Incidence of HPA-9b in Testing for Neonatal Alloimmune Thrombocytopenia.
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AbstractBackground: Neonatal alloimmune thrombocytopenia (NAT) is caused by maternal alloantibodies that cross the placenta and cause increased clearance of fetal platelets. The alloantibodies are directed to incompatible human platelet antigens (HPA) inherited from the father and expressed on fetal platelet glycoproteins. Most cases of NAT are caused by HPA-1a, -5a, -5b, -15a, or -15b. Some are associated with immunization to a low frequency antigen found only in the paternal lineage. We investigated the incidence of the low frequency antigen HPA-9b in a population with suspected NAT, and compared the frequency to that found in a normal control population. HPA-9b is caused by a Val837Met polymorphism on alpha-IIb and is expressed only in a rare subset of individuals with a corresponding serine at position 843 that defines the HPA-3b antigen.Methods: We used PCR-SSP for HPA-9b genotyping. Antibody studies were performed by incubating maternal serum with intact platelets using flow cytometry, monoclonal antigen capture enzyme immunoassay, and radioimmunoprecipitation.Results: Of 294 normal control blood donors, 4 typed positive for HPA-9b, yielding a gene frequency of 0.0068. However, if only HPA-3b positive donor controls are considered (n=177) the gene frequency for HPA-9b is 0.011. Archived DNA from HPA-3b positive (HPA-3a3b or -3b3b) fathers of children with NAT were tested for HPA-9b. Of 94 fathers, 3 (3.2%) typed HPA-9a9b, yielding a gene frequency for HPA-9b of 0.016, not significantly different from the frequency for HPA-9b found in the HPA-3b-positive healthy controls (p>0.1). Similarily, when DNA from HPA-3b positive mothers was tested in tandem, 3 of 60 were positive for HPA-9b, yielding a gene frequency of 0.026. Of the 3 cases of suspected NAT (platelet count range 15,000 to 63,000) in which the mother and father were incompatible for HPA-9b, 2 had no other platelet antigen incompatibility, and one was incompatible for HPA-15b. None of the 3 maternal sera was positive for anti-platelet reactivity using radioimmunoprecipitation and paternal platelets as a target, and no anti-platelet antibody was detected either by flow cytometry or by GPIIb/IIIa antigen capture immunoassay with platelets from a HPA-9a9b donor.Interpretation: These results support the findings that HPA-9b is distributed in the general population at a frequency higher than initially suspected. However, we also found that the frequency of HPA-9b in fathers of children with suspected NAT was similar to that in the normal control population when only HPA-3b-positive (HPA-3a3b or -3b3b) targets were analyzed. Therefore, in the absence of a positive anti-platelet antibody, the significance of a maternal/paternal incompatibility for HPA-9b alone is not predictive of an increased risk of NAT.
