Trait Document

Inherited thrombophilias are a group of genetic conditions that increases the chance of developing abnormal clots (i.e., thrombosis) in the veins (blood vessels that carry blood from the body back to the heart) or arteries (blood vessels that carry oxygenated blood away from the heart to the body). A blood clot that obstructs or blocks a vein is called a venous thrombosis, and a blood clot that obstructs an artery is called an arterial thrombosis. Common sites for venous thrombosis include the veins deep inside the body (i.e., DVT: deep vein thrombosis which occurs when a blood clot develops in the large veins in the legs or arms), and in the lungs (PE: pulmonary embolism which occurs when a blood clot travels through the bloodstream and ends up in the lungs). DVTs and PEs are known as venous thromboembolisms (VTE). Some signs and symptoms of VTE are pain, tenderness or swelling in the legs or arms (usually only one leg or arm); warmth in the swollen leg or arm; sudden shortness of breath; chest pain; and fast heart rate. VTE are medical emergencies that require immediate medical attention.

Thrombophilias can be inherited, acquired or both. Inherited or hereditary thromobophilias are changes or mutations in the genes that are responsible for the body’s blood clotting system. The most common inherited thrombophilias are frequently caused by particular mutations in the F5 gene (called factor V leiden) and F2 gene. Mutations that cause deficiency of protein C, protein S, or antithrombin III also cause inherited thromobophilias. Mutations in these genes increase the chance of developing VTE. Having an inherited thrombophilia does not guarantee the development of a VTE. There are several non-genetic risk factors such as certain medications, major surgeries, cancer, heart failure, pregnancy, smoking, obesity, non-active lifestyle, and age, that also contribute to increasing the risk of developing VTE.

Individuals under the age of 50 with a history of an unprovoked VTE, individuals with a history of more than one VTE or a VTE in an unusual location, individuals with a personal and family history of VTE, women with a history of VTE during pregnancy or when taking oral birth control, and women with recurrent pregnancy loss may have an underlying inherited thrombophilia.

Although many factors influence an individual’s chance of developing VTE, changes or variants in certain genes are known to play an important role. The F5 gene is responsible for making the coagulation factor V protein, and the F2 gene is responsible for making the coagulation factor II protein, also known as prothrombin. These two genes are one of many that are involved in the body’s complex blood clotting process. A particular mutation in the F5 gene (i.e., factor V Leiden) allows the blood clotting process to remain active for a longer period of time, thus increasing the chance of developing abnormal blood clots. A mutation in the F2 gene (i.e. prothrombin G20210A) causes the gene to produce too much prothrombin. This can lead to the formation of abnormal blood clots. The PROC gene is responsible for making protein C, the PROS1 gene is responsible for making protein S, and the SERPINC1 gene is responsible for making the antithrombin III protein. Mutations in these genes that cause deficiencies these proteins can lead to the formation of abnormal blood clots.

Individuals with a history of thrombosis are often treated with medication (e.g., blood thinners). In women with an inherited thrombophilia, certain oral birth control pills and hormone replacement therapy are discouraged.

The chance of developing VTE is a multifactorial (i.e., caused by many factors) trait that follows a multifactorial inheritance pattern. This means that an individual’s risk of VTE is the product of the interactions of multiple genetic (e.g., having an inherited thrombophilia) and non-genetic factors.

The chance of developing VTE is a complex condition, which means that it is caused by a combination of many different factors. These factors can be genetic or non-genetic (such as environmental factors and lifestyle choices such as smoking). Complex conditions are inherited in a multifactorial pattern. This means that the chance for an individual to develop a VTE is influenced by the number and type of genetic and non-genetic factors that occur together to which an individual is exposed. In other words, no single gene, and no single environmental factor cause VTE. However, not all of these genetic factors and environmental factors are known.

Multifactorial conditions tend to recur in families because they are partly caused by genes. An individual with a family history of VTE has an increased risk of developing VTE.

The most common genetic risk factor for VTE is the factor V Leiden mutation. This mutation is found in approximately 3% of European Americans and <1% of African Americans in the general population. The common prothrombin mutation is found in approximately 2% of European Americans and <1% of African Americans in the general population. On the other hand, the factor V Leiden mutation is found in approximately 20% of individuals with a history of VTE, and the prothrombin mutation is found in approximately 6% of individuals with a history of VTE.