Trombofilia în sarcină: fiziopatologie, diagnostic şi strategii de management

Introduction

Thrombophilia refers to a group of disorders with an increased tendency toward thrombosis, which may originate from genetic mutations (hereditary) or  be acquired. Thrombus formation develops when there is disruption in one or more components of the hemostatic system – such as coagulation factors, plasma proteins, vascular endothelium, blood flow, or cellular elements. This leads to a hypercoagulable state, leading to arterial or venous thrombosis. The risk of thrombotic events is elevated by various factors, such as advanced age, prolonged immobility, extended standing, obesity, smoking, increased estrogen levels, and the use of hormonal contraceptives. Pregnancy and the postpartum period are also of increased thrombotic vulnerability^(1,2).

Pregnancy is a prothrombotic physiological state, further intensified by a reduced activity of protein S, a key endogenous anticoagulant, and an increased resistance to activated protein C. These physiological adaptations contribute significantly to the elevated risk of venous thromboembolism (VTE) during pregnancy, pulmonary embolism, miscarriage, intrauterine growth restriction (IUGR) and preeclampsia^(3,4).

The diagnosis of inherited thrombophilia involves genetic testing for mutations, such as factor V Leiden, prothrombin and MTHFR, alongside laboratory evaluations for deficiencies in antithrombin, protein C and protein S. Identifying specific thrombophilia variants may play a vital role in the early detection of pregnancies at risk for IUGR, allowing for an early management to prevent maternal and fetal complications and decrease the risk of stillbirth⁽²⁾.

Pathophysiology

Common obstetric complications include fetal loss, recurrent miscarriage, intrauterine growth restriction, preeclampsia and preterm labor⁽⁵⁾.

Inherited thrombophilia can disrupt the normal coagulation process by impairing natural anticoagulant mechanisms or altering the levels of specific coagulation factors, including Factor V Leiden (FVL), the prothrombin G20210A gene mutation, and deficiencies in protein C, protein S and antithrombin⁽⁵⁾.

The Factor V Leiden mutation is caused by a substitution of adenine with guanine at position 1691 of the gene, resulting in a variant of factor V that is resistant to inactivation by activated protein C.  Similarly, the 677C>T mutation in the MTHFR gene leads to an alanine-to-valine substitution, which reduces the conversion of homocysteine to methionine. The resulting hyperhomocysteinemia impairs endothelial cell function and promotes thrombosis^(6,7).

Factor V Leiden (FVL) is recognized as the most frequent inherited thrombophilic mutation, with its prevalence estimated between 1% and 10% across various populations. While early fetal loss does not appear to be significantly associated with heterozygous carriage of the Factor V Leiden mutation⁽⁶⁾.

Antithrombin, an anticoagulant synthesized in the liver and endothelial cells, inhibits thrombin, as well as clotting factors X, IX, XI, XII and tissue factor-bound VIIa. Deficiencies in antithrombin, protein C and protein S are genetically heterogeneous and less common than Factor V Leiden and the prothrombin gene mutation among women with recurrent pregnancy loss⁽⁵⁾.

Inherited thrombophilia has been implicated in pregnancy failure, although the relationship remains controversial. While some studies suggest that coagulation abnormalities account for 55-62% of recurrent miscarriages, approximately 90% of first-time miscarriages are attributed to chromosomal abnormalities. The underlying pathophysiology is not fully understood, but it is believed to involve thrombosis in the uteroplacental circulation, leading to inflammation and placental insufficiency. According to findings by Dawood et al. (2003)⁽⁸⁾, individuals with acquired activated protein C resistance (APCR) exhibited a markedly elevated rate of fetal loss – approximately 75% – in contrast to a 39% loss rate observed in the control population^(5,8).

The most well-established acquired thrombophilia linked to early pregnancy loss is antiphospholipid syndrome (APS). APS is a noninflammatory autoimmune disorder characterized by the occurrence of thrombosis or pregnancy-related complications in the presence of antiphospholipid antibodies⁽⁵⁾.

Antiphospholipid syndrome is a form of autoantibody-mediated thrombophilia associated with pregnancy complications. The presence of antiphospholipid antibodies leads to activation of endothelial cells, monocytes and platelets, resulting in the overproduction of tissue factor and thromboxane A₂. The most common obstetric manifestation is recurrent miscarriage; however, other complications include preeclampsia and placental insufficiency. It is estimated that antiphospholipid syndrome affects approximately 15% of women with a history of recurrent miscarriage^(5,9).

