Glanzmann thrombasthenia is a bleeding disorder that is characterized by prolonged or spontaneous bleeding starting from birth. People with Glanzmann thrombasthenia tend to bruise easily, have frequent nosebleeds (epistaxis), and may bleed from the gums. They may also develop red or purple spots on the skin caused by bleeding underneath the skin (petechiae) or swelling caused by bleeding within tissues (hematoma). Glanzmann thrombasthenia can also cause prolonged bleeding following injury, trauma, or surgery (including dental work). Women with this condition can have prolonged and sometimes abnormally heavy menstrual bleeding. Affected women also have an increased risk of excessive blood loss during pregnancy and childbirth.

About a quarter of individuals with Glanzmann thrombasthenia have bleeding in the gastrointestinal tract, which often occurs later in life. Rarely, affected individuals have bleeding inside the skull (intracranial hemorrhage) or joints (hemarthrosis).

The severity and frequency of the bleeding episodes in Glanzmann thrombasthenia can vary greatly among affected individuals, even in the same family. Spontaneous bleeding tends to become less frequent with age.

Mutations in the ITGA2B or ITGB3 gene cause Glanzmann thrombasthenia. These genes provide instructions for making the two parts (subunits) of a receptor protein called integrin alphaIIb/beta3 (αIIbβ3). This protein is abundant on the surface of platelets. Platelets are small cells that circulate in blood and are an essential component of blood clots. During clot formation, integrin αIIbβ3 helps platelets bind together. Blood clots protect the body after injury by sealing off damaged blood vessels and preventing further blood loss.

ITGA2B or ITGB3 gene mutations result in a shortage (deficiency) of functional integrin αIIbβ3. As a result, platelets cannot clump together to form a blood clot, leading to prolonged bleeding.

Three types of Glanzmann thrombasthenia have been classified according to the amount of integrin αIIbβ3 that is available. People with type I (the most common type) have less than 5 percent of normal integrin αIIbβ3 levels, people with type II have between 5 and 20 percent of normal integrin αIIbβ3 levels, and people with the variant type have adequate integrin αIIbβ3 levels but produce only nonfunctional integrin.

Some people with Glanzmann thrombasthenia do not have an identified mutation in either the ITGA2B or ITGB3 gene; the cause of the disorder in these individuals is unknown.

Normal Function

The ITGA2B gene provides instructions for making one part, the alphaIIb subunit, of a receptor complex called integrin alphaIIb/beta3 (αIIbβ3), which is found on the surface of small cells called platelets. Platelets circulate in blood and are an essential component of blood clots. The alphaIIb subunit attaches (binds) to the beta3 subunit, which is produced from the ITGB3 gene, to form integrin αIIbβ3. It is estimated that 80,000 to 100,000 copies of integrin αIIbβ3 are present on the surface of each platelet.

During clot formation, integrin αIIbβ3 binds to a protein called fibrinogen. Attachment of integrin αIIbβ3 from adjacent platelets to the same fibrinogen protein helps platelets cluster together (platelet cohesion) to form a blood clot. Blood clots protect the body after injury by sealing off damaged blood vessels and preventing further blood loss. Integrin αIIbβ3 can also bind other proteins on platelets and in blood as well as proteins within the intricate lattice that forms in the space between cells (extracellular matrix) to ensure proper clot formation and promote wound healing.

Health Conditions Related to Genetic Changes

Glanzmann thrombasthenia

At least 200 mutations in the ITGA2B gene have been found to cause Glanzmann thrombasthenia, which is a rare bleeding disorder. The mutations that cause this disorder occur in both copies of the gene in each cell and impair the production or activity of the alphaIIb subunit, which disrupts the formation of functional integrin αIIbβ3. A shortage (deficiency) of functional integrin αIIbβ3 prevents sufficient binding of fibrinogen or other proteins, impairing the formation of blood clots. A lack of platelet cohesion leads to prolonged or spontaneous bleeding episodes experienced by people with Glanzmann thrombasthenia.

Other disorders

Mutations in the ITGA2B gene can also cause another rare bleeding disorder called platelet-type bleeding disorder 16. People with this disorder have signs and symptoms similar to Glanzmann thrombasthenia (described above), including frequent nosebleeds (epistaxis), bleeding from the gums, or red or purple spots on the skin caused by bleeding underneath the skin (petechiae), but the episodes are typically milder.

