Introduction

Have you ever wondered what goes inside the body when you accidentally cut yourself, for example, while cooking? The human body is armoured with a complex yet remarkable system that prevents blood loss by forming blood clots when necessary to keep blood within vessels. However, a defect in this mechanism can result in not only excessive bleeding following injury, but also the formation of unwanted blood clots inside blood vessels. The abnormally increased tendency to form blood clots, which can occur if the body makes too many clots or doesn’t break down the old ones, is called thrombophilia. Thrombophilia can be caused due to acquired problems of clotting or genetic issues.¹

Factor V Leiden is an inherited blood-clotting disorder that results from a mutation in the gene coding for factor V, an essential part of the clotting cascade. This mutation allows Factor V to resist normal mechanisms that prevent excessive clot formation.² This condition can lead to serious long-term health problems and can be life-threatening. 

Genetics and underlying mechanism

During the normal blood clotting process, Factor V activates a protein called prothrombin to form thrombin, which can activate further downstream factors. When adequate amounts of thrombin is produced it can stimulate another molecule named protein C, that degrades Factor V to limit the formation of blood clots.²

Factor V Leiden is a genetic disorder passed down from parents to children in an autosomal dominant pattern. Information for producing Factor V (i.e. the gene) is located in chromosome 1. The mutation causes a change in one of the amino acids of the protein, making protein C no longer able to cleave and deactivate Factor V.²

Continued, uncontrolled activity of Factor V results in abnormal blood clot formation, commonly in the legs (deep vein thrombosis) that can travel into the lungs as well (pulmonary embolism). The presence of one faulty gene with one normal copy (heterozygous) increases the risk by 5 to 10 times while inheritance of both copies as defective genes (homozygous) increases the risk by almost 50 to 100 times.³ However, not everybody with the gene defect will have symptoms, which is known as incomplete penetrance.²

Prevalence and risk factors

Factor V Leiden is the most common inherited thrombophilia and primarily affects people of European decent, with around 3-8% carrying one copy of the mutated gene and approximately 1 in 5000 who have both copies mutated.³ 

Certain factors increase the risk of abnormal blood clots in those with Factor V Leiden. These include,⁴

• Carrying two copies of the mutated gene (being homozygous)
• Presence of other medical conditions that increases the risk of clots such as antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria, and myeloproliferative disorders 
• Pregnancy
• Malignancy
• Being immobile for an extended time period (during travel, following a surgery, etc.)
• Use of combined oral contraceptives
• Oral hormone replacement therapy
• Obesity
• Older age
• Having a family member with a history of abnormal clotting

Clinical manifestations of factor V Leiden mutation

The main clinical manifestation of Factor V Leiden mutation is venous thromboembolism (VTE), which is the formation of blood clots in veins that travel into other smaller blood vessels. VTE can present as deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Factor V Leiden is detected in 1 in 4 individuals who experience an event of venous thromboembolism for the first time and in almost 50% of those with recurrent episodes.⁴

Deep Vein Thrombosis (DVT)

DVT occurs when blood clots occur in the veins of the legs. More rarely, they can occur in arms, kidneys, liver, brain, and intestines. 

Symptoms of DVT are,⁵

• Sudden pain and swelling of arms or legs
• Redness of the skin with larger than normal veins
• Severe abdominal pain
• Sudden severe headache 

Pulmonary Embolism (PE)

PEs occur when a blood clot travels through the blood and lodges in a vein in the lungs. However, the occurrence of PEs is less common than DVT.

Features of PE include,⁶

• Chest pain worsened with inspiration
• Difficulty in breathing
• Coughing up blood (hemoptysis)
• Faintishness (syncope)

Diagnosis of factor V Leiden mutation

Doctors will suspect the presence of Factor V Leiden mutation and will offer testing for those with,²

• Venous thromboembolism (VTE) at a young age (<50 years)
• Recurrent episodes of VTE 
• Blood clots occurring at unusual sites (i.e. brain, liver)
• Blood clots in arteries
• VTE despite being on drugs to prevent it while hospitalised

Individuals who develop VTE for the first time, especially after a known provocation factor (i.e. immobilisation), and those who develop VTE after 50 years of age are not usually tested.²

Laboratory tests used in diagnosis include:²

Activated protein C resistance assay

• This test is less costly compared to genetic testing, but can give false positive results in those with certain other conditions.

Genetic testing

Mutation testing (based on polymerasechainreaction - PCR)

• This is considered the gold standard test for detection of Factor V Leiden mutation, and therefore used to establish the diagnosis.

Management of factor V Leiden mutation

For those who have the mutation but never have experienced any clots in the past, long term treatment is not necessary as the risk of bleeding due to treatment outweighs the risk of clotting.

