A new platelet alloantigen (Efsa, HPA‐35bw) on glycoprotein IIIa leading to neonatal alloimmune thrombocytopenia

Transfusion ◽  
2019 ◽  
Vol 59 (7) ◽  
pp. 2463-2464 ◽  
Author(s):  
Gérald Bertrand ◽  
Yannic Danger ◽  
Laure Croisille ◽  
Emilie Le Toriellec ◽  
Franck Verite ◽  
...  
Keyword(s):  
Glycoprotein Iiia ◽  
Alloimmune Thrombocytopenia

scholarly journals A novel murine model of fetal and neonatal alloimmune thrombocytopenia: response to intravenous IgG therapy

Blood ◽  
2006 ◽  
Vol 107 (7) ◽  
pp. 2976-2983 ◽  
Author(s):  
Heyu Ni ◽  
Pingguo Chen ◽  
Christopher M. Spring ◽  
Ebrahim Sayeh ◽  
John W. Semple ◽  
...  
Keyword(s):  
High Titer ◽  
Maternal Antibodies ◽  
Platelet Glycoprotein ◽  
Wild Type ◽  
Wild Type Male ◽  
Glycoprotein Iiia ◽  
Life Threatening ◽  
Β3 Integrin ◽  
Pathogenic Antibodies ◽  
Alloimmune Thrombocytopenia

AbstractFetal and neonatal alloimmune thrombo cytopenia (FNAITP) is a life-threatening bleeding disorder caused by maternal antibodies directed against fetal platelet antigens. The immunoreactive epitopes in FNAITP are primarily located in the extracellular regions of the platelet glycoprotein IIIa (β3 integrin). Here we have established a novel animal model of FNAITP using β3 integrin–deficient (β3-/-) mice. We demonstrated first that these mice are immunoresponsive to β3 integrin; β3-/- mice transfused with wild-type platelets generated specific anti–β3 antibodies which were able to induce thrombocytopenia in wild-type mice. Subsequently, β3-/- female mice (both naive and immunized) were bred with wild-type male mice to recapitulate the features of FNAITP. The titer of generated maternal antibodies correlated with the severity of FNAITP. High titer maternal anti–β3 anti-bodies caused severe fetal thrombocytopenia, intracranial hemorrhage, and even miscarriage. Furthermore, maternal administration of intravenous immunoglobulin G (IgG) ameliorated FNAITP and down-regulated pathogenic antibodies in both the maternal and fetal circulations.

scholarly journals A new low-frequency alloantigen (Khab) located on platelet glycoprotein IIIa as a cause of maternal sensitization leading to neonatal alloimmune thrombocytopenia

Transfusion ◽  
2014 ◽  
Vol 55 (6pt2) ◽  
pp. 1584-1585 ◽  
Author(s):  
Mia J. Sullivan ◽  
Julie Peterson ◽  
Janice G. McFarland ◽  
Daniel Bougie ◽  
Richard H. Aster ◽  
...  
Keyword(s):  
Low Frequency ◽  
Platelet Glycoprotein ◽  
Glycoprotein Iiia ◽  
Alloimmune Thrombocytopenia

scholarly journals Sra, a private platelet antigen on glycoprotein IIIa associated with neonatal alloimmune thrombocytopenia

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2296-2302 ◽  
Author(s):  
H Kroll ◽  
V Kiefel ◽  
S Santoso ◽  
C Mueller-Eckhardt
Keyword(s):  
Blood Donors ◽  
Gene Dosage ◽  
Clinical Signs ◽  
German Population ◽  
Immunochemical Analysis ◽  
Proteolytic Fragment ◽  
Healthy Mother ◽  
Platelet Antigen ◽  
Glycoprotein Iiia ◽  
Alloimmune Thrombocytopenia

Abstract A new platelet alloantigen, Sra, is described that was defined by an alloantibody detected in the serum of a healthy mother who delivered a child with typical clinical signs of neonatal alloimmune thrombocytopenia (NAIT). The antibody reacted strongly with the child's and father's platelets, but not with platelets of the mother or with those of a highly selected panel representing all known platelet alloantigens. Platelets from 300 unselected normal blood donors also tested negative, suggesting a phenotype frequency in the German population of less than 0.01. The antigen was present in 9 of 20 members within three generations of the paternal family, indicating autosomal codominant inheritance. By immunochemical analysis using a glycoprotein (GP)-specific immunoassay and a variety of GP IIb/IIIa- specific monoclonal antibodies for antigen immobilization (MAIPA assay), radioimmunoassay, and Western blotting, we could show that the antigen resides on a 68-Kd proteolytic fragment of GP IIIa. Immunogenetic data and gene dosage studies revealed that the Sra antigen is not related to any of the other known platelet alloantigens. In accordance with established criteria, the Sra antigen represents the first example of a “private” platelet alloantigen that bears significance in rare instances of NAIT.

