Inherited thrombophilia and venous thromboembolism

Pulmonary thromboembolism (PTE) is the major cause of maternal death in the UK. Underlying PTE is the problem of deep venous thrombosis (DVT). Inherited thrombophilia will be found in about 50% of women with a personal history of venous thromboembolism (VTE), and screening for thrombophilia should be considered in women with a personal or family history of VTE. There is currently no place for universal screening for thrombophilia in pregnancy. There are particular considerations with regard to the management of thrombophilia in pregnancy. Low-molecular-weight heparins are now the heparin of choice in pregnancy because of a better side-effect profile (substantially reduced risk of heparin-induced osteoporosis and heparin-induced thrombocytopaenia) compared to unfractionated heparin, good safety record for mother and fetus and convenient once-daily dosing for prophylaxis.     

Prothrombin 20210 G-->A, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy

Over 50 unselected women with maternal venous thromboembolism were screened for the prothrombin 20210 G→A and MTHFR C677T mutations, in addition to screening for other thrombophilias. The prevalence of thrombophilia in these women was compared with its prevalence in the general population in our area. The prothrombin (OR 4.4; 95% CI 1.2-16) and factor V Leiden (OR 4.5; 95% CI 2.1-14.5) mutations were more common in our patients, compared with the general population, whereas women homozygous for the C677T mutation in the methylene tetrahydrofolate reductase gene (OR 0.45; 95% CI 0.13-1.58) were not. It is recommended that women with a personal or strong family history of venous thromboembolism should be screened for the prothrombin mutation either before or early in pregnancy, in addition to screening for other thrombophilias. Screening for the MTHFR mutation does not appear to identify women at increased risk of maternal venous thrombosis.     

Hormone replacement therapy, thrombosis and thrombophilia

Hormone replacement therapy increases the risk of venous thromboembolism. The risk is already increased in those with a personal or family history of thrombosis and in those with a hereditary thrombophilia. This article gives estimates of the absolute risk of using hormone replacement therapy and practical advice on its use in these groups and on the role of thrombophilia screening.     

Thromboembolism in pregnancy

PURPOSE OF REVIEW: Venous thromboembolism is the leading cause of maternal death in the UK. Thrombophilia underlies many thrombotic disorders in pregnancy. The high prevalence of thrombophilic defects in the population, the association of defects with venous thromboembolism and the special considerations for management make it a widely debated subject. RECENT FINDINGS: A limited number of studies measuring the risk of venous thromboembolism in pregnancy with thrombophilia have been conducted within the last year. Studies confirm that heritable thrombophilias are associated with increased risk of venous thromboembolism in pregnancy. However, estimated risks vary between individual studies. The risk of venous thromboembolism with acquired thrombophilia remains unclear. Guidelines have been published to guide clinicians in preventing and treating venous thromboembolism in pregnancy; however, large-scale, randomized controlled trials need to be conducted to establish the effectiveness of administering antithrombotic agents in pregnancy. Although selective thrombophilia screening based on prior history of venous thromboembolism has been proposed, the overall clinical and economic benefit of universal and selective screening is unsupported. SUMMARY: Due to the lack of studies, gaps still exist in our knowledge of the risk of pregnancy-related venous thromboembolism associated with thrombophilia. In particular, accurate estimates are required for the risks of acquired thrombophilias. Furthermore, the true effectiveness of anticolagulants in pregnancy needs to be established through well-conducted studies and randomized controlled trials. These studies will inform clinicians and help to determine the optimum management and prevention strategies for thrombophilia and venous thromboembolism in pregnancy.     

Venous thromboembolism in pregnancy

Venous thromboembolism remains a common cause of direct maternal deaths in high-income settings such as the United Kingdom. Pregnancy alone increases the risk of deep vein thrombosis and pulmonary embolus at least five-fold, and many women develop or have additional risk factors for venous thrombosis during pregnancy and the puerperium, the latter representing the period of highest risk. Early and repeated risk stratification and adequate thromboprophylaxis, usually with low molecular weight heparin, is the key to preventing venous thromboembolism (VTE). Women with a past history of VTE, and those affected by thrombophilia, require multidisciplinary care involving an obstetric haematologist. Women suspected of having acute thromboembolism should be commenced on empirical treatment promptly prior to diagnostic confirmation. Pulmonary embolism should be considered as a differential diagnosis in maternal collapse.     

