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PubMed2004

Human platelet antigen-specific alloantibodies implicated in 1162 cases of neonatal alloimmune thrombocytopenia.

BACKGROUND: Neonatal alloimmune thrombocytopenia (NATP) caused by fetomaternal mismatch for human platelet (PLT) alloantigens (HPAs) complicates approximately 1 in 1000 to 1 in 2000 pregnancies and can lead to a serious bleeding diathesis, intracranial hemorrhage, and sometimes death of the fetus or neonate. As a national reference center for NATP investigations, our experience with this entity over a 12-year period was reviewed. STUDY DESIGN AND METHODS: The laboratory records of all cases of suspected NATP referred for evaluation from January 1, 1990, to December 31, 2002, were analyzed. The spectrum of PLT alloantibody specificities identified was compared with an earlier reported series of serologically verified NATP cases. RESULTS: HPA-specific alloantibodies were identified in 1162 (31%) of 3743 sera of mothers of infants with clinically suspected NATP. Maternal HPA-1a (PlA1) alloimmunization accounted for the majority (79%) of confirmed NATP cases, with HPA-5b (Bra), HPA-3a (Baka), and HPA-1b (PLA2) alloantibodies accounting for 9, 2, and 4 percent of cases, respectively. In addition, an increase in the number of cases in which multiple HPA-specific alloantibodies were present in maternal sera was observed during the study period. CONCLUSION: Although, as with the earlier series, maternal HPA-1a alloimmunization was the dominant cause of NATP, the identification of an increasing number of cases due to alternative HPA polymorphisms suggests that investigation for HPA-1 incompatibility alone is no longer sufficient to fully evaluate clinically suspect NATP cases.

Antigens, Human Platelet↗
PubMed2005

Quantification of human platelet antigen-1a antibodies with the monoclonal antibody immobilization of platelet antigens procedure.

BACKGROUND: Fetal-neonatal alloimmune thrombocytopenia results from a maternal alloimmunization against fetal platelet (PLT) antigens. In Caucasian persons, human PLT antigen-1a (HPA-1a) is the most frequently implicated antigen. Our aim was to develop a method supported by a mathematical approach to quantify HPA-1a antibodies. STUDY DESIGN AND METHODS: The monoclonal antibody immobilization of PLT antigens (MAIPA) protocol was applied on serial dilutions of a serum with high concentration of HPA-1a antibodies used as reference. Two mathematical procedures were used: the standard curve was constructed with a linear and a logistic regression. These regressions were used to calculate the amount of antibody in 14 test serum samples from mothers with detectable anti-HPA-1a. RESULTS: Similar quantifications were obtained with both mathematical procedures. In 11 serum samples, the results, expressed in arbitrary units (AU), ranged from 62 +/- 4 to 1096 +/- 19 with the linear regression and from 62 +/- 4 to 1117 +/- 38 with the logistic regression. In addition, the linear regression allowed us to measure 3 test serum samples with low antibody concentrations from 4 +/- 2 to 44 +/- 3 AU, whereas the logistic regression was not suitable for the quantification of antibodies in these serum samples. CONCLUSION: A simple quantification method was developed for anti-HPA-1a, based on the MAIPA procedure, allowing further studies concerning correlations between anti-HPA-1a quantification and clinical relevance.

Antibodies, Monoclonal↗
PubMed2005

Prospective epidemiologic study of the outcome and cost-effectiveness of antenatal screening to detect neonatal alloimmune thrombocytopenia due to anti-HPA-1a.

BACKGROUND: To assess the value of antenatal screening to detect neonatal alloimmune thrombocytopenia (NAIT) due to anti-HPA-1a, a prospective study was carried out to quantify the potential clinical benefits and determine whether screening would be cost-effective. STUDY DESIGN AND METHODS: An observational prospective controlled study was carried out on 26,506 pregnant women over 2 years. HPA-1a phenotyping was performed in the first trimester and women confirmed HPA-1a-negative were tested for anti-HPA-1a during pregnancy, at delivery, and 10 to 14 days after birth. Babies of HPA-1a-negative women were tested at delivery for thrombocytopenia and examined for signs of bleeding. Economic evaluation was undertaken on the basis of the data collected during the study. RESULTS: Twenty-five of 318 women (7.9%) had anti-HPA-1a detected for the first time. Eight women (43 per 100,000) gave birth to babies with NAIT, and 5 (27 per 100,000) had severe thrombocytopenia. Three babies had mild signs of bleeding, and no cases of intracranial hemorrhage (ICH) or fetal loss were detected. It is estimated that it would cost 60,596 pounds (98,771 US dollars) to detect a case of severe NAIT, where anti-HPA-1a has been identified for the first time, and 1,151,323 pounds (1,876,656 US dollars) to prevent a case of ICH, assuming that detection allowed successful intervention. CONCLUSIONS: Our data suggest that severe HPA-1a NAIT is underdiagnosed in the absence of routine antenatal screening. Serious bleeding complications and ICH, however, occur less frequently in first cases of NAIT than suspected from the literature, and the costs of screening and possible intervention must be balanced against the procedural risks.

