Anti‐α_IIbβ₃ immunization in Glanzmann thrombasthenia: review of literature and treatment recommendations

Abstract

Glanzmann thrombasthenia (GT) is caused by inherited defects of the α β platelet glycoprotein. This bleeding disorder can be treated with platelet transfusion therapy, but some patients will be immunized and begin to form anti-human leucocyte antigen (HLA) and/or anti-α β antibodies. These antibodies can bind and interfere with the function of the transfused platelets, rendering treatment ineffective. However, platelet transfusion refractoriness attributable to HLA antibodies may be managed by the selection of compatible donors, although they are not always readily available, particularly in an emergency. Thus, anti-α β antibodies represent one of the most severe complications in GT. Both genetic and environmental factors may contribute to the risk of anti-α β development, but the underlying pathogenic mechanisms are still unknown. This review will summarize the current knowledge of the risk factors for development of anti-α β antibodies in patients with GT and discuss how these findings may influence the clinical management of patients.

Glanzmann Thrombasthenia: Perspectives from Clinical Practice on Accurate Diagnosis and Optimal Treatment Strategies

“… 1 Clot formation and stabilization is further enhanced by β 3 ’s ability to bind von Willebrand factor, fibronectin, and vitronectin. 1 , 28 , 31 Furthermore, β 3 promotes cleavage of Factor Xa, assisting with conversion of prothrombin to thrombin. 8 , 32–34 β 3 has also been shown to have a role in fibrin clot retraction that is independent from its ability to bind fibrinogen.…”

“… 1 GT inheritance is typically autosomal recessive and patients may exhibit homozygosity, particularly if consanguinity is present, or compound heterozygosity. 8 , 20 , 31 , 38 ITGB3 mutations are more common, presumably due to its relatively larger coding region of 30 exons in comparison to the 15 exons comprising ITGA2B . 1 As of February 2021, 475 ITGA2B and ITBG3 GT-causing mutations have been catalogued in the Glanzmann Thrombasthenia Database ( https://glanzmann.mcw.edu/ ) and most commonly include nonsense, missense, and splice site variants.…”

“… 94 Pregnant women who are known to have GT should also be screened for anti- α IIb β 3 antibodies via monoclonal antibody-specific immobilization of platelet antigen (MAIPA) assay regularly throughout gestation, 95 as these antibodies can cross the placenta and cause dangerously low platelet levels in the fetus. 31 , 96 , 97 Mothers must be counseled about this risk and for this reason, it is important to test the newborn’s platelet count within the first few hours life 8 if maternal antibodies have been detected. While mothers with GT are not expected to experience increased bleeding during the pregnancy itself, specific planning surrounding labour and delivery is indicated in order to prevent excessive bleeding in the intra- and post-partum periods (see Site-Specific considerations below).…”

Immunization against αIIbβ3 and αvβ3 in Glanzmann thrombasthenia patients carrying the French Gypsy mutation

“…In contrast, the prevalence of HPA‐1b allele in the Gypsy GT patients is high (approximately 90%). The HPA‐1bb Gypsy patients are at risk of isoimmunization against α IIb β 3 , as this complex is not expressed at their platelet surface 14,15 . However, the common β 3 chain can also associate with α v subunit to function as a vitronectin receptor.…”

“…The HPA-1bb Gypsy patients are at risk of isoimmunization against α IIb β 3 , as this complex is not expressed at their platelet surface. 14,15 However, the common β 3 chain can also associate with α v subunit to function as a vitronectin receptor. α v β 3 integrin is predominantly found on endothelial cells (ECs), but also in lower amounts at the platelet surface.…”