Glanzmann Thrombasthenia

The platelet integrin αIIbβ3, also known as the glycoprotein GPIIb/IIIa (CD41/CD61) complex, is essential for normal platelet function.[4] 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.[5] Acquired Glanzmann thrombasthenia is characterized by anti-αIIbβ3 autoantibodies or paraproteins that block platelet aggregation.[6]

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.[7]  More than 100 mutations have been reported.[3] 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. 

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.[2, 8, 9, 6]

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. Higher rates have also been reported in India and France.[3] Cases are observed most often in populations that have increased consanguinity, consistent with its autosomal recessive inheritance.[10]  

There may a slightly higher female preponderance for Glanzmann thrombasthenia. For a review of pregnancy in women with Glanzmann thrombasthenia, see Siddiq et al.[11]

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.[3]

Patients with Glanzmann thrombasthenia can have severe bleeding problems, but their prognosis remains good with appropriate supportive care and platelet transfusions if necessary. 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.[12]  

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:

• Aspirin or other NSAIDs

• Heparin

• Warfarin

• Ticlopidine or clopidogrel

• Glycoprotein IIb/IIIa antagonists, such as abciximab

• Streptokinase, urokinase, or tissue plasminogen activator (tPA)

• Volume expanders, such as dextran or hydroxyethyl starch

• Dipyridamole

The history in patients with Glanzmann thrombasthenia may include the following:

• Excessive bleeding after dental extraction (this may often be the first sign of the disease)
• Petechiae and ecchymoses (although spontaneous petechiae are uncommon)
• Menorrhagia, often worse at menarche
• Gingival bleeding (worse with poor dental hygiene)
• Epistaxis
• Hemarthroses (rare)
• Family history of a bleeding disorder may or may not exist
• Gastrointestinal bleeding or hematuria is less common

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:

• Complete blood cell (CBC) count
• Peripheral blood smear
• Prothrombin time (PT)
• Activated partial thromboplastin time (aPTT)
• Platelet Function Analyzer 100 (PFA-100) study
• Flow cytometry
• Monoclonal antibody assays
• Platelet aggregation studies

Results are as follows:

• The platelet count and coagulation tests should be normal.
• The red blood cell count may be decreased due to bleeding and/or concomitant iron deficiency.
• The platelet morphology on peripheral blood smears is normal.
• The bleeding times should be prolonged.
• On PFA-100 testing in patients with Glanzmann thrombasthenia, the platelets fail to plug the collagen-based filter.
• Flow cytometry and monoclonal antibodies confirm the diagnosis of Glanzmann thrombasthenia.
• On platelet aggregation studies, the primary platelet aggregation response to platelet agonists such as adenosine diphosphate (ADP), epinephrine, and collagen are decreased, whereas the response to ristocetin is normal; if the secondary platelet aggregation response is abnormal, suspect a platelet storage pool defect or an abnormality in platelet signal transduction.

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:

• Patients should be vaccinated against hepatitis B due to the infectious risks associated with multiple transfusions
• Avoid medications that affect platelet function, such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs)
• Consider oral contraceptives to control menorrhagia

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.[14] An alysis 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.

Pregnancy

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.[18]

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.[19]

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.

Class Summary

Coagulation factor agents promote hemostasis.

Factor VIIa, recombinant (NovoSeven RT)

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.

Class Summary

Estrogen-progestin combinations of oral contraceptives reduce the secretion of LH and FSH from the pituitary by decreasing amount of gonadotropin-releasing hormones (GnRHs).

Norethindrone/ethinylestradiol (Ovcon 50)

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.

Class Summary

Viral vaccines provide immunity against viral infections.

Hepatitis B vaccine (Recombivax HB, Engerix-B)

Recombinant vaccine used to provide immunization against all the known subtypes of the hepatitis B virus.