Antigens, Human Platelet↗
PubMed2007

Maternal human platelet antigen-1a antibody level correlates with the platelet count in the newborns: a retrospective study.

BACKGROUND: Maternal plasma and/or serum levels of anti-HPA-1a at delivery were compared to neonatal platelet (PLT) counts. STUDY DESIGN AND METHODS: Samples from HPA-1bb women who gave birth to children with thrombocytopenia or had anamnestic information about a previous child with neonatal alloimmune thrombocytopenia (NAIT) were collected at delivery. A modified monoclonal antibody immobilization of PLT antigen method was used for quantification of anti-HPA-1a. RESULTS: The anti-HPA-1a level in women with severely thrombocytopenic children was higher than the corresponding level in mothers of children born with moderate thrombocytopenia or normal PLT counts. CONCLUSION: Our data show a significant correlation between maternal anti-HPA-1a level and the neonatal PLT count and indicate strongly that this may be a reliable predictive measure for NAIT. Suitable test systems for quantitative measurements of anti-HPA-1a must be developed and evaluated for this particular purpose.

Antigens, Human Platelet↗
PubMed2005

Mutations in GPIIIa molecule as a cause for Glanzmann thrombasthenia in Indian patients.

BACKGROUND: Glanzmann thrombasthenia (GT) results from a quantitative or qualitative defect of GPIIb-IIIa complex, the fibrinogen receptor on platelets, which plays a very important role in platelet aggregation. In this report we describe the molecular studies on 22 patients with Glanzmann Thrombasthenia at our institute. OBJECTIVES: The main objective was to identify the mutations present in our GT population in order to establish a strategy for genetic counseling and antenatal diagnosis. METHODS: Twenty-two patients with GT were included in the present study. Complete blood count (CBC), platelet aggregation, flow cytometry, Western blot, single strand conformation polymorphism (SSCP) and denaturing gradient gel electrophoresis (DGGE) were performed in all the patients. The patients showing an abnormal migration pattern in SSCP or DGGE were sequenced further on an automated sequencer. RESULTS: Of the 22 patients studied, mutations were detected in 12 individuals. Of these, 11 were novel mutations and one mutation Y115C was reported earlier. Flow cytometric analysis showed the absence of receptors in type I GT, highly reduced levels in type II GT and normal levels in type III GT. The DGGE analysis and SSCP analysis of the patients showed different migration patterns. Sequencing was performed in all patients showing an abnormal migration pattern. Of the 22 cases studied mutations could be detected in 12 cases of GT. We could detect six patients with point mutations, four patients with insertions and five patients with deletion mutations. Exon 4 has been found to be the most common site for mutations in our patients. CONCLUSION: This study has shown a wide array of mutations present in our GT patients which would be extremely useful in genetic counseling and prenatal diagnosis, essential in preventing these disorders in succeeding generations.

DNA Mutational Analysis↗
PubMed2006

Predictive value of sequential maternal anti-HPA-1a antibody concentrations for the severity of fetal alloimmune thrombocytopenia.

