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PubMed1994

A simplified method for large-scale HPA-1a phenotyping for antenatal screening.

A simplified method for large-scale HPA-1a phenotyping of platelets was developed for use in an antenatal screening programme for fetomaternal alloimmune thrombocytopenia (FMAIT). The test was based on the MAIPA assay, which was modified for antigen-typing with a well-characterized anti-HPA-1a reagent. The resulting assay gave reliable results, was inexpensive and allowed testing of large batches using semiautomated equipment.

Antibodies, Monoclonal↗
PubMed1994

Antenatal management of fetomaternal alloimmune thrombocytopenia--report of 15 affected pregnancies.

The recognition that spontaneous intracranial haemorrhage (ICH) may occur in utero in fetomaternal alloimmune thrombocytopenia (FMAIT) led us to attempt to prevent this in 15 pregnancies of 11 women who had previously affected infants with FMAIT due to anti-HPA-1a. The antenatal management included fetal platelet transfusions and maternal steroids and/or high-dose intravenous immunoglobulin (IVIgG). In the first pregnancy, ICH occurred between 32 and 35 weeks' gestation before any treatment had been given, emphasizing the need for earlier intervention. Five of the 14 subsequent pregnancies in this study were considered to be severely affected (severe haemorrhagic complications in a previous infant and initial fetal platelet count < 20 x 10(9)/L in this study); four were managed successfully with weekly fetal platelet transfusions started between 18 and 29 weeks and continued until delivery at 33-35 weeks, and one severely affected case who was referred at 36 weeks was managed successfully with a single platelet transfusion prior to delivery. Five pregnancies were considered to be mildly affected (previous infants were unaffected by severe bleeding and initial fetal platelet count > 50 x 10(9)/L in this study). The platelet counts were maintained in one case with steroids and in three with IVIgG without the need for repeated platelet transfusions, but in the fifth the fetal platelet count fell despite steroids and IVIgG and serial platelet transfusions were required. Four pregnancies were unsuccessful; two pregnancies were terminated after severe ICH occurred at an early stage before fetal blood sampling had been carried out, one fetus died after the mother had a severe fall despite the successful initiation of fetal platelet transfusions and one died due to a cord haematoma which occurred at the time of the initial fetal blood sampling. The optimal management of FMAIT to reduce the risk of antenatal ICH remains uncertain. Steroids and IVIgG may be effective in some mildly affected cases but serial fetal platelet transfusions are the preferred therapy for those who are severely affected.

Antigens, Human Platelet↗
PubMed1994

Maternal intravenous immunoglobulin treatment does not prevent intracranial haemorrhage in fetal alloimmune thrombocytopenia.

In fetal alloimmune thrombocytopenia (FAIT) the fetus is threatened by intracranial haemorrhage (ICH); therefore early diagnostic and therapeutic intervention is required. We followed the clinical course of a 30-year-old woman during her fifth pregnancy after she had given birth to a child with alloimmune thrombocytopenia due to anti-Zwa. The fetus was monitored by 13 fetal blood samplings (FBS) always followed by transfusion of either maternal or compatible donor platelets. Intravenous immunoglobulin (ivIg) treatment of the mother was begun at 20 weeks of gestation when the fetal platelet count was 36 x 10(9)/l. The fetal platelets were typed Zwa positive by DNA analysis. Despite 11 weeks of maternal ivIg treatment fetal platelet counts progressively declined to 6 x 10(9)/l and ICH occurred. Subsequently, the fetus was successfully managed by intrauterine platelet transfusions at shorter intervals (3-5 days) and elective Cesarean section was carried out at 35 weeks of gestation. We conclude that maternal ivIg treatment does not prevent ICH in FAIT. The treatment of choice for severely affected cases is serial FBS combined with transfusion of compatible platelets.

Antigens, Human Platelet↗
PubMed1995

Platelet alloantigens HPA-1, -2, -3, -5 and -6b in Finns.

