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。     

围产期易栓症的抗凝治疗

易栓症会增加妊娠期间及产后发生静脉血栓的风险,并且与反复自然流产、子痫前期、胎儿宫内生长受限等不良妊娠结局相关。本文将结合易栓症人群妊娠期处理相关指南和文献,介绍合并易栓症人群妊娠期及产后预防性抗凝治疗以降低血栓和不良妊娠结局风险的方案选择。     

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。     

易栓症与复发性流产

研究表明,易栓症与不良妊娠结局呈正相关。孕妇存在凝血、抗凝血功能紊乱或者障碍,可导致母体血液高凝状态,并且伴随妊娠的进展而加重,增加各种妊娠并发症的发病率,约66%的复发性流产患者存在凝血功能障碍。本文就遗传性及获得性易栓症与复发性流产的关联性,对有血栓栓塞病史或相关高危因素的复发性流产女性进行易栓症筛查的必要性,以及对复发性流产合并易栓症的治疗手段,预防各种产科并发症的发生,降低妊娠丢失率进行讨论。     

妊娠期易栓症的病因

近年来,研究发现许多妊娠期妇女具有血栓形成倾向,这种由于抗凝蛋白、凝血因子、纤溶蛋白等的遗传性缺陷或存在获得性危险因素而使妊娠期容易发生血栓栓塞的疾病状态被称为易栓症(thrombophilia),也称为血栓前状态.这种血栓前状态不一定发生血栓性疾病,但可能因凝血-抗凝机制或纤溶活性失衡,子宫螺旋动脉或绒毛血管微血栓形成,导致胎盘灌注不良,甚至梗死,从而发生不良妊娠结局,其病因可分为遗传性和获得性两类.     

遗传性易栓症的妊娠期筛查与抗凝治疗评价

汉族人群遗传性易栓症以蛋白C或蛋白S缺乏为主,抗凝血酶缺乏少见,罕见凝血因子ⅤLeiden(FⅤL)突变及PGM突变。遗传性易栓症增加妊娠期血栓栓塞性疾病的风险,是胎盘介导的妊娠并发症的协同性促进因素,而不是主要病因。如果已经明确具有进行治疗的指征,没有必要再行遗传性易栓症的筛查;如果病因不明,而遗传性易栓症筛查的阳性结果可能会影响治疗决策时,筛查或许是有用的。现有证据仅表明,预防性应用低剂量阿司匹林可以减少子痫前期复发。低分子肝素是否能改善胎盘介导的妊娠并发症的再发风险,单中心和多中心研究的结论并不一致。虽然缺乏有力的证据支持,目前仍建议对具有胎盘介导的妊娠并发症病史的遗传性易栓症患者进行选择性、个体化抗凝治疗。     

蛋白S缺乏症与产科并发症研究现状

妊娠期妇女血液系统呈生理性的高凝状态,以减少分娩相关的出血并发症。易栓症是一种异常的高凝状态,蛋白S缺乏症是一种常见的遗传性易栓症。研究发现蛋白S缺乏症与产科不良妊娠结局,如复发性流产、妊娠期高血压疾病、胎儿生长受限、死胎等有着密切联系,但对于孕期蛋白S缺乏的检验指标和正常参考范围,存在着较大争议,本文对蛋白S缺乏症与产科不良妊娠结局的研究现状进行综述,以期为临床工作提供参考。     

妊娠期易栓症的临床诊断进展

易栓症是各种遗传性或获得性因素导致血栓形成和血栓栓塞倾向的病理状态,其主要临床表现是静脉血栓栓塞症(venous thromboembolism,VTE)[1]。易栓症不一定发生血栓性疾病,但可能影响子宫-胎盘循环,导致胎盘微血栓形成,从而造成不良妊娠结局。易栓症根据病因分为遗传性易栓症和获得性易栓症。     

妊娠期易栓症并发症的预防

目前易栓症与病理性妊娠的关系备受多学科关注.许多研究都显示,遗传性与获得性易栓症增加了与胎盘发生发展障碍有关的产科并发症,提高易栓症预防及处理水平能够改善与之相关的妊娠不良结局.     

