Glanzmann thrombasthenia

Other Names: Thrombasthenia of Glanzmann and Naegeli; GT; Platelet fibrinogen receptor, deficiency of; Platelet glycoprotein 2B 3A deficiency; Deficiency of GP 2B 3A complex; Glanzmann thrombasthenia type A; Diacyclothrombopathia 2B 3A

Thrombocytes

Glanzmann thrombasthenia (GT) is a rare inherited blood clotting disorder that is present at birth. It is characterized by the impaired function of specialized blood cells, called platelets, that are essential for proper blood clotting. 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).

Types

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.

Cause

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 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.

Inheritance

Autosomal recessive inheritance, a 25% chance

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.

Symptoms

Symptoms usually include abnormal bleeding, which can be severe. Other symptoms may include easy bruising, nose bleeds, bleeding from the gums, and/or heavy menstrual bleeding. Rarely, internal bleeding and blood in the urine (hematuria) can occur. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Prolonged bleeding time
• Spontaneous, recurrent epistaxis(Recurring nosebleed)

30%-79% of people have these symptoms

• Bruising susceptibility(Bruise easily)
• Gingival bleeding(Bleeding gums)
• Prolonged bleeding after surgery(Excessive bleeding during surgery)
• Prolonged bleeding following circumcision

5%-29% of people have these symptoms

• Ecchymosis
• Gastrointestinal hemorrhage(Gastrointestinal bleeding)
• Macroscopic hematuria(Bloody urine)
• Menometrorrhagia
• Menorrhagia(Abnormally heavy bleeding during menstruation)
• Spontaneous hematomas

1%-4% of people have these symptoms

• Impaired ristocetin-induced platelet aggregation.

Diagnosis

One must remember to include GT in the differential diagnosis, carefully analyzing the medical history (eg, asking about unprovoked bruising or bleeding episodes, or episodes of severe bleeding after minor trauma), family history (eg, inquiring about possible consanguinity), and clinical presentation (eg, examining for purpura and ecchymoses). When considering a diagnosis of GT, selecting the appropriate laboratory evaluation is essential. For example, a normal platelet count on a routine blood smear does not rule out a diagnosis of GT, as patients with GT usually show no abnormalities in the platelet count. The complete blood count may be entirely normal, or may reveal iron deficiency. The prothrombin time and activated partial thromboplastin time will also be normal. However, the bleeding time will be prolonged, which warrants further investigation. '''Light transmission aggregometry''' (LTA) is widely accepted as the gold standard diagnostic tool for assessing platelet function. Centrifuged platelet-rich plasma samples are monitored before and after the addition of an agonist (ADP, collagen, epinephrine, arachidonic acid, ristocetin, thrombin receptor activating peptide, and thromboxane A2 mimetic), assessing shape change, lag phase, percent of aggregation, slope of aggregation, and deaggregation. This test is highly specific for GT, as platelet aggregation fails to occur with any agonist, except ristocetin, where the reaction is preserved.

Platelet function analyzer (PFA) is a highly sensitive test for detecting GT. Flow cytometry can be beneficial, as GT includes glycoprotein receptor deficiency and/or dysfunction. The best way to diagnose GT in its entirety is through mutation analysis. Genomic DNA sequencingof the 45 exons comprising the αIIbβ3 unit, along with the splice sites of the ITGB3 and ITGA2B gene, should be investigated, and the established mutations should be confirmed with a second DNA sample analysis.

Overall, the diagnosis of GT includes the presence of normal platelet count (typically on the lower end of normal), prolonged bleeding time, and prolonged PFA time. Platelets fail to aggregate under the conditions utilized in LTA, which is uniquely indicative of GT.

Treatment

Therapy involves both preventive measures and treatment of specific bleeding episodes.

• Dental hygiene lessens gingival bleeding
• Avoidance of antiplatelet agents such as aspirin and other anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen, and anticoagulants
• Iron or folate supplementation may be necessary if excessive or prolonged bleeding has caused anemia
• Hepatitis B vaccine
• Antifibrinolytic drugs such as tranexamic acid or ε-aminocaproic acid (Amicar)
• Desmopressin (DDAVP) does not normalize the bleeding time in Glanzmann's thrombasthenia but anecdotally improves hemostasis
• Hormonal contraceptives to control excessive menstrual bleeding
• Topical agents such as gelfoam, fibrin sealants, polyethylene glycol polymers, custom dental splints
• Platelet transfusions (only if bleeding is severe; risk of platelet alloimmunization)
• Hematopoietic stem cell transplantation (HSCT) for severe recurrent hemorrhages

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Coagulation Factor VIIa (Recombinant)(Brand name: NovoSeven RT) NovoSeven RT was approved for the prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX. Previously in March 1999, NovoSeven RT was approved for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX. July 2014, NovoSeven RT was approved for the treatment of bleeding episodes and peri-operative management in adults and children with Glanzmann's thrombasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets.

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