Low-molecular-weight heparins for the prevention and treatment of venous thromboembolism in at-risk pregnant women: a review

Certain pregnant populations are at high risk of developing venous thromboembolism (VTE) during pregnancy. Patients at particularly high risk of VTE are those with a history of VTE, thrombophilia or adverse pregnancy outcomes or with mechanical heart valves. In these high-risk patients, evidence-based guidelines recommend the use of thromboprophylaxis. Low-molecular-weight heparin (LMWH) is a safe and effective thromboprophylaxis option in these patients and has a number of administrative and pharmacokinetic advantages over unfractionated heparin. Furthermore, LMWH has also been shown to be a safe and effective treatment for confirmed deep vein thrombosis in pregnant women.     

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.     

Antithrombin III deficiency in pregnancy

Thromboembolism is one of the most significant and common medical problems occurring during pregnancy. Some pregnant women are at a higher risk of thromboembolism because of inheritable hypercoagulable states. Antithrombin III deficiency is one of the inheritable coagulable states that may lead to an increase in thromboembolism during pregnancy. It is inherited as an autosomal dominant condition and should be thought of when a patient gives a personal history or a strong family history of thromboembolism. Treatment consists of anticoagulation with Heparin throughout pregnancy until delivery at which time the patient can be managed with either Heparin or Antithrombin III concentrates. Women with Antithrombin III deficiency during pregnancy should be counseled regarding the risks of transmission to their offspring.     

Inherited thrombophilias and anticoagulation in pregnancy

Thromboprophylaxis, primary or secondary, should be considered in selected pregnant women with inherited thrombophilias; such women may be divided into high-, medium- and low-risk categories on the basis of the specific thrombophilic defect and any personal or family history of venous thromboembolism (VTE). Women at high risk of VTE should receive treatment doses of low-molecular-weight heparin (LMWH) throughout pregnancy and should remain on anticoagulation for 6 weeks postpartum, or, where appropriate, long-term. Women at moderate risk should be treated with prophylactic fixed-dose LMWH throughout pregnancy and for 6 weeks postpartum. Women at low risk should receive prophylactic fixed-dose LMWH for 6 weeks postpartum, and low-dose aspirin LDA should be considered during pregnancy. LWMH offers important advantages over unfractionated heparin (UFH); heparin-induced thrombocytopaenia (HIT) and osteopaenia are rarely seen. For treatment doses of LMWH, dosage adjustment based on anti-Xa levels is usually required as pregnancy progresses. Warfarin should be avoided throughout pregnancy. LMWH, UFH and warfarin are safe for breast-feeding mothers.     

PREVENTION AND TREATMENT OF VENOUS THROMBOEMBOLISM (VTE) IN OBSTETRICS

OBJECTIVE: to identify risk factors for venous thromboembolism (VTE) in the peripartum period and to provide guidelines for risk assessment and thromboprophylactic measures for VTE in pregnant women. Guidelines for diagnostic testing and for acute and long term treatment of VTE are also provided.OPTIONS: specific subgroups of pregnant women are defined and appropriate prophylactic measures are outlined. OUTCOMES: venous thromboembolism remains a major cause of morbidity and mortality in pregnancy and the postpartum period. Identification of risk and adequate prophylaxis can decrease the incidence of VTE.EVIDENCE: evidence was gathered using Medline (National Library of Medicine) to identify relevant studies and from bibliographies of articles thus identified.RECOMMENDATIONS: although evidence is lacking to date from Grade I studies (properly controlled randomized studies) in pregnant patients, there is good evidence to support the role of prophylaxis in reducing the incidence of VTE in patients identified to be at risk in the non-pregnant population (II B). Based on risk assessment more patients should be considered for thromboprophylaxis, including women with a past history of a VTE and a known thrombophilia on long-term anticoagulation, women with a past history of a VTE, women with a known thrombophilia who have never experienced a VTE and potentially considered in women at the time of Caesarean section (II B; III C). The occurrence of VTE is effectively reduced by the use of low dose unfractionated heparin. Experience with low molecular weight heparin and pregnancy is building, but is limited at present. Unfractionated heparin remains the standard for the treatment of VTE in pregnancy at the present time. Following initial heparinization for the treatment of VTE, patients should be continued on anticoagulation throughout pregnancy and for six to 12 weeks postpartum or a total of three months of anticoagulation (II A).     

