196-妊娠期血栓栓塞症(上)

2018年7月，美国妇产科医师学会(ACOG)发布了关于妊娠期血栓栓塞症的临床实践指南，替代2011年8月发布的第123号指南。

1. 摘要

问：妊娠期或产后女性更易患血栓栓塞性疾病吗？

答：妊娠期或产后女性患血栓栓塞性疾病的风险是非妊娠期女性的4-5倍[1,2]。

问：妊娠期血栓大多是哪种血栓？发病率是多少？

答：大约80%的妊娠期血栓是静脉血栓，在妊娠期女性中的发生率为0.5-2.0‰[4-9]。

问： 静脉血栓栓塞会导致孕产妇死亡吗？概率是多少？

答：在美国，静脉血栓栓塞(venous thromboembolism ,VTE)是孕产妇死亡的主要原因之一，占所有孕产妇死亡的9.3%[10]。

问：VTE的治疗手段有哪些？

答：鉴于VTE在妊娠期的发生率和严重程度，相应的管理和治疗亟待特殊关注。这些治疗手段包括急性血栓事件的处理及对高风险患者的预防治疗。

问：本文的宗旨是什么？

答：本文旨在为VTE的高危因素、诊断、治疗以及预防提供信息参考，特别是妊娠期血栓栓塞症。

问：本文献对哪些以往的指南进行了修订？

答：本文已对妊娠期血栓栓塞风险筛查以及分娩前后抗凝治疗的指南相关部分进行了更新。

2. 背景

问：静脉血栓栓塞包括哪些部位的栓塞？

答：深静脉血栓形成(deep vein thrombosis, DVT)和肺栓塞(pulmonary embolism, PE)统称为静脉血栓栓塞(VTE)。

问：妊娠相关的VTE中，DVT和PE各占多少比例？

答：妊娠相关的VTE中，大约75-80%是由DVT引起的，20-25%由PE引起[3,7,11]。

问：妊娠期和产后哪个时段VTE的风险最高？

答：尽管静脉血栓栓塞(VTE)大约一半发生在妊娠期，一半发生在产后，但产后发生VTE的风险要高于妊娠期[1]，分娩后几周每天的风险都是最高的[3–8, 12]，尤其是在产后第一周[1]。

3. 妊娠相关的变化与静脉血栓栓塞

问：为什么妊娠期静脉血栓栓塞风险增加了？

答：妊娠期生理上和解剖学上的变化增加了血栓栓塞的风险，这些变化包括高凝状态、静脉瘀血增加、静脉流出减少[13,14]、增大的子宫压迫下腔静脉和盆腔静脉[15]以及活动量的减少[16-19]。妊娠也改变了凝血因子水平(见表1)。所有这些改变使形成血栓的风险增高。

表1. 功能正常的凝血系统在孕期的变化

凝血因子

孕期改变

促凝物质

纤维蛋白原

升高

Ⅶ因子

升高

Ⅷ因子

升高

Ⅹ因子

升高

Von Willerbrand因子

升高

纤溶酶原激活物抑制剂-1

升高

纤溶酶原激活物抑制剂-2

升高

Ⅱ因子

不变

Ⅴ因子

不变

Ⅸ因子

不变

抗凝物质

游离蛋白S

降低

蛋白C

不变

抗凝血酶Ⅲ

不变

数据来源于 Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol 2003;16:153–68 and Medcalf RL, Stasinopoulos SJ. The undecided serpin. The ins and outs of plasminogen activator inhibitor type 2. Febs J 2005;272:4858–67.

问：妊娠期深静脉血栓易发生于哪些部位？为什么？

答：与非妊娠期相比，妊娠期发生的深静脉血栓更常发生在左下肢以及髂静脉和髂股静脉的近端[20-22]。此项差异可能是与右髂动脉压迫左髂静脉(May–Thurner解剖学综合征)加之妊娠子宫压迫下腔静脉导致的左下肢静脉瘀血增加有关。

4. 危险因素

问：在妊娠哪个时期VTE的风险增加？

答：妊娠晚期发生VTE的风险可能比早期和中期要高[2]，但是VTE的风险从妊娠早期即开始增加[21,2]，且通常早于妊娠期解剖学出现明显的变化。

问：妊娠期VTE最重要的个体风险因素是什么？

答：妊娠期VTE最重要的个体风险因素是既往血栓病史。

问：既往妊娠期VTE患者在后续妊娠中复发VTE的风险会增加吗？

答：妊娠期间VTE复发的风险增加3-4倍(RR, 3.5；95%CI, 1.6-7.8)，并且在所有妊娠期VTE的病例中15-25%为复发者[23]。

问：妊娠期VTE第二个主要个体风险因素是什么？发生率是多少？

答：妊娠期发生VTE的第二个主要个体风险因素是易栓症[3, 22]。在妊娠期和产后发生VTE的妇女中，有20-25%存在易栓症[24]。

问：哪种易栓症增加VTE的风险？

答：获得性和遗传性易栓症都增加VTE的风险[25-27]。

问：妊娠和分娩相伴的生理改变也会导致VTE吗？

答：除了个人血栓病史或易栓症或两者兼而有之外，妊娠相关VTE的主要风险因素是妊娠和分娩相伴的生理改变。

问：还有哪些因素增加VTE的风险？

答：剖宫产(尤其是伴有产后出血或感染)以及医学因素或肥胖、高血压、自身免疫性疾病、心脏病、镰状细胞性贫血、多胎妊娠、子痫前期等妊娠并发症也会增加VTE的风险[3, 6-8, 28-31]。

