Glanzmann thrombasthenia (GT) is a rare genetic platelet disorder in which the platelets have qualitative or quantitative deficiencies of the fibrinogen receptor αIIbβ3.
Signs and symptoms of GT include the following:
See Clinical Presentation for more detail.
The workup for GT may include complete blood cell count, prothrombin time, and activated partial thromboplastin time. Flow cytometry and monoclonal antibodies confirm the diagnosis.
See Workup for more detail.
Treatment of GT includes preventive measures such as avoidance of antiplatelet agents (e.g., aspirin and NSAIDs), iron or folate supplementation for anemia, and vaccination for hepatitis B due to the infectious risks associated with multiple transfusions.
Patients with GT who are bleeding require platelet transfusion.
Recombinant coagulation factor VIIa was approved by the FDA in July 2014 for bleeding episodes and perioperative management in patients with GT refractory to platelet transfusions, with or without antibodies to platelets.
See Treatment and Medication for more detail.
Glanzmann thrombasthenia is a genetic platelet disorder in which the platelet have qualitative or quantitative deficiencies of the fibrinogen receptor αIIbβ3. The genes of both of these proteins are on chromosome 17, and 50% activity of each protein is enough to support normal platelet aggregation. Defects in the αIIbβ3 complex leads to defective platelet aggregation and subsequent bleeding.[1, 2, 3, 4, 5, 6, 7]
Glanzmann thrombasthenia is rare and it is inherited in an autosomal recessive pattern. The disorder was first described by Dr. Eduard Glanzmann in 1918.
When an injury occurs, the αIIbβ3 receptors play an important role in the adherence of platelets to the endothelium as well as have a role in platelet aggregation.
The αIIbβ3 complex binds fibrinogen and/or von Willebrand factor (vWF). Adjacent platelets are cross-linked through the αIIβ3. When the complex functions abnormally, platelets cannot aggregate. This then leads to increased bleeding.
The αIIbβ3 is a heterodimer that requires calcium for it to associate normally.The ITGA2B and ITGB3 code the αIIbβ3 integrin. Both genes are needed for the normal platelet function. The ITGA2B gene code for the αIIb and the ITGB3 codes for the β3. A defect in either glycoprotein can lead to a bleeding disorder. The majority of the patients have a normal platelet size and count.[8]
Glanzmann thrombasthenia is quite rare, is inherited in an autosomal recessive manner, and is observed most often in populations that have increased consanguinity.[9] Reports of families with a high incidence have been observed from countries such as Iran, Israel, and Jordan, where marriage among close relatives is not uncommon.
Bleeding problems can be severe in patients with Glanzmann thrombasthenia, but the prognosis remains good with appropriate supportive care. The bleeding is primarily mucocutaneous in nature. Generally, bleeding incidence decreases with age.
There may a slightly higher female preponderance for Glanzmann thrombasthenia. For a review of pregnancy in women with Glanzmann thrombasthenia, see Siddiq et al.[10]
Patients with thrombasthenia typically present with mucocutaneous bleeding at birth or early in infancy.
The clinical history of Glanzmann thrombasthenia may include the following:
See the list below:
See the list below:
The workup for Glanzmann thrombasthenia may include the following:
Results are as follows:
The platelet morphology on peripheral blood smears is normal in patients with Glanzmann thrombasthenia.
Platelet transfusion is the standard treatment for severe bleeding and perioperative hemostasis in patients with Glanzmann thrombasthenia. A hematologist may be consulted for transfusion recommendations. Control of less severe bleeding episodes may be achieved with local measures such as fibrin sealants and topical thrombin, or with antifibrinolytics or desmopressin.[13]
As platelet counts are normal in Glanzmann thrombasthenia, response to platelet transfusions must be assessed functionally, principally by monitoring for clinical reduction in bleeding. Laboratory testing of platelet function may also be used, but may be difficult to perform, may take several hours, and are not available at all hospitals.[13]
Because patients often require multiple transfusions during their lifetime, they are at risk for developing antiplatelet alloantibodies targeting human leukocyte antigens (HLAs) or glycoproteins (GPIIb/IIIa) that are deficient in patients with Glanzmann thrombasthenia. However, antiplatelet antibodies have been reported in patients who had not received platelet transfusions.[13]
To reduce the potential for platelet alloimmunization, patients should receive leukocyte-depleted blood products. Leukocyte depletion can be accomplished with mechanical filtration. Only filtered blood products should be given. Use of platelets from HLA-matched donors is a further attempt to prevent platelet alloimmunization.
Other treatment considerations include the following:
Recombinant activated factor VII (rFVIIa) has been used in patients with antibodies to platelet glycoprotein IIb/IIIa and/or HLA that render transfusions ineffective. In July 2014, the US Food and Drug Administration (FDA) approved rFVIIa (NovoSeven RT) for treatment of bleeding episodes and perioperative management in adults and children with Glanzmann thrombasthenia that is refractory to platelet transfusions, with or without antibodies to platelets.[14]
Analysis of data from the prospective Glanzmann’s Thrombasthenia Registry (829 bleeds and 206 procedures in 218 GT patients) found that rFVIIa was frequently used in nonsurgical and surgical bleeds, with high efficacy rates and good safety profile, irrespective of platelet antibodies/refractoriness status.[15, 16, 17]
Patients with Glanzmann thrombasthenia who require surgical intervention should receive platelet transfusions preoperatively, to prevent excessive bleeding during surgery. Further platelet transfusions are considered, based on maintaining hemostasis. Alternatively, rFVIIa may be useful for preventing or controlling perioperative bleeding.
The goals of pharmacotherapy in patients with Glanzmann thrombasthenia are to induce active immunity, reduce morbidity, and prevent complications. Platelet transfusions are the principal form of therapy, but recombinant activated factor VII (rFVIIa) can be used in patients with antibodies that render transfusions ineffective. Vaccination against hepatitis B is indicated, because of the increased risk of infection with multiple transfusions. In women, oral contraceptives may be used to control menorrhagia.
Clinical Context: Vitamin K–dependent glycoprotein that promotes hemostasis by activating the extrinsic pathway of the coagulation cascade, forming complexes with tissue factor. Promotes activation of factor X to factor Xa, factor IX to factor IXa, and factor II to factor IIa. It is indicated for treatment of bleeding episodes and perioperative management in adults and children with Glanzmann thrombasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets.
Clinical Context: Suggested mechanisms by which hormonal therapy might affect bleeding include improvement in coagulation, alterations in the microvascular circulation, and improvements in endothelial integrity. One active tablet contains ethinyl estradiol 0.05 mg and norethindrone 1 mg. Used in women to prevent menorrhagia.
Estrogen-progestin combinations of oral contraceptives reduce the secretion of LH and FSH from the pituitary by decreasing amount of gonadotropin-releasing hormones (GnRHs).
Clinical Context: Recombinant vaccine used to provide immunization against all the known subtypes of the hepatitis B virus.
Patients with Glanzmann thrombasthenia should avoid drugs that decrease platelet function or coagulation, such as the following:
With platelet transfusions for bleeding complications, patients with Glanzmann thrombasthenia generally have a good prognosis.
Educate patients with Glanzmann thrombasthenia that regular dental care is necessary to avoid gingivitis and gingival bleeding.