Factor XII deficiency is a rare genetic blood disorder that causes prolonged clotting (coagulation) of blood in a test tube without the presence of prolonged clinical bleeding tendencies. It is caused by a deficiency of the factor XII (Hageman factor), a plasma protein (glycoprotein). Specifically, factor XII is a clotting factor. Clotting factors are specialized proteins that are essential for proper clotting, the process by which blood clumps together to plug the site of a wound to stop bleeding. Although it is thought that factor XII is needed for proper blood clotting, when it is deficient, other blood clotting factors appear to compensate for its absence. Therefore, the disorder is thought to be benign and usually presents no symptoms (asymptomatic); it is usually only accidentally discovered through pre-operative blood tests that are required by hospitals.
Factor XII deficiency was first described in the medical literature in 1955 by doctors Oscar Ratnoff and Jane Colopy in a patient named John Hageman. The disorder is sometimes known as Hageman factor deficiency or Hageman trait.
Factor XII deficiency is rarely associated with any symptoms (asymptomatic). However, when blood from a patient is subjected to a partial thromboplastin time test (PTT), a test measuring clotting time, it takes an abnormally long time for the blood to clot. Serum prothrombin (PT) time, another test of blood clotting, is also abnormally long. The blood level of factor XII tends to vary greatly.
According to some older medical reports, factor XII deficiency may predispose affected individuals to developing blood clots (thrombi) at an early age. For example, individuals may have a greater risk than the general population in developing deep vein thrombosis or acquired thrombotic disorders. However, such an association remains unproven.
Researchers are now studying drugs to block (inhibit) factor XII as a potential therapy for individuals who are prone to developing blood clots. More research is necessary to determine the exact role that factor XII plays in the development or prevention of blood clots and its overall functions in the body.
There are also reports in the medical literature that suggest an association between factor XII deficiency and repeated unexplained miscarriages in some affected women. However, such an association remains controversial and unproven.
Factor XII deficiency is inherited as an autosomal recessive disorder. Genetic diseases are determined by two genes, one received from the father and one from the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined that factor XII deficiency occurs due to mutations of the F12 gene located on the long arm of chromosome 5 (5q33-qter). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 5q33” refers to band 33 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The F12 gene creates (encodes) factor XII, which is a clotting factor. Mutations of the F12 gene lead to low levels of functional factor XII in the blood (potentially less than 1%). The exact role that factor XII plays in the clotting process and any additional effects it has on the body are not fully understood. In addition to the clotting process, factor XII is believed to play a role tissue repair and the formation of blood vessels (angiogenesis).
Factor XII deficiency affects persons of Asian descent more often than individuals of other ethnicities. Males and females are affected in equal numbers. Since no symptoms are usually associated with factor XII deficiency, many individuals remain undiagnosed. The exact incidence of the disorder in the general population is unknown, but estimated to be approximately 1 in 1 million individuals.
Factor XII deficiency is often diagnosed accidentally during a routine blood clotting (coagulation) tests as in one done before surgery. In affected individuals, it will take longer for their blood to clot during these tests. Further tests can reveal low levels of factor XII in the blood.
Clinical Testing and Work-up
A diagnosis of factor XII deficiency may be suspected in individuals without clinical signs or a previous history of a bleeding disorder in whom specialized tests called screening coagulation tests known as activated partial thromboplastin time (aPTT) or prothrombin time PT) are abnormal. These tests measure how long it takes the blood to clot.
Individuals with abnormal results on these tests but no bleeding symptoms may then be screened for a condition known as antiphospholipid syndrome. A test will be run to detect a specific inhibitor called lupus anticoagulant, which is present in individuals with acquired antiphospholipid syndrome and can cause similar abnormal results on the aPTT or PT tests.
A diagnosis of factor XII deficiency can be confirmed by a test called an assay. An assay is a test that measures the activity of coagulation factors. It can demonstrate a deficiency of factor XII.
Treatment for this disorder is usually not necessary since bleeding abnormalities only mild or nonexistent.
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