New low‐frequency platelet glycoprotein polymorphisms associated with neonatal alloimmune thrombocytopenia

Abstract

BACKGROUND Recent reports suggest that maternal immunization against low-frequency, platelet (PLT)-specific glycoprotein (GP) polymorphisms is a more common cause of neonatal alloimmune thrombocytopenia (NATP) than previously thought. STUDY DESIGN AND METHODS Serologic and molecular studies were performed on PLTs and DNA from three families in which an infant was born with apparent NATP not attributable to maternal immunization against known PLT-specific alloantigens. RESULTS Antibodies reactive only with paternal PLTs were identified in each mother. In Cases 2 (Kno) and 3 (Nos), but not Case 1 (Sta), antibody recognized paternal GPIIb/IIIa in solid-phase assays. Unique mutations encoding amino acid substitutions in GPIIb (Case 2) or GPIIIa (Cases 1 and 3) were identified in paternal DNA and in DNA from two of the affected infants. Antibody from all three cases recognized recombinant GPIIIa (Case 1 [Sta] and Case 3 [Nos]) and GPIIb (Case 2, Kno) mutated to contain the polymorphisms identified in the respective fathers. None of 100 unselected normal subjects possessed the paternal mutations. Enzyme-linked immunosorbent assay and flow cytometric studies suggested that failure of maternal serum from Case 1 (Sta) to react with paternal GPIIIa in solid-phase assays resulted from use of a monoclonal antibody AP2, for antigen immobilization that competed with the maternal antibody for binding to the Sta epitope. CONCLUSION NATP in the three cases was caused by maternal immunization against previously unreported, low-frequency GP polymorphisms. Maternal immunization against low-frequency PLT-specific alloantigens should be considered in cases of apparent NATP not resolved by conventional serologic and molecular testing.

αIIbβ3 integrin: new allelic variants in Glanzmann thrombasthenia, effects onITGA2BandITGB3mRNA splicing, expression, and structure-function

“…It might indirectly impair the interaction(s) of the a5 and/or a6 helix with the b-propeller. The last four mutations described, p.K137Q [Peterson et al, 2009], p.T140I (HPA-16bw) [Jallu et al, 2002], p.R143Q (HPA-4) [Wang et al, 1992] and p.T195N (HPA-17bw) [Stafford et al, 2008] only lead to allelic variants involved in alloimmune thrombocytopenia that are not related to GT phenotype. All these amino acids locate at the surface of the b-I domain with their side chains directed outside.…”

A new platelet alloantigen, Swia, located on glycoprotein Ia identified in a family with fetal and neonatal alloimmune thrombocytopenia

“…In a recent large cohort study on antibodies in FNAIT, low‐frequency HPAs were estimated as not significant 24 . However, intensive analysis of maternal sera with paternal PLTs in experienced laboratories revealed a constantly growing number of low‐frequency PLT antigens as well as first examples of repeated immunizations against already known HPAs 10,22,25,26 . In addition, our report demonstrates that not only combinations of antibodies against the more frequently involved HPAs occur, for example, HPA‐1a and HPA‐5b, 4 but also combinations of anti‐HPA‐1a with antibodies against a low‐frequency HPA must be expected.…”

The human platelet antigen‐21bw is relatively common among Asians and is a potential trigger for neonatal alloimmune thrombocytopenia

“…We and others have identified more than 20 low‐frequency human platelet (PLT) antigens (HPAs) that can induce antibodies capable of causing neonatal alloimmune thrombocytopenia (NAIT) 1‐4 . Like HPA‐1a and HPA‐4b, the antigens that most often trigger NAIT in Caucasian and Asian populations, respectively, the incidence of low‐frequency antigens is likely to vary significantly in different ethnic and racial populations.…”

“…We recently described HPA‐21bw, a low‐frequency antigen, responsible for a single case of severe NAIT in a presumed Caucasian family 1 . The HPA‐21bw antigen results from a G>A1960 mutation (RS70940817), in ITGB3, encoding PLT glycoprotein (GP) β3 subunit (GPIIIa) and creates a Glu>Lys substitution at Residue 628 in mature β3.…”

“…The HPA‐21bw antigen results from a G>A1960 mutation (RS70940817), in ITGB3, encoding PLT glycoprotein (GP) β3 subunit (GPIIIa) and creates a Glu>Lys substitution at Residue 628 in mature β3. No examples of HPA‐21bw were identified in 100 unrelated Caucasian individuals 1 . We recently encountered a second case of NAIT apparently caused by HPA‐21bw in an Asian family (unpublished).…”