Genetic and structural characterization of an amino acid dimorphism in glycoprotein Ibα involved in platelet transfusion refractoriness

The platelet-specific alloantigen, Sib^a, located within the α-subunit of the glycoprotein (GP) Ib-IX membrane receptor, has been found to be involved in the pathogenesis of platelet transfusion refractoriness. We have identified the existence of a naturally occurring threonine/methionine dimorphism at position 145 of the GPIbα sequence, and determined that the Sib^a antigen corresponds to the molecule containing methionine¹⁴⁵. The diallelic codons can be detected by restriction enzyme analysis of amplified genomic DNA fragments from the GPIbα gene. Evaluation of 61 healthy blood donors showed that the allele frequencies are 89% and 11% for the threonine¹⁴⁵ and methionine¹⁴⁵ codons, respectively. A positive correlation exists between platelet reactivity with the anti-Sib^a antibody and the presence of a methionine¹⁴⁵-encoding allele. Moreover, recombinant expression of two soluble GPIbα fragments differing only at residue 145, provided definitive evidence that the human anti-Sib^a antibody reacts only with the molecule containing methionine¹⁴⁵. These results explain the structural basis of the Sib^a human alloantigen system and define screening methodologies useful in transfusion medicine to match donor and recipient platelets accordingly.