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

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.

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Neonatal alloimmune thrombocytopenia due to a new platelet-specific alloantibody

Blood ◽

10.1182/blood.v81.12.3318.bloodjournal81123318 ◽

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.

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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 ◽

10.1182/blood.v99.4.1205 ◽

2002 ◽

Vol 99 (4) ◽

pp. 1205-1214 ◽

Cited By ~ 55

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.

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

Blood ◽

10.1182/blood-2005-06-2562 ◽

2006 ◽

Vol 107 (7) ◽

pp. 2976-2983 ◽

Cited By ~ 60

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.

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Immunization against a low-frequency human platelet alloantigen in fetal alloimmune thrombocytopenia is not a single event: characterization by the combined use of reference DNA and novel allele-specific cell lines expressing recombinant antigens

Transfusion ◽

10.1111/j.1537-2995.2005.04218.x ◽

2005 ◽

Vol 45 (3) ◽

pp. 353-358 ◽

Cited By ~ 39

Author(s):

Hartmut Kroll ◽

Julie Yates ◽

Sentot Santoso

Keyword(s):

Cell Lines ◽

Human Platelet ◽

Low Frequency ◽

Specific Cell ◽

Single Event ◽

Recombinant Antigens ◽

Combined Use ◽

Allele Specific ◽

Alloimmune Thrombocytopenia ◽

Novel Allele

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

Blood ◽

10.1182/blood.v81.1.70.70 ◽

1993 ◽

Vol 81 (1) ◽

pp. 70-76 ◽

Cited By ~ 3

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.

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Alloimmunization against ly, a Low-Frequency Antigen on Platelet Glycoprotein Ib/IX as a Cause of Severe Neonatal Alloimmune Thrombocytopenic Purpura

Vox Sanguinis ◽

10.1159/000462848 ◽

1995 ◽

Vol 69 (3) ◽

pp. 250-254 ◽

Cited By ~ 3

Author(s):

V. Kiefel ◽

M. Vicariot ◽

Y. Giovangrandi ◽

H. Kroll ◽

M. Böhringer ◽

...

Keyword(s):

Low Frequency ◽

Platelet Glycoprotein ◽

Glycoprotein Ib ◽

Thrombocytopenic Purpura

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Platelets: New Understanding of Platelet Glycoproteins and Their Role in Disease

Hematology ◽

10.1182/asheducation.v2000.1.222.222 ◽

2000 ◽

Vol 2000 (1) ◽

pp. 222-240 ◽

Cited By ~ 2

Author(s):

James B. Bussel ◽

Thomas J. Kunicki ◽

Alan D. Michelson

Keyword(s):

Point Of View ◽

Platelet Glycoprotein ◽

Clinical Implications ◽

New Developments ◽

Advantages And Disadvantages ◽

Current State ◽

Platelet Antigen ◽

Low Platelet Count ◽

Case Presentations ◽

Alloimmune Thrombocytopenia

Abstract This review covers new developments and their clinical implications in three areas: platelet antigen polymorphisms, inhibition of platelet glycoprotein IIb-IIIa, and autoimmune thrombocytopenia (ITP). In Section I, Dr. Kunicki reviews platelet polymorphisms and their clinical implications. A current tabulation of the numerous platelet antigens, both those that are platelet specific and not platelet specific, are summarized. The immunogenic clinical implications of these polymorphisms are considered, including fetal and neonatal alloimmune thrombocytopenia, post transfusion purpura, and refractoriness to platelet transfusion. The functional relationship to hemostasis and thrombosis is also discussed, in particular whether one haplotype of the PIA1/PIA2 (HPA-1a/1b) polymorphism predisposes to myocardial infarction. Finally, novel investigations of polymorphisms will be considered, including hormonal induction of certain polymorphisms. In Section II, Dr. Michelson reviews the newest generation of platelet inhibitors, those blocking glycoprotein IIB/IIIA, from the point of view of the hematologist who might be consulted about a patient receiving this form of treatment. The current use of available IIb-IIIa inhibitors and those in trial and the accepted and possible future indications for their use are addressed. The mechanism of action and actual and theoretical advantages and disadvantages of each inhibitor are explored. Scenarios that prompt consultation with a hematologist are presented, including management of bleeding, thrombocytopenia, and management of the patient requiring emergency surgery. In Section III, Dr. Bussel reviews controversies in ITP, looking at both the current state of the art and the potential for the future. Case presentations are used to illustrate the issues in both children and adults. Three primary areas are addressed: 1) the diagnosis of ITP, 2) when and for which patient to recommend splenectomy, and 3) the management of the refractory splenectomized patient who still has a low platelet count and bleeding symptoms.

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