Inherited thrombophilias are genetic conditions that increase the risk of forming abnormal blood clots (venous thromboembolism or VTE). The two most common inherited forms involve variations in Factor V and Factor II, proteins central to the blood clotting cascade. Co-inheritance of both genetic variations is biologically possible and significantly increases an individual’s lifetime risk of developing a serious blood clot.
Factor V Leiden and Factor II Mutations Explained
Factor V Leiden (FVL) and the Prothrombin Gene Mutation affect the clotting process through different mechanisms. FVL involves a specific change in the gene for Factor V, a necessary cofactor in the clotting cascade. The mutation causes the resulting protein to become resistant to inactivation by Activated Protein C (APC), one of the body’s natural anticoagulants. This failure means Factor V remains active longer, leading to prolonged and increased thrombin generation.
The Prothrombin Gene Mutation (PGM) affects the gene for Factor II, the precursor protein to thrombin. This genetic change leads to an overproduction of prothrombin. Individuals with this mutation typically have a prothrombin level that is approximately 30% higher than those without the mutation. This elevated level of prothrombin results in the production of more thrombin, increasing the propensity for clot formation. Both mutations ultimately increase thrombin production, but they do so by distinct functional pathways: FVL through impaired breakdown and PGM through overproduction.
The Genetics of Co-Inheritance
Yes, a person can inherit both the Factor V Leiden and Prothrombin Gene Mutations, a combination referred to as compound heterozygosity. These two genes are located on entirely different chromosomes (Chromosome 1 and Chromosome 11, respectively), allowing them to be inherited independently.
The likelihood of co-inheritance is determined by population prevalence, calculated as the product of the individual frequencies of each mutation. While both mutations are relatively common in Caucasian populations (FVL in about 5% and PGM in 1–4%), co-inheritance is considered rare. Studies of patients with VTE have found that compound heterozygosity affects less than 1% of the general population.
Assessing the Combined Thrombotic Risk
The presence of both Factor V Leiden and Prothrombin Gene Mutations has a synergistic effect, meaning the combined risk of venous thromboembolism (VTE) is significantly amplified compared to carrying only one mutation. While a single heterozygous Factor V Leiden mutation may increase the risk of VTE by about three to eight times, and the Prothrombin Gene Mutation by two to five times, the co-inheritance of both mutations can increase the risk by seven to 20 times, or even greater than 40-fold in some studies.
This amplified risk is particularly relevant when other acquired risk factors are present. Periods of high thrombotic risk, such as surgery, prolonged immobilization, or trauma, can trigger a clotting event in compound heterozygotes. For women, oral contraceptives or hormone replacement therapy dramatically increase the risk of thrombosis. Pregnancy and the postpartum period are also high-risk times, and the presence of both mutations necessitates careful monitoring and often prophylactic treatment.
Individuals with compound heterozygosity also face a significantly higher risk of recurrent deep vein thrombosis (DVT) after a first event. The risk of recurrence for double carriers can be 2.6 to 3.7 times higher than for those with Factor V Leiden alone. This substantial increase in recurrence risk often necessitates long-term or lifelong anticoagulant therapy.
Diagnostic Testing and Treatment Approaches
Diagnosis of these inherited thrombophilias is accomplished primarily through specific laboratory tests. The most definitive method is genetic testing, which looks for the specific point mutations in the Factor V and Factor II genes. Genetic testing can identify whether a person has one copy (heterozygous) or two copies (homozygous) of either or both mutations.
Investigation may begin with a functional blood test, such as an Activated Protein C (APC) resistance assay, which screens for the Factor V Leiden mutation. If APC resistance is detected, genetic testing is then performed to confirm the Factor V Leiden mutation and to determine the zygosity. Due to the synergistic risk, laboratories often offer a combined test to screen for both mutations simultaneously from a single blood sample.
Management strategies depend on a patient’s personal history of VTE. For those who have never had a clot, treatment focuses on prophylaxis (preventive measures) during periods of increased risk, such as major surgery or prolonged immobility. If a clotting event occurs, treatment involves anticoagulants (such as warfarin or DOACs) to prevent the clot from growing and reduce the risk of recurrence. Compound heterozygotes who have experienced a VTE often require long-term anticoagulation due to their significantly elevated risk of recurrence.