The human platelet alloantigens HPA-1, -2, -3, -5 and -6b in the Finnish population were determined using allele specific restriction analysis (PCR-ASRA) for HPA-1, -2, -3 and -5 and monoclonal antibody immobilized platelet antigen (MAIPA) assay for HPA-1, -3a, -5b and -6b. No discrepancies were observed between the results obtained with the PCR-method and those obtained serologically. The gene frequencies obtained from 200 unrelated Finns were 0.86 and 0.14 for HPA-1a and -1b, 0.91 and 0.09 for HPA-2a and -2b, 0.59 and 0.41 for HPA-3a and -3b and 0.95 and 0.05 for HPA-5a and -5b. The frequency of the HPA-5b allele (10%) is lower in Finns than in Central- or South-European populations (20-30%). The HPA-1, -2 and -3 frequencies did not deviate from those observed in other European populations. The rare HPA-6b antigen was observed in three of 127 individuals from south-eastern Finland (2.4%), which suggests that the frequency of this allele in Finland is higher than previously thought.

Antigens, Human Platelet↗
PubMed1996

Evidence for an expression of blood group A antigen on platelet glycoproteins IV and V.

Blood group ABO antigens are known to be carried by several platelet glycoproteins (GP), e.g. GPIb, GPIIa, GPIIb, GPIIa and PECAM. Beside these proteins, we recently observed that blood group A antigen was also expressed on some other uncharacterized platelet proteins (70-90 kDa) having electrophoretic mobilities closely resembling those of GPIV and GPV. These findings prompted us further to characterize these latter ABO-expressing platelet proteins. By antigen capture ELISA, wherein the monoclonal antibodies (mAbs) CLB-IVC7 and CLB-SWI6 were used to hold the corresponding antigens GPIV and GPV, human anti-A specifically bound to these proteins derived from A1-platelets; neither GPIV nor GPV derived from A2-, B- or O-platelets bound anti-A. In a Western blot assay using immunoprecipitated GPIV and GPV as antigens, mAb anti-A immunostained GPIV and GPV precipitated from A1, but not from A2 and O platelets. These results conclusively demonstrate that blood group A antigen is expressed on platelet GPIV and GPV.

ABO Blood-Group System↗
PubMed2004

The natural history of maternal immunization against foetal platelet alloantigens.

Foetomaternal alloimmune thrombocytopenia (FMAIT) occurs when maternal antibodies of an antigen-negative mother cause destruction of sensitized foetal platelets. In Caucasian populations, 6-12% of human platelet antigen (HPA)-1a-negative women develop anti-HPA-1a, and the incidence of clinically affected cases is estimated to be 10-20% of immunized women. This study was performed in order to elucidate the rate of maternal immunization, incidence of FMAIT and the likely outcome of the condition in Asians. Excluding two or more pregnancies during the period, serum samples from 24 630 pregnant women, mainly Japanese, were screened for antibodies against platelet alloantigens by means of mixed passive haemagglutination (MPHA) (Anti-HPA-MPHA, Olympus, Tokyo). Antibodies were detected in 0.91% (223/24 630) of the women's samples and the immunization rate was correlated with the number of pregnancies. Antibody specificity included anti-HPA-4b (49), anti-HPA-5a (three), anti-HPA-5b (168), anti-HPA-4b + 5b (one) and anti-Nak(a) (CD36) (two). No alloimmunization was observed within the HPA-1, HPA-2, HPA-3 or HPA-6 systems. Among HPA-4b- or HPA-5b-negative women, 24% or 14% estimated, respectively, had antibodies and 26% (10/38) or 10% (12/125) of neonates, respectively, born to these mothers developed thrombocytopenia. Two neonates born to mothers having anti-HPA-4b developed generalized purpura. No cases of intracranial bleeding or death due to FMAIT were recorded. Generalized purpura due to FMAIT occurs in one in 9359 (95% CI: 1 in 77 519-1 in 2591) pregnancies solely because of HPA-4b incompatibility.

Antigens, Human Platelet↗
PubMed2004

Survey of the use and clinical effectiveness of HPA-1a/5b-negative platelet concentrates in proven or suspected platelet alloimmunization.

