Inherited thrombophilias

Many inherited thrombophilias have been detected and the pathophysiologic insight has increased tremendously during the last decades. Despite, however, the overwhelming observational evidence on the association between inherited thrombophilia and several women's health issues, including VTE, thus far the implications for clinical practice are uncertain. Although there is firm epidemiologic evidence that is helpful in counseling women who have inherited thrombophilia to prevent a first or recurrent VTE, the uncertainty is particularly present for women who have other pregnancy complications, such as recurrent pregnancy loss and pre-eclampsia. For this group, well-designed placebo-controlled trials to assess the harm-benefit ratio are urgently needed.     

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 thrombophilias and pre-eclampsia in Brazilian women

OBJECTIVE: The aim of the present study was to compare the distribution of G1691A, G20210A and C677T mutations in pre-eclamptic Brazilian women and in matched control women with an uncomplicated normal pregnancy. STUDY DESIGN: these mutations were investigated by PCR-RFLP in 83 normal pregnancies (control group) and in 30 pre-eclamptic pregnant women (severe form). RESULTS: G1691A mutation was detected neither in the control group nor in pre-eclamsia women. G20210A mutation was detected in heterozygosis in 3 (3.61%) control subjects, but not in pre-eclampsia group. C677T mutation was detected in homozygosis in 6 (7.23%) control subjects and 2 (6.67%) pre-eclamptic women and in heterozygosis in 31 (37.3%) control subjects and 12 (40%) pre-eclamptic women. Differences in the mutation frequencies detected in the two groups were not statistically significant. CONCLUSION: No correlation was observed between pre-eclampsia and presence of G1691A, G20210A and C677T mutations in Brazilian women.     

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。     

Acquired thrombophilias and pregnancy

Acquired thrombophilias are hypercoagulable states secondary to various aetiologies. In particular, during pregnancy the risks are exaggerated due to the underlying physiological changes. The commonest cause of acquired thrombophilia in pregnancy is antiphospholipid syndrome. Antiphospholipid syndrome (APS) is a complex multisystem disorder that has been associated with varied medical and obstetric complications. The pathogenesis of APS has been further elucidated in recent studies. The two most clinically significant antiphospholipid antibodies that are associated with recurrent pregnancy loss and thromboembolism are anticardiolipin antibodies (aCL) and lupus anticoagulant (LA). The laboratory diagnosis is based on the presence of moderate to high positive aCL and/or LA antibodies. It is crucial that APS is not inappropriately diagnosed as this has implications for counselling and management with thromboprophylaxis during pregnancy. Over the last decade there have been significant changes in the laboratory and clinical criteria for the diagnosis of APS. National and international collaborations have made efforts to standardize the laboratory methods. There have been very few randomized placebo-controlled trials of drug therapy and so not all drug treatment strategies have a strong evidence base. With current management strategies, using low-molecular-weight heparin and aspirin, a greater than 70% live birth rate may be achieved in affected pregnancies. A multidisciplinary approach in the management of these women is vital.     

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.     

Inherited thrombophilias are not increased in "idiopathic" small-for-gestational-age pregnancies

OBJECTIVE: The purpose of this study was to determine (1). whether the inherited thrombophilias (the factor V Leiden and prothrombin gene mutations and the methylenetetrahydrofolate reductase [C677T] polymorphism) are increased in women with "idiopathic" (normotensive) small-for-gestational-age pregnancies and/or in their babies and (2). whether fetal carriage of a thrombophilia is associated with abnormal umbilical Doppler studies. STUDY DESIGN: This was a case-controlled study of normotensive women who were delivered of a singleton small-for-gestational-age baby (birth weight, <10th percentile adjusted for sex) with no clinical evidence of chromosomal or congenital abnormality. Control subjects were healthy women who were delivered of appropriate-for-gestational-age babies. RESULTS: One hundred forty-five women with small-for-gestational-age pregnancies and 290 control subjects were recruited. Small-for-gestational-age babies were born at an earlier gestational age (38 +/- 3.0 weeks) and with a lower birth weight (2373 +/- 521 g) than control babies (39.7 +/- 1.3 weeks and 3606 +/- 423 g, P <.01). There were no differences in the rates of factor V Leiden (2.8% vs 3.8%; relative risk, 0.79; 95% CI, 0.34-1.85), prothrombin gene mutation (2.8% vs 3.1%; relative risk, 0.92; 95% CI, 0.40-2.09), and methylenetetrahydrofolate reductase C677T polymorphism (13% vs 9%; relative risk, 1.27; 95% CI, 0.87-1.84) between mothers with small-for-gestational-age babies and control subjects, respectively. Inherited thrombophilias were not increased in small-for-gestational-age babies compared with control babies. Of small-for-gestational-age babies with abnormal umbilical artery Doppler studies (n = 25), 21% had a thrombophilia compared with 11% with normal umbilical artery Doppler studies (n = 68; relative risk, 1.75; 95% CI, 0.81-3.81). CONCLUSION: The rates of these inherited thrombophilias are not increased in normotensive women with small-for-gestational-age pregnancies. Further studies are required to determine whether thrombophilias are increased in small-for-gestational-age babies with abnormal umbilical Doppler study results.     

