Inherited thrombophilias in pregnant patients: detection and treatment paradigm,

doi:10.1016/S0029-7844(01)01760-4

Obstetrics & Gynecology

Volume 99, Issue 2, February 2002, Pages 333-341

https://doi.org/10.1016/S0029-7844(01)01760-4 Get rights and content

Abstract

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.

Section snippets

Physiologic initiation and control of hemostasis

The primary initiator of coagulation is tissue factor (TF), a cell membrane-bound glycoprotein expressed by perivascular cells throughout the body, but not by cells in contact with the circulation (ie, endothelial cells) (Figure 1). After vascular disruption, perivascular, cell membrane-bound TF complexes with plasma-derived factor VII. The complex of TF and factor VII bound to negatively charged (anionic) phospholipids in the presence of ionized calcium initiates clotting. Factor VII is the

Pregnancy-associated changes in hemostasis and fibrinolysis

The net effect of pregnancy-associated changes in hemostatic, anticoagulant, and fibrinolytic proteins is to enhance the risk of thromboembolism and, thus, exacerbate the clinical effects of the inherited thrombophilias.1 Pregnancy is associated with a 20–200% increase in levels of fibrinogen and factors II, VII, VIII, X, and XII, whereas concentrations of factors V and IX are unchanged. In contrast, endogenous anticoagulant levels increase minimally (tissue factor pathway inhibitor), remain

Factor v leiden mutation

The factor V Leiden mutation is present in 5–9% of white European populations, but is rare in Asian and African populations.1, 13 It arises from a (G → A) mutation in nucleotide 1691 of the factor V gene’s 10th exon resulting in a substitution of a glutamine for an arginine at position 506 in the factor V polypeptide (factor V Q506). The resultant amino acid substitution impairs the activated PC and PS complex inactivation of factor Va. This defect is termed the factor V Leiden mutation and is

Summary

Taken as a group, inherited thrombophilias clearly increase the risk of maternal thromboembolism and latter adverse pregnancy outcomes. In contrast, there does not appear to be a strong link between the inherited thrombophilias and early (less than 10 weeks) pregnancy loss.10 Our ability to predict which women are at highest risk for thromboembolism or which pregnancies are greatest at risk for fetal loss, abruptions, severe preeclampsia, and IUGR remains extremely poor. Moreover, there are no

Treatment

Regardless of their antecedent history, asymptomatic pregnant patients with AT deficiency or those who are homozygotes or compound heterozygotes for the factor V Leiden or prothrombin (G20210A) mutations are at very high risk for maternal thromboembolic disorders and require therapeutic unfractionated or therapeutic low molecular weight heparin therapy throughout pregnancy.1 The latter regimen has several advantages including less need for monitoring antifactor Xa activity and lower risks of