The optimal treatment of neonatal alloimmune thrombocytopenia (NAIT) is the transfusion of compatible donor platelets. The National Blood Service in England has established panels of "accredited" donors negative for human platelet antigens HPA-1a and HPA-5b, the most commonly implicated alloantigens. We have retrospectively surveyed the frequency of use and clinical effectiveness of donations collected over a 13-month period from the Oxford accredited panel. Ninety-five per cent of hyperconcentrated platelets (HPCs) collected were issued, all for intrauterine transfusion to fetuses at risk of NAIT due to the presence of maternal platelet alloantibodies and previously affected siblings. Thirty-one per cent of paediatric platelet concentrates (PPCs) collected were issued, of which 57% were used for cases of suspected NAIT. Fifty-four per cent of adult therapeutic doses collected were issued; 5% of these were used in cases of suspected NAIT or proven post-transfusion purpura (PTP). Good increments were seen in most NAIT cases transfused with HPCs or PPCs, and a moderate increment in the one PTP case. We conclude that the establishment of accredited panels is justified and enables delivery of a clinically effective treatment for NAIT. Increased use and cost-effectiveness could be achieved by the delivery of an educational programme to neonatal unit clinical staff to increase the awareness and appropriate treatment of NAIT.

Antigens, Human Platelet↗
PubMed2005

Anti-HPA-1a in a case of post-transfusion purpura: binding to antigen-negative platelets detected by adsorption/elution.

Post-transfusion purpura (PTP) is a rare transfusion reaction almost exclusively observed in female patients. Affected patients develop severe immune-mediated thrombocytopenia in the course of a strong anamnestic alloimmune reaction against a platelet-specific antigen. The pathophysiology of thrombocytopenia has remained elusive. Immunological analysis in the HPA-1a-alloimmunized patient described in this report revealed an antibody with features considered typical of PTP: not only was anti-HPA-1a detectable in plasma, but it could also be eluted from the patients' (alloantigen negative) platelets, and anti-HPA-1a could be detected in eluates from both antigen positive and negative test platelets, which had been incubated in the patient's serum. This is in contrast to two sera with HPA-1a alloantibodies obtained from mothers of children with neonatal alloimmmune thrombocytopenia which were strictly HPA-1a specific. It is proposed that alloantibodies with HPA-1a-like specificity explain the patient's immune thrombocytopenia. The technique described in this report is proposed for further investigation, as it might be useful for discrimination of alloantibodes in PTP and alloantibodies of transfused thrombocytopenic patients.

Aged↗
PubMed2006

Post-transfusion purpura in a patient with HPA-1a and GPIa/IIa antibodies.

Post-transfusion purpura is a rare bleeding disorder characterized by severe and sudden thrombocytopenia within 3-12 days after blood transfusion. Typically, preformed antibodies directed against human platelet antigens, especially HPA-1a, are associated with the clinical symptoms. A 46-year-old female presenting to the hospital with acute progressive kidney insufficiency and anaemia received two units of packed red blood cells (RBC) within 2 days. On day 7, platelet count felt from 414 to 189 x 10(9) L(-1) and 1 day later dropped to 4 x 10(9) L(-1). Four platelet concentrates were applied without success. After serological confirmation of an HPA-1a antibody, the patient was treated with intravenous gamma immunoglobulin (ivIgG), and the platelet count increased to normal values on day 17. In addition to the persisting HPA-1a alloantibody, an antibody reactive with GPIa/IIa of HPA-5a- and HPA-5b-positive platelets was detected during the acute phase of thrombocytopenia. After complete remission, the patient was transfused with four units of packed RBC from HPA-1a-negative donors, and platelet counts remained normal.

Anemia↗
PubMed1985

Microplate enzyme immuno-assay for detection of platelet antibodies.