Unlike Glanzmann thrombasthenia, this disorder results from a mutation in only one copy of the ITGA2B gene in each cell, and the mutations result in the formation of some integrin αIIbβ3 that is abnormally turned on (active), even when no clot is being formed. This abnormally active protein is unable to reach the surface of the platelet where it is needed to bind to other platelets during clot formation. The overactive integrin αIIbβ3 binds inappropriately to clotting proteins within the cell during the formation of platelets, causing the platelets to become misshapen and large. The abnormally shaped platelets have a shortened lifespan, so platelet numbers are often reduced, which impairs clot formation. (The combination of reduced numbers of enlarged platelets is referred to as macrothrombocytopenia.)

Because the mutation that causes this disorder affects only one copy of the ITGA2B gene, some normal integrin is formed and normal platelets produced, which accounts for the mild signs and symptoms in affected individuals.

Other Names for This Gene

• alphaIIb protein
• CD41
• CD41B
• GP2B
• GPIIb
• integrin alpha 2b
• integrin alpha-IIb preproprotein
• integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41)
• integrin, alpha-2B
• platelet fibrinogen receptor, alpha subunit
• platelet glycoprotein IIb
• platelet membrane glycoprotein IIb

Genomic Location

Normal Function

The ITGB3 gene provides instructions for making the beta3 subunit of a receptor protein called integrin alphaIIb/beta3 (αIIbβ3), which is found on the surface of small cells called platelets. Platelets circulate in blood and are an essential component of blood clots. The beta3 subunit attaches (binds) to the alphaIIb subunit, which is produced from the ITGA2B gene, to form integrin αIIbβ3. It is estimated that 80,000 to 100,000 copies of integrin αIIbβ3 are present on the surface of each platelet.

During clot formation, integrin αIIbβ3 binds to a protein called fibrinogen. Attachment of integrin αIIbβ3 from adjacent platelets to the same fibrinogen protein helps platelets cluster together (platelet cohesion) to form a blood clot. Blood clots protect the body after injury by sealing off damaged blood vessels and preventing further blood loss. Integrin αIIbβ3 can also bind other proteins on platelets and in the blood as well as proteins within the intricate lattice that forms in the space between cells (extracellular matrix) to ensure proper clot formation and promote wound healing.

Health Conditions Related to Genetic Changes

Glanzmann thrombasthenia

At least 130 mutations in the ITGB3 gene have been found to cause Glanzmann thrombasthenia, which is a rare bleeding disorder. The mutations that cause this disorder occur in both copies of the gene in each cell and impair the production or activity of the beta3 subunit, which disrupts the formation of functional integrin αIIbβ3. A shortage (deficiency) of functional integrin αIIbβ3 prevents sufficient binding of fibrinogen or other proteins, impairing the formation of blood clots. A lack of platelet cohesion leads to prolonged or spontaneous bleeding episodes experienced by people with Glanzmann thrombasthenia.

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Other disorders

Mutations in the ITGB3 gene can also cause another rare bleeding disorder called platelet-type bleeding disorder 16. People with this disorder have signs and symptoms similar to Glanzmann thrombasthenia (described above), including frequent nosebleeds (epistaxis), bleeding from the gums, or red or purple spots on the skin caused by bleeding underneath the skin (petechiae), but the episodes are typically milder.

Unlike Glanzmann thrombasthenia, this disorder results from a mutation in only one copy of the ITGB3 gene in each cell, and the mutations result in the formation of some integrin αIIbβ3 that is abnormally turned on (active), even when no clot is being formed. This abnormally active protein is unable to reach the surface of the platelet where it is needed to bind to other platelets during clot formation. The overactive integrin αIIbβ3 binds inappropriately to clotting proteins within the cell during the formation of platelets, causing the platelets to become misshapen and large. The abnormally shaped platelets have a shortened lifespan, so platelet numbers are often reduced, which impairs clot formation. (The combination of reduced numbers of enlarged platelets is referred to as macrothrombocytopenia.)

Because the mutation that causes this disorder affects only one copy of the ITGB3 gene, some normal integrin is formed and normal platelets produced, which accounts for the mild signs and symptoms in affected individuals.

Other Names for This Gene

• beta 3 integrin
• CD61
• GP3A
• GPIIIa
• integrin beta 3
• integrin beta-3 precursor
• integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61)
• platelet glycoprotein IIIa
• platelet GPIIIa
• platelet membrane glycoprotein IIIa
• vitronectin receptor beta chain

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Glanzmann thrombasthenia is estimated to affect 1 in one million individuals worldwide, but may be more common in certain groups, including those of Romani ethnicity, particularly people within the French Manouche community.