Glanzmann Thrombasthenia

Glanzmann thrombasthenia (GT)

Glanzmann thrombasthenia (GT) is a rare inherited blood clotting (coagulation) disorder characterized by the impaired function of specialized cells (platelets) that are essential for proper blood clotting. Symptoms of this disorder usually include abnormal bleeding, which may be severe. Prolonged untreated or unsuccessfully treated hemorrhaging associated with Glanzmann thrombasthenia may be life threatening.

Signs & Symptoms

The symptoms of Glanzmann thrombasthenia usually begin at birth or shortly thereafter and include the tendency to bruise and bleed easily and sometimes profusely, especially after surgical procedures. Other symptoms may include susceptibility to easy bruising, nosebleeds (epistaxis), bleeding from the gums (gingival), intermittent gastrointestinal bleeding, and/or variably large red or purple colored spots on the skin that are caused by bleeding in the skin (purpura). Women with GT often also have unusually heavy menstrual bleeding, irregular uterine bleeding, and excess bleeding in childbirth. Rarely, internal bleeding and blood in the urine (hematuria) can occur. The severity of the symptoms varies greatly. Some affected individuals have mild bruising and others have severe hemorrhages that can be life threatening.

Causes

Glanzmann thrombasthenia is inherited in an autosomal recessive pattern. An abnormality in either the gene for IIb (glycoprotein IIb; GPIIb) or the gene for β3 (glycoprotein IIIa; GPIIIa) results in an abnormal platelet IIbβ3 (GPIIb/IIIa) integrin family receptor and prevents platelets from forming a plug when bleeding occurs. Many different abnormalities in these genes have been identified. Recent evidence suggests that approximately 0.5% of healthy individuals in the general population are probably carrying one gene with an abnormal variant of aIIb or β3.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits an abnormal variant of a gene from each parent. If an individual receives one normal gene and one abnormal variant gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. This is true for carriers of Glanzmann thrombasthenia. 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 the normal genes from both parents and therefore be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Affected Populations

Glanzmann thrombasthenia is a rare disorder that affects males and females in equal numbers. The symptoms of this disease are usually apparent at birth (neonates) or during infancy. Approximately 500 cases have been reported, but many cases have probably not been reported. This condition occurs with greater frequency in populations in which intermarriage within a group (consanguinity) is more prevalent such as in some regions of the Middle East, India, and France.

Diagnosis

Most individuals affected with Glanzmann thrombasthenia have a normal number of platelets but have a prolonged bleeding time, which means it takes longer than usual for a standardized cut to stop bleeding. Platelet aggregation studies are abnormal and show that platelets are not able to clump together when stimulated as they should to form platelet aggregates. Glanzmann thrombasthenia is definitively diagnosed by tests that determine if there is a deficiency of the aIIbβ3 (GPIIb/GPIIIa) receptor. These tests usually involve monoclonal antibodies and flow cytometry. Genetic tests can identify the DNA mutations responsible for the disorder.

Carrier and prenatal testing by DNA analysis is possible if the specific gene abnormality has been identified in an affected family member. Otherwise prenatal testing can be performed based on analyzing the fetus’s platelet aIIbβ3.

Standard Therapies

Treatment

Some individuals with GT may require blood platelet transfusions. Since transfusions may continue to be necessary throughout life, affected individuals may benefit from transfusions from HLA matched donors. Some patients develop antibodies to transfused platelets and these antibodies may diminish the benefit from subsequent platelet transfusions.

In 2014, NovoSeven RT, a recombinant factor VIIa product, was approved to treat Glanzmann thrombasthenia. This medication is indicated to treat bleeding episodes and perioperative management when platelet transfusions are not effective. NovoSeven RT is manufactured by Novo Nordisk.

Treatment is usually given prior to most surgical procedures or should be available if needed. Platelet transfusions are usually necessary prior to delivery.

Nosebleeds can usually be treated with nasal packing or application of foam soaked in thrombin. Regular dental care is important to prevent bleeding from the gums.

Hormonal therapy can be used to suppress menstrual periods.

Other treatment of GT is symptomatic and supportive, including use of antifibrinolytic agents.

Genetic counseling is recommended for people with GT and their families.

Investigational Therapies

Bone marrow transplantation has successfully cured a number of patients with severe disease.
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