Immunization against alpha(IIb)beta(3) and alpha(v)beta(3) in Glanzmann thrombasthenia patients carrying the French Gypsy mutation

Background Glanzmann thrombasthenia (GT) is a rare bleeding disorder caused by the absence or the dysfunction of the platelet alpha(IIb)beta(3) 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 alpha(IIb)beta(3), 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 alpha(IIb)beta(3) on platelets from random platelet transfusions. However, the beta(3) chain can also associate with the alpha(v) subunit expressed at the platelet surface. Because Gypsy GT patients express normal alpha(v)beta(3) carrying HPA-1b epitopes, these patients might develop anti-HPA-1a alloantibodies reacting with alpha(v)beta(3) and/or beta(3). 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 alpha(IIb)beta(3) or alpha(v)beta 3 together with soluble monomeric chimeric beta(3) (as absorbent) were used to differentiate anti-beta(3) and anti-alpha(v)beta(3) 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 beta(3) and/or alpha(v)beta(3). Conclusion In this study, we found that HPA-1bb patients who failed to express alpha(IIb)beta(3) on the platelet surface can develop alloantibodies against HPA-1a reacting with beta(3) as well as alpha(v)beta(3). This is of particular importance as anti-HPA-1a alloantibodies might cause fetal neonatal alloimmune thrombocytopenia and/or platelet transfusion refractoriness.