Introduction

Thrombophilia is a condition characterised by an increased risk of blood clots, which can be severe and life-threatening. It can either be inherited, meaning there are variations in a person’s genes that are then passed on from parents to children, or acquired, usually due to another disease or an issue with the liver or kidneys. Thrombophilia develops secondary to a change in one or more components of haemostasis, such as coagulation factors, plasmatic proteins, blood flow, vascular surfaces, and other cellular elements.²

In pregnancy, the body’s haemostatic system is in a hypercoagulable state, which increases throughout the pregnancy period and then peaks near delivery. Pregnant individuals may need additional treatment and monitoring to reduce the complications associated with thrombophilia.^1,2

Risks associated with thrombophilia in pregnancy

In pregnancy affected by thrombophilia, there is an increased risk of complications. These include:

• Increased risk of venous thromboembolism (VTE)

Venous thromboembolism (VTE) refers to blood clots in the veins and constitutes both deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT is when a blood clot develops in a deep vein, usually in the lower limbs, but can also happen in the arms. PE happens when a portion of the blood clot breaks off and travels to the lungs.³ Pregnancy remains a risk factor for thrombophilia and increases the likelihood of a thrombotic episode. Thrombophilias are the cause of more than half of the thrombotic events diagnosed during pregnancy and after birth. Research states that the rate of VTE in pregnancy rises to five times, but most events occur postpartum.²

• Higher likelihood of pregnancy complications

Numerous studies have shown that there is a strong link between thrombophilia and adverse pregnancy outcomes. The common problems in pregnancy include:^2,4

• Recurrent miscarriage
• Intrauterine growth restriction (IUGR, when the foetus does not grow as much as expected)
• Pre-eclampsia (when blood pressure rises sharply during pregnancy)
• First-trimester abortion (FTA)
• Mid-trimester abortion (MTA)
• Placental abruption (when the placenta tears away from the womb, causing complications)
• Stillbirth

Common types of thrombophilia in pregnancy

Inherited thrombophilia

Thrombophilias due to the genetic defect can be categorised by:

1. Decreased levels of coagulation inhibitors (proteins in the body that stop blood clotting)

These are the less common but more severe causes of inherited thrombophilia.²

• Protein C & S deficiency - protein C and protein S are vitamin K-dependent glycoproteins (complex proteins with a carbohydrate attached to them) that play roles in the anticoagulant system. Both deficiencies are rare and can lead to an increase in the risk of thrombosis by 20% and 10%, respectively^2,5
• Antithrombin III (AT III) deficiency - AT III is a crucial plasmatic inhibitor (a protein that contributes to stopping the clotting of blood) for the activated coagulation factors, especially thrombin, and prevents excessive blood clotting. A mutation on the SERPINC1 gene is the cause of antithrombin III deficiency, and the risk of thrombosis is increased by up to 50%^2,6

2. Elevated coagulation factors

These are the most common (about 70%) causes of inherited thrombophilia and are less predisposed (less at risk) to thrombosis.²

• Factor V Leiden mutation - this is a common condition caused by a variant of the Factor V protein that is necessary for blood clotting. This causes low-risk thrombophilia, and most affected persons may never experience thrombosis⁷
• Prothrombin gene G20210A mutation - prothrombin or factor II is the precursor (a primitive form) of thrombin, and the gene mutation causes more prothrombin to be generated. This condition affects approximately 6% of the population^2,8
• Activated protein C resistance (APC) - this phenomenon is recognised as a poor anticoagulant response upon activating protein C^2,9
• Increased levels of VIII, IX, XI factors - factors VIII, IX, and XI are all clotting proteins that facilitate the clotting process. Normally, patients with VTE have high levels of these factors, and they are known to increase the risk of thrombosis by up to 10%, especially factor VIII² 
• Dysfibrinogenaemia - this is a rare coagulation ailment caused by abnormalities in the structure of fibrinogen, a glycoprotein, or coagulation factor that has numerous functions in blood clotting. The result is dysfunction and an increased risk of bleeding, thrombosis or both^2,10

