Thrombophilia in Pregnancy: What It Is and the Risks for Pregnancy

Pregnancy is a time of profound transformations in a woman’s body, including natural adaptations in the coagulation system to reduce the risk of hemorrhages during childbirth. However, in some women, these changes may increase the risk of complications due to a condition called thrombophilia.

In the context of reproductive health, thrombophilia not only raises the likelihood of thromboembolic events but can also directly impact the health of both the mother and baby. From conditions such as preeclampsia to fetal growth restriction, early identification of this condition is crucial for appropriate management and preventing adverse outcomes.

This article explores what thrombophilia is, the associated risks during pregnancy, and how it can be monitored and treated to ensure a safer pregnancy.

What is thrombophilia?

Thrombophilia refers to a group of disorders characterized by an increased tendency for blood clot formation (thrombi), primarily due to the interaction of multiple hereditary and/or acquired predisposing factors (1, 2). These clots can obstruct blood flow in veins or arteries, leading to serious complications such as deep vein thrombosis (DVT), pulmonary embolism, cerebral thrombosis, and even heart attacks (1).

According to the World Health Organization (WHO), thrombosis is one of the leading causes of death among cardiovascular conditions, emphasizing the importance of its prevention and proper management.

Thrombophilia can be classified as hereditary or acquired, with clinical manifestations varying widely (2). In some cases, the condition remains asymptomatic until adulthood, while in others, it can result in recurrent thromboembolic events before the age of 30. Clots may develop in common sites, such as the legs and lungs, or in less typical areas, including splanchnic, cerebral, and retinal veins (1).

While many individuals with thrombophilia may never develop thrombosis, others may experience severe and recurrent symptoms, highlighting the complexity of this condition, which requires a personalized approach for diagnosis and treatment.

What causes thrombophilia?

The coagulation system typically maintains a balance between pro-coagulant and anticoagulant factors. However, this balance can shift toward a prothrombotic state, resulting in thromboembolic disease (3).

Understanding the mechanisms behind this shift—characterized by excessive thrombin generation—is clinically complex due to the interplay among various coagulation factors and their interactions with blood vessels, endothelial cells, platelets, and other circulating cells.

Thrombophilia has a multifactorial and complex etiology, being both hereditary and acquired. The presence of a thrombophilic defect is just one of several factors influencing the risk of developing the condition.

Hereditary Thrombophilia

The term hereditary thrombophilia commonly refers to conditions where genetic mutations or variants affect the quantity or function of proteins involved in coagulation.

Hereditary thrombophilias include a group of genetic disorders, with the most notable being Factor V Leiden mutation, prothrombin (Factor II) gene mutation, and deficiencies in antithrombin III, protein C, or protein S (4-6). These conditions disrupt the natural balance of coagulation, favoring clot formation.

• Factor V Leiden Mutation: The most common hereditary cause of thrombophilia, with a prevalence of 3–8% for a single mutation copy in the general populations of the U.S. and Europe. About 1 in 5000 individuals carries two copies of the mutation (7). This mutation increases thrombosis risk by causing resistance to activated protein C, a crucial coagulation regulator.
• Prothrombin (Factor II) Gene Mutation: The second most common genetic thrombophilia, occurring in approximately 1.7–3% of populations (8). This mutation raises thrombin levels, promoting clot formation.
• Natural Anticoagulant Protein Deficiencies: Deficiencies in protein C, protein S, and antithrombin are also significant causes of thrombophilia. Moderate protein C or S deficiency affects about 1 in 500 individuals, while severe protein C deficiency occurs in approximately 1 in 4,000,000 newborns (9). Hereditary antithrombin III deficiency has a prevalence of 1 in 500 to 5000 in the general population (10).

Other genetic factors include dysfibrinogenemia, hyperhomocysteinemia, and variants in genes like F2 (G20210A) and F5 (G1691A), associated with venous thromboembolism (VTE) , (11, 12).

