The role of inherited thrombophilia in venous thromboembolism associated with pregnancy.

Venous thromboembolism is an important cause of maternal morbidity and mortality. The puerperium should be regarded as the period of greatest risk. However, fatalities in early pregnancy emphasise the need to assess thrombotic risk at all stages of pregnancy. In many cases those at increased risk are potentially identifiable on clinical grounds alone such as those with a personal or family history of venous thromboembolism, obesity, or surgery. Identification of women with multiple clinical risks for thrombosis during pregnancy remains the key to reducing the incidence of this condition. In women who present with a personal or family history of proven venous thromboembolism, thrombophilia screening should be performed in early pregnancy, since the results may influence subsequent management during pregnancy. The investigation and management of patients considered at increased risk of venous thrombosis during pregnancy requires close liaison between obstetricians and haematologists familiar with this rapidly expanding and complex field of thrombophilia.     

Antithrombotic therapy during pregnancy.

Antithrombotic therapy is required during pregnancy for the prevention and treatment of venous and arterial thromboembolism and for the prevention of pregnancy loss in women at risk. The choice of anticoagulant for venous thromboembolism during pregnancy is limited to unfractionated heparin or low molecular weight heparin because the use of warfarin is relatively contraindicated. Much of the information surrounding the pharmacokinetics and dosing of unfractionated heparin and low molecular weight heparin obtained from non-pregnant patients has been applied to pregnant women. Whether this is appropriate in the presence of significant physiological changes in pregnancy is unclear. Specific to pregnancy and unfractionated heparin use, activated partial prothrombin time may be unreliable. In addition, the appropriate dosing of low molecular weight heparin is uncertain. Because venous thromboembolism can cause significant maternal morbidity and mortality, these important issues surrounding appropriate drug dosing of anticoagulants should be addressed.     

Thrombophilia and pregnancy

The incidence of venous thromboembolism is increased five to six times in pregnancy; and it is estimated that thromboembolic episodes- superficial and deep venous thromboembolism and pulmonary embolism occur in 1:1000 to 1:1500 pregnancies. These complications during pregnancy and puerperium, are not common but serious and leading cause of maternal morbidity and mortality. Thrombophilias--acquired or inherited, result of anticoagulant regulatory proteins deficiency, could compromise normal pregnancy by increasing the risk of developing first or recurrent thromboembolic incidents and adverse obstetric events.     

New methodological guidelines for the prevention and treatment of venous thromboses during pregnancy and in the puerperal period in Kuwait. Thrombophilia Clinic, Al-Adan Hospital

The high incidence of venous thromboembolic problems among women during pregnancy and puerperium in Kuwait require a new guidelines to cope with the increased number of thrombotic events and complications in this group. Pregnant ladies should be refer red in very early trimester to a Thrombophilia Clinic where they will be checked routinely for general and special laboratory tests accordingly. They will be classified to high risk category or low risk category. The high risk category group should receive a prophylactic measures throughout pregnancy and puerperium, while the low risk group do not need further action. Those who develop venous thrombosis from any categories should be classified in the high risk category during next pregnancies.     

Genetic factors associated with thrombosis in pregnancy in a United States population

OBJECTIVE: Polymorphisms in the genes for factor V (factor V Leiden), prothrombin, methylenetetrahydrofolate reductase, and angiotensin-converting enzyme have been associated with the occurrence of venous thrombosis. The objective of this study was to determine the relationships of these polymorphisms to thrombosis during pregnancy. STUDY DESIGN: This case-control study included 41 case patients with venous thrombosis during pregnancy and 76 control subjects matched for hospital and for race (white vs black) who had a normal pregnancy. RESULTS: Among white subjects, mutations in the genes for factor V and prothrombin were associated with increased risks of venous thrombosis during pregnancy (factor V: odds ratio, 18.3; 95% confidence interval, 2.7-432; P =.001; prothrombin: odds ratio infinity; 95% lower confidence limit, 1.7; P =.01). No black subject had either of these two mutations. For both black and white subjects the D/D genotype of the gene for angiotensin-converting enzyme entailed increased risk compared with the other genotypes (odds ratio, 2.7; 95% confidence interval, 1.2-6.3; P =.02). The polymorphism in the gene for methylenetetrahydrofolate reductase was unrelated to thrombosis during pregnancy among both blacks and whites. CONCLUSION: Women who had thrombotic complications during pregnancy demonstrated an increased prevalence of genetic mutations related to coagulation. The additional risk of thrombosis during pregnancy associated with such genetic mutations can be substantial.     

