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Clinical management of thrombophilia in peripartum

  • Lingyue Huyan ,
  • Chong Qiao ,
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Received date: 2022-10-12

  Online published: 2023-08-14

Copyright

Copyright by Chinese Medical Association No content published by the journals of Chinese Medical Association may be reproduced or abridged without authorization. Please do not use or copy the layout and design of the journals without permission. All articles published represent the opinions of the authors, and do not reflect the official policy of the Chinese Medical Association or the Editorial Board, unless this is clearly specified.

Abstract

Thrombophilia is a series of high-risk diseases of thrombosis caused by abnormal hereditary coagulation factors or acquired high risk factors of thrombosis. Thrombophilia in pregnancy not only increases the risk of thrombotic events, but also is associated with adverse pregnancy outcomes. Thromboembolism caused by thrombophilia is mainly venous thromboembolism, which mainly occurs before and six weeks after delivery. Therefore, scientific and systematic peripartum clinical management is of great significance for thrombophilia patients to reduce the risk of thrombosis.

Cite this article

Lingyue Huyan , Chong Qiao . Clinical management of thrombophilia in peripartum[J]. Chinese Journal of Obstetric Emergency(Electronic Edition), 2023 , 12(02) : 81 -84 . DOI: 10.3877/cma.j.issn.2095-3259.2023.02.004

易栓症是一类易发生血栓栓塞性疾病的统称,与动脉和静脉血栓事件的高风险相关,分为遗传性易栓症和获得性易栓症[1]。遗传性易栓症是由一种或多种凝血因子的结构异常或数量异常引起的、临床表现为凝血功能增强的遗传性疾病,包括凝血因子Ⅴ Leiden(factor V Leiden,FVL)和凝血酶原(凝血因子Ⅱ)G20210A基因突变、蛋白C和蛋白S缺乏、抗凝血酶-Ⅲ缺乏及遗传性高同型半胱氨酸血症等。西方人群遗传性易栓症最常见的发病机制是FVL和凝血酶原G20210A基因突变,而这两种基因变异在中国人群中罕见,我国的遗传学研究显示,蛋白C系统基因缺陷最为常见[2]。获得性易栓症是获得性血栓危险因素所导致的促凝蛋白水平升高、抗凝蛋白水平下降,使血栓栓塞倾向增加。常见的获得性疾病/获得性危险因素包括抗磷脂综合征、自身免疫性疾病、慢性心肺疾病、慢性肾病、高龄、肥胖、手术、长期卧床、多发性外伤和骨折等[3]

一、易栓症

易栓症的血栓栓塞类型主要为静脉血栓栓塞症(venous thromboembolism,VTE),VTE是孕期和产后孕产妇死亡的主要原因[4]。与同龄的非孕妇女相比,妊娠期女性VTE发生风险增加了5~10倍[5,6,7]。孕期血栓形成的风险从妊娠前3个月开始出现,随后逐渐增加,在分娩前和产后风险达到最高[7,8]。一项荟萃分析显示,三分之二的妊娠期VTE发生在临产前[6];一项基于伦敦围产期数据库的研究发现,43%~60%的妊娠相关的肺栓塞发生在产后4~6周[9];产后6周内孕妇患深静脉血栓的风险大大高于产前[10]。在此期间,与同龄的非产妇相比,产妇每日VTE风险增加15~35倍[5],此后风险会迅速下降[7,11,12]。围产期血栓风险增高可能与腹腔压力明显增高、静脉回流速度减慢和产后卧床时间长等相关。
目前尚未有关于"围分娩期易栓症"的相关概念,易栓症通常在孕前或血栓发生后诊断。对易栓症患者在围产期进行科学系统的管理,对于降低VTE发生率和死亡率具有重大意义。
此外,易栓症可导致复发性流产,也与先兆子痫、胎儿生长受限和胎盘早剥等不良妊娠结局相关,在不良妊娠结局中有49%~65%的患者有易栓症[13]。一项前瞻性队列研究表明,与未经治疗的易栓症女性相比,使用低分子肝素预防不良妊娠结局的女性围产期结局更好[14]。但目前的指南并不支持抗凝治疗对易栓症妇女妊娠期不良结局具有预防作用[15]

