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PubMed1986

Alloimmunization against the platelet-specific Zwa antigen, resulting in neonatal alloimmune thrombocytopenia or posttransfusion purpura, is associated with the supertypic DRw52 antigen including DR3 and DRw6.

The strong association between HLA-DR3 and Zwa alloimmunization in Zwa-negative mothers, resulting in the production of anti-Zwa antibodies and ultimately in neonatal alloimmune thrombocytopenic purpura (NAITP) in the newborn, could be confirmed. In addition, we have shown an equally strong association between HLA-DR3 and Zwa alloimmunization in Zwa-negative recipients of blood transfusions, resulting in posttransfusion purpura (PTP). However, the strongest association both in mothers of NAITP patients and in PTP patients was observed with the supertypic DRw52 antigen. In fact, all individuals carried this antigen. Normally, DRw52 includes DR3, DR5, DRw6, and DRw8 almost completely. However, in our material, DRw52 included only DR3 and DRw6 with one exception. Another interesting observation is that all PTP patients were women with previous pregnancies without any clinical signs of a bleeding disorder in their children. This indicates that alloimmunization against Zwa during pregnancy is DR3- and/or DRw52-positive women does not always lead to the development of NAITP, but these women may be at risk for the development of PTP after blood transfusion.

Antibody Formation↗
PubMed1990

HLA-DRw52a is involved in alloimmunization against PL-A1 antigen.

The alloimmunization against the platelet PL-A1 antigen is strongly associated with a HLA class II structure in mothers of thrombocytopenic neonates. Most of the immunized women have first been shown to possess the DR3 specificity and subsequently the DRw52 allele. The 18 immunized mothers studied here by restriction fragment length polymorphism analysis had the DRw52a specificity at the DRB3 locus whatever their HLA-DRB1 gene product. This finding strongly suggests that the DRB3 chain is directly involved in the presentation of the PL-A1 antigen to the specific T cell. In addition, the similarities between DR3 and DRw52 structures due to a hypothetical gene conversion event should be considered in order to understand the high frequency of DR3 among the DRw52a-responding women. Alternatively, the high frequency of DR3 among the DRw52-responding mothers might be due to the high responder status associated with the former specificity.

Antigens, Human Platelet↗
PubMed1992

Leucine33-proline33 substitution in human platelet glycoprotein IIIa determines HLA-DRw52a (Dw24) association of the immune response against HPA-1a (Zwa/PIA1) and HPA-1b (Zwb/PIA2).

Alloantibody formation against HPA-1a (Zwa/PIA1) has, to date, only been found in HLA-DRw52(a+) (Dw24) individuals. Alloimmunization against the product of the other HPA-1 allele, HPA-1b, is rare. We have been able to evaluate ten cases of HPA-1b alloimmunization in Europe in order to study whether there is an association between HLA phenotype and anti-HPA-1b antibody formation. HLA typing of these patients was performed with particular attention to the DRw52a specificity using specific T-cell clones. No association with DRw52a or any other known HLA phenotype was found. This finding implies that the amino acid substitution leucine33-proline33 in GPIIIa, responsible for HPA-1a/b, is of primary importance for the association of anti-HPA-1a antibody formation with DRw52a. These data show that the amino acid polymorphism affects the presentation of the immunogenic oligopeptides of HPA-1a and -1b in the HLA class-II groove.

Antigens, Human Platelet↗
PubMed1994

Susceptibility to alloimmunization to platelet HPA-1a antigen involves TAP1 polymorphism.

The alloimmunization against platelet HPA-1a antigen in mothers of thrombocytopenic neonates is strongly associated with HLA class II structures (DR3 and DR13) and especially with HLA-DR52a antigen (98% of the cases reported here). Because new genes have recently been mapped within the MHC class II region, we typed TAP1 and TAP2 gene polymorphisms by ARMS-PCR in order to characterize more effectively MHC genes involved in this alloimmunization. Our results showed that TAP1*0102 allele was significantly associated with NAIT only in the population of HLA-DR 13-DR52a-immunized women (50%) versus HLA-DR 13-DR52a controls (20%) (p < 0.05), and not in HLA-DR3-DR52a-immunized women versus HLA-DR3-DR52a controls. There is no linkage disequilibrium between TAP1*0102 and DRB1*13 alleles (delta = -0.0063) that could account for this result. The higher frequency of TAP1*0102 allele among HLA-DR 13-DR52a-immunized women suggests that HPA-1a antigen presentation and recognition may be influenced by nonclassic HLA class II gene polymorphisms, or that other linked but yet unknown genes could interfere.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Neonatal alloimmune thrombocytopenia.