scholarly journals Single point mutation in human glycoprotein IIIa is associated with a new platelet-specific alloantigen (Mo) involved in neonatal alloimmune thrombocytopenia

Blood ◽  
1993 ◽  
Vol 81 (1) ◽  
pp. 70-76 ◽  
Author(s):  
RW Kuijpers ◽  
S Simsek ◽  
NM Faber ◽  
R Goldschmeding ◽  
RK van Wermerkerken ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Single Point ◽  
Blot Hybridization ◽  
Platelet Glycoprotein ◽  
Single Point Mutation ◽  
Polymorphism Analysis ◽  
Coding Region ◽  
Dot Blot ◽  
Glycoprotein Iiia ◽  
Alloimmune Thrombocytopenia

Abstract Here we describe a new platelet-specific alloantigen that was identified in a case of neonatal alloimmune thrombocytopenia. This antigen has provisionally been called “Mo.” By studying the Mo family, it was shown to be inherited in an autosomal dominant manner. Immunoprecipitation and Western blot analysis showed that the antigen resides on platelet glycoprotein IIIa (GP IIIa). Genomic analysis, performed by applying polymerase chain reaction and sequencing, showed a C-->G substitution of base pair 1267 of the coding region of the DNA for GP IIIa, resulting in a substitution of Proline407 by Alanine407. That this substitution is associated with the antigen could be demonstrated by restriction fragment length polymorphism analysis of cDNA, prepared from platelet RNA, and of genomic DNA. It was confirmed by dot-blot hybridization with allele-specific oligonucleotides. All family members, also those being Mo antigen-positive, were healthy. None of them appeared to suffer from increased tendency of bleeding or thrombosis. Thus, the Mo mutation does not lead to significant platelet dysfunction in vivo with heterozygous carriers. One of 450 random healthy blood donors who were tested was positive for the Mo antigen. Typing was performed by the classical serologic methods as well as by DNA analysis.

A New Private Platelet Antigen, Groa, Localized on Glycoprotein IIIa, Involved in Neonatal Alloimmune Thrombocytopenia

Vox Sanguinis ◽  
1994 ◽  
Vol 67 (3) ◽  
pp. 302-306 ◽  
Author(s):  
Suat Simsek ◽  
André B.J. Vlekke ◽  
Robert W.A.M. Kuijpers ◽  
Roel Goldschmeding ◽  
Albert E. G. Kr. Borne
Keyword(s):  
Platelet Antigen ◽  
Glycoprotein Iiia ◽  
Alloimmune Thrombocytopenia

scholarly journals Preclinical evaluation of immunotherapeutic regimens for fetal/neonatal alloimmune thrombocytopenia

2021 ◽  
Vol 5 (18) ◽  
pp. 3552-3562
Author(s):  
Huiying Zhi ◽  
Maria T. Ahlen ◽  
Björn Skogen ◽  
Debra K. Newman ◽  
Peter J. Newman
Keyword(s):  
Amino Acid ◽  
Amino Acid Polymorphism ◽  
Preclinical Development ◽  
Blocking Antibody ◽  
Central Target ◽  
Female Mice ◽  
Wild Type Female ◽  
Glycoprotein Iiia ◽  
Life Threatening ◽  
Alloimmune Thrombocytopenia

