Inherited thrombophilia and pregnancy loss

A growing body of evidence obtained during the past 6 years suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. Case-control and cross-sectional studies have demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss.Placental pathological findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition. Preliminary case-control studies suggest that low-molecular-weight heparins (LMWH) are effective in preventing pregnancy loss in women with thrombophilia and previous fetal wastage.     

如何正确看待复发性流产中的易栓因素

易栓症是复发性流产多种病因中的一类。易栓症包括获得性易栓症(即抗磷脂综合征)和遗传性易栓症。抗磷脂综合征是目前唯一得到广泛认可、与复发性流产明确相关的易栓因素,但是其诊断应满足相应的分类标准及标准外定义,治疗应遵从循证医学证据及指南。现有证据不足以证实遗传性易栓症与不良妊娠结局的相关性,不建议在既往不良孕产史的患者中常规检测抗凝蛋白活性。对于明确诊断的遗传性易栓症患者,妊娠期间抗凝的目的是预防血栓形成。血小板聚集率与复发性流产的相关性目前尚不明确。     

Acquired thrombophilia in pregnancy: essential thrombocythemia

The management of pregnant patients with essential thrombocythemia (ET) is a difficult problem. The clinical course of ET is mainly determined by thromboembolic complications. Pregnancy itself is a physiological hypercoagulable state. When ET affects women during pregnancy, an adverse outcome caused by thrombotic complications is a matter of concern. We reviewed 155 pregnancies in 86 women with ET. The success rate (baby alive) was 59%. First-trimester abortion was the most frequent complication and occurred in 31% of pregnancies. Placental infarction caused by thrombosis seemed to be the most consistent pathologic event. Maternal thrombotic or hemorrhagic complications were rare but were more common than those seen in normal pregnancy. Pregnancy itself does not appear to affect adversely the natural course and prognosis of ET. A meta-analysis revealed a significant benefit for aspirin in comparison to no treatment. If cytoreductive therapy becomes necessary, interferon alpha appears to be the drug of choice. The value of heparin prophylaxis has not been established but may have a role in selected cases.     

Management of thrombophilia in pregnancy

Thromboembolism remains a major cause of maternal morbidity and mortality. The incidence of thrombosis associated with pregnancy is stated to be around 0.09%1 but is greater in women with familial or acquired thrombophilia. Around 50% of pregnancies in women with antithrombin III deficiency are complicated by thrombosis. Anticoagulation throughout pregnancy and the puerperium is recommended in women with antithrombin III deficiency. Because thrombosis is less common in women with protein C or protein S deficiency less aggressive management may be appropriate during pregnancy but anticoagulation post partum is generally recommended. The most important acquired thrombophilic abnormality is the development of antiphospholipid antibodies ('lupus anticoagulants'). Women with these antibodies may present major problems but no clear guidelines for their management currently exist. The majority of women with a history of thrombosis have no identifiable haemostatic abnormality. Management of pregnancy in these patients depends on individual circumstances.     

Recurrent pregnancy loss and autoantibody profile in autoimmune diseases

OBJECTIVE: To explore the association of non-organ-specific autoimmune responses against three distinct Ro antigen-related reactivities (Ro52, Ro60, p57) with a history of pregnancy loss in women with autoimmune disorders. Materials and methods. Seventy unselected anti-Ro/SSA-positive women were studied in a retrospective cohort study. Forty anti-Ro/SSA-positive women were age matched to an equal number of women with autoimmune disorders who were anti-Ro/SSA negative in a case-control study. The association of reactivities against three distinct antigen specificities (Ro52, Ro60, p57) with recurrent pregnancy loss was investigated. Independence and modification of these associations from the effect of antithyroglobulin, antithyroid peroxidase and anticardiolipin antibodies were also examined. RESULTS: In the cohort study, reactivity against each of the three antigen specificities (Ro52, Ro60, p57) was independently associated with a history of recurrent pregnancy loss. In the case-control study, the effects were still independent and were not modified when other autoantibodies were considered. In particular, the number of reactivities against Ro52, Ro60 and p57 peptides, and the presence of antithyroglobulin antibodies, were independent predictors of recurrent pregnancy loss (odds ratios 3.35 per each additional reactivity and 5.54 in the presence of antithyroglobulin; P=0.002 and 0.025, respectively). CONCLUSIONS: In women with autoimmune disorders, a history of recurrent pregnancy loss is independently associated with reactivity against each of the three antigen specificities (Ro52, Ro60, p57) and also with the presence of antithyroglobulin antibodies, suggesting that cumulative autoimmune responses against these non-organ-specific and organ-specific antigens correlate with the risk of stillbirth and spontaneous abortion.     