Neonatal alloimmune thrombocytopenia (NAIT) occurs when maternal alloantibodies to antigens present on fetal platelets cause their immune destruction resulting in thrombocytopenia in the newborn infant or fetus. Bleeding may be severe; intracranial haemorrhage and permanent neurological damage are the most serious complications. Despite the severity of the disease, there is often a delay in making the correct diagnosis and instigating appropriate treatment. Recent evidence that NAIT is more common than has previously been recognised, a better understanding of the molecular basis of platelet serology and advances in technology, which have made it possible to take blood samples from fetuses and transfuse them in utero, have all contributed to a growing interest in this condition. In addition, it is exciting to realise that an aggressive approach to the management of established cases and 'at risk' pregnancies can prevent serious neurological sequelae and dramatically improve the outcome for affected infants.

Antigens, Human Platelet↗
PubMedDate not supplied

Perinatal intracranial hemorrhage due to severe neonatal alloimmune thrombocytopenic purpura (NAITP) associated with anti-Yukb (HPA-4a) antibodies.

Neonatal alloimmune thrombocytopenic purpura (NAITP) is one of the causes of thrombocytopenia in the newborn period. The thrombocytopenia is caused by maternal transplacental antiplatelet alloantibodies. We report a case of NAITP in a newborn infant having subarachnoid hemorrhage. Examination of platelet antibodies revealed anti-Yukb, that is, human platelet antigen (HPA)-4a incompatibility. Cranial ultrasound and brain magnetic resonance imaging revealed subarachnoid hemorrhage in the temporal region inferior to the cephalohematoma. The lesion seemed to have been sustained during delivery. The patient was treated with high-dose gamma-globulin and several transfusions of random donor platelets and showed a good clinical course. This is the second reported case of NAITP associated with the Yuk antigen system having intracranial hemorrhage.

Antigens, Human Platelet↗
PubMed2004

Interaction between a genetic variant of the platelet fibrinogen receptor and fibrinogen levels in determining the risk of cardiovascular events.

BACKGROUND: The PlA1A2 polymorphism of glycoprotein IIIa (GPIIIa), which affects postoccupancy signaling by the platelet fibrinogen receptor IIbIIIa, has been investigated as a potential genetic risk factor for cardiovascular events in numerous studies, without consistent results. We investigated whether the effect of this genetic variant of the platelet fibrinogen receptor on the risk of cardiovascular events is affected by fibrinogen plasma levels. METHODS: The GPIIIa PlA1A2 polymorphism and fibrinogen levels were determined in 455 men with angiographically documented coronary atherosclerosis. RESULTS: Neither carriership of the rare PlA2 allele nor fibrinogen plasma levels affected the time to cardiovascular event, as assessed in a proportional hazards model. However, there was a significant interaction between PlA2 carriership and fibrinogen plasma levels (P =.002). Carriership of the variant PlA2 allele significantly affected event-free survival only in individuals within the highest fibrinogen quartile (hazard ratio, 2.7; 95% CI, 1.1 to 7.1; P =.03). CONCLUSIONS: We observed a statistically significant interaction between a genetic variant of the platelet fibrinogen receptor and fibrinogen levels in determining the risk of cardiovascular events. This interaction may account for the inconsistent results of genetic association studies investigating this genotype as a genetic risk factor in thrombotic cardiovascular events.

Coronary Artery Disease↗
PubMed2005

The role of platelet glycoprotein IIIa polymorphism in the high prevalence of in vitro aspirin resistance in patients with intracoronary stent restenosis.