A simplified and sensitive enzyme immuno-assay employing microtiter plates as the solid phase carrier for detection of circulating platelet antibodies and bound antiplatelet IgG has been described. The assay was done using fresh as well as frozen platelets and commercially available peroxidase labeled anti-human IgG. The sensitivity of the enzyme immuno-assay was found similar or superior to that of the platelet suspension immunofluorescence test and superior to the lymphocyte cytotoxicity test and the platelet complement fixation test. The use of platelets frozen in the wells of the microtiter plates (stored for up to 17 months at -20 degrees C without loss of antigenicity) facilitates the performance of the test. In addition the small volumes of sera and platelets needed in using microtiter plates makes the assay particularly suitable in testing platelets from thrombocytopenic patients. In one of 31 sera from normal Zwa-negative donors a weak anti-Zwa (P1A1) was found only detectable by enzyme immuno-assay. Alloantibodies were found in 14 of 23 patients suffering from non-haemolytic transfusion reactions. All of three patients with post-transfusion purpura had anti-Zwa antibodies in serum. Anti-Zwa antibodies were demonstrated in the sera from all of 9 Zwa-negative mothers, who had given birth to children with alloimmune neonatal thrombocytopenia. In 8 of 12 Zwa-positive mothers alloantibodies of other specificities were found in the serum. In one case the antibody was a known anti-Baka. Six of 7 patients with autoimmune thrombocytopenic purpura had values of platelet-bound IgG exceeding the normal range and circulating platelet antibodies were seen in 4 patients.

Antigens, Human Platelet↗
PubMed1985

Immunogenicity of and immune response to the human platelet antigen Zwa is strongly associated with HLA-B8 and DR3.

In a prospective study the immunogenicity of the Zwa antigen during gestation was investigated. Twenty-six out of 1,211 pregnant women were Zwa negative (2.15%). In 2 out of 23 Zwa negative mothers who delivered Zwa positive children, an antibody to Zwa was detected. To determine the relationship between the immune response of pregnant women towards Zwa and the MHC, the phenotype frequencies of HLA-A, B, C, DR, and complement BF, C2, C4A, C4B allotypes of "non-responders" without detectable Zwa antibodies (N = 20) were compared with a group of "responders", i.e. Zwa negative mothers giving birth to Zwa positive children with typical neonatal alloimmune thrombocytopenia (NAIT; N = 39) and with a normal control population. When compared to the normal control group, "non-responders" showed a significant increase of the DRw6 frequency, whereas in the "responders" group HLA-A1, B8, DR3, and C4A*QO were significantly elevated. If "non-responders" and "responders" were directly compared, only B8 and DR3 remained significantly different. The strongest association with a hypothetical immune response gene appeared to exist with DR3.

Antigens, Human Platelet↗
PubMed1986

The resolution of platelet serologic problems using Western blotting.

Serologic identification of anti-PLAl and other platelet specific antibodies is difficult because other platelet reactive antibodies (e.g. anti-HLA) are commonly found in the samples. We have developed and evaluated a method using Western blotting to identify platelet specific antibodies. Since anti-PLAl is the most frequently encountered antibody, we used this antibody to validate the method. The PLAl antigen was found on a 95,000 Dalton protein, confirmed as glycoprotein IIIa by two-dimensional electrophoresis. The usefulness of Western blotting in resolving difficult platelet serologic problems was compared to a radiolabeled antiglobulin test using intact platelets. Our results showed that all sera with anti-PLAl identified by serology were confirmed by Western blotting. In addition, one anti-PLAl was detectable only by the proposed method. Western blotting was also as useful as a serologic method to PLAl type platelets. HLA antibodies were not demonstrable by this technique. In summary, Western blotting is a highly specific and sensitive way of identifying anti-PLAl in a variety of clinical situations. This approach may be used to identify antibodies to other platelet specific antigens and to standardize platelet antigen typing sera.

Antibody Specificity↗
PubMed1997

Characterization of the porcine homologue to human platelet glycoprotein IIb-IIIa (CD41/CD61) by a monoclonal antibody.

