The αIIb p.Leu841Met (Cab3a+) polymorphism results in a new human platelet alloantigen involved in neonatal alloimmune thrombocytopenia

BACKGROUND: Fetal-neonatal alloimmune thrombocytopenia (FNAIT) diagnosis relies on maternofetal incompatibility and alloantibody identification. Genotyping for rare platelet (PLT) polymorphisms allowed the identification of three families with suspected or confirmed maternofetal incompatibility for the IIb-c.2614C>A mutation (Halle etal., Transfusion 2008;48:14-15). STUDY DESIGN AND METHODS: A polymerase chain reactionsequence-specific primers amplification assay was designed to genotype the IIb-c.2614C>A mutation. HEK293 cells expressing IIb-Leu841 or IIb-Met841 IIb3 forms were used to probe the reactivity of maternal sera from these families and to study the effects of the substitution on IIb3 expression and functions. RESULTS: Tested by flow cytometry (FCM), one serum sample specifically reacted with IIb-Met841 but not with IIb-Leu841 IIb3. This specificity revealed the IIb-Leu841 polymorphism as a new alloantigen named Cab3a+. Cross-match testing using FCM also showed the Cab3a+ antigen to be expressed at the PLT surface. As for anti-human PLT alloantigen (HPA)-3a (or -3b) and anti-HPA-9bw, detection of anti-Cab3a+ alloantibodies appeared difficult and required whole PLT assays when classical monoclonal antibodyspecific immobilization of PLT antigen test failed. In our FNAIT set, the immune response to Cab3a+ maternofetal incompatibility could induce severe thrombocytopenias and life-threatening hemorrhages. The p.Leu841Met substitution has limited effects, if any, on local IIb structure, preserving both IIb3 expression and functions. CONCLUSION: The Cab3a+ polymorphism is a new rare alloantigen (allelic frequency <1%) carried by IIb that might result in severe life-threatening thrombocytopenias. In Sub-Saharan African populations, higher Cab3a+ gene frequencies (up to 8.2%; Halle etal., Transfusion 2008;48:14-15) and homozygous people are observed.