Acquired thrombophilia

Thrombophilia due to acquired states can be because of:²

• Hyperhomocysteinaemia - this is presented as an abnormally high level of homocysteine in the blood (greater than 15 micromol/L) and is associated with various causes and diseases, such as genetics and poor diet. It is an independent risk factor of thrombotic conditions, but causes low-risk thrombophilia^2,11
• Antiphospholipid syndrome (APS) - also known as Hughes syndrome, this is an autoimmune disorder, whereby excess APS antibodies (antiphospholipids) attack the phospholipids of healthy cells and cause abnormal blood clots to form^2,12
• Elevated levels of procoagulant factors (proteins that support clotting)
• Decreased anticoagulants (proteins that prevent clotting)

Diagnosis and screening

Currently, routine screening for thrombophilic defects is not recommended in persons assigned female at birth (AFAB) unless there is a history of pregnancy complications and venous thromboembolism (VTE). The screening does not precede any change in the current thrombophilia management in pregnancy, recurrent pregnancy losses, or infertility losses.^2,4

For hereditary thrombophilia, there is a wide range of coagulation and genetic tests, which can be expensive and require clinical competence for interpretations. Testing for hereditary associations is not always considered to be useful, but it is always necessary to test for acquired conditions of thrombophilia.²

Common screening tests for thrombophilia may involve the following parameters:²

• Prothrombin G20210A
• Factor V Leiden (FVL)
• Factor V HR2
• Factor XIII V34L
• Plasminogen activator inhibitor-1 4G/5G (PAI-1)
• Methylene tetrahydrofolate reductase (MTHFR) C677T
• MTHFR A1298C
• β-fibrinogen-455 G>A
• Apolipoprotein E (Apo E)
• Angiotensin-converting enzyme I/D
• Apolipoprotein B R3500Q 
• Measurements of protein C
• Measurements of protein S
• Measurements of antithrombin III 
• Analysis of homocysteine levels 
• Measurements of lupus anticoagulant, anticardiolipin antibodies and anti-beta 2 glycoprotein-I antibody values to confirm the presence of antiphospholipid syndrome (APS)

Some tests should not take place during a thrombotic event, as the results may be affected. The influence of prescribed drugs such as low molecular weight heparin (LMWH) must be considered at the time of testing, as they can affect the levels of factors and glycoproteins as well.² 

Management and treatment

 A proper therapeutic approach is necessary to manage thrombophilia in pregnancy due to the maternal and fetal complications involved. For pregnant persons with inherited thrombophilia, there are numerous options like anticoagulants, antiplatelet drugs and vitamins and additional safety and efficacy risks should always be considered.²  

Due to the early development of VTE linked to inherited thrombophilia, antepartum prophylactic interventions are suggested immediately for those with a family history of VTE. Postpartum prophylaxis is also indicated in high-risk cases with or without a family history of VTE, low-risk cases with a family history of VTE, and individuals with one or multiple episodes of VTE.² 

Anticoagulation therapy 

Anticoagulants, namely low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH), are safer for the foetus. Anticoagulants, however, are likely to cause bleeding, allergic reactions or pain at the injection sites. UFH may also be related to thrombocytopenia and osteoporosis, so LMWH is recommended for long-term prophylaxis.² 

Antiplatelet drugs

Antiplatelet drugs, such as aspirin, can be given to expectant birth parents and are considered not to be associated with pregnancy loss during the second and third trimesters of pregnancy.² 

Monitoring strategies 

High-risk cases with the absence of a family history of VTE, low-risk cases with the absence or presence of a family history of VTE, as well as low-risk cases where persons have had a non-pregnancy-related VTE episode, warrant mainly antepartum and sometimes post-delivery clinical monitoring.² 

Prognostic outcomes

At present, D-dimer is the most utilised biomarker to predict the risk of VTE as this task is difficult. Pre-eclampsia (PE) is a common pregnancy complication that results in maternal morbidity and mortality globally and is linked to genetic conditions such as thrombophilia.² 

Summary

Thrombophilia is a condition that increases the risk of blood clots, which can be dangerous during pregnancy. It may be inherited through genetic mutations or acquired due to other health conditions. Pregnancy naturally increases blood clotting, further raising the risk of complications such as venous thromboembolism (VTE), recurrent miscarriage, preeclampsia and stillbirth.

Screening is not routine unless there is a history of complications of VTE. Management includes anticoagulants like low-molecular-weight heparin (LMWH) and, in some cases, aspirin. High-risk individuals may require early prophylactic (preventative) treatment and close monitoring to reduce maternal and foetal risks.