A comprehensive genetic analysis conducted by the ThromboGenomics group in the UK demonstrated the efficacy of next-generation sequencing in diagnosing thrombotic disorders, identifying a genetic basis in 48.9% of cases (13). Hereditary thrombophilia, combined with acquired risk factors—whether transient or persistent—can lead to VTE at younger ages (14).

Hereditary thrombophilia not only increases the relative risk of a first thrombosis but can also exacerbate risks in individuals with other predisposing factors (15). However, genetic causes do not decisively influence the risk of recurrent thrombosis (16).

Acquired Thrombophilia

Acquired thrombophilia refers to conditions that develop over a person’s lifetime without a genetic predisposition. It is characterized by immune system alterations that result in the production of antibodies attacking blood vessel walls, thereby increasing thrombosis risk.

These secondary disorders include factors disrupting coagulation balance, such as heparin-induced thrombocytopenia, antiphospholipid syndrome (APS), malignancies, oral contraceptive use, obesity, smoking, and surgical interventions (17).

Among acquired causes, oral contraceptive use is particularly noteworthy. These medications alter anticoagulant and fibrinolytic pathways, increase pro-coagulant factor levels, and create a circulatory imbalance that contributes to thrombosis.

It is estimated that over 100 million women use oral contraceptives, which not only elevate the risk of venous thromboembolism but also arterial thrombosis in women of reproductive age. The risk is even higher in women over 40 years. Choosing the appropriate contraceptive method can significantly reduce this risk.

Other acquired factors increasing thrombosis risk include exogenous hormone use and chemotherapy treatments (17).

APS, for instance, is an autoimmune disorder linked to recurrent thrombosis. Pregnancy, a naturally pro-coagulant state, further contributes to this risk.

Although acquired factors play a significant role in thrombosis development, genetic predisposition is considered the most severe risk factor, accounting for up to 60% of cases.

What are the main symptoms of thrombophilia?

Many individuals with thrombophilia are asymptomatic until complications like thrombosis occur.

The primary symptoms of thrombophilia may include:

• Deep vein thrombosis (DVT): Swelling, pain, redness, a heavy sensation, or tightness in the affected leg;
• Sudden and severe pain in an arm, leg, or abdomen;
• Visible, dilated veins;
• Pulmonary embolism: Sudden shortness of breath, chest pain, and coughing up blood;
• Recurrent miscarriages in pregnant women with thrombophilia.

The Risks of Thrombophilia During Pregnancy

Thrombophilia during pregnancy and the postpartum period is exacerbated by the pro-coagulant characteristics of these conditions, affecting approximately 15% of the general population.

Physiological adaptations in the body, blood circulation, and coagulation system during pregnancy increase the risk of thrombosis. This risk is influenced by various factors (16):

Antepartum period: Related to body mass index (BMI), maternal age, number of deliveries, and presence of varicose veins;

Postpartum period: Events such as preterm delivery, cesarean section, and hemorrhage play a significant role. However, women with hereditary thrombophilia and a positive family history are at especially high risk for venous thromboembolism (VTE).

Among the possible obstetric complications associated with thrombophilic defects, preeclampsia, often related to antithrombin or protein S deficiency, and fetal growth restriction, associated with the Factor V Leiden mutation and the prothrombin gene mutation, stand out (18).

Other gestational complications caused by thrombophilia account for approximately 75% of neonatal morbidity and mortality causes, including:

• Placental thrombosis;
• Severe forms of gestational hypertension;
• Premature placental abruption;
• Intrauterine fetal growth restriction, potentially leading to fetal death.

For these patients, a detailed personal risk assessment is critical before initiating prophylactic medications against thromboembolic events. Monitoring during pregnancy is also essential. Timing, dosage, and treatment duration must be tailored individually (16).

Effective monitoring and management are vital to reducing risks, requiring an interdisciplinary approach involving gynecologists, midwives, anesthesiologists, and hematologists throughout pregnancy, delivery, and postpartum. This collaboration ensures maternal-fetal safety.

How is thrombophilia diagnosed?