OBJECTIVES: The aim of our study was to determine the relation between platelet glycoprotein IIIa (Pl A ) polymorphism and aspirin resistance in patients with intracoronary stent restenosis. BACKGROUND: Clinically, aspirin resistance is defined as having thrombotic and embolic cardiovascular events despite regular aspirin therapy. Platelet glycoprotein IIIa polymorphism is said to be a possible mechanism of aspirin resistance. METHODS: We studied the prevalence of aspirin resistance in 204 previously intracoronary stent-implanted patients with stable coronary artery disease. In 102 of these patients, intracoronary stent restenosis was present. Platelet functions were analyzed in a platelet function analyzer (PFA-100, Dade Behring, Germany) with collagen and/or epinephrine (Col/Epi) and collagen and/or adenosine diphosphate cartridges. Closure time <186 seconds was defined as aspirin resistance with Col/Epi cartridges of PFA-100. The Pl A polymorphisms of 43 aspirin-resistant and 51 aspirin-sensitive subjects were determined with polymerase chain reaction and restriction fragments length polymorphism. RESULTS: A total of 31.3% (n = 32) of patients with intracoronary stent restenosis and 10.7% (n = 11) of patients with patent intracoronary stents were resistant to aspirin by PFA-100. The Pl A1,A1 allele of glycoprotein IIIa was present in 36 subjects (83.7.%) and the Pl A1,A2 allele was present in 7 subjects (16.2.%) in the aspirin-resistant patients group. The Pl A1,A1 allele of glycoprotein IIIa was present in 37 subjects (72.5%) and the Pl A1,A2 allele was present in 14 subjects (27.5%) in the aspirin-sensitive patients group ( P = .195). CONCLUSION: Our results suggest that platelets of patients with intracoronary stent restenosis with or without Pl A2 heterozygosity of glycoprotein IIIa are more likely to be resistant to low-dose aspirin therapy.

Aged↗
PubMed2006

Estradiol increases platelet aggregation in Pl(A1/A1) individuals.

BACKGROUND: The platelet glycoprotein IIb/IIIa receptor is a key mediator of platelet aggregation and intracoronary thrombosis. Studies have suggested that hormone replacement therapy (HRT) may increase coronary events in postmenopausal women. OBJECTIVES: We sought to characterize the relationship between the estrogen concentration expected in HRT and platelet aggregation. DESIGN AND RESULTS: Platelet aggregation studies were performed using epinephrine on 30 healthy individuals (15 Pl(A1/A1) and 15 Pl(A1/A2)) before and after incubation with beta-estradiol (E2) (10(-11) mol/L). The effect of E2 10(-11) mol/L on Pl(A1/A1) platelets demonstrated a significant increase (P = .03) in aggregation compared with baseline. In contrast, with the same concentration of E2, aggregation of Pl(A1/A2) platelets decreased significantly compared with baseline (P < .0001). CONCLUSIONS: Estrogen concentration similar to that expected in HRT resulted in an increase in platelet aggregation in Pl(A1/A1) individuals, but not in Pl(A1/A2) individuals. The data may provide further insight for the increase in coronary events seen in HRT clinical trials and suggest that further evaluation is needed to better define the role of pharmacogenetics in HRT.

Antigens, Neoplasm↗
PubMed2004

Different levels of platelet activation in preeclamptic, normotensive pregnant, and nonpregnant women.

OBJECTIVE: The aims of our study were to determine the basal platelet activation state in women with preeclampsia compared with normotensive pregnant women and nonpregnant women and to investigate the platelet reactivity on in vitro stimulation with adenosine diphosphate or thrombin receptor activation peptide. STUDY DESIGN: Platelet expression of CD61 (fibrinogen receptor), CD42a (von Willebrand factor receptor), CD62P (P-selectin), CD63 (Glycoprotein 53), and PAC-1 binding (activated fibrinogen receptor) were determined in 20 pairs of women with preeclampsia/normotensive pregnant women and in 12 nonpregnant women, with the use of flow cytometry. RESULTS: Basal platelet expression of CD61, CD42a and CD62P, and adenosine diphosphate-stimulated CD62P expression were increased in women with preeclampsia compared with normotensive pregnant women. Platelets from women with preeclampsia and normotensive pregnant women differed from platelets from nonpregnant women by expressing higher basal CD63 levels and being more responsive to in vitro agonist stimulation, which was demonstrated by increased expression of CD61, CD62P, and CD63. CONCLUSION: This study supports the notion that platelets are important in the pathophysiologic condition of preeclampsia.

