Severe fetal anemia caused by anti‐Jr^a: Burst forming unit‐erythroid colony formation inhibition assay suggesting possible erythroid suppression mechanism

Abstract Background The Jr blood group system includes a single, high‐prevalence antigen, Jr a , encoded by the ABCG2 gene. The impact of anti‐Jr a in pregnancy is variable, ranging from no clinical effect to severe anemia including some fetal deaths. Case reports have postulated that anti‐Jr a mediated fetal anemia is poorly hemolytic, suggesting other mechanisms of anemia may be involved. Study Design and Methods We describe the case of severe anti‐Jr a mediated fetal anemia. At Canadian Blood Services laboratories, maternal anti‐Jr a was tested for phagocytic activity via a monocyte monolayer assay (MMA) and erythroid suppression via inhibition of burst forming unit‐erythroid (BFU‐E) colony formation assays. The New York Blood Center sequenced exons 4 and 7 of the ABCG2 gene. Results and Discussion Sequencing of exons 4 and 7 of the ABCG2 gene revealed maternal compound heterozygosity for two nonsense mutations at exon 7 (c.706 C > T and c.784G > T). Fetal sequencing revealed the c.706C > T polymorphism. The MMA showed a borderline phagocytic index (around the cutoff of five for both donor segments tested [5 ± 1 and 7 ± 3]). The BFU‐E colony formation inhibition assay suggested a dose‐dependent inhibition of BFU‐E colony formation with inhibition percentages of 4%, 11%, and 43% at maternal serum concentrations of 2%, 5%, and 10%, respectively. Our findings support the hypothesis that anti‐Jr a may impair erythropoiesis leading to clinically significant fetal/neonatal anemia. A referral to maternal fetal medicine is recommended if anti‐Jr a is detected in pregnancy, regardless of the titer.