Single amino acid mutation of Fc gamma receptor is associated with the development of heparin-induced thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) is mediated by a heparin-dependent antibody/platelet factor 4/heparin complex binding to platelets via the Fc gamma receptor (type IIA). A single base polymorphism at position 131 of Fc gamma RIIA changes the native arginine to histidine. In the presence of murine monoclonal IgG1 the former phenotype (Fc gamma RIIAArg131) is functionally characterized by strong platelet aggregation (high responder) and the latter (Fc gamma RIIAHis131) by poor aggregation (low responder). In the presence of human IgG2 the opposite response is observed. It has recently been shown that the heparin-dependent antibody is predominantly of this subclass. We hypothesize that a relationship exists between Fc gamma RIIAHis131 and the development of HIT. We studied 24 normal individuals and 20 HIT patients using VM58, a murine monoclonal IgG1, to characterize the phenotype by platelet aggregrometry, and PCR products, amplified with primers bordering the Fc gamma RIIA polymorphism and hybridized with oligonucleotide probes specific for the single base mutation, to determine the genotype. The distribution of phenotypes and genotypes in the two populations differed, with a greater prevalence of the Fc gamma RIIAHis131 allele in the HIT patient population. Homozygous Fc gamma RIIAArg131 individuals were absent from this group. We conclude that the presence of the Fc gamma RIIAHis131 allele is associated with a predisposition to HIT.
Burgess
J K
JK
Centre for Thrombosis and Vascular Research, University of New South Wales, Sydney, Australia.
Lindeman
R
R
Chesterman
C N
CN
Chong
B H
BH
D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D005260:Female; D005838:Genotype; D006493:Heparin / Q000009:adverse effects*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D017452:Receptors, IgG / Q000235:genetics*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000235:genetics
D017452:Receptors, IgG; D006493:Heparin