Inherited causes of Thrombosis

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Antithrombin deficiency

Antithrombin deficiency is a blood disorder characterized by the tendency to form clots in the veins (thrombosis). An inherited tendency to thrombosis is known as thrombophilia. Antithrombin is a substance in the blood that limits the blood’s ability to clot (coagulation) and the primary inhibitor of thrombin, which is required for the development of blood clots; it also is the primary inhibitor of two clotting factors, factor Xa and factor IXa, that are required for the generation of thrombin. In people with congenital antithrombin deficiency, there is a reduced amount of this substance in the blood due to a genetic abnormality. Antithrombin deficiency may also be acquired; in such cases, the disorder may be reversible with resolution/improvement in the disease process responsible for the deficiency.

Chance to inherit thrombophilia

Every individual inherits two copies of each gene. One copy is inherited from their mother, the other copy from their father. To predict the risk to a child, a few factors must be considered.
The first is whether or not you are heterozygous (only one of your two gene copies contains a mutation) or homozygous (both copies of your two genes contain a mutation). A genetic test can tell you whether you are heterozygous or homozygous.

The first is whether or not you are heterozygous for the gene mutation, there is a 50:50 (or one half) chance that your child will inherit the gene mutation, because there is an equal chance of passing on the gene copy with the mutation OR the gene copy without the mutation. The gene copy your child inherits is due to chance, and there is nothing an individual can do to alter this chance. (See diagram below.)

If you are homozygous for the gene mutation, your child will inherit the mutation. Since you do not have a copy of the gene without a mutation, it is impossible to pass on a gene without a mutation to your child.

Another consideration is whether the child’s other parent carries a gene mutation that leads to thrombophilia. This would also influence your child’s chances of inheriting thrombophilia.
Genetic counselors are medical professionals who can help interpret genetic concepts. If you are interested in learning more about genetic risks, you can consult with a genetic counselor, or a healthcare professional who has specialized training in genetics.

Factor V Leiden Mutation

Factor V Leiden, named after the city in the Netherlands where it was first described, is a variant of the normal clotting factor V. The gene for factor V Leiden differs from the gene for normal factor V by a single nucleotide (nucleotides are the building blocks of DNA). As a result, it produces a protein that differs by one amino acid (amino acids are the building blocks for proteins) from normal factor V. While factor V Leiden is completely normal in terms of its ability to prevent bleeding, the one amino acid difference makes factor V Leiden resistant to being degraded or inactivated by protein C and protein S. Consequently, factor V Leiden lingers in the circulation longer and, therefore, contributes to the formation of blood clots.

Individuals who have inherited one copy of the gene for factor V Leiden (heterozygotes) have a 3- to 10-fold increased risk of DVT or PE; individuals who have inherited two copies of the gene (homozygotes) have an 80- to 100-fold increased risk. Among individuals of northern European ancestry who appear to have inherited a tendency to form blood clots, 20 to 40 percent have been found to carry the factor V Leiden gene. Prior to the discovery of factor V Leiden, fewer than 10 percent of cases of thrombosis could be explained by an inherited thrombophilia.

The percentage of people who have factor V Leiden depends on the population studied. Higher percentages are reported among people of European ancestry compared to people from other continents. In the United States, factor V Leiden has been found in 5 percent of individuals of European ancestry, 2 percent of individuals of African ancestry, 2 percent of individuals of Hispanic ancestry, 2 percent of Native Americans, and less than 1 percent of individuals of Asian ancestry.


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Protein C Deficiency

Protein C deficiency is a rare genetic disorder characterized by a deficiency of protein C, which is a natural anticoagulant. This means it helps to prevent the blood from clumping together (clotting) too much. There is a mild form in which affected individuals are at risk for developing blood clots, particularly a type of blood clot called deep vein thrombosis. This is a clot that forms in the legs. Although very rare, there is a severe form that is present at birth (congenital) and can potentially cause widespread small clots in the body and life-threatening complications in infancy. Protein C deficiency is caused by alterations (mutations) in the PROC gene. The milder form is caused by an alteration in one PROC gene and is inherited in an autosomal dominant manner. The severe form is caused by an alteration in both PROC genes and is inherited in an autosomal recessive manner.

Protein S Deficiency

Protein S deficiency is a rare genetic disorder of blood coagulation that is caused by a variation in the PROS1 gene. This variation is inherited in an autosomal dominant manner. Affected individuals are at an increased risk of developing blood clots in the legs (deep venous thrombosis), which can break off and travel to the lungs, which is termed pulmonary embolism. Affected individuals are deficient in protein S, which is a specialized blood protein. Specifically, protein S is involved in inhibiting coagulation. This means that it helps to prevent the blood from clotting too much. Affected individuals who inherit one abnormal protein S gene are at risk for developing blood clots. Although very rare, there is a severe form that is present at birth (congenital) due to the presence of 2 abnormal protein S genes that can potentially cause widespread small clots in the body and life-threatening complications in infancy. Occasionally protein S deficiency may be acquired as a result of acquired conditions such as kidney disease (i.e., nephrotic syndrome), pregnancy, or the use of oral contraceptives.

Prothrombin G20210A Mutation

Prothrombin 20210 Mutation, also called Factor II Mutation is a genetic condition that causes an increase in the likelihood of your blood forming dangerous blood clots.

All individuals make the prothrombin (also called factor two) protein that helps blood clot. However, there are certain individuals who have a DNA mutation in the gene used to make prothrombin (also called prothrombin G20210A or the factor II (two) mutation). They are said to have an inherited thrombophilia (clotting disorder) called prothrombin G20210A. When this occurs, they make too much of the prothrombin protein.

Prothrombin G20210A and the tendency to develop blood clots

  • Normally, the prothrombin protein is produced to help the blood clot, and is produced in greater amounts after a blood vessel is damaged.
  • People who have a mutation in the prothrombin gene produce more prothrombin protein than is normal. Since there is more of the prothrombin protein in the blood, this increases the tendency to form clots.