)LMWH (Low Molecular Weight Heparin)UH or LMWH + Warfarin + UH + LMWH,Practical Anticoagulation Strategies,Practical Anticoagulation Strategies,Strategy A:,Practical Anticoagulation Strategies,Strategy B:,
32、Practical Anticoagulation Strategies,Strategy C:,LMWH or UH Warfarin LMWH or UHI I 1st Trimester 2nd Trimester 3rd Trimester,Delivery,Pregnancy with Mechanical Valve,Mitral position Older Mechanical Valve,Aortic position Newer Mechanical Valve,aPTT: 2.5-3.0 x INR: 3-4.5Anti-Xa: 0.35-0.7 U/ml (4 hour
33、s after injection),aPTT: 2.0-3.0 x INR: 2-3Anti-Xa: 0.35-0.7 U/ml (4 hours after injection),General recommendations,Long-term anticoagulation should be resumed postpartum regardless of which regimen is used. Heparin can be restarted:12 hours post-cesarean delivery 6 hours post-vaginal birthWarfarin
34、can restart,Patient QW Lesion Learned,High risk patient: (mitral mechanical)High risk period: 6-12 weeks,CC (Chief Complaint): QW is an 25 year-old woman Mechanical (bi-leaflet) mitral valve 7 weeks of pregnancy presented at the high risk pregnancy clinic for consult (April 2002):,Do not be fooled,
35、she took a chance last time.,Patient QW Lesion Learned,HPI (History of Present Illness):Mechanical mitral valve replacement 8 years ago. On coumadin sinceHad one successful pregnancy and delivery 4 years agoHad been on coumadin throughout her first pregnancy until the endSwitched to unfractionated h
36、eparin before C-section,Patient QW Lesion Learned,PE (Physical Exam): BP: 100/60 mmHg, HR 80sAppropriate for 8 weeks pregnancyThe rest of the physical exam is normal,Patient QW Lesion Learned,Laboratory tests: Normal except INR = 2.2Echocardiogram: Dilated left atrium, normal functioning bi-leaflet
37、mechanical mitral valve, LVEF = 65%,Risk and benefit discussed with the patientCoumadin was stopped, LMW heparin startedPost injection Anti-Xa level monitored at 2, 4, 6, 8 hoursLMW heparin dose was adjusted,She spent the whole day in the clinic,Patient QW Lesion Learned,Unfortunately, patient did n
38、ot come back to clinic for follow-up,Call her, we did and left messages, follow-up is critically important,Patient QW Lesion Learned,She gambled again, this time she lost,Patient QW Lesion Learned,Patient presented to the ER for acute onset of left-sided paralysis at the end of the 12th week.Head MR
39、I suggest embolic strokeEcho: thrombus on the mechanical mitral valve, mechanical mitral stenosis,Patient QW Lesion Learned,Treatment:Un-fractionated heparin started and titratedRepeat echocardiogram: mechanical mitral function normalizedPatient stabilized but remain with significant right-sided par
40、alysis and dysphasia,Treatment:Successfully c-section for a healthy boy at near-termPatient went to nursing home for rehabilitation with significant residue right-sided paralysis and dysphasiaHer children were taken care of by the grand parents.,Patient QW Lesion Learned,Take Home Message:In young w
41、oman with mechanical valves, serious discussion with patient and patient education should be done with every patient,Patient QW Lesion Learned,Take Home Message:Pregnancy is a gambleWith her life With her childrens well being.,Patient QW Lesion Learned,Take Home Message:Careful, stringent clinical f
42、ollow-up is absolutely necessaryDiscuss with her about the blood test scheduleTelephone follow-up,Patient QW Lesion Learned,If single, do not allow marriage. If fertile, do not allow pregnancy. If pregnant, do not allow delivery. If delivered, do not allow breastfeeding.,Mechanical Valves in Young Women,XIX Century Obstetric Aphorism Referring To Women With Heart Disease,
