Immunization against αIIb β3 and αv β3 in Glanzmann thrombasthenia patients carrying the French Gypsy mutation

Abstract

Essentials The c.1544+1G>A mutation was identified in Gypsy Glanzmann thrombasthenia (GT) patients. Gypsy GT patients express normal α_v β₃ carrying HPA-1b epitopes. To demonstrate HPA-1a alloimmunization by modified antigen capture assays. Gypsy GT patients could develop anti-HPA-1a alloantibodies against β₃ and α_v β₃ . ABSTRACT: Background Glanzmann thrombasthenia (GT) is a rare bleeding disorder caused by the absence or the dysfunction of the platelet α_IIb β₃ integrin. A founder mutation in the ITGA2B gene was previously identified in French Gypsy patients. Interestingly, this mutation was strongly linked to the human platelet antigen-1b (HPA-1b). The HPA-1bb Gypsy patients are at risk of isoimmunization against α_IIb β₃ , as this complex is not expressed at their platelet surface. Tentatively, they would, however, not have an increased risk of developing anti-HPA-1a alloantibodies by exposure of α_IIb β₃ on platelets from random platelet transfusions. However, the β₃ chain can also associate with the α_v subunit expressed at the platelet surface. Because Gypsy GT patients express normal α_v β₃ carrying HPA-1b epitopes, these patients might develop anti-HPA-1a alloantibodies reacting with α_v β₃ and/or β₃ . Objectives/Patients/Methods To demonstrate this hypothesis, sera from HPA-1bb (n = 5) and HPA-1ab (n = 1) Gypsy GT patients were investigated by modified antigen capture assay using platelets or stable transfected cells. Furthermore, stable transfected cells expressing either α_IIb β₃ or α_v β3 together with soluble monomeric chimeric β₃ (as absorbent) were used to differentiate anti-β₃ and anti-α_v β₃ reactivity. Results Only HPA-1bb patients developed alloantibodies reacting with HPA-1a cells. Further analysis showed that HPA-1bb patients developed anti-HPA-1a alloantibodies reacting with β₃ and/or α_v β₃ . Conclusion In this study, we found that HPA-1bb patients who failed to express α_IIb β₃ on the platelet surface can develop alloantibodies against HPA-1a reacting with β₃ as well as α_v β₃ . This is of particular importance as anti-HPA-1a alloantibodies might cause fetal neonatal alloimmune thrombocytopenia and/or platelet transfusion refractoriness.

Keywords: GP IIb/IIIa; endothelial cells; inherited/acquired platelet disorders; integrins; transfusion medicine.