Abstract Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder caused by maternal antibodies directed against paternally inherited antigens present on the surface of fetal platelets. The human platelet alloantigen HPA-1a (formerly known as the PlA1 alloantigen), is the most frequently implicated HPA for causing FNAIT in Whites. A single Leu33Pro amino acid polymorphism residing within the ∼50-amino-acid plexin-semaphorin-integrin domain near the N-terminus of the integrin β3 subunit (platelet membrane glycoprotein IIIa [GPIIIa]) is responsible for generating the HPA-1a and HPA-1b epitopes in human GPIIIa and serves as the central target for alloantibody-mediated platelet destruction. To simulate the etiology of human FNAIT, wild-type female mice were pre-immunized with platelets derived from transgenic mice engineered to express the human HPA-1a epitope on a murine GPIIIa backbone. These mice developed a strong alloimmune response specific for HPA-1a, and when bred with HPA-1a+ males, gave birth to severely thrombocytopenic pups that exhibited an accompanying bleeding phenotype. Administering either polyclonal intravenous immunoglobulin G or a human monoclonal blocking antibody specific for the HPA-1a epitope into pregnant female mice resulted in significant elevation of the neonatal platelet count, normalized hemostasis, and prevented bleeding. The establishment of an alloantigen-specific murine model that recapitulates many of the clinically important features of FNAIT should pave the way for the preclinical development and testing of novel therapeutic and prophylactic modalities to treat or prevent FNAIT in humans.

A New Private Platelet Antigen, Gro^a, Localized on Glycoprotein IIIa, Involved in Neonatal Alloimmune Thrombocytopenia

Vox Sanguinis ◽  
1994 ◽  
Vol 67 (3) ◽  
pp. 302-306 ◽  
Author(s):  
Suat Simsek ◽  
André B.J. Vlekke ◽  
Robert W.A.M. Kuijpers ◽  
Roel Goldschmeding ◽  
Albert E.G.Kr. von dem Borne
Keyword(s):  
Platelet Antigen ◽  
Glycoprotein Iiia ◽  
Alloimmune Thrombocytopenia

Construction of a Human Platelet Alloantigen-1a Epitope(s) Within Murine Glycoprotein IIIa: Identification of Residues Critical to the Conformation of the Antibody Binding Site(s)

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 2959-2967 ◽  
Author(s):  
Emily A. Barron-Casella ◽  
Gaia Nebbia ◽  
Ophelia C. Rogers ◽  
Karen E. King ◽  
Thomas S. Kickler ◽  
...  
Keyword(s):  
Amino Acids ◽  
Human Platelet ◽  
Site Directed Mutagenesis ◽  
Antibody Binding Site ◽  
N Terminus ◽  
Glycoprotein Iiia ◽  
Human Polymorphism ◽  
Pathogenic Antibodies ◽  
Posttransfusion Purpura ◽  
Alloimmune Thrombocytopenia

Abstract The human platelet alloantigen 1 system (HPA-1) is determined by a polymorphism at position 33 in the N-terminus of human glycoprotein IIIa (GPIIIa). This naturally occurring substitution creates a conformation in the HPA-1a allelic form that can be antigenic when presented to an individual expressing the HPA-1b form. Anti–HPA-1a antibodies generated by this immune response can lead to the destruction of platelets, as seen in the clinical disorders, neonatal alloimmune thrombocytopenia (NAIT) and posttransfusion purpura (PTP). To understand better the structural requirements for recognition by these pathogenic antibodies, we investigated the N-terminal 66 amino acids from the HPA-1a form of human GPIIIa and the analogous amino acids from the nonimmunogenic murine homolog. Our objectives were to define further the boundaries of the HPA-1a epitope(s) in the N-terminus of human GPIIIa, to isolate the murine 5’ nucleotide sequence and compare the deduced murine N-terminal sequence to that of human, and to mutate the murine sequence systematically to include an HPA-1a epitope(s). Murine amino acids that differed from human were changed by site-directed mutagenesis to the analogous residues in the HPA-1a form of human GPIIIa, starting and radiating from murine position 33 (site of human polymorphism). This systematic approach allowed us to pinpoint amino acids critical to a conformation recognized by anti–HPA-1a antibodies. Our results show that an HPA-1a epitope can be created within the N-terminus of murine GPIIIa and raise the possibility that murine models of HPA-1a sensitization can be developed.

A new platelet alloantigen, Tua, on glycoprotein IIIa associated with neonatal alloimmune thrombocytopenia in two families

1993 ◽  
Vol 83 (2) ◽  
pp. 306-310 ◽  
Author(s):  
R. Kekomäki ◽  
T. Jouhikainen ◽  
J. Ollikainen ◽  
P. Westman ◽  
M. Laes
Keyword(s):  
Glycoprotein Iiia ◽  
Alloimmune Thrombocytopenia
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