BACKGROUND: Fetal/neonatal alloimmune thrombocytopenia results from maternal immunization against fetal platelet alloantigens (HPAs), and the major risk is intracranial hemorrhage. The severity of thrombocytopenia increases in subsequent pregnancies, and antenatal therapy has been developed. Until now, the fetal status can only be assessed by fetal blood sampling, which carries a risk of fetal loss or premature delivery. OBJECTIVES: To develop non-invasive methods to gain information on the fetal condition. PATIENTS/METHODS: Quantification of the maternal anti-HPA-1a alloantibody concentration was performed with a standardized monoclonal antibody-specific immobilization of platelet antigens (MAIPA) procedure for 43 mothers. A correlation between this concentration and the fetal/neonatal platelet counts was studied. RESULTS: (i) Before antenatal therapy, there was a significant correlation between maternal anti-HPA-1a concentrations > or =250 AU mL(-1) and fetal thrombocytopenia (2-66 x 10(9) L(-1)) whatever the gestational age (Fisher's exact test P = 0.0021). (ii) During subsequent pregnancies, we observed a decrease of the maternal anti-HPA-1a concentration for 14/19 women. Just before delivery, all women had anti-HPA-1a concentrations <250 AU mL(-1). In four cases, there was a therapy failure and the severely thrombocytopenic babies required postnatal therapy. CONCLUSION: The maternal anti-HPA-1a concentration could provide obstetricians with clinically useful information concerning the appropriateness and the timing of invasive monitoring procedures. However, though we observed a tendency toward a decrease in maternal antibody concentration after treatment, this finding does not allow us to draw any conclusions on the effectiveness of therapy.

Antigens, Human Platelet↗
PubMed2006

Fibrinogen and von Willebrand factor-independent platelet aggregation in vitro and in vivo.

BACKGROUND: Fibrinogen (Fg) has been considered essential for platelet aggregation. However, we recently demonstrated formation of occlusive thrombi in Fg-deficient mice and in mice doubly deficient for Fg and von Willebrand factor (Fg/VWF(-/-)). METHODS AND RESULTS: Here we studied Fg/VWF-independent platelet aggregation in vitro and found no aggregation in citrated platelet-rich plasma of Fg/VWF(-/-) mice. Surprisingly, in Fg/VWF(-/-) plasma without anticoagulant, adenosine diphosphate induced robust aggregation of Fg/VWF(-/-) platelets but not of beta(3)-integrin-deficient (beta(3) (-/-)) platelets. In addition, beta(3) (-/-) platelets did not significantly incorporate into thrombi in Fg/VWF(-/-) mice. This Fg/VWF-independent aggregation was blocked by thrombin inhibitors (heparin, hirudin, PPACK), and thrombin or thrombin receptor activation peptide (AYPGKF-NH(2)) induced aggregation of gel-filtered Fg/VWF(-/-) platelets in 1 mm Ca(2+) PIPES buffer. Notably, aggregation in PIPES buffer was only 50-60% of that observed in Fg/VWF(-/-) plasma. Consistent with the requirement for thrombin in vitro, hirudin completely inhibited thrombus formation in Fg/VWF(-/-) mice. These data define a novel pathway of platelet aggregation independent of both Fg and VWF. Although this pathway was not detected in the presence of anticoagulants, it was observed under physiological conditions in vivo and in the presence of Ca(2+)in vitro. CONCLUSIONS: beta(3) integrin, thrombin, and Ca(2+) play critical roles in this Fg/VWF-independent aggregation, and both plasma and platelet granule proteins contribute to this process.

Animals↗
PubMed2006

Allosteric disulfide bonds in thrombosis and thrombolysis.

Allosteric disulfide bonds control protein function by mediating conformational change when they undergo reduction or oxidation. The known allosteric disulfide bonds are characterized by a particular bond geometry, the -RHStaple. A number of thrombosis and thrombolysis proteins contain one or more disulfide bonds of this type. Tissue factor (TF) was the first hemostasis protein shown to be controlled by an allosteric disulfide bond, the Cys186-Cys209 bond in the membrane-proximal fibronectin type III domain. TF exists in three forms on the cell surface: a cryptic form that is inert, a coagulant form that rapidly binds factor VIIa to initiate coagulation, and a signaling form that binds FVIIa and cleaves protease-activated receptor 2, which functions in inflammation, tumor progression and angiogenesis. Reduction and oxidation of the Cys186-Cys209 disulfide bond is central to the transition between the three forms of TF. The redox state of the bond appears to be controlled by protein disulfide isomerase and NO. Plasmin(ogen), vitronectin, glycoprotein 1balpha, integrin beta(3) and thrombomodulin also contain -RHStaple disulfides, and there is circumstantial evidence that the function of these proteins may involve cleavage/formation of these disulfide bonds.

Allosteric Site↗
PubMed2006

Releasing growth factors from activated human platelets after chitosan stimulation: a possible bio-material for platelet-rich plasma preparation.