Pregnancy loss and thrombophilia: the elusive link

Recurrent pregnancy loss (RPL) affects 1% pregnancies and is multi-factorial in origin. The role of the acquired thrombophilia antiphospholipid syndrome (APS) as a common and potentially treatable cause of RPL is well established but this is less so for inherited thrombophilia. In obstetric APS the combination of aspirin and heparin has improved outcomes. By analogy, the use of low molecular weight heparin (LMWH) has become commonplace in women with inherited thrombophilia and also those with unexplained miscarriage to help safeguard the pregnancy. This review will examine the pathophysiological role of thrombophilia in pregnancy loss, and the evidence for anticoagulant-based intervention. The limited data supporting the use of heparin for women with RPL and inherited thrombophilia suggests adoption of a more cautious and judicious approach in this setting.     

Inherited thrombophilia and fetal loss

Acquired thrombophilia is a well-established cause of pregnancy loss. Increasing numbers of recent observations suggest that inherited thrombophilia is not only associated with gestational thromboembolism but is also a major cause of fetal loss. This review focuses on association of fetal loss with inherited thrombophilias, including dysfibrinogenemia and protein C, protein S, and antithrombin III deficiencies. Activated protein C resistance and factor V Leiden mutation are frequent causes of pregnancy loss. Thrombophilic states such as factor V Leiden and hyperhomocysteinemia may also play a role in other gestational vascular complications, including intrauterine growth restriction, preeclampsia, and placental abruption. Preliminary reports suggest that antithrombotic therapy may be of value in this setting. The potential application of antithrombotic modalities to prevent fetal loss in women with thrombophilia is discussed.     

Prophylaxis and treatment of thrombophilia in pregnancy

PURPOSE OF REVIEW: This review addresses the prophylaxis and treatment of thrombophilia in pregnancy, which is associated with increased risk of venous thromboembolism and placental vascular complications. RECENT FINDINGS: Topics include preventing deep vein thrombosis recurrence in pregnant women with constitutional thrombophilias, using prophylactic heparins throughout pregnancy and postpartum anticoagulants. Cases of thrombosis still occur in the postpartum period and other therapeutics should be tested. Primary prophylaxis is acceptable for high-risk thrombophilias. Early pregnancy losses (before the 10th week) are not associated with constitutional thrombophilias. The natural prognosis of embryonic losses associated with current thrombogenic polymorphisms is good, unlike fetal losses associated with the same thrombophilias: in this case, a prophylactic low-molecular-weight heparin given from the beginning of the 8th week is more efficient than low-dose aspirin. Data are lacking on the prevention of severe preeclampsia, placental abruption, or intrauterine growth restriction in women with constitutional thrombophilias; preliminary results indicate that low-molecular-weight heparin may have some preventive effect. Specific studies are needed. SUMMARY: Recent studies have shown the limits of available procedures for women with constitutional thrombophilia and have helped define the clinical situations in thrombophilia-related placental insufficiency in which prophylactic low-molecular-weight heparin may be indicated.     

Multifactorial thrombophilia in a pregnancy: a case report.

Thrombophilias are inherited or acquired conditions that predispose individuals to thromboembolism. Thrombophilic disorders increase obstetric complications, such as early pregnancy loss, fetal growth retardation, placental abruption, and preeclampsia. Recurrent pregnancy loss affects 1% to 3% of women of reproductive age, and a large proportion of these losses remain unexplained. Thrombophilic defects were found in 49% to 65% of women with pregnancy complications compared with 18% to 22% of women with normal pregnancies, suggesting a 3- to 8-fold increase in risk. We report a case of a pregnant woman who had a history of recurrent pregnancy losses that was complicated with protein S deficiency, factor V Leiden mutation, methylene tetrahydrofolate reductase mutation, and antiphospholipid syndrome in her pregnancy.     

Recurrent intracardiac thrombosis as an unusual manifestation of inherited thrombophilia

Patients with inherited thrombophilia are at high risk for the development of venous thrombosis that manifests mainly as deep venous thrombosis of the legs and/or pulmonary embolism. We report spontaneous right-sided intracardiac thrombosis in a young man as an unusual manifestation of inherited thrombophilia. The diagnosis of thrombophilia was confirmed by demonstration of the prothrombin-G20210A-mutation in the homozygous state. A second spontaneous intracardiac thrombosis occurred 3 years after discontinuation of oral anticoagulant treatment. This indicates the high risk for recurrence in patients developing intracardiac thrombosis in the absence of an underlying cardiac disease and warrants long-term oral anticoagulant treatment.     