However, it is beneficial for them to be treated with blood thinning agents that prevent blood from clotting easily (anticoagulants) prophylactically in high risk situations, such as during surgery, and during prolonged immobilisation, such as during travel.⁷

Management of episodes of thrombosis in those with Factor V Leiden mutation is not different from the general population.² Anticoagulants used in these instances are:⁷

Direct oral anticoagulants (DOACs)

• These are the first-line agents used due to lower risk of bleeding. Examples include rivaroxaban, apixaban, and dabigatran

Warfarin with low molecular weight heparin (LMWH)

• Both drugs are started together and their efficiency of preventing clots is measured using a blood test called the PT/INR. Once INR is around 2.5, LMWH can be stopped. Warfarin has a higher risk of bleeding and therefore it is important to be vigilant about any bleeding manifestations if you are on warfarin.

The duration for which these individuals should be on anticoagulants is dependent on the risk for recurrences. Patients who have VTE associated with reversible risk factors would normally be on anticoagulants for 3 months, whereas patients who have their first of repeated VTE episodes without provocation would likely be on anticoagulants indefinitely.⁷

Pregnancy

Women with Factor V Leiden mutation are at a 2 to 3 times higher risk of recurrent pregnancy loss. Some research also suggests that it may be associated with other complications in pregnancy like increased blood pressure (preeclampsia) and slowed growth of the baby (intrauterine growth restriction) although these have not been confirmed.⁸

The need for anticoagulants during pregnancy is based on individual circumstances including number of mutated copies, previous episodes of VTE, family history and the presence of other risk factors. Low molecular weight heparin is used as the drug of choice in pregnancy.⁴

Genetic counselling 

Since carrying a single mutated copy of the gene (heterozygosity) does not increase the risk of clots significantly, screening of asymptomatic family members of an individual known to have Factor V Leiden mutation is not recommended.⁴ However, testing for the status in women with a positive family history before starting estrogen-containing contraceptives or when planning pregnancy can be useful.⁴

Lifestyle modifications

People with Factor V Leiden mutation can lower their risk of blood clot formation by adopting some lifestyle changes such as,⁹

• Avoiding smoking, vaping and tobacco use
• Limiting alcohol intake
• Drinking enough water
• Maintaining a health weight
• Involving in moderate intensity exercises like walking and cycling for 150 minutes a week
• Frequently moving your legs while on long-haul flights
• Wearing compression stockings
• Being cautious about estrogen containing medications

Complications and long-term outlook

Many people who have the Factor V Leiden mutation never experience blood clots. But when they do, it can result in serious conditions. Deep vein thrombosis (DVT) and pulmonary embolisms (PE) carry significant morbidity and mortality. However, anticoagulants can be effectively used to treat them and prevent disastrous complications and fatal outcomes.⁷

Those who get recurrent episodes of clotting may be started on anticoagulant drugs that need to be continued for long durations even throughout life.It is important to note however, that anticoagulant medicines used in treating the disorder have their own side effects particularly the risk of bleeding, which can be serious.⁷

Future perspectives

The emergence of direct oral anticoagulants (DOACs), as novel anticoagulants has changed the way of management due to their low risk of bleeding, reduced need for regular monitoring and fewer dietary restrictions, compared to warfarin.¹⁰

In addition research is being carried out regarding gene therapy using CRISPR technology to correct the Factor V Leiden mutation at the root level. Personalised medicine approaches are also seeing a rise with individual genetic profile,risk factors and family history used to determine the necessity for treatment.¹¹

Summary

Thrombophilia is a condition in which there is a higher than normal tendency to form blood clots within the body. Factor V Leiden mutation is a common cause of thrombophilia that is passed down from parents to children. Normal Factor V plays an important role in blood clotting and is destroyed by another factor called “protein C”, to control clot formation. However, the Factor V leiden mutation makes Factor V resistant to deactivation by protein C, leading to uncontrolled production of blood clots.

The condition is more common in individuals of European decent and certain circumstantial factors like pregnancy, prolonged immobility, obesity and use of certain drugs increases the risk of thrombosis. Factor V leiden mutation results in blood clots within veins (venous thromboembolism) which usually manifest as deep vein thrombosis and/or pulmonary embolism. Deep vein thrombosis causes legs to swell up and become painful while pulmonary embolism gives rise to chest pain and difficulty in breathing.

Factor V Leiden mutation is diagnosed by activated protein C assays, genetic studies and mutation analysis. A key component in the management of the condition is the use of anticoagulants (blood thinning agents) which include warfarin and direct oral anticoagulants (apixaban, rivaroxaban). Pregnant women with the disorder may experience recurrent pregnancy losses and other complications like high blood pressure, slowed growth of the fetus.

The risk of blood clotting can be minimised by adopting an active lifestyle, maintaining a healthy weight, avoiding smoking and excessive alcohol and being cautious with estrogen-containing medications.

CRISPR based gene therapies to correct the mutation and use of personalised medicine to understand individual genetic profiles and risk factors to formulate treatment plans are shaping the future of Factor V Leiden management.