遗传性血栓形成倾向与反复自然流产的研究进展

反复自然流产大约影响1%-3%生育年龄的妇女,近年来研究证明反复自然流产与血栓形成倾向/易栓症(thrombophilia)有密切的关系。易栓症引起的复杂妊娠与凝血及抗凝系统缺陷的关系成为近几年研究的热点问题,本文主要对遗传性血栓形成倾向在反复自然流产中的作用及影响进行综述。     

How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review.

OBJECTIVE: To determine whether inherited and acquired thrombophilias are associated with adverse obstetric complications. STUDY DESIGN: A systematic review; studies where women with adverse obstetric complications were tested for one or more acquired and inherited thrombophilias were included. MAIN OUTCOME MEASURES: Prevalence of thrombophilia in women with severe pre-eclampsia/eclampsia, severe placental abruption, intrauterine growth restriction or unexplained stillbirth. RESULTS: Compared with controls, placental abruption was more often associated with homozygous and heterozygous factor V Leiden mutation, heterozygous G20210A prothrombin gene mutation, homocysteinaemia, activated protein C resistance or anticardiolipin IgG antibodies. Women with pre-eclampsia/eclampsia were more likely to have heterozygous factor V Leiden mutation, heterozygous G20210A prothrombin gene mutation, homozygous MTHFR C677T mutation, protein C deficiency, protein S deficiency or activated protein C resistance compared with controls. Unexplained stillbirth, when compared with controls, was more often associated with heterozygous factor V Leiden mutation, protein S deficiency, activated protein C resistance, anticardiolipin IgG antibodies or lupus anticoagulant. Women with intrauterine growth restriction had a higher prevalence of heterozygous G20210A prothrombin gene mutation, homozygous MTHFR C677T gene mutation, protein S deficiency or anticardiolipin IgG antibodies than controls. There was wide heterogeneity in the prevalence of thrombophilia between the studies. CONCLUSIONS: Women with adverse pregnancy outcome are more likely to have a positive thrombophilia screen but studies published so far are too small to adequately assess the true size of this association. Screening for thrombophilia should not become standard practice until clear evidence emerges that thromboprophylaxis during pregnancy improves perinatal outcome. Further research into the link between the observed association, causality and heterogeneity is required.     

Inherited thrombophilias and adverse pregnancy outcome: screening and management

Inherited thrombophilias are a heterogenous group of conditions which have been implicated in a variety of pregnancy complications. Evidence is mounting that implicates these inherited disorders in a range of pregnancy outcomes, including recurrent miscarriage, late fetal loss, preeclampsia, abruptio placentae, and intrauterine growth restriction. The most commonly identified inherited thrombophilias consist of Factor V Leiden and the prothrombin gene mutation G20210A. Rarer inherited thrombophilic conditions include deficiencies of protein S, C and antithrombin. More recently, deficiency of protein Z has been linked to pregnancy complications, including preterm delivery. Clinical manifestations often are associated with the presence of more than one inherited thrombophilia, consistent with their multigenic nature. Some, but not all, studies investigating the use of heparin to prevent adverse pregnancy outcome have demonstrated a benefit. However, an adequate randomized trial is required to definitively determine whether heparin anticoagulation is the best prevention option in patients who harbor one or more inherited thrombophilias and are at risk for adverse pregnancy outcome. This review will summarize the association of thrombophilic conditions and obstetrical complications.     

Inherited thrombophilia and pregnancy with fetal loss

Maternal thrombophilia (inherited and acquired) has recently been identified as a major cause of thrombembolism (TE), but it may also contribute to adverse pregnancy outcomes and recurrent pregnancy loss. If the acquired thrombophilia is a well-established factor in etiology of fetal loss, the contribution of specific inherited thrombophilic genes is still controversial. The most common inherited traits are deficiency of antithrombin, protein C or protein S; Factor V Leiden; prothrombin G20210A; MTHFR C677T This review focuses on association of recurrent fetal loss with specific gene thrombophilic defects. Overall 52% of women with obstetric complication other than TE carry thrombophilic gene defects. The role of specific genes is different in etiology of early and late pregnancy loss. Inherited thrombophilia is now view as multicausal model; clinical manifestation can be heterogeneous result of gene-gene and gene-environment interactions. Therefore the criteria for genetic screening affected women with history of fetal loss should not be very stringent. The implication of screening for thrombophilic mutations allow to find women at risk of thrombosis and vascular gestational abnormalities in which antithrombotic drugs may have potential therapeutic benefit.     

