Factor V Leiden is a gene mutation of one of the clotting factors in the blood, which leads to an increased risk of blood clotting and thrombotic events. According to NCBI, Factor V Leiden thrombophilia is characterized by ”a poor anticoagulant response to activated protein C (APC) and an increased risk for venous thromboembolism (VTE).” The Factor V Leiden mutation should not be confused with factor V deficiency.
As the most common VTE, deep vein thrombosis (DVT) often affects the leg veins. Individuals with Factor V Leiden have a low relative risk of experiencing thrombosis in unusual locations. After the treatment of the first VTE, the Leiden variant has a lower absolute risk of recurrent thrombosis.
According to a systematic review by NCBI, the Leiden variant is the most common cause of the activated protein C resistance (APC resistance) phenotype. Discrepancies in heterozygotes and homozygotes have been described in the context of protein C resistance. Activated protein C (APC) is a naturally occurring anticoagulant that plays a critical role in maintaining the balance of procoagulant and anticoagulant mechanisms in the human body.
Individuals born with a copy of the mutation are at a higher risk of developing vein clots (deep vein thrombosis, DVT) and pulmonary embolism (PE) due to protein C resistance (PCR), but are not more prone to heart attacks, strokes, or arterial blood clots than the general population. Combined with antiphospholipid antibodies, another thrombotic defect, factor V Leiden can significantly increase an individual’s risk of thrombosis.
Inheriting a copy of the factor V Leiden mutation increases the risk of developing abnormal blood clots and experiencing symptoms of DVT and pulmonary embolism (PE). While most individuals born with the Leiden mutation never develop abnormal blood clots, some are at a high risk of long-term health problems, like venous thrombosis, adverse pregnancy outcomes, recurrent miscarriages, and life-threatening blood clots.
The Factor V Leiden mutation occurs when offspring inherit a copy of the factor V mutation from one or both parents. Factor V Leiden gene mutations have a higher prevalence among individuals with Northern European family members compared to the general population.
The genetic disorder involves a point mutation in the factor V (f5) gene, which makes up one of the proteins in the coagulation system. Because two different genes (one from each parent) make up each protein in the human body, two types of factor V Leiden exist: heterozygous factor V Leiden, in which only one copy of the factor V gene mutation was inherited through Mendelian inheritance, and homozygous factor V Leiden, in which two copies of the factor V Leiden mutation were inherited through Mendelian inheritance.
Normal pregnancies involve changes in the coagulation system, including an increase in clotting factors and the decreased activity of APC, an important anticoagulant. These factors can lead to a higher risk of thrombotic events during childbirth in pregnant women with the Leiden variant.
According to a case-control study by NCBI, the prevalence of factor V Leiden was 44 percent among pregnant women with venous thromboembolism. Venous thrombosis can lead to pregnancy loss in the first trimester, placental abruption, placental infarction, and recurrent miscarriage. A screening test for the Leiden variant is recommended for pregnant women with familial thrombophilia and women with a history of VTE.
In the U.S., the f5 gene mutation is present among approximately five percent of the general population. The Leiden mutation has a lower prevalence among Native Americans and African Americans and is a more common mutation in Caucasian and European populations.
In some parts of Northern Europe, factor V Leiden gene mutations are present in approximately 10–15 percent of the general population. The prevalence of Factor V Leiden is lower in South America, Africa, and Asia, where the mutation is present in less than one to three percent of the general population.
Factor V Leiden is caused by a point mutation in the factor V gene, which encodes a substitution of arginine and glutamine at position 506 of the factor V molecule where activated protein C cleaves factor VA. The f5 gene produces the coagulation factor V protein, one of the proteins in the coagulation system that helps blood to clot. The factor V Leiden mutation makes factor VA, a cofactor in thrombin activation, resistant to the anticoagulant effects of activated protein C, causing a genetic predisposition to thrombotic events.
In other words, the mutation causes an increased tendency of blood to clot, leaving individuals with a copy of the mutation at a higher risk of abnormal blood clots, recurrent miscarriages, stillbirths, and thrombophilic defects.
Many people born with a copy of the mutation will never experience the symptoms of FVL. Consequently, many individuals with FVL are unaware that they inherited a copy of the mutation.
When individuals with the factor V Leiden mutation develop symptoms, these symptoms are related to DVT/PE. Understanding and recognizing the risk factors and symptoms DVT and PE, like swelling, pain, and tenderness, are imperative to ensure an early diagnosis, lower your relative risk, and minimize additional risk factors.
Individuals born with the factor V Leiden mutation may have a family history of deep vein thrombosis (DVT) or pulmonary embolism (PE) at a young age, DVT/PE leading to pregnancy loss or placental abruption, and DVT/PE soon after starting birth control pills or oral contraceptives with estrogen. Although individuals with FVL may have a family history of venous thromboembolism and abnormal blood clotting, many will never experience abnormal clotting, pregnancy complications, or any form of thrombophilia in their lifetime.
The management of individuals diagnosed with factor V Leiden thrombosis or PE involves anticoagulants (blood thinners). Depending on the clinical circumstances and the type of blood clot, treatments may be required in combination with anticoagulants. Severe symptoms of venous thromboembolism, such as a hypercoagulable state, require hospitalization and antithrombotic therapy.
Women at an increased risk for the Leiden variant with or without a history of VTE should ask their doctor about the use of oral contraceptives containing estrogen. Women with a family history of factor V Leiden thrombophilia and pregnancy complications, including pregnancy loss, stillbirths, and clotting in pregnant women, should also be cautious with estrogen.
Oral contraceptive use and hormone replacement medications can lead to an increased risk of blood clots and abnormalities in healthy women at a young age, so discuss the risks of estrogen-containing oral contraceptives and hormone replacement therapy with your doctor if you have concerns about Leiden or thrombophilic defects. Additionally, short-term hormone replacement therapy (HRT) oral contraceptives should be avoided for postmenopausal women.
Other circumstantial risk factors for VTE include malignancy, central venous catheter use, obesity, major surgery, oral and transdermal HRT use, and age. Individuals with a family history of thrombophilia are at a higher risk of experiencing thrombosis after the age of 45.
Individuals born with the factor V Leiden gene mutation who do not display symptoms of DVT or PE do not need anticoagulant medications or any temporary treatment.
If you have a family history of thrombosis, or if one or both of your parents have homozygous factor V Leiden or heterozygous factor V Leiden, your doctor may recommend genetic testing to determine the genetic status of your factor V Leiden gene. High-risk individuals with recurrent VTE, especially at a young age (or a family history of VTE at a young age), talk to your doctor about a protein C activity assay, thrombin assay, or coagulation screening test to determine the genetic status of your factor V Leiden mutation.
Understanding the symptoms of DVT and PE, recognizing the circumstantial risk factors, and undergoing a screening test can help minimize your relative risk and give you peace of mind.