低分子肝素在产科常见疾病中的应用

低分子肝素(LMWH)在达到有效的抗凝血作用的同时,可以减少肝素所致的出血等不良反应,在临床上具有一定的应用价值。目前LMWH广泛应用于产科临床,其不仅能预防妊娠期和产褥期深静脉血栓形成(DVT),还能预防、治疗易栓症引起的子痫前期(PE)、胎儿生长受限(FGR)等产科常见并发症。对妊娠期及产褥期DVT的危险因素进行评估后,可考虑使用LMWH。研究发现,LMWH也能改善非易栓症孕妇的不良妊娠结局,降低高危人群(有胎盘早剥、早发型PE病史的孕妇)患早发型PE、重度PE、FGR及晚期流产的风险,延长妊娠时间,提高新生儿存活率和出生体质量。现综述近年来LMWH应用于产科DVT、PE和FGR的相关研究进展。     

《中国实用妇科与产科杂志》2017年第7期中心内容预告北大核心CSCD

中心内容:抗凝在产科的临床应用重视妊娠期抗凝药物的合理应用心脏人工瓣膜置换术后孕妇的围产期抗凝管理复发性流产的抗凝治疗抗磷脂综合征的围产期抗凝治疗遗传性易栓症的妊娠期筛查与抗凝治疗评价妊娠合并自身免疫性疾病的抗凝治疗阿司匹林预防子痫前期的相关问题     

妊娠期及产褥期静脉血栓栓塞症暂时性危险因素的应对策略

静脉血栓栓塞症( venous thromboembolism,VTE) 包括深静脉血栓形成(deep venous thrombosis,DVT)和 肺栓塞(pulmonary embolism,PE),是孕产妇死亡的重 要却又可以预防的原因之一。 深静脉血液不正常凝 结引起静脉回流障碍,所导致的疾病称为 DVT,以下 肢静脉最常见;若血栓脱落通过血液循环阻塞肺动脉 则引起 PE [1] 。 妊娠本身就是 VTE 的危险因素。 随着 我国生育政策的调整,高龄、肥胖、辅助生殖技术受 孕、多胎等高危孕妇增加,发生 VTE 的危险因素明显 增加。 当前国内外针对高危孕产妇在妊娠期及产褥 期的产前、产后 VTE 的危险因素如 VTE 史、易栓症、 抗磷脂综合征等的筛查、诊断、治疗和预防已得到极 大的重视和规范治疗,但是对于妊娠期及产褥期相关 VTE 的暂时性危险因素容易忽视,也未予以规范的临 床管理。     

《中国实用妇科与产科杂志》2017年第7期中心内容预告

正中心内容:抗凝在产科的临床应用重视妊娠期抗凝药物的合理应用心脏人工瓣膜置换术后孕妇的围产期抗凝管理复发性流产的抗凝治疗抗磷脂综合征的围产期抗凝治疗遗传性易栓症的妊娠期筛查与抗凝治疗评价妊娠合并自身免疫性疾病的抗凝治疗阿司匹林预防子痫前期的相关问题     

ACOG “妊娠期遗传性易栓症指南（2018）”解读

遗传性易栓症与静脉血栓栓塞症（VTE）的风险增加及不良妊娠结局有关［1］。但目前用于指导筛查和管理这些不良妊娠结局的证据并不充分。本文对ACOG 2018年发布的“妊娠期遗传性易栓症指南”进行解读,该指南是ACOG在2013年版基础上的更新,回顾了遗传性易栓症与母体VTE风险和不良妊娠结局的关系,提出易栓症筛查的适应证以及妊娠期间的管理建议,为易栓症患者的评估及孕期、产后遗传性易栓症的预防和产科椎管内麻醉提供了更多指导意见。 浏览更多请关注本刊微信公众号及当期杂志。     

《中国实用妇科与产科杂志》2017年第7期中心内容预告

<正>中心内容:抗凝在产科的临床应用重视妊娠期抗凝药物的合理应用心脏人工瓣膜置换术后孕妇的围产期抗凝管理复发性流产的抗凝治疗抗磷脂综合征的围产期抗凝治疗遗传性易栓症的妊娠期筛查与抗凝治疗评价妊娠合并自身免疫性疾病的抗凝治疗阿司匹林预防子痫前期的相关问题     