APS induces an inflammatory reaction through the interaction of antiphospholipid antibodies with vascular endothelial and placental or chorionic cells, thereby facilitating thrombus formation⁽⁶⁾.

Clinical implications

1. Miscarriage is defined by the spontaneous pregnancy loss before the fetus reaches viability, and it is the most frequent complication in the first trimester. Around 15% of clinically confirmed pregnancies end in miscarriage. Recurrent miscarriage refers to three or more consecutive pregnancy losses before 24 weeks of gestation (including spontaneous conception and assisted reproductive technology). Multiple factors have been implicated in recurrent pregnancy loss, including parental chromosomal rearrangements, inherited or acquired maternal thrombophilic conditions, and anatomical abnormalities of the uterus. In approximately 75% of cases, the cause remains undetermined (idiopathic). Recent studies have demonstrated that certain treatments, such as heparin, are ineffective in managing idiopathic recurrent miscarriage^(5,6,10).

Studies have demonstrated that pregnant women with inherited thrombophilia have a significantly increased risk of recurrent pregnancy loss (RPL) compared to control cases.

In a meta-analysis by Liu et al. (2021)⁽¹¹⁾, the presence of Factor V Leiden (FVL) mutation, prothrombin gene mutation (PGM) and protein S (PS) deficiency was associated with an increased risk of recurrent pregnancy loss (RPL) by approximately 2.44-fold, 2.08-fold, and 3.45-fold, respectively. However, the study found no significant association between antithrombin (AT) or protein C (PC) deficiency and RPL when compared to control populations. A study conducted by Alecsandru et al. (2021)⁽¹²⁾ revealed that mutations in the prothrombin gene (PG), particularly those associated with recurrent pregnancy loss, have been identified in approximately 2-4% of individuals of European Caucasian descent, but are considerably less prevalent among women of African or Asian ancestry. As with the Factor V Leiden mutation, heterozygous carriers of the G20210A prothrombin variant do not exhibit a significantly elevated risk of early pregnancy loss⁽⁶⁾.

Antiphospholipid antibodies are detected in approximately 15-20% of women experiencing recurrent pregnancy loss. Furthermore, cases of recurrent pregnancy loss linked to antiphospholipid syndrome (APS) reported the live birth rate as low as 10% without pharmacological intervention⁽⁶⁾.

2. Intrauterine growth restriction is defined as the inability of a fetus to reach its genetically determined growth potential due to a variety of maternal, fetal and placental factors. It complicates up to 10% of pregnancies, and is an important cause of perinatal morbidity and mortality. IUGR is diagnosed by ultrasonographic measurements of fetal biometry, with estimated fetal weight (EFW) below the 10^th percentile for gestational age. This doubles the stillbirth risk compared to normally growing fetuses. Further evaluations such as amniotic fluid index and umbilical artery Doppler velocimetry provide additional information on fetal well-being. A thorough ultrasound examination is also essential to exclude structural malformations and genetic syndromes that may underlie or contribute to growth restriction. Maternal risk factors for intrauterine growth restriction include hypertensive disorders, insulin-dependent diabetes mellitus with vasculopathy, renal disease, autoimmune conditions such as antiphospholipid syndrome, hyperhomocysteinemia, hereditary thrombophilia, chronic malnutrition, severe anemia, and exposure to teratogenic substances including tobacco, illicit drugs and alcohol^(2,13).

In a study reported by Mihai et al. (2023)⁽¹³⁾, thrombophilia was identified in 68% of the intrauterine growth restriction group, as opposed to 32% in the control group. A statistically significant association was observed between IUGR and certain types of inherited thrombophilia, specifically MTHFR mutations, protein S deficiency, and the presence of multiple thrombophilic defects.

A study published by Berks et al. (2015)⁽¹⁴⁾ indicated that intrauterine growth restriction was strongly associated with an increased presence of thrombophilia factors and a higher prevalence of antiphospholipid antibodies compared to pregnancies with normally grown fetuses.