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.     

Venous thromboembolism in pregnancy

Venous thromboembolism (VTE) includes deep vein thrombosis (DVT) and pulmonary embolism (PE). In pregnancy, deep vein thrombosis accounts for 75–80% of venous thromboembolism, the remainder are pulmonary embolisms. One half of these VTEs occur during pregnancy and the other half in the postpartum period. Venous thromboembolism is one of the leading causes of maternal mortality worldwide and is also the cause of significant maternal morbidity. This article discusses the risk factors for VTE in pregnancy, the management of the pregnant woman at risk both antenatally and postpartum and the acute management of VTE when it occurs during pregnancy.     

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.     

Management of thromboembolism in pregnancy

The incidence of venous thromboembolism is increased during pregnancy and the postpartum period. This risk is high for women with documented hereditary or acquired risk factors who have experienced a prior thrombotic event. These individuals require a minimum of prophylactic dose anticoagulation with unfractionated or low molecular weight heparin during pregnancy, with anticoagulation continuing for 4 to 6 weeks postpartum. Women receiving therapeutic dose anticoagulation with warfarin before pregnancy for a hereditary or acquired condition should be transitioned to therapeutic doses of unfractionated heparin or low molecular weight heparin before or within 6 weeks of becoming pregnant, and can then resume warfarin postpartum. Women experiencing a thromboembolic event during pregnancy should receive therapeutic treatment with unfractionated heparin or low molecular weight heparin during pregnancy, with anticoagulation continuing for 4 to 6 weeks postpartum, and for a total of at least 6 months.     

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.     

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.     

Thromboembolism in pregnancy

Venous thromboembolism in pregnancy is a clinical emergency that has been associated with significant risk for maternal and fetal morbidity and mortality. The adaptation of the maternal hemostatic system to pregnancy predisposes women to an increased risk of thromboembolism. A timely diagnosis of deep venous thrombosis is crucial because up to 24% of patients with untreated deep venous thrombosis develop a pulmonary embolism. Recent clinical guidelines identify compression venous ultrasound as the best way to diagnose deep venous thrombosis in pregnancy and CT pulmonary angiography as the best way to diagnose pulmonary embolism in pregnancy. Therapy involves supportive care and anticoagulation with unfractionated or low molecular weight heparin, depending on the clinical scenario.     

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。     

Factor V Leiden mutation in pregnancy

Normal maternal adaptation to pregnancy significantly increases the risk for thrombus formation. Inherited thrombophilias further increase risk for deep venous thrombosis and adverse outcome in pregnancy. Factor V Leiden mutation is the most common inherited thrombophilia, occurring in approximately 5% of the White and 1% of the Black populations. Nurses should be knowledgeable about screening for and diagnosis of factor V Leiden mutation, risk reduction counseling, recommended care of the affected patient, and implications of anticoagulant therapy during the perinatal period.     

妊娠期及产褥期静脉血栓栓塞症风险评估及预防

目的:评估妊娠期及产褥期女性的静脉血栓栓塞症(VTE)发生风险,明确风险因素,并予以针对性预防,为探索妊娠相关VTE风险评估及预防策略提供依据.方法:根据2015年英国皇家妇产科医师学会(RCOG)妊娠期及产褥期静脉血栓栓塞疾病诊治指南推荐量表,对2018年11月1日至2019年12月31日在首都医科大学附属北京妇产医...     