Recurrent pulmonary embolism secondary to hereditary thrombophilia (case report)

Pulmonary embolism is seen commonly but diagnosed difficulty and has high mortality. There are too many risk factors that have been described for pulmonary embolism. However, the hereditary factors are important risk factors for the cases especially with recurrent pulmonary embolism. In our case who had been diagnosed as pulmonary embolism three times before and treated with anticoagulants, because of the recurrent pulmonary embolism, the genetic risk factors were investigated. Homozygous factor V Leiden mutation, deficiency of protein S and hyperhomocysteinaemia were determined in our case. In addition, in the investigation of the family, protein S, protein C and factor V Leiden mutation were determined in all three daughters of our case. Since our patient has recurrent pulmonary embolism and has more than one genetic risk factors, anticoagulant treatment was planned for lifelong. Recurrent thromboembolism is too important because of threatening the life. Identification of the genetic risk factors that result in increased tendency to thrombosis has important implications for the patients and their families.     

Screening and treatment for heritable thrombophilia in pregnancy failure: inconsistencies among UK early pregnancy units

The significance of heritable thrombophilia in pregnancy failure is controversial. We surveyed all UK Early Pregnancy Units and 70% responded. The majority test routinely for heritable thrombophilias; 80%, 76% and 88% undertook at least one screening test in late miscarriage, recurrent miscarriage and placental abruption, respectively. The range of thrombophilias sought is inconsistent: testing for proteins C and S deficiency and F5 R506Q (factor V Leiden) is most prevalent. Detection of heritable thrombophilia frequently leads to administration of antithrombotics in subsequent pregnancies. Thus, thrombophilia testing and use of antithrombotics are widespread in the UK despite controversies regarding the role of heritable thrombophilia in the pathogenesis of pregnancy complications, and the lack of robust evidence for the efficacy of antithrombotic therapy.     

Inherited thrombophilia, pregnancy, and oral contraceptive use: clinical implications

Inherited thrombophilia has been reported to be associated with an increased risk for complications of pregnancy, including venous thromboembolism (VTE) as well as preeclampsia (PEC), fetal loss (FL), fetal growth retardation (FGR), and abruptio placentae (AP), the latter probably due to inadequate placental perfusion. The estimate of risk largely depends on the kind of thrombophilia and on the criteria applied for the selection of the patients, producing in some cases contradictory results. Convincing evidence is available that deficiency of antithrombin III (AT), protein C (PC), and protein S (PS) is a risk factor for VTE and late FL. Factor V (Leiden) is associated with an increased risk for VTE, unexplained recurrent FL, late FL, and perhaps PEC; prothrombin G20210A is a weak risk factor for VTE. So far, the data available for FGR and AP are scarce. However, the absolute risk for VTE during pregnancy and puerperium is between 1 and 3%, in comparison with the baseline risk of 0.08%. Antithrombotic prophylaxis with subcutaneous heparin is warranted during puerperium in all women with thrombophilia and throughout all pregnancy in women at higher risk (AT deficiency, homozygosity for factor VLeiden, and perhaps PC and PS deficiencies); treatment with subcutaneous heparin for prevention of FL among women with thombophilia is under investigation. Presence of inherited thrombophilia increases the risk for VTE due to oral contraceptives up to an absolute risk of 3 per 1000 person-years, in comparison with the baseline risk of 3 to 6 per 10000 person-years; the risk is further increased by first usage, the use of preparations containing third-generation progestins, and thrombophilia due to AT, PC, and PS deficiency as well as homozygous factor V (Leiden) and combined defects.     

Arrhythmias in pregnancy: etiology and perinatal outcomes

We analysed 132 case forms of pregnant women who delivered in a special maternity hospital for patients with cardiovascular diseases. Complex disorders of heart rhythm (paroxysmal supraventricular tachycardia, atrial fibrillation, frequent ventricular extrasystoles, and II - III degree atrioventricular block) were revealed in 64 (48.5%) of women. Etiological factors of these arrhythmias and blocks in 50% of cases were organic and functional derangements of cardiovascular system. In other 50% of cases causes of heart rhythm disorders were not established and they were classified as idiopathic. Perinatal outcomes in women with arrhythmias and blocks were worse than in women without this pathology. They appeared as intrauterine retardation of fetus development and various derangements of central nervous system in newborns.