(一)易栓症的筛查

一般来说,不建议在妊娠期进行易栓症检测,只有在检测结果会影响治疗决策时才应进行检测[4]。美国妇产科医师学会(American College of Obstetricians and Gynecologists,ACOG)指南建议仅在2种情况下筛查易栓症:(1)与一过性危险因素有关的静脉血栓栓塞史;(2)一级亲属患有高危的易栓症[15]。英国皇家妇产科医师学会(Royal College of Obstetricians and Gynaecologists, RCOG)建议对有中期流产史的女性进行FVL、凝血酶原基因突变和蛋白S缺乏症筛查[16]

(二)易栓症的风险评估

易栓症不是单一疾病,涉及众多病因和危险因素,全面筛查项目多、费用高,《易栓症诊断与防治中国指南(2021年版)》建议依据患者年龄、病史、潜在病因发生率的高低及常规检查结果的提示等确定筛查方向和顺序[17]。上海市的专家共识采用评分法进行风险评估,将危险因素分为产前因素、产后因素和临时因素3个类别;同时存在多种因素者,分数可以叠加。产前风险评估包括产前因素和临时因素;产后风险评估包括产前因素、临时因素和产后因素;临时因素消失后不再作为危险因素;根据风险程度将影响分为极高危(≥4分)、高危(产前为3分或产后为2~3分)和低危(0~1分)3个等级[18]

二、易栓症在围分娩期的管理

(一)健康教育

使孕产妇认识到VTE的危害性,了解VTE的先兆表现,了解自身发生VTE的风险级别与相应的预防策略,可以提高孕产妇的依从性。可以通过新媒体等多种手段进行宣教,建议孕产妇适量运动、健康饮食、改善心理状态[18]

(二)物理预防

对于无法下地活动且没有下肢静脉血栓的孕产妇可以采取物理预防措施,包括穿戴弹力袜、使用机械泵和按摩双腿等方法来促进外周血液循环。

(三)药物预防

1.抗凝药物的种类:

目前临床上常用的抗凝药物有低分子肝素(low-molecular-weight heparin,LMWH)、普通肝素(unfractionated heparin,UFH)、维生素K拮抗剂(如华法林)以及凝血酶抑制剂等。LMWH是治疗和预防妊娠期VTE的首选药物[15,16,19,20],但患有肝素诱导的血小板减少症、有血小板减少症病史或严重肾功能障碍的患者除外。对于有明显肾功能障碍的患者,UFH是首选[21]
孕期应尽可能避免口服抗凝剂,如华法林,因为华法林可能对胎儿产生不良影响。对于需要长期服用维生素K拮抗剂的备孕女性,建议进行频繁的妊娠测试,一旦确认妊娠,需在6周内尽早用治疗剂量的UFH或LMWH替代口服抗凝药进行治疗[20,22]。UFH、LMWH及华法林对母乳喂养的婴儿是安全的。母乳喂养期间不应使用口服凝血酶抑制剂和凝血因子Xa抑制剂[23]

2.抗凝方案的选择:

上海专家共识认为,高危孕产妇在无明显禁忌证的情况下可在采用LMWH等药物行预防,根据孕产妇的体重调整药物的预防剂量;评分为3分者在妊娠28周后开始应用LMWH,≥4分者在评估后即刻开始应用LMWH,持续至分娩前24小时[18]。因临时因素应用LMWH者,在临时风险因素消除后,需重新评估是否需继续应用药物抗凝。而未发生VTE的遗传性易栓症在评分系统中评分3分,意味着没有高危因素的遗传性易栓症患者可以在28周后开始预防性使用LMWH,在孕28周前出现高危因素需要立即开始应用LMWH,并在高危因素消除后重新评估[18]
目前预防产科抗磷脂综合征患者妊娠并发症的策略是使用小剂量阿司匹林和预防性剂量的UFH或LMWH[24]。妊娠期小剂量阿司匹林通常被推荐给没有血栓形成或妊娠并发症病史的抗磷脂综合征患者[25]。没有血栓病史的抗磷脂综合征患者在产后至少需要接受6周的预防剂量的LMWH治疗[26]