问：分娩方式也会影响VTE的发生率吗？

答：一项关于剖宫产分娩后VTE风险的荟萃分析发现，剖宫产是VTE发生的独立危险因素，据估计发生率为3‰，是阴道分娩后VTE发生率的4倍[32]。

5. 妊娠期抗凝药物的应用

问：妊娠期抗凝药物的应用原则有哪些？

答：妊娠期使用抗凝治疗需要同时考量母亲和胎儿。抗凝治疗前，应与患者充分讨论风险和收益，让她们参与选择合乎自己偏好和价值观的治疗方案[30]。多数在妊娠前已使用抗凝治疗的妇女在妊娠期和产后仍需继续治疗。常用的抗凝药物包括低分子肝素、普通肝素和华法林。一般来说，妊娠期推荐使用的抗凝药物是肝素化合物。

5.1 肝素化合物

问：妊娠期能用肝素吗？

答：能。无论是普通肝素还是低分子肝素均不能通过胎盘[33, 34]，在妊娠期是安全的[35]。

问： 妊娠期抗凝治疗需要考虑哪些问题？

答：在妊娠期使用抗凝治疗时，需要特别考虑到：妊娠期母体血容量会增加40%-50%；肾小球滤过增加导致肝素化合物肾脏排泄增加；肝素与蛋白的结合增加[36]。妊娠期间，普通肝素和低分子肝素的半衰期均会变短，血浆峰值浓度均会降低，为了保持药物有效浓度，通常需要更高的剂量和更频繁的使用[37-43]。在描述普通肝素或低分子肝素治疗方案时，调整剂量的普通肝素或低分子肝素是指根据活化部分凝血活酶时间(APTT)(对于普通肝素)或孕妇的体重(对于低分子肝素)调整的剂量，而预防性或中间剂量则是基于所使用的药物剂量指定(表2)。

表2. 抗凝方案

抗凝方案

抗凝药物剂量

预防性LMWH*

依诺肝素40mg SC Qd

达肝素5000U SC Qd

亭扎肝素4500U SC Qd

低分子肝素2850U SC Qd

中间剂量LWMH

依诺肝素40mg SC Q12h

达肝素5000U SC Q12h

调整剂量 (治疗性) LMWH†

依诺肝素1mg/kg Q12h

达肝素200U/kg Qd

亭扎肝素175 U/kg Qd

低分子肝素100 U/kg Q12h

使目标抗Xa因子水平在Q12h疗法最后注射4小时后达治疗范围，即0.6-1.0U/mL；Qd疗法则可能需要更高的剂量

预防性UFH

妊娠早期UFH 5000–7500U SC Q12h

妊娠中期UFH 7500–10000U SC Q12h

妊娠晚期UFH 10000U SC Q12h，除非APTT升高

调整剂量 (治疗性) UFH

UFH 10000U或以上SC Q12h，调整剂量使目标APTT在注射后6小时达治疗范围(1.5 - 2.5)

产后抗凝

预防性、中等或调整剂量LMWH治疗至产后6 - 8周

口服抗凝血药的时间则根据计划治疗时间、是否哺乳和患者的偏好而不同

监测

临床上应当警惕和观察孕产妇是否有可疑深静脉血栓或肺栓塞的风险。应当在妊娠前或妊娠早期即开始进行VTE风险评估，如果并发症进展则应进行再次评估，尤其是那些需要住院治疗或长时间不活动的患者。

缩写：APTT 活化部分凝血活酶时间；INR 国际标准化比值；LMWH 低分子肝素；SC皮下注射；UFH(unfractionated heparin)普通肝素；VTE深静脉血栓形成

*在极端体重情况下，剂量可能需要修改

†也称为依据体重调整、全治疗剂量。

问：临床更推荐使用肝素还是低分子肝素预防和治疗静脉血栓栓塞？

答：由于低分子肝素更加可靠且易于管理，无论是否妊娠，均推荐应用低分子肝素预防和治疗静脉血栓栓塞，而非普通肝素[30]。

问：相比于普通肝素，低分子肝素有哪些优势？

答：妊娠期关于低分子肝素和普通肝素应用对比的研究很少，但在非妊娠期，低分子肝素的不良反应要少于普通肝素[30]。低分子肝素的潜在优势包括出血风险小、可预见的治疗反应较好、肝素诱发的血小板减少症风险更小、半衰期更长、骨质流失更少[35, 44, 45]。重要的是，在妊娠期使用抗凝剂量时，无论低分子肝素还是普通肝素，都不会引起明显的骨质流失[46-48]。

