Glanzmann thrombasthenia (GT) is a rare platelet disorder in which the platelet count is normal but platelet function is impaired due to qualitative or quantitative deficiencies of integrins αIIb and β3 (glycoprotein [GP]IIb/IIIa), the principal platelet receptor for fibrinogen.[1, 2] Most cases are hereditary, inherited in an autosomal recessive pattern, but acquired GT also occurs.[3] The disorder is named after the Swiss pediatrician Eduard Glanzmann, who first described it in 1918.[2]
Signs and symptoms of GT include the following:
See Presentation for more detail.
Laboratory findings in GT include the following:
See Workup for more detail.
Treatment of GT includes preventive measures such as avoidance of antiplatelet agents (eg, aspirin and NSAIDs), iron or folate supplementation for anemia, and vaccination against hepatitis B due to the infectious risks associated with multiple transfusions.[4]
Patients with GT who are bleeding require platelet transfusion.
Recombinant coagulation factor VIIa is approved 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.
The platelet integrin αIIbβ3, also known as the glycoprotein GPIIb/IIIa (CD41/CD61) complex, is essential for normal platelet function.[5] With platelet activation, the αIIbβ3 complex shifts into its active configuration, which allows the binding of fibrinogen and/or von Willebrand factor (vWF). Adjacent platelets are cross-linked through the αIIβ3, resulting in platelet aggregation and hemostasis. When the complex functions abnormally, platelets cannot aggregate, which leads to increased bleeding.[1]
The αIIbβ3 is a heterodimer.The ITGA2B gene codes for the αIIb and the ITGB3 gene codes for the β3. A defect in either glycoprotein can lead to a bleeding disorder. Most patients have a normal platelet size and count.[6] Acquired Glanzmann thrombasthenia is characterized by anti-αIIbβ3 autoantibodies or paraproteins that block platelet aggregation.[7]
Hereditary Glanzmann thrombasthenia is caused by autosomal recessive mutations in the ITGA2B or ITGB3 genes, composed of 30 and 15 exons, respectively; they are near-neighbors localizing to chromosome 17q21.31 and 17q21.32.[8] More than 100 mutations have been reported.[4] The disease is clinically apparent in patients who are homozygous. Glanzmann thrombasthenia is normally of no clinical significance in patients who are heterozygous for this condition.
Additionally, a very small number of cases of autosomal dominant Glanzmann thrombasthenia have been reported. These cases have been named Glanzmann thrombasthenia–like syndrome (GTLS) or ITGA2B/ITGB3-related thrombocytopenia.[9]
Rare acquired forms caused by antibodies against αIIb β3 integrin have been described. Cases have been reported in patients with a variety of underlying disorders, including primary immune thrombocytopenia (ITP); leukemia, lymphoma, solid cancers, and myeloma; other autoimmune diseases; following organ transplantation; during viral and bacterial infections, as well as with the use of certain drugs.[3, 10, 11, 7]
Glanzmann thrombasthenia is quite rare; the global prevalence is estimated to be one per million, with higher prevalence rates found in the Middle East, including Iran, Iraq, Saudi Arabia, Jordan, and among both Palestinians and Israelis.[12] Higher rates have also been reported in India and France.[4] Cases are observed most often in populations that have increased consanguinity, consistent with its autosomal recessive inheritance.[13]
The preponderance for Glanzmann thrombasthenia is higher in females compared to males (58% versus 42%).[12] For a review of pregnancy in women with Glanzmann thrombasthenia, see Siddiq et al.[14]
Patients with thrombasthenia may present with mucocutaneous bleeding at birth or early in infancy, however most patients are diagnosed later in childhood. The risk and prevalence of severe bleeding increases with age.[4]
There is a considerable spectrum of clinical manifestations that ranges from only minimal bruising to fatal hemorrhages. Even in patients with severe bleeding problems, the prognosis remains good with appropriate supportive care and platelet transfusions if necessary.[12] The bleeding is primarily mucocutaneous in nature. Clinically significant heavy menstrual bleeding is common and can result in repeated hospital admissions and blood transfusions with a resulting adverse effect on quality of life.[15]
Educate patients with Glanzmann thrombasthenia that regular dental care is necessary to avoid gingivitis and gingival bleeding. Patients with Glanzmann thrombasthenia should avoid drugs that decrease platelet function or coagulation, such as the following:
The history in patients with Glanzmann thrombasthenia may include the following:
In patients suspected of Glanzmann thrombasthenia, examine the skin and oral mucosa for petechiae, ecchymoses, and any current bleeding. The spleen should normally be nonpalpable.
The workup for Glanzmann thrombasthenia may include the following:
Characteristic results in patients with Glanzmann thrombasthenia are as follows:
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.[19]
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.[19]
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.[19]
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. The US Food and Drug Administration (FDA) has 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.18 Analysis of data from the prospective Glanzmann’s Thrombasthenia Registry (829 bleeds and 206 procedures in 218 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.[20, 21, 22]
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.
Hematopoietic stem cell transplantation (HSCT) is a curative but controversial treatment for severe cases, with potential complications that include alloimmunization of platelets.[23] Gene therapy is a possible future option.[24]
Pregnancy should be closely monitored in woman affected by GT, particularly in cases of anti‐αIIbβ3 immunization. Unfortunately, information is scarce on this matter. Maternal anti‐αIIbβ3 immunization may be associated with fetal thrombocytopenia and in utero death. In GT patients, anamnestic response with rise in antibodies against αIIbβ3 titer during pregnancy has been reported, suggesting that immunization may also be a consequence of exposure to fetal platelet antigens. In these cases, absence of platelet‐specific antibodies at the start of pregnancy does not preclude their appearance at a later date.[25]
For management of peripartum bleeding, platelet transfusion is generally the first-line treatment, although use of rFVIIa has been reported to avoid development of, or to treat patients with, antibodies to platelet glycoprotein IIb/IIIa.[26]
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.