INTRODUCTION: Thrombin is commonly used for activating the platelets and releasing the growth factors on the application of platelet-rich plasma (PRP). We have previously reported that chitosan can enhance rabbit platelet aggregation. In this study, the effects of chitosan on the subsequent growth factors release after human platelets activation were examined to evaluate the possibility of chitosan being used as a substitute for thrombin during PRP preparation. MATERIAL AND METHODS: Human platelet activation was determined by aggregation, adhesion and alpha-granule membrane glycoprotein expression. Platelet aggregation was measured by the turbidimetric method, the adhesion was directly examined on chitosan-coated glass plates under light microscope and scanning electron microscope (SEM), and the alpha-granule membrane glycoprotein was detected by fluorescent isothiocyanate (FITC)-conjugated anti-CD61 antibody through flow cytometry. The subsequent epidermal growth factor (EGF), platelet-derived growth factor (PDGF)-AB and transforming growth factor (TGF)-beta1 release from platelets were assayed by ELISA after mixing with chitosan. RESULTS: The enhancing effects on the platelet adhesion and the aggregation from chitosan were observed. Under both microscopes, the adhesive platelets on the chitosan-coated plates were not only greater in number but also earlier in activation than those on the control plates. With flow cytometry, increased glycoprotein IIIa expression in platelets was detected after chitosan treatment. Greater concentrations of growth factors were measured from PRP after chitosan treatment than after the solvent treatment. CONCLUSION: Because of the observations of growth factors releasing from activated human platelets after chitosan stimulation, we suggest that chitosan may be an appropriate substitute for thrombin in PRP preparation.

Biocompatible Materials↗
PubMed1997

Immunoglobulin G subclasses of anti-human platelet antigen 1a in maternal sera: relation to the severity of neonatal alloimmune thrombocytopenia.

The monoclonal antibody immobilization of platelet antigen (MAIPA) technique was employed to detect and semiquantitatively assess total IgG anti-HPA-1a and its subclasses in sera of mothers who gave birth to severely thrombocytopenic (< 50 x 10(9) platelets/L)(n = 14) or mildly thrombocytopenic/unaffected (> 50 x 10(9) platelets/L)(n = 13) neonates. There was no statistically significant difference between the IgG anti-HPA-1a subclass composition of the 2 groups of sera. The majority of sera (26/27, 96%) showed IgG1 + IgG3 while 17/27 (63%) had all 4 subclasses of the antibody. No significant differences between the severely thrombocytopenic and mildly thrombocytopenic/unaffected groups were detected in the levels of IgG, IgG1, IgG2 or IgG4 of the antibody. However, the values of IgG3 anti-HPA-1a were significantly higher in the severely thrombocytopenic than in the mildly thrombocytopenic/unaffected group of sera with only little overlap (median 2.94 vs. 1.68, range 1.36-9.71 vs. 1.50-2.84, respectively; p < 0.01). The results suggest that maternal IgG3 anti-HPA-1a has predictive value for severe thrombocytopenia of the neonate. However, a prospective study of IgG HPA-1a subclasses in a greater number of maternal sera at different times of pregnancy is needed to test if IgG3 anti-HPA-1a is predictive of the degree of fetal/neonatal thrombocytopenia.

Antigens, Human Platelet↗
PubMed1983

Neonatal alloimmune thrombocytopenia. Case reports, diagnostic and therapeutic considerations.

Two families are presented, where the mothers have given birth to children with neonatal alloimmune thrombocytopenia (NAITP) due to immunization towards the platelet specific antigen PIA1, which is responsible for most of the cases with NAITP. Anti-PIA1 has previously been difficult to demonstrate, but current techniques, such as the platelet suspension immunofluorescence test (PSIFT) used here, have made routine laboratory diagnosis possible. Both mothers in these families were HLA-B8 positive. This antigen shows strong association with PIA1 immunization.

Antigens, Human Platelet↗
PubMed1986

Alloimmune neonatal thrombocytopenia and hydrocephalus. Platelet antigen Zwa, ABO-antigens and HLA-antigens in mothers to infants with hydrocephalus.

In 27 mothers to infants with hydrocephalus determinations of platelet antigen Zwa, HLA-typing and ABO-typing were performed in order to evaluate whether undiagnosed alloimmune neonatal thrombocytopenia (AINT) could be an aetiological factor in hydrocephalus. All mothers were Zwa-positive, and the frequency of HLA-antigens and ABO-antigens was as in the normal population. Though sporadic cases of hydrocephalus following AINT are reported, this is not a common cause of intracranial haemorrhage and hydrocephalus.

ABO Blood-Group System↗