遗传性易栓症与不良妊娠结局的研究进展

近年研究发现妊娠期易栓症的发生呈增加趋势。易栓症分为遗传性易栓症和获得性易栓症,遗传性易栓症主要与凝血基因突变所致的蛋白表达异常有关,包括因子V Leiden(FVL)、凝血酶原基因G20210A、亚甲基四氢叶酸还原酶(MTHFR)基因突变以及蛋白S(PS)、蛋白C(PC)和抗凝血酶(AT)缺乏等。凝血、抗凝及纤溶系统功能失调可引起胎盘灌注不良,不良妊娠结局如子痫前期(PE)、胎盘早剥、胎儿生长受限(FGR)和习惯性流产等可能与此有关。但遗传性易栓症是否是造成不良妊娠结局的直接因素以及预防性抗凝是否可以改善妊娠结局仍需进一步探讨。综述遗传性易栓症与不良妊娠结局的关系,评估预防性抗凝的必要性,为临床诊断和治疗提供思路。     

遗传性易栓症与不良妊娠结局的研究进展

近年研究发现妊娠期易栓症的发生呈增加趋势。易栓症分为遗传性易栓症和获得性易栓症,遗传性易栓症主要与凝血基因突变所致的蛋白表达异常有关,包括因子VLeiden(FVL)、凝血酶原基因G20210A、亚甲基四氢叶酸还原酶(MTHFR)基因突变以及蛋白S(PS)、蛋白C(PC)和抗凝血酶(AT)缺乏等。凝血、抗凝及纤溶系统功能失调可引起胎盘灌注不良,不良妊娠结局如子痫前期(PE)、胎盘早剥、胎儿生长受限(FGR)和习惯性流产等可能与此有关。但遗传性易栓症是否是造成不良妊娠结局的直接因素以及预防性抗凝是否可以改善妊娠结局仍需进一步探讨。综述遗传性易栓症与不良妊娠结局的关系,评估预防性抗凝的必要性,为临床诊断和治疗提供思路。     

妊娠相关静脉血栓栓塞症风险评估模型研究进展

妊娠相关静脉血栓栓塞症（pregnancy associated venous thromboembolism，PA-VTE）包括妊娠期和产褥期发生的静脉系统的血栓形成疾病，由深静脉血栓形成（deep vein thrombosis，DVT）和肺栓塞（pulmonary embolism，PE）组成的PA-VTE是发达国家孕产妇发病和死亡的主要原因。采用高效、便捷的风险评估模型评估PA-VTE的发病风险并进行分级预防是目前多个国家推荐的主要措施，但由于各国医学水平、经济发展和传统习惯的不同，各国相继开发风险评估模型或根据实际情况对其他国家的风险评估模型进行改良，进而对妊娠期及产褥期VTE风险进行个体化评估，并实施相应的血栓预防策略。通过回顾国内外的PA-VTE风险评估模型，旨在为我国进一步建立孕产妇的VTE防治指南提供依据，为产科医务工作者制定出适合我国产科人群的VTE风险评估模型提供参考。     

阿司匹林和低分子肝素预防子痫前期的研究进展

阿司匹林可改善胎盘微循环,预防胎盘功能障碍导致的一系列不良妊娠结局。国内外指南普遍推荐妊娠早期使用小剂量阿司匹林(LDA)能够预防子痫前期(PE),特别是早产型PE(37孕周分娩),但对小于胎龄儿(SGA)、流产、死胎等方面有待进一步研究。低分子肝素(LMWH)具备安全抗凝血的作用,但在预防PE、SGA、死胎、流产方面的作用微小或无作用,妊娠期长期应用均不增加胎盘早剥和产前产后出血的风险。本文综述指南推荐的PE危险因素以及早期筛查模型,讨论LDA和LMWH应用的理论依据以及两者预防效益的研究进展,帮助产科医生在临床实践中对LDA和LMWH的使用有更深层次的理解。     