Inheritance and perinatal consequences of inherited thrombophilia in Greece.

OBJECTIVE: To investigate the impact of inherited thrombophilic factors on the gestational outcome of unselected pregnant women. METHOD: A total of 392 women with spontaneous pregnancy were investigated for Factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations. Adverse pregnancy outcomes were recorded. RESULTS: Thrombophilic genotypes were significantly higher in women with placental abruption. Heterozygocity for Factor V Leiden increased the risk for placental abruption 9.1 times. The MTHFR T677T genotype increased the risk for placental abruption 4.8 times despite folate supplements, and normal serum folate and B(12) levels. Women with inherited thrombophilia and previous obstetric complications were at significant risk for complications in a subsequent pregnancy (P<0.05). CONCLUSION: Women with placental abruption should be screened for thrombophilic factors and plasma homocysteine should be measured. Subgroups of women with inherited thrombophilia and obstetric complications might benefit from prophylactic anticoagulation in subsequent pregnancies.     

Inherited thrombophilias in pregnant patients: detection and treatment paradigm

Inherited thrombophilias are the leading cause of maternal thromboembolism and are associated with an increased risk of certain adverse pregnancy outcomes including second- and third-trimester fetal loss, abruptions, severe intrauterine growth restriction, and early-onset, severe preeclampsia. Current information suggests that all patients with a history of prior venous thrombotic events and those with these characteristic adverse pregnancy events should be evaluated for thrombophilias. The most common, clinically significant, inherited thrombophilias are heterozygosity for the factor V Leiden and prothrombin G20210A mutations. The autosomal-dominant deficiencies of protein C and protein S are of comparable thrombogenic potential but are far less common. Homozygosity for the 4G/4G mutation in the type-1 plasminogen activator inhibitor gene and the thermolabile variant of the methylenetetrahydrofolate reductase gene, the leading cause of hyperhomocysteinemia, although relatively common, confer a low risk of thrombosis. In contrast, autosomal-dominant antithrombin deficiency and homozygosity or compound heterozygosity (ie, carriers of one copy of each mutant allele) for the factor V and prothrombin mutations are very rare but highly thrombogenic states. Regardless of their antecedent histories, pregnant patients with these highly thrombogenic conditions are at very high risk for both thromboembolism and characteristic adverse pregnancy outcomes, require full therapeutic heparin therapy throughout pregnancy, and need at least 6 weeks of postpartum oral anticoagulation. There is also compelling evidence that patients with the less thrombogenic thrombophilias and a history of venous thrombotic events or characteristic adverse pregnancy outcomes require prophylactic anticoagulant therapy during pregnancy and, in the case of prior thromboembolism, during the puerperium. Antepartum anticoagulation does not appear warranted among patients with less thrombogenic thrombophilias who are without a history of venous thromboembolism, characteristic adverse pregnancy outcomes, or other high risk factors for venous thrombosis.     

Combined inherited thrombophilia and adverse pregnancy outcome

Inherited thrombophilia has been suggested as a possible condition of increased susceptibility to adverse pregnancy outcomes. In our prospective study, we investigated the association between combined inherited thrombophilia and adverse pregnancy outcome in the South-Western Greek population. Three hundred and ninety-six healthy Greek women with spontaneous pregnancies were investigated for combinations of the three commonest thrombophilic mutations (Factor II G20210A, Factor V Leiden and MTHFR C677T) and followed for adverse pregnancy outcomes. Statistical analysis was performed by Pearson's chi-square test. Four women (1%) had the FV Leiden/MTHFR T677T double genotype and two women (0.5%) had the FII G20210A/MTHFR T677T double genotype. Although the small number of cases of combined inherited thrombophilia, it seems that the presence of FV Leiden/MTHFR T677T double genotype increases the risk for placental abruption.     

