Rare Polymorphisms Associated with Neonatal Alloimmune Thrombocytopenia (NATP) and New Mutations Identified in Platelet Glycoproteins (GP)

Neonatal Alloimmune Thrombocytopenia (NATP) is caused by maternal immunization against alloantigens carried on paternal platelet glycoproteins (GP). Although common antigens and their corresponding antibodies can be reliably detected, about two-thirds of suspected cases of NATP go unresolved. We are investigating the extent to which maternal immunization against low frequency antigens not usually tested for contributes to the relatively low diagnostic yield in NATP evaluations. In the course of this work, we have identified eight previously undescribed amino acid substitutions located in four different platelet GPs (Table 1).

Table 1. Eight new mutations identified in platelet glycoproteins

The incidence of each mutation in the general population is less than 1.0%. Antigens Sta and Kno were each identified in fathers of suspected NATP cases and in the affected infants. In addition, maternal antibodies reacted with recombinant GPs modified to contain the relevant mutations, making it very likely that the antibodies were the cause of NATP in these instances. Antigen Sol was identified in the father and maternal antibody reacted strongly with paternal GPIIb/IIIa. However, the infant has not yet been typed. It is likely, but not certain that immunization against Sol caused NATP in this case. Mutation Brc was found in the father of an infant with possible NATP. However maternal serum failed to react with GPIa from father’s platelets and it was not possible to type the affected infant. Mutations Bec, Aus and Rou2 were identified in paternal DNA but the affected infants were negative for these mutations. Mutation Rou1 was identified in maternal DNA and could not have been an immunogen. It is highly likely that three of the eight new mutations (Sta, Kno, and Sol) caused maternal immunization leading to NATP. However, the other five (Bec, Aus, Brc, Rou1 and Rou2) appear to have been identified incidentally in the course of the NATP evaluations. Before concluding that maternal-fetal incompatibility for a rare antigen identified in the father is the immunogen responsible for triggering NATP these findings emphasize the importance of typing an affected infant to determine whether a low frequency antigen identified in the father was inherited. In addition it is necessary to confirm that maternal serum reacts with the suspected paternal antigen incorporated into a recombinant protein or carried on platelets from an unrelated individual.