3.产前抗凝治疗停止的时机:

接受肝素预防的孕妇在分娩期间出血的风险可能会增加[20],可以在分娩前期停止使用UFH、LMWH或者将肝素降低到非预防水平(每小时5000国际单位,持续8~12 h)。应测量部分凝血活酶时间和血小板计数以确保停用或减少肝素后凝血指标处于正常范围内[19]
虽然还没有研究评估出最后一次LMWH注射与分娩应间隔的确切时间,但通常建议在最后一次LMWH注射和分娩之间间隔24 h[27,28,29]。我国专家共识也建议在在分娩前24 h停用LMWH[18]
美国局部麻醉和疼痛医学学会指南建议在最后一次预防剂量LMWH后10~12 h,或最后一次治疗性剂量LMWH后24 h进行神经阻滞[30]。美国产科麻醉和围产期学会(The Society for Obstetric Anesthesia and Perinatology,SOAP)发表的指南建议,神经阻滞应与治疗剂量的LMWH、预防性LMWH分别间隔24 h、12 h[31]

4.产后抗凝治疗开始的时机:

分娩后重新开始抗凝治疗的最佳时间尚不清楚。Freedman等[32]认为,LMWH和UFH需在阴道分娩后4~6 h或剖宫产后6~12 h内重新开始使用。我国专家共识也基本与其观点一致,在无产后出血风险、无椎管内麻醉的情况下,经阴道分娩者推荐于产后4~6 h开始,行剖宫产者在产后12 h开始。需要注意的是,椎管内麻醉的患者,若使用预防剂量的LMWH,应在停药至少12 h后拔管,若为治疗剂量的LMWH,应在停药24 h后拔管[18]。且拔管后4 h内不注射LMWH。有产后出血风险的患者(包括产前出血、凝血功能障碍、进行性发展的伤口血肿、疑似腹腔内出血和产后出血),可使用物理方法预防[18]。在有明确使用肝素的指征的情况下,可以考虑使用UFH,因为UFH的半衰期短,鱼精蛋白可抑制其效用,而LMWH只是部分可逆[32]
本次妊娠期间发生静脉血栓栓塞症的妇女可能需要在分娩后继续服用华法林6周以上,直至凝血系统恢复正常,一些专家建议至少服用华法林3~6个月[29]

(四)VTE的治疗

VTE的诊断主要依靠病史、临床体征和症状,明确诊断则依靠影像学检查,如下肢超声、静脉造影和CT肺动脉造影等[33]
VTE治疗主要包括抗凝、溶栓和安装滤网等方法。在确诊VTE后,需第一时间采取抗凝治疗,同时请专科医师会诊,进行多学科联合诊疗[34]

三、总结与展望

虽然关于易栓症在围产期的临床管理已有相关内容的指南出版,但从上文可以看出,将指南的内容应用于临床还面临着以下几个问题:(1)不同指南的抗凝治疗方案不统一,药物剂量和持续治疗时间仍存在较多争议;(2)抗凝方案的实施细节仍需推敲,例如相同预防剂量的LMWH是否适用于体重相差较大的孕妇;(3)目前认为产后抗凝治疗的剂量需要与产前相同,但产后是否需要重新评估风险以及产时状况对产后血栓事件的影响是否需要纳入评估范围;(4)目前的指南均为欧美国家根据当地人种和发病特点所制定,是否可以直接用于我国孕产妇仍未知。
综上所述,关于易栓症围产期的临床管理仍然需要更多的多中心、多人种的临床对照研究,通过科学合理的方式比较不同治疗方案的效果来推选出最安全有效的抗凝治疗方案。此外,抗凝治疗对易栓症妇女的妊娠期不良结局是否具有预防作用,仍需要更多的随机对照研究和荟萃分析来证明。
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