Acquired and inherited thrombophilia disorders in pregnancy

Thromboembolism is the leading cause of antepartum and postpartum maternal mortality. The presence of antiphospholipid antibodies is responsible for many pregnancy losses and other morbidities in pregnant women, and is the most prevalent and treatable cause of acquired thrombophilia in pregnancy. There is also evidence that women with thrombophilia are at increased risk not only of pregnancy-related venous thromboembolism but other vascular pregnancy complications. Many studies have examined the association between thrombophilia and pregnancy complications. This article reviews the most up-to-date knowledge of prevalence, pathogenesis, and diagnosis of acquired and inherited thrombophilias and their relationship and association with pregnancy complications.     

Anticoagulant prophylaxis in women affected by thrombophilia and previous obstetric complications

Pregnancy is a condition of excessive clotting due to a decrease of some coagulation factors and a reduction of anticoagulant proteins, such as protein S. It is known that the causes of congenital or acquired thrombophilia may be associated with an increased risk of venous thromboembolism during pregnancy and/or obstetric complications, such early or late fetal loss, intrauterine fetal deaths, pre-eclampsia, fetal growth restriction. During pregnancy the use of a prophylaxis with antithrombotic drugs is considered at present a promising opportunity to significantly reduce the prevalence of thromboembolic complications, improving maternal and fetal outcomes. This article is a review to most recent evidence of pregnant anticoagulant prophylaxis in women with previous thromboembolic events.     

Practice bulletin no. 123: thromboembolism in pregnancy

Pregnant women have a fourfold to fivefold increased risk of thromboembolism compared with nonpregnant women (1, 2). Approximately 80% of thromboembolic events in pregnancy are venous (3), with a prevalence of 0.5–2.0 per 1,000 pregnant women (4–9). Venous thromboembolism, including pulmonary embolism, accounts for 1.1 deaths per 100,000 deliveries (3), or 9 % of all maternal deaths in the United States (10). In the developing world, the leading cause of maternal death is hemorrhage (11); however, in developed nations, where hemorrhage is more often successfully treated and prevented, thromboembolic disease is one of the leading causes of death (12). The prevalence and severity of this condition during pregnancy and the peripartum period warrant special consideration of management and therapy. Such therapy includes the treatment of acute thrombotic events and prophylaxis for those at increased risk of thrombotic events. The purpose of this document is to provide information regarding the risk factors, diagnosis, management, and prevention of thromboembolism, particularly venous thromboembolism in pregnancy.     

Prevention and treatment of venous thromboembolism in pregnancy

During pregnancy, women have a 4- to 5-fold increased risk of thromboembolism. Candidates for anticoagulation in pregnancy include women with current thrombosis, a history of thrombosis, risk factors for postpartum thrombosis, and some women with thrombophilia and a history of poor pregnancy outcome. Although, there are no large trials of anticoagulants in pregnancy and recommendations for their use are based on case series and the opinion of experts, observational studies demonstrate the benefit of heparins in reducing the risk of recurrent thromboembolism in pregnancy. A practical approach to the prevention and treatment of thromboembolism in pregnancy is outlined.     