3. Preeclampsia affects approximately 2-8% of pregnancies, and it is considered a heterogeneous disorder. One mechanism involves the maternal prothrombogenic state that can arise from either inherited or acquired thrombophilia. This may contribute to improper remodeling of the spiral arteries during early pregnancy, resulting in placental thrombosis and infarction during mid to late gestation. Studies have suggested a correlation between maternal thrombophilia and preeclampsia; however, conflicting findings may reflect the heterogeneity of preeclampsia, with various phenotypes. Preeclampsia can be categorized by severity (mild or severe) and may be accompanied by complications such as hemolysis, elevated liver enzymes and low platelet count (HELLP syndrome), and intrauterine growth restriction. Histopathological examination of placentas from preeclamptic pregnancies often reveals extensive infarction, or no abnormal histological findings⁽¹⁴⁾.

A study published by Berks et al. (2015)⁽¹⁴⁾ described that 29% of the women presented one or more abnormal thrombophilia markers. Severe preeclampsia was significantly correlated with a higher incidence of thrombophilia abnormalities, particularly protein S deficiency, when compared to mild preeclampsia. Early-onset preeclampsia (before 34 weeks of gestation) was also statistically associated with the presence of thrombophilia abnormalities, more frequent antiphos­pholipid antibodies, compared to late-onset preeclampsia (after 34 weeks). HELLP syndrome showed no significant association with any thrombophilia markers. Additionally, protein C deficiency, activated protein C (APC) resistance, Factor V Leiden mutation and prothrombin gene mutation were not linked to any specific preeclampsia phenotype. The presence of thrombophilia was notably higher in cases of severe preeclampsia, especially when it was associated with intrauterine growth restriction, delivery before 34 weeks, placental infarction affecting more than 10% of the tissue, or placental weight below the 5^th percentile. Protein S deficiency was more common in severe preeclampsia cases, while antiphospholipid antibodies had increased prevalence when preeclampsia occurred alongside IUGR⁽¹⁴⁾.

In a study by Dawood et al. (2003)⁽⁸⁾, significant differences were observed between the study and control groups in the rates of stillbirth, placental abruption and preeclampsia. In the study group, the stillbirth rate was 4%, compared to 1% in the control group. Placental abruption occurred in 3% of cases in the study cohort, whereas it was absent or markedly lower in the control group. The incidence of preeclampsia was notably higher in the study group at 10%, compared to only 1% among controls.

Diagnosis

Currently, there is inconsistency among professional society guidelines concerning the classification and diagnosis of high- and low-risk thrombophilia during pregnancy, and no standardized approach exists for subsequent management. The American College of Obstetricians and Gynecologists (ACOG) recommends screening for Factor V Leiden, the prothrombin G20210A mutation, and deficiencies in protein C, protein S and antithrombin in women with a personal history of venous thromboembolism (VTE). In contrast, for women with a history of recurrent pregnancy loss or stillbirth, ACOG recommends testing for antiphospholipid antibodies^(13,15).

While inherited thrombophilia may be associated with pregnancy loss, current guidelines from ESHRE (The European Society of Human Reproduction and Embryology) and ASRM (The American Society for Reproductive Medicine) do not support routine screening for MTHFR, Factor V Leiden, prothrombin gene mutations, or other thrombophilia-related variants in cases of recurrent pregnancy loss. Testing for inherited thrombophilia is recommended only in women with a personal history of venous thromboembolism in conjunction with recurrent miscarriage^(6,16).

The diagnosis can be complex, typically involving a combination of clinical manifestations and the detection of lupus anticoagulant, anticardiolipin antibodies, or both⁽⁵⁾.

Women presenting with a history of three or more consecutive early pregnancy losses prior to 10 weeks of gestation, a single unexplained intrauterine fetal demise at or beyond 10 weeks in a morphologically normal fetus, or one or more preterm births before 34 weeks associated with severe preeclampsia or placental insufficiency should undergo evaluation for antiphospholipid syndrome. Diagnostic workup should include testing for antiphospholipid antibodies (aPL), specifically lupus anticoagulant (LAC) and anticardiolipin antibodies (aCL), as these serological markers are integral to confirming the diagnosis⁽¹⁰⁾.