Thromboembolic complications of pregnancy

Physiologic changes in clotting parameters and venous flow during pregnancy increase the likelihood of deep venous thrombosis. Conditions that place the pregnant patient at a higher risk include a previous history of thromboembolic disease and surgery or bedrest for any reason during the pregnancy. In the high-risk patient, prophylactic therapy with low-dose heparin is advised beginning around the 34th week of pregnancy and continuing until 4-6 weeks after delivery. The clinical diagnosis of thrombophlebitis or pulmonary embolus is unreliable and should be confirmed objectively before therapy is started. During pregnancy, doppler ultrasound and impedance plethysmography should be the first-line diagnostic tests, but one should seek confirmation with venography if in doubt. The preferred method of therapy for the acute thrombolic event is full anticoagulation with continuous intravenous heparin from 7-10 days, followed by therapy with subcutaneous heparin for the remainder of the pregnancy and the puerperium, although there is considerable controversy regarding long-term therapy. Fibrinolytic agents have little place in pregnancy, and surgical therapy should be reserved for the critically ill patient only.     

Anticoagulants

Pregnancy is a period of heightened coagulability and enhanced risk for thrombotic complications. Thromboembolism is the leading cause of maternal mortality. Anticoagulants are very useful during pregnancy for the acute treatment of venous thromboembolism and for the prevention of recurrent venous thromboembolism. They may also be beneficial in patients with thrombophilias, particularly among women who have experienced adverse pregnancy outcomes such as recurrent pregnancy loss. Anticoagulation is essential but problematic in the management of pregnant women with mechanical heart valve prostheses. When utilizing these medications among pregnant women the potential benefits must be balanced against the possibility of maternal haemorrhagic complications, adverse effects on the pregnancy or toxic effects on the fetus. This chapter summarizes current knowledge about the anticoagulant agents, their potential toxicities and their therapeutic role in pregnant women with various indications for anticoagulant therapy.     

Drugs in pregnancy. Anticoagulants.

Pregnancy is a period of heightened coagulability and enhanced risk for thrombotic complications. Thromboembolism is the leading cause of maternal mortality. Anticoagulants are very useful during pregnancy for the acute treatment of venous thromboembolism and for the prevention of recurrent venous thromboembolism. They may also be beneficial in patients with thrombophilias, particularly among women who have experienced adverse pregnancy outcomes such as recurrent pregnancy loss. Anticoagulation is essential but problematic in the management of pregnant women with mechanical heart valve prostheses. When utilizing these medications among pregnant women the potential benefits must be balanced against the possibility of maternal haemorrhagic complications, adverse effects on the pregnancy or toxic effects on the fetus. This chapter summarizes current knowledge about the anticoagulant agents, their potential toxicities and their therapeutic role in pregnant women with various indications for anticoagulant therapy.     

Trombosis de senos venosos cerebrales con afectación parcial de la tórcula de Herófilo en el sexto día de puerperio

Thrombosis of the cerebral venous sinuses is rare during pregnancy and the puerperium, even though pregnancy-specially in the last trimester and puerperium-together with prothrombotic states, head trauma and oral contraceptive use are risk factors for this common condition. Thrombosis of the cerebral venous sinuses occurs in 12 out of every 100,000 births. We report a case of venous thrombosis of the sigmoid and left transverse sinuses with partial involvement of torcular Herophili in a 25-year-old patient on the sixth day of the puerperium.     

Venous thromboembolism during pregnancy and the post-partum period: incidence and risk factors in a large Victorian health service

BACKGROUND: There is a strong recommendation for post-partum thromboprophylaxis following emergency caesarean sections, particularly in overweight women, and following prolonged labour. AIMS: To analyse the incidence and epidemiological factors associated with antepartum and post-partum venous thromboembolism in a large Victorian health service. METHODS: A retrospective study of all 6987 women delivering at Ballarat Health Services between March 1999 and June 2006. Case notes of women with confirmed venous thromboembolism during this period were subjected to detailed analysis. The data were analysed for possible risk factors, the timing of thromboembolism in relation to the pregnancy and any correlation with thromboprophylaxis, if administered. Results: The rate of venous thromboembolism was 1.14 per 1000 deliveries, with risk factors of age > 30 (100%), obesity (75%), previous history of thromboembolism (62.5%) and caesarean section (37.5%). Majority of cases were diagnosed in first trimester (62.5%), and in the right lower limb (75%). None of the patients had been given thromboprophylaxis. CONCLUSION: While the incidence and risk factors were similar to those generally quoted, a much higher incidence was found in early pregnancy, and in the right lower limb. The importance of meticulous screening for risk factors in early pregnancy cannot be overemphasised.