Thromboprophylaxis during pregnancy and the puerperium: highlights from current guidelines

Venous thromboembolism (VTE) is one of the leading causes of maternal deaths worldwide. Mortality and morbidity of VTE are potentially preventable, since two-thirds of these women have identifiable risk factors and may benefit from appropriate thromboprophylaxis. Individual and careful assessment of the personal and family history as well as the assessment of pre-existing and new-onset/transient risk factors during pregnancy and after delivery are mandatory for an effective prevention of VTE. Current guidelines (American College of Chest Physicians 2008, AWMF-Guideline 003/001 2009 and the Royal College Guideline No. 37 2009) provide practical recommendations for risk stratification regarding low, intermediate and high risk conditions. At high risk are women with previous VTE or thrombophilia. Corresponding to risk stratification grade C recommendations have been made for VTE prophylaxis during pregnancy and the puerperium. Prophylaxis with low molecular weight heparin (LMWH) should begin as early in pregnancy as practical. In women with lower risk mobilisation, avoidance of dehydration and mechanical methods (e. g., graduated compressive stockings) are sufficient. After delivery women with intermediate risk should be given LMWH for 7 days, women at high risk for 6 weeks or as long as additional risk factors are present. All women who have additional risk factors and who have had an elective Caesarean section should receive prophylactic LMWH for 7 days as should also all women who have had a Caesarean section in labour or an emergency Caesarean section. At the onset of labour, in case of any vaginal bleeding, prior to induction of labour or 12 h before an elective Caesarean section, antenatal LMWH prophylaxis should be discontinued, LMWH prophylaxis can be continued for 4-6 h after vaginal and for 6-12 h after Caesarean delivery when the women do not have an increased risk of haemorrhage. Current guidelines recommend than LMWH are the agents of choice for antenatal thromboprophylaxis; in comparison to unfractionated heparin, LMWH are associated with a substantially lower risk of heparin-induced thrombocytopenia and osteoporosis. Both oral anticoagulants and heparin are safe when breast-feeding.     

Severe Preeclampsia Associated with Coinheritance of Factor V Leiden Mutation and Protein S Deficiency

Background: Inherited thrombophilic disorders are associated with an increased risk of venous thromboembolism during pregnancy. Preliminary research suggests that these disorders might also increase the risk for preeclampsia.Case: A 29-year-old primigravida developed severe, early onset preeclampsia and postpartum deep venous thrombosis. Subsequent testing revealed coinheritance of the factor V Leiden mutation and protein S deficiency. Heparin prophylaxis was administered during two subsequent pregnancies without recurrence of either preeclampsia or venous thromboembolism.Conclusion: Our patient’s inherited thrombophilia may have played a role in the development of preeclampsia, and anticoagulation during subsequent pregnancies may have prevented preeclampsia recurrence. An association between inherited thrombophilic disorders and preeclampsia is biologically plausible.     

Hormontherapie bei Thrombophilie

Female sexual steroids influence coagulation and fibrinolysis in different ways leading to an increased risk of thrombosis during pregnancy, confinement as well as during intake of oral contraceptives and hormonal therapy. Furthermore, a correlation between age and thrombotic risk is well known. Although hereditary and acquired thrombophilia are rare they have a major impact on the development of venous thromboembolism while undergoing hormonal therapy. Thrombotic events can be minimized by increasing the awareness of procoagulatory effects of hormonal therapy especially in women with thrombophilia. The aim of this review article is to summarize current knowledge concerning hormonal therapy in the subgroup of patients with thrombophilia.     

Thromboembolic disease in pregnancy

Venous thromboembolic disease is a major cause of maternal morbidity and mortality. Virchow's triad of hypercoagulability, venous stasis, and vascular damage all occur during pregnancy. The risk of venous thromboembolism is five to six times higher during pregnancy and the puerperium. Risk factors include age greater than 35, antiphospholipid antibodies, inherited thrombophilias, operative delivery, increased parity, obesity, mechanical heart valves,and family history. Prophylactic and therapeutic anticoagulation is recommended for women at risk. Low molecular weight heparins are safe and effective in most cases.