Adenosine Diphosphate↗
PubMed2005

Fetal and neonatal alloimmune thrombocytopenia in pregnancies involving in vitro fertilization: a report of four cases.

OBJECTIVE: We report four cases of neonatal alloimmune thrombocytopenia (NATP) in pregnancies achieved with in vitro fertilization. STUDY DESIGN: Three cases used surrogate carriers, and the fourth a donor egg. Sera from gestational carriers were tested for platelet antibodies by flow cytometry and enzyme-linked immunosorbent assay. Platelet antigen genotyping of biologic mothers, fathers, and surrogates was performed by amplification of DNA by using polymerase chain reaction with sequence-specific primers. RESULTS: In all 4 cases, NATP resulted from an incompatibility between the fetus and gestational carrier for the platelet-specific alloantigen HPA-1a. Four infants were born severely thrombocytopenic (platelets <50,000/muL), 2 had antenatal intracranial hemorrhage, and 1 fetus expired in utero at 29 weeks. CONCLUSION: NATP can occur in the setting of assisted reproductive technology. Because of the great costs, both financial and emotional, associated with these pregnancies, we strongly recommend that all women be typed for HPA-1a before serving as a surrogate mother.

Adult↗
PubMed2006

Alloimmune thrombocytopenia: state of the art 2006.

In alloimmune thrombocytopenia maternal immunoglobulin G anti-platelet alloantibodies cross the placenta and cause fetal thrombocytopenia. The diagnosis requires laboratory demonstration of incompatibility between a maternal and paternal platelet alloantigen, and detection of maternal antibody to the discordant paternal alloantigen. This disorder should be treated in utero because of its propensity to cause fetal intracranial bleeding. Administration of intravenous immunoglobulin 1 gm/kg/wk to the mother is successful in substantially raising the platelet count in many fetuses, but this is most successful if the count is >20,000/mL3 at the time that the therapy is initiated. The addition of prednisone administered daily to the mother and/or increasing the dose of intravenous immunoglobulin has a therapeutic benefit in cases that have failed to respond to initial therapy with intravenous immunoglobulin alone. The only reliable noninvasive indicator of the potential for severe fetal thrombocytopenia is a history of an antenatal intracranial hemorrhage in a prior affected sibling. Because fetal blood sampling to determine the fetal platelet count may be associated with significant fetal morbidity, attempts are being made to derive a rational, non-invasive, stratified approach to patient-specific therapy of this disorder in affected pregnancies.

Antigens, Human Platelet↗
PubMed2006

Antenatal noninvasive treatment of patients at risk for alloimmune thrombocytopenia without a history of intracranial hemorrhage.

OBJECTIVE: The purpose of this study was to evaluate noninvasive management of alloimmune thrombocytopenia that included only the blind administration of immunoglobulin. STUDY DESIGN: Seventeen women with 30 pregnancies that were at risk of neonatal alloimmune thrombocytopenia were included. Except for 6 cases, in which the women refused treatment, 24 pregnancies were managed by the weekly administration of intravenous immunoglobulin without monitoring platelet count. RESULTS: The mean platelet count at birth after intravenous immunoglobulin treatment was 118,000/microL, compared with 25,000/microL among the 17 first affected infants and 24,000/microL among the 6 infants whose mothers refused treatment (P < .05). Only 8% of the treated fetuses had platelet counts of <30,000/microL at birth, compared with 70% of the untreated infants (P < .05). None of the treated and nontreated fetuses had an intracranial hemorrhage. CONCLUSION: Noninvasive management of alloimmune thrombocytopenia that consists of only immunoglobulin administration is highly effective and seems safe in women without a history of fetal/neonatal intracranial hemorrhage.