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Pathophysiological, immunogenetic, anatomopathological profile of thrombophilia in pregnancy
2023, Transfusion Clinique et Biologique
Thrombophilic states have been associated with early and/or late pregnancy loss and possibly other severe obstetrical complications. Pregnancy-induced hypercoagulability, increased stasis, and the consequences of inherited and acquired thrombophilia are just a few of the factors that contribute to the development of thrombosis in pregnancy. In this review, we illustrate the impact that these factors have on the development of thrombophilia during pregnancy. We also explore how thrombophilia impact pregnancy outcomes. Next, we discuss how human leukocyte antigen G plays a part in thrombophilia during pregnancy by regulating cytokine release to prevent trophoblastic cell invasion and maintain local immunotolerance constant. Human leukocyte antigen class E is briefly explored with thrombophilia in pregnancy. Regarding the anatomopathologic aspect, we describe the different histopathological lesions of the placenta found in women with thrombophilia.
Inherited antithrombin deficiency in pregnancy
2022, Thrombosis Update
Inherited AntiThrombin Deficiency (ATD) is a rare and high-risk thrombophilia. It is associated with a high risk of venous thromboembolism, thrombosis, and the risk is escalated further in the prothrombotic state of pregnancy. Due to the thrombotic tendency it is also associated with placental dysfunction due to placental thrombosis. Untreated mothers with ATD have increased rates of second and third trimester loss, pre-eclampsia & eclampsia, placental abruption, and intra-uterine growth restriction resulting in small for gestational age babies.
We have conducted a comprehensive review of the literature and guidelines & summarise the role of antithrombin, how to test for it, the evidence for its role in thrombosis and obstetric complications and how best to manage this. We also aim to present what we believe is best practise for managing ATD during pregnancy and therefore provide a much needed practical guide.
Managing these women during pregnancy is designed to reduce their risk of thrombosis and late obstetric complications. Due to the rarity of the condition and the ethical difficulties surrounding clinical trials in pregnant women no randomised controlled trials or large observational studies have been conducted in this area; evidence is limited to small cohort studies, which are usually retrospective. Definitions such as ‘miscarriage’ and ‘fetal loss’ are also discordant between studies and associations which makes data comparison difficult. Thus there is limited guidance on the management of ATD in pregnancy. We recommend the use of low molecular weight heparin (LMWH) during pregnancy with regular anti- Xa monitoring to ensure that women receive adequate antithrombotic therapy. Due to the efficacy of LMWH working through potentiation of antithrombin, in those with ATD, high levels of LMWH are usually required. We discuss the use of antithrombin concentrates at times where the use of LMWH is contraindicated, such as during delivery.
Emerging evidence suggests that the type of antithrombin deficiency is important in risk stratification along with the individual's own thrombotic risk factors, thrombosis history and family history.
Potential causes of male and female infertility in Qatar
2020, Journal of Reproductive Immunology
A steady decline in the fertility rate has been observed in Qatar during the past fifty years. Therefore, infertility is considered a national priority in Qatar, a pronatalist society. This review article summarises the potential causes of infertility that are
particularly prevalent in the Qatari population. The high rate of consanguinity leading to genetic abnormalities, the high incidence of metabolic disease, environmental contamination due to the rapid urbanization and oil and natural gas extraction procedures are discussed. In addition, the particular lifestyle of the Qatari population and the influence of religion and culture on sexual and reproductive behavior in an Arab/Islamic society are considered. The active response of the state of Qatar in implementing ways to mitigate the effects of these factors to protect fertility are also presented.
Prenatal Screening for Thrombophilias: Indications and Controversies, an Update
2016, Clinics in Laboratory Medicine
Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): A multinational open-label randomised trial
2014, The Lancet
Thrombophilias are common disorders that increase the risk of pregnancy-associated venous thromboembolism and pregnancy loss and can also increase the risk of placenta-mediated pregnancy complications (severe pre-eclampsia, small-for-gestational-age infants, and placental abruption). We postulated that antepartum dalteparin would reduce these complications in pregnant women with thrombophilia.