Current management of thromboembolism in pregnancy and puerperium

Venous thromboembolism (VTE) remains the leading cause of maternal death. Today, various risk factors and conditions are known to increase the risk for VTE associated with pregnancy. Having identified the individual risk of a pregnant women, appropriate preventive measures can be taken. If VTE occurs during pregnancy, an appropriate immediate diagnostic work-up is essential in order to avoid further complications. For deep vein thrombosis (DVT) the diagnostic tool of choice is color-coded duplex-sonography, for pulmonary embolism (PE) perfusion/ventilation lung scan can be used. Integrating a detailed individual and family history, the presence of thrombophilia or other risk factors, a risk stratification can be undertaken. These risk categories are defined in the present paper and the appropriate treatment measures are described. As oral anticoagulants cross the placenta and may cause embryopathy in any trimester, oral anticoagulants should be avoided throughout pregnancy. Therefore, heparin is the anti-coagulant of choice for pregnant women, with low molecular weight heparins (LMWH) having distinctive pharmacological advantages over unfractionated heparins. Besides a potential for bleeding, the main side effects of heparin include heparin-induced thrombocytopenia which prompts for platelet monitoring, especially in the first weeks of heparin treatment, and, secondly, heparin-induced osteoporosis, which is a potential sequel of long-term heparin administration. Even though there are abundant reports in the literature on the use of LMWH in pregnant women, that show that they are safe and effective, LMWH are not specifically licensed for the use in pregnancy.     

Evaluating patient values and preferences for thromboprophylaxis decision making during pregnancy: A study protocol

ABSTRACT: BACKGROUND: Pregnant women with prior venous thromboembolism (VTE) are at risk of recurrence. Low molecular weight heparin (LWMH) reduces the risk of pregnancy-related VTE. LMWH prophylaxis is, however, inconvenient, uncomfortable, costly, medicalizes pregnancy, and may be associated with increased risks of obstetrical bleeding. Further, there is uncertainty in the estimates of both the baseline risk of pregnancy-related recurrent VTE and the effects of antepartum LMWH prophylaxis. The values and treatment preferences of pregnant women, crucial when making recommendations for prophylaxis, are currently unknown. The objective of this study is to address this gap in knowledge. METHODS: We will perform a multi-center cross-sectional interview study in Canada (2 sites), USA, Norway and Finland. The study population will consist of 100 women with a history of lower extremity deep vein thrombosis (DVT) or pulmonary embolism (PE), and who are either pregnant, planning pregnancy, or may in the future consider pregnancy (women between 18 and 45 years). We will exclude individuals who are on full dose anticoagulation or thromboprophylaxis, who have undergone surgical sterilization, or whose partners have undergone vasectomy. We will determine each participant's willingness to receive LMWH prophylaxis during pregnancy through direct choice exercises based on real life and hypothetical scenarios, preference-elicitation using a visual analog scale ("feeling thermometer"), and a probability trade-off exercise. The primary outcome will be the minimum reduction (threshold) in VTE risk at which women change from declining to accepting LMWH prophylaxis. We will explore possible determinants of this choice, including educational attainment, the characteristics of the women's prior VTE, and prior experience with LMWH. We will determine the utilities that women place on the burden of LMWH prophylaxis, pregnancy-related DVT, pregnancy-related PE and pregnancy-related hemorrhage. We will generate a "personalized decision analysis" using participants' utilities and their personalized risk of recurrent VTE as inputs to a decision analytic model. We will compare the personalized decision analysis to the participant's stated choice. DISCUSSION: The preferences of pregnant women at risk of VTE with respect to the use of antithrombotic therapy remain unexplored. This research will provide explicit, quantitative expressions of women's valuations of health states related to recurrent VTE and its prevention with LMWH. This information will be crucial for both guideline developers and for clinicians.     

Recurrence and severity of abnormal pregnancy outcome in patients treated by low-molecular-weight heparin: a prospective pilot study

Objective: This prospective pilot study assesses the recurrence rate and severity of abnormal pregnancy outcome (APO), excluding early pregnancy complications, in pregnant patients, without acquired thrombophilia, treated by prophylactic doses of low-molecular-weight heparin (LMWH), independently from their congenital thrombophilic condition. Methods: We recruited a cohort of 128 pregnant patients with previous APO; 100 of whom with APO and intrauterine growth restriction (IUGR) and 28 with maternal APO only. LMWH treatment was started at recruitment. Composite cross-over recurrence rate IUGR, gestational hypertension, preeclampsia, help syndrome, abruptio placenta were analyzed. The main outcome measure was severe APOs with iatrogenic delivery ≤ 32 weeks of gestation. Results: Median gestational age at LMWH treatment was 20 weeks. Severe APO decreased in treated pregnancies from 45% to 4% (relative risk = 0.3, confidence interval 95% = 0.2–0.8). This value was not significantly different in thrombophilic and nonthrombophilic patients. When severe and minor complications were analyzed altogether, the recurrence rate was 28%. In patients with APO and fetal growth restriction (FGR) in the index pregnancy, newborn weights were significantly better in the treated pregnancy: 1090 g (1035–1145) vs. 850 g (535–1200), p < 0.01. Conclusions: Prophylactic regimen of LMWH significantly reduced the recurrence rate of severe composite APO in pregnancies affected in the index pregnancy by APO and FGR or small for gestational age newborns. This result was independent from the patients’ inherited thrombophilic conditions.     

