Hereditary antithrombin deficiency is a disorder of blood clotting. People with this condition are at higher than average risk for developing abnormal blood clots, particularly a type of clot that occurs in the deep veins of the legs. This type of clot is called a deep vein thrombosis (DVT). Affected individuals also have an increased risk of developing a pulmonary embolism (PE), which is a clot that travels through the bloodstream and lodges in the lungs. In hereditary antithrombin deficiency, abnormal blood clots usually form only in veins, although they may rarely occur in arteries.

About half of people with hereditary antithrombin deficiency will develop at least one abnormal blood clot during their lifetime. These clots usually develop after adolescence.

Other factors can increase the risk of abnormal blood clots in people with hereditary antithrombin deficiency. These factors include increasing age, surgery, or immobility. The combination of hereditary antithrombin deficiency and other inherited disorders of blood clotting can also influence risk. Women with hereditary antithrombin deficiency are at increased risk of developing an abnormal blood clot during pregnancy or soon after delivery. They also may have an increased risk for pregnancy loss (miscarriage) or stillbirth.

Hereditary antithrombin deficiency is caused by mutations in the SERPINC1 gene. This gene provides instructions for producing a protein called antithrombin (previously known as antithrombin III). This protein is found in the bloodstream and is important for controlling blood clotting. Antithrombin blocks the activity of proteins that promote blood clotting, especially a protein called thrombin.

Most of the mutations that cause hereditary antithrombin deficiency change single protein building blocks (amino acids) in antithrombin, which disrupts its ability to control blood clotting. Individuals with this condition do not have enough functional antithrombin to inactivate clotting proteins, which results in the increased risk of developing abnormal blood clots.

Normal Function

The SERPINC1 gene provides instructions for making a protein called antithrombin (previously known as antithrombin III), which is a type of serine protease inhibitor (serpin). Serpins help control several types of chemical reactions by blocking the activity of certain proteins. Antithrombin is found in the bloodstream and is important for controlling blood clotting.

Antithrombin blocks the activity of proteins that promote blood clotting, especially a protein called thrombin. Antithrombin attaches (binds) to thrombin and certain other clotting proteins, which are then cleared from the bloodstream by the liver.

While one part of antithrombin binds to thrombin and other clotting proteins, another part of the protein binds to a substance called heparin. Antithrombin changes its shape when it binds to heparin. This change in shape allows antithrombin to inactivate clotting proteins at a much faster rate.

Health Conditions Related to Genetic Changes

Hereditary antithrombin deficiency

At least 220 mutations in the SERPINC1 gene have been found to cause hereditary antithrombin deficiency. Most of these mutations change single protein building blocks (amino acids) in antithrombin, which disrupts its ability to control blood clotting.

Hereditary antithrombin deficiency can be divided into type I and type II based on the mutation in the SERPINC1 gene.

Hereditary antithrombin deficiency type I is caused by SERPINC1 gene mutations that prevent the cell from producing antithrombin from the altered gene. Individuals with this type have only one working copy of the SERPINC1 gene in each cell, which results in approximately half of the normal amount of antithrombin. Affected individuals do not have enough antithrombin to inactivate clotting proteins, which causes the increased risk for abnormal blood clots in hereditary antithrombin deficiency.

Mutations that cause hereditary antithrombin deficiency type II result in the production of an altered antithrombin with reduced activity. Individuals with this form of the condition typically have normal levels of antithrombin, but the protein does not function properly. Type II can be further divided based on whether the mutation affects binding to thrombin and other clotting factors (type IIa), heparin (type IIb), or both (type IIc). Individuals with hereditary antithrombin deficiency type IIb have a lower risk of forming an abnormal blood clot than people with other forms of this condition because antithrombin is able to inactivate clotting proteins without heparin.

Other Names for This Gene

• ANT3_HUMAN
• antithrombin (aa 375-432)
• antithrombin III
• AT3
• ATIII
• coding sequence signal peptide antithrombin part 1
• heparin cofactor I
• MGC22579
• serine (or cysteine) proteinase inhibitor, clade C (antithrombin), member 1
• serine-cysteine proteinase inhibitor clade C member 1
• serpin peptidase inhibitor, clade C (antithrombin), member 1
• serpin peptidase inhibitor, clade C, member 1
• signal peptide antithrombin part 1

Genomic Location

Hereditary antithrombin deficiency is typically inherited in an autosomal dominant pattern, which means one altered copy of the SERPINC1 gene in each cell is sufficient to cause the disorder. Inheriting two altered copies of this gene in each cell is usually incompatible with life; however, a few severely affected individuals have been reported with mutations in both copies of the SERPINC1 gene in each cell.

Hereditary antithrombin deficiency is estimated to occur in about 1 in 2,000 to 3,000 individuals. Of people who have experienced an abnormal blood clot, about 1 in 20 to 200 have hereditary antithrombin deficiency.