In this open-label randomised trial undertaken in 36 tertiary care centres in five countries, we enrolled consenting pregnant women with thrombophilia at increased risk of venous thromboembolism or with previous placenta-mediated pregnancy complications. Eligible participants were randomly allocated in a 1:1 ratio to either antepartum prophylactic dose dalteparin (5000 international units once daily up to 20 weeks' gestation, and twice daily thereafter until at least 37 weeks' gestation) or to no antepartum dalteparin (control group). Randomisation was done by a web-based randomisation system, and was stratified by country and gestational age at randomisation day with a permuted block design (block sizes 4 and 8). At randomisation, site pharmacists (or delegates) received a randomisation number and treatment allocation (by fax and/or e-mail) from the central web randomisation system and then dispensed study drug to the local coordinator. Patients and study personnel were not masked to treatment assignment, but the outcome adjudicators were masked. The primary composite outcome was independently adjudicated severe or early-onset pre-eclampsia, small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or venous thromboembolism. We did intention-to-treat and on-treatment analyses. This trial is registered with ClinicalTrials.gov, number NCT00967382, and with Current Controlled Trials, number ISRCTN87441504.
Between Feb 28, 2000, and Sept 14, 2012, 292 women consented to participate and were randomly assigned to the two groups. Three women were excluded after randomisation because of ineligibility (two in the antepartum dalteparin group and one in the control group), leaving 146 women assigned to antepartum dalteparin and 143 assigned to no antepartum dalteparin. Some patients crossed over to the other group during treatment, and therefore for on-treatment and safety analysis there were 143 patients in the dalteparin group and 141 in the no dalteparin group. Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis (dalteparin 25/146 [17·1%; 95% CI 11·4–24·2%] vs no dalteparin 27/143 [18·9%; 95% CI 12·8–26·3%]; risk difference −1·8% [95% CI −10·6% to 7·1%)) and on-treatment analysis (dalteparin 28/143 [19·6%] vs no dalteparin 24/141 [17·0%]; risk difference +2·6% [95% CI −6·4 to 11·6%]). In safety analysis, the occurrence of major bleeding did not differ between the two groups. However, minor bleeding was more common in the dalteparin group (28/143 [19·6%]) than in the no dalteparin group (13/141 [9·2%]; risk difference 10·4%, 95% CI 2·3–18·4; p=0·01).
Antepartum prophylactic dalteparin does not reduce the occurrence of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications in pregnant women with thrombophilia at high risk of these complications and is associated with an increased risk of minor bleeding.
Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.
Obstetric implications of fetal inherited thrombophilia in thrombophilic women
2014, Pregnancy Hypertension
The relationship between fetal thrombophilic polymorphism and adverse pregnancy outcomes is still unclear. The aim of this study is to evaluate if fetal thrombophilia may affect obstetric and perinatal outcomes in thrombophilic women.
From 2007 to 2011 all patients with a known inherited thrombophilic mutation consecutively admitted to our labor ward at ⩾25 weeks of gestation with a singleton viable pregnancy were considered eligible for the purpose of the study. At the age of 1 year, the infants were tested for inherited thrombophilic mutations. Patients were then divided into two groups according to the presence or absence of any neonatal mutation.
The following outcome variables were then compared between the two groups: gestational age at delivery, birth weight, incidence of hypertensive disorders of pregnancy and SGA neonates.
Overall, 67 pregnancies of 49 women were studied. Among them, the G20210A Prothrombin (32/67 or 47.7%) mutation and the Factor V Leiden mutation (31/67 or 46.3%) were the commonest findings, with a single patient presenting both. A thrombophilic mutation was found in 38 mother–infant pairs. The risk of all maternal and perinatal events including the incidence of hypertensive disorders disorders (5/29 or 17.2% vs 6/38 or 15.7% p = 1.00) and of SGA neonates (3/29 or 10.3% vs 7/38 or 18.4%, p = 0.49) was comparable between the two groups irrespective of the associated fetal thrombophilia.
Our data suggest that women with inherited thrombophilia carrying a thrombophilic fetus are not at increased risk of adverse pregnancy outcomes.

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^☆: This work was supported in part by a grant from the National Institutes of Health 5 RO1 HL33937-06.

¹: We have invited select authorities to present background information on challenging clinical problems and practical information on diagnosis and treatment for use by practitioners.

²: We would like to thank the following individuals who, in addition to members of our Editorial Board, will serve as referees for this series: Dwight P. Cruikshank, MD, Ronald S. Gibbs, MD, Gary D. V. Hankins, MD, Philip B. Mead, MD, Kenneth L. Noller, MD, Catherine Y. Spong, MD, and Edward E. Wallach, MD.

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High-risk pregnancy series: an expert’s viewInherited thrombophilias in pregnant patients: detection and treatment paradigm1, 2 ☆,

Abstract

Section snippets

Physiologic initiation and control of hemostasis

Pregnancy-associated changes in hemostasis and fibrinolysis

Factor v leiden mutation

Summary

Treatment

Placenta

Lancet

Fertil Steril

Lancet

Obstet Gynecol

Fertil Steril

Metabolism

Fertil Steril