剖宫产术后深静脉血栓形成的临床研究

目的:探讨剖宫产术后DVT的诊治及预防。方法:回顾分析2002年8月至2005年12月我科收治的剖宫产术后并发下肢DVT的患者47例,分析其临床特点及诊断治疗的方法,并结合文献复习讨论预防措施。结果:既往有血栓病史、经产妇、肥胖是剖宫产术后DVT的危险因素,主要临床症状为患肢粗肿、疼痛,部分患者有呼吸系统的非特异性症状,DVT的辅助诊断首选血浆D-二聚体检测结合静脉彩色多普勒超声显像。采用全身或局部抗凝、溶栓等药物或手术取栓治疗,部分患者放置可回收性IVCF预防致死性PE,均取得较好的近期疗效。结论:对于存在DVT危险因素的孕产妇,剖宫产手术前后应采取积极预防措施。LMWH是常用的和安全的抗凝药物,能有效预防和治疗DVT。     

Safety and Efficacy of Low Molecular Weight Heparin Therapy During Pregnancy: Three Year Experience at a Tertiary Care Center

Purpose

To evaluate safety and efficacy of low molecular weight heparin given for various indications during pregnancy.

Methodology

A detailed retrospective analysis of all the patients who received low molecular weight heparin (LMWH) for various indications over a period of 3 years (2010–2012) at a tertiary care hospital in Northern India was performed.

Results

Fifty-five patients received LMWH over the period of 3 years, for various indications. Enoxaparin (1 mg/kg body weight OD/BD subcutaneously) was used. The indications were valvular heart disease with valve replacement, atrial fibrillation, or thrombus in 60 % patients; chronic deep vein thrombosis (DVT) in 7 % patients; thrombophilia in 9.1 % patients; recurrent pregnancy losses in 18 % patients; and DVT prophylaxis in 5.5 % patients. Abortion was seen in 7.2 % patients; fetal growth restriction in 10.9 % patients; and oligohydramnios, preeclampsia, gestational hypertension, placenta previa, abruptio placentae, and postpartum hemorrhage in 1.8 % patients. Stillbirth occurred in 3.6 % patients. No thromboembolic event was noted in any of the patients. None of the patients had any documented thrombocytopenia or clinical fracture.

Conclusion

Low molecular weight heparin can be used in pregnancy for various indications as an alternative to unfractionated heparin or warfarin as it is efficacious and safe.     

阿司匹林及低分子肝素在子痫前期中应用的研究进展

子痫前期是妊娠中晚期常见的一种特发疾病，其病情变化快，发生HELLP综合征、胎盘早剥、子痫、早产、胎儿窘迫等严重并发症的概率高，是导致发展中国家孕妇不良妊娠结局的主要原因之一，目前缺乏有效的防治措施。子痫前期的基本病理改变为全身小动脉痉挛，致滋养细胞受损、侵蚀不良，胎盘浅着床，合体滋养细胞缺血、缺氧，炎性因子、促凝物质释放，使血压升高、凝血与纤溶系统失衡，血液早期处于高凝状态。低分子肝素（low molecular weight heparin，LMWH）和阿司匹林是产科常用的两种具有抗凝作用的药物，由于子痫前期患者与正常孕妇的凝血状态存在差异，这两种药物在子痫前期中的应用引起了国内外学者的关注。现就其在子痫前期防治过程中的有效性及安全性的研究进展进行综述。     

Recommendations for the diagnosis and treatment of deep venous thrombosis and pulmonary embolism in pregnancy and the postpartum period

