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 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 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.

scholarly journals New low-frequency platelet glycoprotein polymorphisms associated with neonatal alloimmune thrombocytopenia

Transfusion ◽  
2010 ◽  
Vol 50 (2) ◽  
pp. 324-333 ◽  
Author(s):  
Julie A. Peterson ◽  
Maria L. Gitter ◽  
Adam Kanack ◽  
Brian Curtis ◽  
Janice McFarland ◽  
...  
Keyword(s):  
Low Frequency ◽  
Platelet Glycoprotein ◽  
Alloimmune Thrombocytopenia

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

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.

scholarly journals Neonatal alloimmune thrombocytopenia due to a new platelet-specific alloantibody

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3318-3323 ◽  
Author(s):  
JG McFarland ◽  
V Blanchette ◽  
J Collins ◽  
PJ Newman ◽  
R Wang ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Binding Site ◽  
Low Frequency ◽  
Platelet Glycoprotein ◽  
Platelet Surface ◽  
Alloimmune Thrombocytopenia ◽  
Murine Monoclonal Antibodies

Abstract An infant with severe neonatal alloimmune thrombocytopenia is described in whom an antibody directed at a new platelet-specific alloantigen, Ca (HPA-6b), is implicated. The new alloantigen is of low frequency in the population and was localized to platelet glycoprotein (GP) IIIa. Immunoprecipitation studies using murine monoclonal antibodies specific for the GP complex IIb-IIIa and GPIIIa alone (AP2 and AP3) suggest that the location of the Ca epitope on GPIIIa may be near the binding site for AP3. Neonatal alloimmune thrombocytopenia associated with Ca is likely to be as severe as that seen in cases due to incompatibilities for the HPA-1 (PIA) and HPA-4 (Pen) platelet alloantigen systems, because each is located on GPIIIa, a densely represented molecule on the platelet surface.

scholarly journals Neonatal alloimmune thrombocytopenia due to a new platelet-specific alloantibody

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3318-3323
Author(s):  
JG McFarland ◽  
V Blanchette ◽  
J Collins ◽  
PJ Newman ◽  
R Wang ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Binding Site ◽  
Low Frequency ◽  
Platelet Glycoprotein ◽  
Platelet Surface ◽  
Alloimmune Thrombocytopenia ◽  
Murine Monoclonal Antibodies

An infant with severe neonatal alloimmune thrombocytopenia is described in whom an antibody directed at a new platelet-specific alloantigen, Ca (HPA-6b), is implicated. The new alloantigen is of low frequency in the population and was localized to platelet glycoprotein (GP) IIIa. Immunoprecipitation studies using murine monoclonal antibodies specific for the GP complex IIb-IIIa and GPIIIa alone (AP2 and AP3) suggest that the location of the Ca epitope on GPIIIa may be near the binding site for AP3. Neonatal alloimmune thrombocytopenia associated with Ca is likely to be as severe as that seen in cases due to incompatibilities for the HPA-1 (PIA) and HPA-4 (Pen) platelet alloantigen systems, because each is located on GPIIIa, a densely represented molecule on the platelet surface.

A functional platelet fibrinogen receptor with a deletion in the cysteine-rich repeat region of the β3 integrin: the Oea alloantigen in neonatal alloimmune thrombocytopenia

Blood ◽  
2002 ◽  
Vol 99 (4) ◽  
pp. 1205-1214 ◽  
Author(s):  
Sentot Santoso ◽  
Volker Kiefel ◽  
Ina G. Richter ◽  
Ulrich J. H. Sachs ◽  
Abdul Rahman ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Disulfide Bonds ◽  
Low Frequency ◽  
Platelet Glycoprotein ◽  
Mutational Event ◽  
Wild Type ◽  
Stable Transfectants ◽  
Fibrinogen Receptor ◽  
Β3 Integrin ◽  
Alloimmune Thrombocytopenia

This report describes a new low-frequency alloantigen, Oea, responsible for a case of neonatal alloimmune thrombocytopenia (NAIT). In a population study none of 600 unrelated blood donors was an Oea carrier. By immunochemical studies the Oea antigen could be assigned to platelet glycoprotein (GP) IIIa. Sequencing of GPIIIa complementary DNA from an Oea (+) individual showed deletion of a lysine residue at position 611 (ΔLys611). Analysis of 20 Oea(−) and 3 Oea (+) individuals showed that the ΔLys611 form of GPIIIa was related to the phenotype. Anti-Oea reacted with the ΔLys611, but not with the wild-type isoforms on stable transfectants expressing GPIIIa, indicating that ΔLys611 directly induces the expression of Oea epitopes. Under nonreducing conditions the Pro33ΔLys611 variant migrated with a slightly decreased molecular weight compared to the Pro33Lys611 isoform suggesting that ΔLys611 has an influence on the disulfide bonds of GPIIIa. The Pro33ΔLys611 GPIIIa could undergo conformational changes and bind to fibrinogen in a similar manner as the Pro33Lys611 isoform. No difference was found in the tyrosine phosphorylation of pp125FAK, suggesting that ΔLys611 has no effect on integrin function. In contrast to all other low-frequency antigens, the ΔLys611 isoform was associated with the HPA-1b, but not with the high frequency HPA-1a allele. Comparison with GPIIIa DNA from nonhuman primates indicated that the HPA-1a allele represents the ancestral form of GPIIIa. It can be assumed that the Oea form did arise as a result of a mutational event from an already mutated GPIIIa allele.

Specific Cross-reaction of IgG Anti-phospholipid Antibody with Platelet Glycoprotein IIIa

1996 ◽  
Vol 75 (01) ◽  
pp. 168-174 ◽  
Author(s):  
Shigeru Tokita ◽  
Morio Arai ◽  
Naomasa Yamamoto ◽  
Yasuhiro Katagiri ◽  
Kenjiro Tanoue ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Heparan Sulfate ◽  
Disulfide Bonds ◽  
Dextran Sulfate ◽  
Human Platelets ◽  
Platelet Glycoprotein ◽  
Activated Platelets ◽  
Fibrinogen Binding ◽  
Dose Dependent Fashion ◽  
Glycoprotein Iiia

SummaryTo study the pathological functions of anti-phospholipid (anti-PL) antibodies, we have analyzed their effect on platelet function. We identified an IgG anti-PL mAb, designated PSG3, which cross-reacted specifically with glycoprotein (GP) IIIa in human platelets and inhibited platelet aggregation. PSG3 bound also to certain polyanionic substances, such as double-stranded DNA, heparan sulfate, dextran sulfate and acetylated-LDL, but not to other polyanionic substances. The binding of PSG3 to GPIIIa was completely inhibited by heparan sulfate and dextran sulfate, indicating that PSG3 recognizes a particular array of negative charges expressed on both GPIIIa and the specified polyanionic substances. Since neither neuraminidase- nor endoglycopeptidase F-treatment of GPIIIa had any significant effect on the binding of PSG3, this array must be located within the amino acid sequence of GPIIIa but not in the carbohydrate moiety. Reduction of the disulfide bonds in GPIIIa greatly reduced its reactivity, suggesting that the negative charges in the epitope are arranged in a particular conformation. PSG3 inhibited platelet aggregation induced by either ADP or collagen, it also inhibited fibrinogen binding to activated platelets in a dose-dependent fashion. PSG3, however, did not inhibit the binding of GRGDSP peptide to activated platelets. These results suggest that the PSG3 epitope on GPIIIa contains a particular array of negative charges, and possibly affects the fibrinogen binding to GPIIb/IIIa complex necessary for platelet aggregation.

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