Double versus single thrombophilias during pregnancy

Objective: The primary objective of this study was to evaluate whether women with double thrombophilias have a greater risk for obstetric complications as compared with women who have single thrombophilias.

Study design: This is a retrospective cohort study of all patients in a single practice with a clinically significant inherited thrombophilia and treated with anticoagulation between 2005 and 2013. Thrombophilias evaluated include: factor V Leiden, prothrombin G20210A gene mutation, protein S deficiency, protein C deficiency, and antithrombin III deficiency. Double thrombophilia was defined as the presence of two thrombophilias or homozygosity for factor V Leiden or prothrombin Gene Mutation. Demographic and obstetrical outcome data were collected. Data on all patients with double thrombophilias who met inclusion criteria was reported. Data was then compared between the patients with double thrombophilias and single thrombophilias with singleton gestations. The data was analyzed with Pearson’s chi-squared or Student’s t-test as appropriate with p value <.05 used for significance.

Results: Eighteen patients with clinically significant double thrombophilias who met inclusion criteria were identified. Most patients delivered full term (88.9%) and appropriate for gestational age (77.8%) infants. One hundred thirty-two patients with single thrombophilias and 14 patients with double thrombophilias with singleton gestations were then compared. Demographic characteristics were not significantly different between the two groups. There were no significant differences in obstetrical outcomes between patients.

Conclusions: There were no significant differences in obstetrical outcomes for patients with clinically significant double thrombophilias versus single thrombophilias when treated with anticoagulation.     

Single inherited thrombophilias and adverse pregnancy outcomes

INTRODUCTION: Inherited thrombophilia is believed to be a multiple gene disease with more than one defect. We aimed to determine the association between single thrombophilic patterns and a variety of pregnancy diseases. METHODS: 284 pregnant women were recruited for the present study and were divided in two groups: A group (176 controls) and B group (108 cases). Patients belonging to the B group had one of the following: severe pre-eclampsia, hemolysis, hepatic enzymes increase, hypertension and low platelet count (HELLP) syndrome, gestational hypertension, fetal growth restriction, intrauterine death, abruptio placentae and disseminated intravascular coagulopathy. To detect methylenetetrahydrofolate reductase (MTHFR) A1298C, MTHFR C677T, factor V Leiden, PAI-1, mutant prothrombin G20210A, an inverse hybridization technology was used. Plasma homocysteine, antithrombin (AT) III and protein S were determined. A modified functional activated protein C resistance was detected. RESULTS: MTHFR C677T and hyperhomocysteinemia were more prevalent than other thrombophilias. Deficiency in AT III was significantly linked with pre-eclampsia (relative risk 0.88; 95% CI 0.83-0.94). Activated protein C resistance (APCR) was significantly related to the abruptio placentae (relative risk 0.71; 95% CI 0.61-0.82). COMMENTS: Apart from the linkage between AT III deficiency and the occurrence of pre-eclampsia, and apart from the increased risk of abruptio placentae in pregnant women with altered APCR, we obtained findings in contrast with some of the published literature. In our case series, no association of pre-eclampsia with factor V Leiden or with prothrombin gene mutation was found.     

Inherited thrombophilia and pregnancy

Inherited thrombophilia include deficiences of antithrombin III, protein C and protein S, and the factor V Leiden mutation, the prothrombin gene variant, and homozygosity for the thermolabile variant of methylenetetrahydrofolate reductase (MTHFR). The incidence of thromboembolism events during pregnancy and postpartum period among women with thrombophilia is not well known and depends on the prethrombotic state resulting from the interaction of the underlying thrombophilic defect(s), history of congenital thrombophilia, and additional risk factors. In that way, many patients with congenital thrombophilia will require antenatal thromboprophylaxis, the timing of which will depend on the patient's history and thrombophilic disorders. Low molecular weight heparin appeared to be a safe alternative to unfractionated heparin for both the fetus and the mother during the pregnancy. Case-control studies have recently demonstrated that serious obstetrical complications i. e severe preeclampsia, abruptio placentae, intrauterine growth restriction, and stillbirth were frequently associated with inherited thrombophilia. Controlled trials are now urgently needed to determine the possible potential benefits of anticoagulant therapy in pregnancy outcome. Finally, there is no evidence to support routine screening for congenital thrombophilia during pregnancy.     