问：普通肝素有哪些不良反应？

答：普通肝素可能引起注射部位瘀青，也可能引起其他皮肤反应和严重的过敏反应[49]。

问：围产期使用低分子肝素有什么缺点？

答：围产期使用低分子肝素的缺点在于，半衰期较长，无法依据标准实验室检查(如APTT)快速评估当前效果，并且无法用药物拮抗其作用，这在椎管内麻醉和有围产期出血风险时要重点考虑。

5.2 华法林

问：华法林是一种什么药？

答：华法林是一种维生素K拮抗剂，是非妊娠期长期抗凝治疗的常用药，但对胎儿可能有一定的潜在损害，尤其是妊娠早期 [50-56]。

问：长期使用抗凝治疗的患者，妊娠期是否可以继续应用华法林？

答：华法林相关的胚胎病变与妊娠6-12周暴露于华法林有关，妊娠前和妊娠早期使用华法林者应予重视 [57]。对于多数长期使用抗凝治疗的患者，建议在妊娠期使用低分子肝素来替代华法林。

问：哪一类孕妇可以继续使用华法林治疗？

答：虽然维生素K拮抗剂很少用于妊娠期，但对于有机械性心脏瓣膜的妊娠妇女，因为使用普通肝素或低分子肝素抗凝治疗仍有较高的血栓风险，故此类患者仍可考虑使用维生素K拮抗剂如华法林治疗[58]。

问：应如何监管妊娠期继续使用华法林治疗的患者？

答：这类患者的抗凝治疗需要多学科协作，需要与患者及其妇产科医生或其他医护人员针对不同治疗方案在不同孕周的利弊进行详细讨论决定取舍。

问：对于有机械性心脏瓣膜的妊娠妇女如何抗凝治疗？

答：治疗方案包括整个妊娠期均使用低分子肝素或普通肝素；或自妊娠6周-13周使用调整剂量的低分子肝素或普通肝素，妊娠13周后使用维生素K拮抗剂直至接近分娩，其后再使用低分子肝素或普通肝素[58]。

问：应用华法林治疗的孕妇意外分娩，应采用哪种分娩方式？

答：应用华法林的患者发生胎儿出血的风险在围产期时最高；因此，如果正在应用维生素K拮抗剂治疗的孕妇意外分娩，就可能需要剖宫产分娩。

问：新生儿需要特殊处置吗？

答：新生儿可能需要维生素K和新鲜冰冻血浆的治疗。

5.3 口服直接凝血酶抑制剂和Xa因子抑制剂

问：妊娠和哺乳期是否能用口服直接凝血酶抑制剂和Xa因子抑制剂？

答：应避免在妊娠期和哺乳期应用口服直接凝血酶抑制剂(达比加群)和Xa因子抑制剂(利伐沙班、阿哌沙班、依度沙班、贝曲西班)，目前尚缺乏足够的数据来评估其对孕产妇、胎儿以及母乳喂养新生儿的安全性[59]。对人类胎盘的体外研究表明，口服直接凝血酶抑制剂和Xa因子抑制剂能够通过胎盘，因此人们担心它们会间接对胎儿凝血系统造成影响[60-62]。同样地，产妇摄入口服直接凝血酶抑制剂和Xa因子抑制剂后，在母乳中也可以检测出来[63, 64]。关于妊娠早期口服直接凝血酶抑制剂(达比加群)和Xa因子抑制剂与先天畸形的关系很大程度上仍属未知。一项前瞻性研究发现，在37名无意中服用利伐沙班的妊娠妇女中，一名患者的胎儿出现了心脏圆锥动脉干畸形；然而，这名患者在未服用利伐沙班时就曾有过一个患有心脏缺陷的孩子[65]。

问：口服直接凝血酶抑制剂或Xa因子抑制剂的患者应当在妊娠前或孕期更换为哪种药？

答：在有新的数据支持前，口服直接凝血酶抑制剂或Xa因子抑制剂的患者应当在妊娠前或妊娠期尽快更换为低分子肝素。

指南针(中)，敬请期待

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中文引用｜尹璐瑶，蔡贞玉，王芸. Q&A:ACOG 196-妊娠期血栓栓塞症(上). 【J】 NPLD-GHI. 2018 October 25; 5(10):25.

英文引用｜Yin LY, Cai ZY, Wang Y. Q&A:ACOG 196 - Thromboembolism in Pregnancy (Part Ⅰ). J NPLD-GHI. 2018 October 25; 5(10):25.

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