Women experiencing recurrent first-trimester pregnancy losses or one or more second-trimester miscarriages should be screened for antiphospholipid antibodies prior to conception. The diagnosis of antiphospholipid syndrome requires two separate positive results – at least 12 weeks apart – for either lupus anticoagulant or anticardiolipin antibodies of the IgG or IgM class, with titres exceeding 40 g/L or above the 99^th percentile. For the detection of lupus anticoagulant, the dilute Russell’s viper venom time (dRVVT) combined with a platelet neutralization procedure is considered more specific and sensitive than tests such as the activated partial thromboplastin time (aPTT) or kaolin clotting time⁽⁶⁾.

Management

Although there are no large clinical trials, The Romanian Society of Obstetrics and Gynecology (SOGR) guideline aims to standardize thromboprophylaxis and thrombotic treatment in pregnant and postpartum women.

Stratifying thromboembolic risk in pregnant and postpartum women is essential. Every physician should assess patients’ thromboembolic risk during prenatal consultations or any hospital admission⁽¹⁷⁾.

• Hereditary thrombophilia with high risk:
  •  Homozygous Factor V Leiden mutation
  •  Homozygous G20210A mutation of the prothrombin gene
  •  Compound heterozygous Factor V Leiden/G20210A prothrombin mutation
  •   ATIII activity.
• Hereditary thrombophilia with low risk:
  •  Heterozygous Factor V Leiden mutation
  •  Heterozygous G20210A mutation of the prothrombin gene
  •  Protein C activity <50%
  •  Free Protein S antigen <55%
  •  PAI
  •  MTHFR.

The following situations should be considered as high thromboembolic risk during pregnancy and the postpartum period: personal history of thromboembolic disease, multiple venous thromboses, major risk thrombophilia, cardiac valve prostheses⁽¹⁷⁾.

Testing for Factor V Leiden, prothrombin gene mutation 20210A, protein S and protein C is applied to any pregnant woman with venous thromboembolism during the current pregnancy or personal history VTE during the current pregnancy. Protein S normally decreases by 40% during pregnancy and leads to an unreliable determination during pregnancy⁽¹⁷⁾.

The prothrombotic state of pregnancy, when combined with the additional risk posed by a thrombophilic defect, makes it essential to provide appropriate anticoagulation – while carefully minimizing potential side effects for both the mother and the fetus⁽³⁾.

Antithrombotic treatment can lead to numerous side effects, including bleeding and localized skin reactions (injection site irritation, pruritus, and swelling). Serious complications like heparin-induced thrombocytopenia and heparin-induced bone loss (osteopenia) may occur less commonly. However, the use of low-molecular-weight heparin (LMWH) has significantly reduced the incidence of these adverse outcomes compared to the earlier, more frequent use of unfractionated heparin⁽¹⁸⁾.

Studies reported no added benefit of high-dose unfractionated heparin compared to low-dose regimens when used in combination with LMWH and aspirin. Additionally, the effectiveness of aspirin alone has been inconsistent across different investigations⁽¹⁹⁾.

The effectiveness of low-molecular-weight heparin in women with recurrent miscarriage and inherited thrombophilia remains inconclusive due to the lack of adequately powered randomized controlled trials. Several studies have investigated the use of LMWH, with or without aspirin, in women with unexplained recurrent miscarriage, but the number of participants with confirmed inherited thrombophilia has been insufficient to draw definitive conclusions⁽¹⁸⁾.

The ALIFE trial evaluated aspirin plus nadroparin, aspirin alone, and placebo in 364 women with unexplained recurrent miscarriage. The results showed similar live birth rates with both treatment or placebo. Similarly, the SPIN study, which compared enoxaparin plus aspirin versus intensive pregnancy monitoring in 294 women, found no significant difference in miscarriage rates^(20,21).

Conclusions

Thrombophilia is an important risk factor during pregnancy, making the risk assessment essential. While routine screening of all pregnant women is not currently recommended, it is imperative to evaluate those with a personal history of thromboembolic events.

Management strategies should be guided by clinical severity, the specific type of thrombophilia and the patient’s obstetric history.

To improve the current understanding of thrombophilia in pregnancy, rigorous research and well-designed clinical trials are essential. Additionally, following current guidelines  plays a key role in guiding the effective management.

Autor corespondent: Andreea Vișan, e-mail: andreea.visan@rez.umfcd.ro

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.