Inherited bleeding disorders in pregnancy

Women with inherited bleeding disorders in pregnancy are a group of pregnant women with varied and often complex healthcare needs. The antenatal, intrapartum and postnatal care of these women and their babies may require specialist planning and support. This article outlines the key principles of care and provides a summary of the existing Royal College of Obstetricians and Gynaecologists’ guidelines on the management of inherited bleeding disorders in addition to practical advice from clinical experience of looking after these women and their pregnancies.     

Inherited bleeding disorders in pregnancy

Women with inherited bleeding disorders may face several haemostatic challenges during pregnancy and childbirth. Pregnancy in these women requires specialised and individualised care. Prenatal diagnosis is primarily considered in families affected by severe bleeding disorder such as haemophilia. Non-invasive fetal sex determination by analysis of free fetal DNA in maternal blood offers carriers of haemophilia a means of avoiding invasive testing and its associated risks in female pregnancies. With the exception of fibrinogen and factor XIII deficiencies, it is currently unclear whether women with inherited bleeding disorders are at increased risk of miscarriage or antepartum haemorrhage. However, they are at increased risk of primary and secondary postpartum haemorrhage. The fetus, if severely affected, is at risk of cranial bleeding during labour and delivery. Appropriate haemostatic cover during labour and delivery, avoidance of prolonged labour and traumatic delivery, and active management of third stage of labour can minimise the risk of bleeding complications for the mother and her fetus.     

Perinatal outcome in women with severe pregnancy complications and multiple thrombophilias

Hypercoagulability leading to placental thrombosis has been implicated in severe pregnancy complications. We compared the perinatal outcome in women with severe preeclampsia, intrauterine growth retardation (IUGR) and severe abruptio placentae and multiple acquired and inherited thrombophilias (study group, n=22) to matched women with similar complications and single thrombophilia (control group, n=22). Gestational age at delivery and birth weight were significantly lower in the study group compared to the control group (p<0.01) and among the study women with severe preeclampsia and IUGR. Severe pregnancy complications may occur earlier during pregnancy and more seriously affect perinatal outcome in women with multiple thrombophilias.     

Practice bulletin no. 124: inherited thrombophilias in pregnancy

Inherited thrombophilias are associated with an increased risk of venous thromboembolism and also have been linked to adverse outcomes in pregnancy. However, there is limited evidence to guide screening for and management of these conditions in pregnancy. The purpose of this document is to review common thrombophilias and their association with maternal venous thromboembolism risk and adverse pregnancy outcomes, indications for screening to detect these conditions, and management options in pregnancy.     

Inherited thrombophilia and poor pregnancy outcome

Gestational vascular complications are a major cause of maternal and fetal morbidity.A growing body of evidence suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. While the majority of women with thrombophilia will have an uneventful gestation, case-control studies demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss and early-onset pre-eclampsia. Placental abruption and severe intrauterine growth restriction (IUGR) may also be associated with thrombophilia. Placental pathological findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition potentially to a greater degree than in normal pregnancy. Preliminary non-randomized studies suggest a benefit for prophylaxis with unfractionated and low-molecular-weight heparin (LMWH), and prospective randomized trials are in progress to define whether LMWH is effective in preventing pregnancy loss and other gestational vascular complications in women with thrombophilia and previous fetal wastage.     

Screening and management of inherited thrombophilias in the setting of adverse pregnancy outcome

Inherited thrombophilic conditions are associated with adverse pregnancy outcomes, including severe pre-eclampsia, fetal loss, abruptio placentae, and intauterine growth restriction. Although the prevalence of these complications is approximately 8% in the general population, their presence is associated with a significantly increased recurrence risk. Thrombophilic conditions most strongly associated with adverse pregnancy outcome include factor V Leiden, prothrombin gene mutation, and deficiencies of protein S, protein C, and antithrombin. Other thrombophilic conditions, such as protein Z deficiency, also appear to be associated with an increased risk of pregnancy complications. Antenatal administration of heparin to prevent pregnancy complications has shown promise in small studies, but a randomized, placebo-controlled trial is necessary to determine whether heparin administration is beneficial in preventing adverse pregnancy outcome.