Venous thromboembolism (VTE) in pregnancy and the postpartum is an important cause of maternal morbidity and mortality; yet, there are few robust data from clinical trials to inform an approach to diagnosis and management. Failure to investigate symptoms suggestive of pulmonary embolism (PE) is a consistent finding in maternal death enquiries, and clinical symptoms should not be relied on to exclude or diagnose VTE. In this consensus statement, we present our recommendations for the diagnosis and management of acute deep venous thrombosis (DVT) and PE. All women with suspected DVT in pregnancy should be investigated with whole leg compression ultrasonography. If the scan is negative and significant clinical suspicion remains, then further imaging for iliofemoral DVT maybe required. Imaging should be undertaken in all women with suspected PE, as the fetal radiation exposure with both ventilation/perfusion scans and CT pulmonary angiography is within safe limits. Low-molecular-weight heparin (LMWH) is the preferred therapy for acute VTE that occur during pregnancy. In observational cohort studies, using once-daily regimens appears adequate, in particular with the LMWH tinzaparin; however, pharmacokinetic data support twice-daily therapy with other LMWH and is recommended, at least initially, for PE or iliofemoral DVT in pregnancy. Treatment should continue for a minimum duration of six months, and until at least six weeks postpartum. Induction of labour or planned caesarean section maybe required to allow an appropriate transition to unfractionated heparin to avoid delivery in women in therapeutic doses of anticoagulation.     

Prophylaxis of recurrent preeclampsia: low-molecular-weight heparin plus low-dose aspirin versus low-dose aspirin alone.

OBJECTIVE: To verify whether prophylaxis with low-molecular-weight heparin (LMWH) and low-dose aspirin (LDA) could positively affect pregnancy outcome in women with a history of severe preeclampsia. METHODS: We compared 23 pregnancies treated with LDA alone to 31 pregnancies treated with LMWH plus LDA. RESULTS: Women treated with LMWH-LDA (n = 31) showed a better pregnancy outcome than those treated with LDA alone (n = 23) in terms of gestational age at delivery (p < 0.05), birth weight (p < 0.01), birth weight percentile (p < 0.01), and rate of preeclampsia (p < 0.01). Furthermore, comparing the intra-group outcome variation between previous and index pregnancies, an improvement appeared in each group, but a more pronounced gain was noted in the LMWH-LDA group in terms of gestational age at delivery (p< 0.005), birth weight (p < 0.005), and birth weight percentile (p < 0.005). CONCLUSIONS: Thromboprophylaxis with LMWH plus LDA can improve pregnancy outcome in women with previous severe preeclampsia.     

Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of low molecular weight heparin. Gynecological ward retrospective analysis

Objectives: To compare the frequency of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing gynecological operations without low molecular weight heparin (LMWH) prophylaxis and those receiving such prophylaxis. Design: Retrospective, hospital record-based study. Material and Methods: About 1785 consecutive patients without LMWH prophylaxis and 1871 ones treated with nadroparin (Fraxiparine) 7500 ICU s.c. 2 h before the operation and repeated daily for 5–7 days or until the patient was fully mobile. DVT was diagnosed on the basis of clinical symptoms and ultrasound examination, and PE on clinical symptoms, gasometric data, electrocardiography and chest X-ray. Results: Among the patients without prophylaxis, four cases of PE occurred (0.22%), two fatal (0.11%), 13 cases of proximal DVT (0.72%) and 41 distal DVT complications (2.3%). In LMWH, group 3 proximal DVT (0.16%) and 18 distal DVT (0.96%) developed but there were no clinically expressed pulmonary embolism. According to the Fisher’s exact test, the difference between the complications in the analyzed groups is significant P<0.05. Conclusion: The perioperative applying of LMWH to prevent DVT in the patients operated on gynecologically is effective.     

低分子肝素治疗前后子痫前期患者血清γ干扰素及白介素-4的变化

目的:通过检测低分子肝素(LMWH)治疗前后子痫前期(PE)患者血清中γ干扰素(INF-γ)及白介素-4(IL-4)含量变化,探讨LMWH治疗PE的作用机制。方法:选取2012年6月至2014年5月我院收治的72例PE患者,其中28例早发型重度PE、26例晚发型重度PE和18例轻度PE患者,给予低分子肝素钙0.4ml皮下注射,1次/d×7d,ELISA法检测治疗前和治疗第3天、7天患者血清中INF-γ和IL-4含量变化。选取同期门诊住院孕周分别为28~33+6周、34~36+6和37周正常孕妇各20例作为对照。结果:正常孕妇随着孕周的增长,INF-γ和IL-4含量均无明显变化。LMWH治疗前,PE患者随着病情加重血清INF-γ呈上升趋势、IL-4呈下降趋势,各组间两两比较差异均有统计学意义。治疗后,PE患者的血清INF-γ均呈下降趋势、IL-4均呈上升趋势,治疗前后比较差异均有统计学意义,轻度PE治疗前后比较差异无统计学意义。结论:LMWH可通过调节PE患者免疫失衡,减少患者血管内皮细胞损伤,缓解PE症状。