Clinical diagnosis is based on personal and family history, physical examination, and laboratory and imaging tests (1).

Genetic testing is helpful for confirming the diagnosis, differential diagnosis, recurrence risk assessment, and identifying asymptomatic cases in families with known mutations, such as mutations in the Factor V Leiden and prothrombin genes.

Pathogenic variants may include missense, nonsense, splicing, or small insertions/deletions. Large deletions/duplications have been reported in F5, SERPINC1, PROS1, PROC, F9, FGA, and FGB genes.

Among the laboratory tests for thrombophilia, the following can be highlighted: assessment of protein C, protein S, and antithrombin levels; evaluation of antiphospholipid syndrome (APS) markers (lupus anticoagulant, anticardiolipin, and beta-2-glycoprotein I antibodies); and measurement of D-dimer levels to investigate active thrombosis.

The differential diagnosis should consider genetic conditions as well as secondary causes of thrombosis.

Thrombophilia evaluation is not solely for determining anticoagulation duration but also for estimating individual recurrence risk, the need for thromboprophylaxis, or decisions to extend anticoagulant therapy (16).

What test does SYNLAB offer for thrombophilia?

SYNLAB provides the THROMBO InCode Genetic Evaluation of Reproductive Health, assessing the risk of venous thromboembolism during pregnancy and postpartum.

This test analyzes 12 variants in 7 genes associated with an increased risk of thrombosis. Results are generated using a mathematical algorithm, offering a risk evaluation in three ways:

• Patient risk for thrombophilia based on the current clinical condition (variable factors like weight, smoking, habits, and lifestyle);
• Patient risk compared to heterozygosity for Factor V Leiden with the same clinical profile;
• Risk considering genetic variants and clinical profile.

This comprehensive analysis provides healthcare professionals with critical insights into the genetic implications of thrombophilia risk and recurrent pregnancy loss.

Who should take the THROMBO InCode Test?

The THROMBO InCode Genetic Evaluation of Reproductive Health is particularly recommended for:

• Patients with a pattern of VTE or a pathology suggesting a hereditary component;
• Idiopathic or recurrent venous thromboembolism;
• Venous thrombosis in unusual vascular sites;
• Neonatal purpura fulminans;
• Warfarin-induced skin necrosis;
• Unexplained arterial thrombosis;
• Women with recurrent fetal loss or miscarriages;
• Pregnant women with venous thrombosis;
• Patients using oral contraceptives;
• Patients with a family history of venous thromboembolism.

How is thrombophilia treated?

Treatment depends on the type of thrombophilia (hereditary or acquired), presence of risk factors, history of thrombotic events, and specific conditions like pregnancy.

Not all cases require treatment. For hereditary thrombophilia without a thrombosis history or additional risk factors, the approach may involve monitoring and prevention only.

Key therapeutic strategies include:

• Anticoagulant use: Medications such as low-molecular-weight heparin and warfarin are commonly used to prevent or treat thrombotic events;
• Obstetric management: Pregnant women with thrombophilia often receive heparin and aspirin to reduce complication risks;
• Safe contraception: Women with thrombophilia should avoid hormone-based oral contraceptives due to increased thrombosis risk;
• Lifestyle changes: Weight control, smoking cessation, and regular physical activity are fundamental measures to minimize risks.

It is essential that treatment is personalized and guided by a medical specialist. Improper anticoagulant use can lead to severe adverse effects, such as bleeding, particularly when there is no clear indication.

Learn About SYNLAB, a Leader in Medical Diagnostic Services!

Accurate and up-to-date tests are essential for precise diagnoses and better treatment strategies. SYNLAB is here to help!

We provide diagnostic solutions with rigorous quality control to companies, patients, and physicians. Operating in Brazil for over 10 years, we are active in 36 countries across three continents and are the European leader in diagnostic services.

Contact the SYNLAB team to explore the available tests.

References

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7) Kujovich JL. Factor V Leiden thrombophilia. GeneReviews. Seattle (WA): University of Washington, Seattle, 2018.

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