Inherited thrombophilia in pregnancy: a systematic review

The purpose of this study was to conduct a systematic review of the literature of studies that examined the association between inherited thrombophilias and adverse pregnancy outcomes. We have evaluated developments in this area published since 1998. The published studies differ widely in design, mostly in patients and controls selection and in data analytic approach. Despite the growing evidence in the literature, there are still gaps in our knowledge of thrombophilia in pregnancy, specially regarding less prevalent thrombophilic defects, such as deficiencies in antithrombin, protein C, and S. Several studies on the association on factor V Leiden showed that it may play a role not only in second trimester losses, but also in pre-eclampsia, intrauterine growth-retardation, and placental abruption. Studies on the prothrombin gene mutation yielded conflicting results. Further large prospective studies are needed to asses the relative clinical and cost effectiveness of anticoagulant therapies in the prevention of pregnancy adverse outcomes.     

Thrombophilia and women's health: An overview

Thrombophilia, whether inherited or acquired, is one of the hot topics in women's health. Several factors, some of which are specific to the female patient, enhance thrombus formation in the presence of thrombophilia and include oral contraception, hormone replacement therapy, pregnancy, and puerperium. Thrombotic events are not only restricted to venous thromboembolism but also are believed to cause repeated embryonic loss, fetal loss, placental abruption, intrauterine growth restriction, and severe pre-eclampsia. It seems that some thrombophilias, and a combination of thrombophilic factors, carry a greater risk than others for a given adverse outcome. The addition of LMWH to the armamentarium was associated with conceptual change in the practice of anticoagulation. Care should be exercised in the interpretation of various risks and the potential of anticoagulation as a remedy to reduce that risk.     

Thrombophilia and adverse pregnancy outcome

PURPOSE OF REVIEW: Recent case-control studies and metaanalyses have attempted to quantify the risks associated with individual thrombophilic defects and adverse clinical events in pregnancy, including fetal loss, preeclampsia, placental abruption and intrauterine growth restriction. This review has examined the evidence. RECENT FINDINGS: The literature is in general agreement that thrombophilia increases the risk of venous thromboembolism and adverse pregnancy outcomes, including pregnancy loss, preeclampsia, placental abruption and intrauterine growth restriction in pregnancy. However, the size of the estimated risks varies between individual studies due to heterogeneity in study design. Low-molecular-weight heparin has been shown to be the superior choice, on the grounds of safety and effectiveness, in preventing venous thromboembolism and improving pregnancy loss. Large-scale, randomized controlled studies are required, however, to confirm these findings. Although selective thrombophilia screening based on prior venous thromboembolism history has been shown to be marginally more cost-effective than universal screening in pregnancy, the overall clinical and economic benefit of universal and selective screening is unsupported. SUMMARY: Despite the growing evidence in the literature, there are still gaps in our knowledge of thrombophilia and pregnancy. In particular, accurate estimates are required of the risks of venous thromboembolism and adverse pregnancy outcomes associated with some thrombophilias and the relative clinical and cost-effectiveness of different anticoagulation therapies in the prevention of venous thromboembolism and pregnancy loss. More large-scale studies are required to better inform clinicians and help determine optimum management and prevention strategies of thrombophilia and associated adverse clinical events in pregnancy.     

The utility of thrombophilia testing in pregnant women with thrombosis: fact or fiction?

Women who either present with an episode of acute venous thrombosis in pregnancy or who have a history of venous thrombosis who present for prenatal care often undergo testing for inherited thrombophilia. The rationale for screening may include questions about whether screening for inherited thrombophilias can help to alter anticoagulation plans in a pregnancy complicated by venous thrombosis, whether patients with a history of venous thrombosis who present for care in a subsequent pregnancy require anticoagulation and at what intensity, whether knowledge of thrombophilia changes the duration and intensity of anticoagulation outside pregnancy, and whether screening of family members is warranted. Data regarding these issues are reviewed, controversies surrounding thrombophilia testing in this setting are discussed, and clinical recommendations are made.