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A point mutation in the EGF-4 domain of β(3) integrin is responsible for the formation of the Sec(a) platelet alloantigen and affects receptor function. Thromb Haemost 2012 Jan;107(1):80-7 PMID: 22116617 PMCID: PMC3564509

Pubmed ID

22116617

DOI

10.1160/TH11-08-0542

Abstract

Neonatal alloimmune thrombocytopenia (NAIT) is caused by fetomaternal platelet incompatibility with maternal antibodies crossing the placenta and destroying fetal platelets. Antibodies against human platelet antigen-1a (HPA-1a) and HPA-5b are responsible for the majority of NAIT cases. We observed a suspected NAIT in a newborn with a platelet count of 25 G/l and petechial haemorrhages. Serological analysis of maternal serum revealed an immunisation against αIIbβ3 on paternal platelets only, indicating the presence of an antibody against a new rare alloantigen (Sec(a)) residing on αIIbβ3. The location of Sec(a) on αIIbβ3 was confirmed by immunoprecipitation. Nucleotide sequence analysis of paternal β3 revealed a single nucleotide exchange (G(1818)T) in exon 11 of the β3 gene (ITGB3), changing Lys(580) (wild-type) to Asn(580) (Sec(a)). Two additional members of the family Sec were typed Sec(a) positive, but none of 300 blood donors. Chinese hamster ovary cells expressing Asn(580), but not Lys(580) αIIbβ3, bound anti-Sec(a), which was corroborated by immunoprecipitation. Adhesion of transfected cells onto immobilised fibrinogen showed reduced binding of the Asn(580) variant compared to wild-type αIIbβ3. Analysis of transfected cells with anti-LIBS and PAC-1 antibody showed reduced binding when compared to the wild-type. No such effects were observed with Sec(a) positive platelets, which, however, are heterozygous for the Lys(580)Asn mutation. In this study, we describe a NAIT case caused by maternal alloimmunisation against a new antigen on αIIbβ3. Analysis with mutant transfected cells showed that the Lys(580)Asn mutation responsible for the formation of the Sec(a) antigenic determinant affects αIIbβ3 receptor function.

Author List

Sachs UJ, Bakchoul T, Eva O, Giptner A, Bein G, Aster RH, Gitter M, Peterson J, Santoso S

Author

Richard H. Aster MD Professor in the Medicine department at Medical College of Wisconsin




Scopus

2-s2.0-84855327041   9 Citations

MESH terms used to index this publication - Major topics in bold

Adult
Animals
Blood Platelets
CD18 Antigens
CHO Cells
Cricetinae
Epidermal Growth Factor
Female
Fetus
Fibrinogen
Genotype
Hemorrhage
Heterozygote
Humans
Infant, Newborn
Integrin beta3
Isoantibodies
Isoantigens
Platelet Adhesiveness
Platelet Membrane Glycoprotein IIb
Point Mutation
Pregnancy
Pregnancy Complications
Sequence Analysis, DNA
Transfection
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e