Human gpIIb-IIIa or CD41/CD61 is a Ca(2+)-complex dependent heterodimer, abundant on platelets, that plays a key role in hemostasis. This report describes a murine monoclonal antibody, JM2E5, able to recognize and immunoprecipitate the gpIIb/IIIa surface glycoprotein from porcine platelets. Immunoprecipitation analysis showed an antigen molecular weight of 115 and 85 kDa under nonreducing conditions, and of 110, 100 and 25 kDa under reducing conditions. Immunohistochemistry analyses of frozen sections from several porcine lymphoid organs gave specific staining on platelets. EDTA treated platelets were studied by flow cytometry indicating that the epitope recognized was Ca(2+)-complex independent. Western-blotting experiments with porcine platelet extracts gave an antigen molecular weight of 85 kDa under nonreducing conditions, thus localizing the epitope recognized by JM2E5 on the complex light chain gpIIIa or CD61. JM2E5 was also cross-reacting with human, bovine and horse platelets, as shown by flow cytometry. This mAb would allow further studies on this important adhesion molecule on horses, ruminants and pigs, and it should be especially useful as a general anti-porcine platelet reagent.

Animals↗
PubMed1998

Identification of a human heavy chain antibody fragment directed against human platelet alloantigen 1a by phage display library.

The human platelet alloantigen HPA-1a (PlA1) is responsible for most cases of post-transfusion purpura and neonatal alloimmune thrombocytopenia in the Caucasian population. HPA-1a and HPA-1b are two allelic forms of the platelet membrane glycoprotein IIIa (GPIIIa) gene that differ by a single amino acid. In this report, we describe the development of a recombinant heavy chain antibody fragment capable of distinguishing between the homozygous forms of HPA-1a and HPA-1b. This antibody fragment was isolated from the lymphocytes of an immunized individual through the use of a phage display library system. The recombinant antibody fragment reacted with human platelet lysates from HPA-1a homozygous donors, the HPA-1a form of recombinant N-terminal GPIIIa and intact HPA-1a platelets, but did not react with platelet lysate from HPA-1b homozygous donors, reduced HPA-1a form of platelet GPIIIa or other platelet glycoproteins. This HPA-1a specific human antibody fragment works well in common laboratory assays such as ELISA and flow cytometry, which can assist in identifying HPA-1b homozygous individuals who are known to have a higher risk for developing neonatal alloimmmune thrombocytopenia and post-transfusion purpura. Thus, selection of recombinant antibody fragment using phage display offers a promising alternative to hybridoma technology for the production of human antibodies against human alloantigens and holds potential as a technique in therapeutic applications.

Antibody Specificity↗
PubMed1984

Effect of the binding of anti-Zwa antibodies on platelet function.

Anti-Zwa antibodies can induce a Glanzmann-like platelet dysfunction in normal Zwa-positive platelets. Although a normal shape change and release reaction was always recorded in response to adenosine diphosphate and collagen, the aggregation on these inducers could be completely inhibited by anti-Zwa antibodies. Analogous to the platelets from patients with Glanzmann's thrombasthenia, normal platelets sensitized with anti-Zwa did not associate with fibrinogen upon exposure to adenosine diphosphate. Our data indicate that the binding site for fibrinogen is closely associated with the Zwa-antigenic determinants on the platelet membrane glycoproteins and thus with glycoprotein IIIa which is known to carry Zwa.

Adenosine Diphosphate↗
PubMed1986

Neonatal alloimmune thrombocytopenia due to fetomaternal Zwb incompatibility.

A case of neonatal alloimmune thrombocytopenia due to fetomaternal incompatibility against the platelet-specific antigen Zwb (PlA2) is described. The antibody was of the IgG class and did not fix complement in vitro. Its specificity was established by panel identification and by comparison to a Zwb antiserum. Gene dosage determinations of Zwa antigens on platelets of parents and child revealed that the mother was homozygous Zwa Zwa, while father and child were heterozygous for this antigen.

Adult↗
PubMed1987

Post-transfusion purpura associated with anti-Baka and anti-PIA2 platelet antibodies and delayed haemolytic transfusion reaction.

The occurrence of post-transfusion purpura (PTP) in a 16-year-old girl with sickle/beta-thalassaemia is described. Clinically this was a typical case of PTP, but it was unusual serologically. Anti-Baka and anti-PIA2 platelet-specific antibodies were identified and the patient's platelets were typed as homozygous PIA1-positive and Baka-negative. The patient also developed red-cell, granulocyte and lymphocytotoxic antibodies in response to the blood transfusion and had a delayed haemolytic transfusion reaction.

Adolescent↗