Adult↗
PubMed2005

Comparison of enoxaparin versus heparin during elective percutaneous coronary intervention performed with either eptifibatide or tirofiban (the ACTION Trial).

Limited data are available with regard to the pharmacodynamics and safety of combining enoxaparin with glycoprotein IIb/IIIa inhibition during elective percutaneous coronary interventions (PCIs). We randomized 200 patients to receive open-label enoxaparin (0.75 mg/kg intravenous bolus) or unfractionated heparin (60 U/kg intravenous bolus) and eptifibatide or tirofiban during PCI. This yielded 4 groups of combination therapy (50 patients/group). The first 10 patients per group had anti-Xa activity and inhibition of platelet aggregation measured at baseline, and at 5 minutes, 10 minutes, 4 hours, and 24 hours. All patients received aspirin and clopidogrel therapy before PCI. Patients who received enoxaparin and heparin achieved therapeutic peak anti-Xa activity observed shortly after drug administration. At 4 hours, a differential anticoagulant effect was observed, with patients who received enoxaparin having a more gradual decrease in anti-Xa activity. Patients who received eptifibatide achieved >80% inhibition of platelet aggregation soon after initiation of therapy more often than did those who received tirofiban. Type of heparin did not affect inhibition of platelet aggregation. Compared with patients who received heparin, periprocedural myocardial infarction and bleeding events occurred less frequently among those who received enoxaparin (14% vs 8% and 10% vs 5%); however, these differences were not statistically significant. Three cases of intraprocedural thrombus occurred among patients who received enoxaparin. Two patients received concomitant tirofiban therapy. Compared with unfractionated heparin, similar levels of anticoagulation and platelet inhibition are achieved with enoxaparin when concomitant therapy with eptifibatide or tirofiban is used during elective PCI, without an observed increase in early bleeding events or periprocedural ischemic complications.

Aged↗
PubMed2006

Endothelial microparticles and platelet and leukocyte activation in patients with the metabolic syndrome.

Accumulating evidence has shown a strong association between the metabolic syndrome (MS) and a chronic inflammatory state predisposing to atherosclerosis. We investigated leukocyte, platelet, and endothelial activation markers and cellular interactions in 33 patients with the MS and 25 healthy controls. Using flow cytometry, we measured: (1)P-selectin expression in platelets; (2) platelet microparticles identified by CD31 expression; (3) endothelial microparticles (EMPs) identified by expression of CD31 (EMP(31)), CD62E (EMP(62E)), and CD51 (EMP(51)); (4) conjugates of leukocytes with platelet microparticles/platelets and with EMPs identified by CD54 (EMP(54)); and (5) CD11b expression in leukocytes. Patients with the MS had markedly elevated EMP(31), although EMP(62E) levels were normal, suggesting that EMP(31) levels were increased because of endothelial cell apoptosis, rather than activation. EMP(51), EMP(54)-lymphocyte conjugates, platelet expression of P-selectin, CD11b expression in leukocytes, and platelet-lymphocyte conjugates were also increased in patients with the MS. Platelet-leukocyte conjugates correlated with leukocyte activation, suggesting that platelet binding to leukocytes regulates leukocyte activation in vivo. In conclusion, our data demonstrate endothelial cell microparticle release, platelet and leukocyte activation, and increased binding of EMPs and platelets to leukocytes in patients with the MS.

Biomarkers↗
PubMed2004

Integrating antithrombin and antiplatelet therapies with early invasive management for non-ST-segment elevation acute coronary syndromes.

Non-ST-segment elevation acute coronary syndromes are a dramatic manifestation of coronary artery disease. Multiple clinical trials have shown that early cardiac catheterization improves clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes. Many antithrombotic agents effectively manage unstable coronary syndromes and serve as adjuncts to percutaneous coronary intervention. Yet, the growing number of pharmacologic agents makes early management of non-ST-segment elevation acute coronary syndromes increasingly complex. We review the current evidence regarding the optimal integration of early antithrombotic and antiplatelet therapies with early coronary angiography and subsequent revascularization.

Algorithms↗