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RH allele variability is caused by several types of variants, resulting in altered RhD and RhCE phenotypes. Most of the weak D phenotypes in European-derived populations are weak D types 1, 2, or 3, which are not involved in alloimmunization episodes. However, the Brazilian population is racially diverse, and the accuracy of molecular and serologic tests developed in recent years has allowed for the identification of other RH variants, that are common in the Brazilian population, such as weak D type 38 or weak partial 11, the latter involved in alloimmunization cases. Furthermore, patients with these two weak D variants must be transfused with D- red blood cell units, as do patients with weak D type 4 or DAR, which are also common D variants in Brazil. Weak D type 38 and weak partial 11 can be serologically misclassified as weak D types 1, 2, or 3 in patients, based on European experience, or as D- in donors. Additionally, pregnant women may unnecessarily be identified as requiring Rh immune globulin. RhCE phenotypes are reliable indicators of RhD variants. For individuals with the Dce phenotype, the preferred approach is to specifically search for RHD*DAR. However, when encountering DCe or DcE phenotypes, we currently lack a developed method that assists us in rapidly identifying and determining the appropriate course of action for the patient or pregnant woman. Two multiplex assays were proposed: one for the identification of RHD*weak partial 11, RHD*weak D type 38, and RHD*weak D type 3 and another for RHD*weak D type 2 and RHD*weak D type 5. The multiplex assays were considered valid if the obtained results were equivalent to those obtained from sequencing. Expected results were obtained for all tested samples. The proposed multiplex allele-specific polymerase chain reaction assays can be used in the molecular investigation of women of childbearing age, patients, and blood donors presenting a weak D phenotype with DCe or DcE haplotypes in a mixed-race population, such as Brazil.

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BACKGROUND AND OBJECTIVES: Transfusion-related acute lung injury (TRALI) is characterized by leukocyte transmigration and alveolar capillary leakage shortly after transfusion. TRALI pathogenesis has not been fully elucidated. In some cases, the infusion of alloantibodies (immune model), whereas in others the combination of neutrophil priming by proinflammatory molecules with the subsequent infusion of biological response modifiers (BRMs) in the hemocomponent (non-immune model) have been implicated. Our aim was to compare the pathological events involved in TRALI induced by antibodies or BRMs using murine models. MATERIALS AND METHODS: In the immune model, human HNA-2(+) neutrophils were incubated in vitro with a monoclonal antibody (anti-CD177, clone 7D8) directed against the HNA-2 antigen and injected i.v. in NOD/SCID mice. In the non-immune model, BALB/c mice were treated with low doses of lipopolysaccharide (LPS) followed by platelet-activating factor (PAF) infusion 2 h later. Forty minutes after PAF administration, or 6 h after neutrophil injection, lungs were isolated and histological analysis, determination of a variety of cytokines and chemokines including keratinocyte-derived chemokine (KC), MIP-2, the interleukins IL-1ß, IL-6, IL-8 as well as TNFα, cell influx and alveolar capillary leakage were performed. RESULTS: In both models, characteristic histological findings of TRALI and an increase in KC and MIP-2 levels were detected. In contrast to the immune model, in the non-immune model, there was a dramatic increase in IL-1ß and TNFα. However, capillary leakage was only detected if PAF was administrated. CONCLUSIONS: Regardless of the triggering event(s), KC, MIP-2 and integrins participate in TRALI pathogenesis, whereas PAF is essential for capillary leakage when two events are involved.

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INTRODUCTION: Autoimmune haemolytic anaemia (AIHA) is defined as the increased destruction of red blood cells (RBCs) in the presence of anti-RBC autoantibodies and/or complement. Its pathogenesis is multifactorial and includes changes in mechanisms of cytokine production and functionality. A number of recent studies have implicated cytokines polymorphisms in the pathogenesis of autoimmune diseases. The aim of this study was to determine the frequency of polymorphisms of tumour necrosis factor alpha (TNF-α), lymphotoxin-α (LT-α), interleukin 10 (IL-10), interleukin 12 (IL-12) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in patients with AIHA in comparison with healthy individuals. METHODS: The study population consisted of 17 patients with AIHA and 40 healthy controls. The polymorphisms for TNF-α-308, LT-α +252, IL-10 -592, IL-12 +1188 and CTLA-4 +49 were examined by polymerase chain reaction followed by specific restriction enzyme digestion. RESULTS: There was no significant difference in the phenotypic distributions of polymorphisms of the TNF-α, IL-10, IL-12 and CTLA-4 between the patients and controls. Compared with healthy controls, patients with AIHA had a significant higher frequency of LT-α (+252) AG phenotype (41%vs. 13%; P = 0.032). CONCLUSION: In this study, no significant differences on the frequency of TNF-α, IL-10, IL-12 and CTLA-4 polymorphisms between patients with AIHA and controls was found, suggesting that the targeted polymorphisms do not influence on the emergence and evolution of the disease. However, the LT-α +252 polymorphism might have an effect for AIHAI development, suggesting that further studies are necessary to clear up this question.

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The RHD gene is highly polymorphic and the existence of a large number of alleles results in RhD variant phenotypes. RHD genotyping has been used to distinguish normal D antigen from D variants due to limitations of serologic methods. The purpose of this study was to determine the phenotypic frequency of RhD and RhCE antigens and to investigate the RHD alleles present in samples with the weak D or D- phenotypes from Brazilian blood donors. A total of 2007 donors were phenotyped for D, C, c, E and e antigens. Samples phenotyped as D- were genotyped by polymerase chain reaction-sequence specific primers, and exon 10 and intron 4 of the RHD gene were analysed. D- samples containing the RHD gene or samples considered weak D were further characterised using genotyping platform or nucleotide sequencing. Using serologic methods we found that 87.3% of the donors were D+, 11.9% D- and 0.8% weak D. The frequency of RHD gene in D- individuals was 9.2%. Five RHD alleles from phenotypically D- donors were characterised in six molecular backgrounds: RHDΨ, RHD-CE-D(s), RHD-CE-(2-9)-D, RHD/RHDΨ, RHDΨ/RHD-CE-D(s) and RHD-CE(2)-D. The most common weak D antigens types found were 1, 3, 4.0/4.1 and 4.2, whereas the most prevalent weak D type was 4.2 (or DAR). The RHD genotyping proved to be a necessary tool to characterise RHD alleles in donors phenotyped as D- or weak D to increase the transfusion safety in highly racial mixed population.

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BACKGROUND AND OBJECTIVES: The human neutrophil antigen-2 (HNA-2) is expressed on a subpopulation of neutrophils as most subjects present a negative plus a positive HNA-2 population of neutrophils. The number of neutrophils expressing HNA-2 is variable and may increase in pregnancy, infections, myeloproliferative disorders and after G-CSF. This study investigated the presence of polymorphisms in the gene encoding HNA-2 (CD177) in individuals presenting different patterns of antigen expression and determined the association of single nucleotide polymorphisms (SNPs) with the heterogeneous HNA-2 expression. MATERIALS AND METHODS: Flow cytometry was employed to analyse the HNA-2 expression on neutrophils from 135 healthy subjects using two monoclonal antibodies (TAG4, 7D8). Sequencing reactions were performed on subjects whose antigen expression was low (< or = 50%), high (> or = 80%) or atypical (a nonreactive population plus two distinct positive cell populations). RESULTS: Five SNPs were detected, two of them (A793C, G1084A) were related to a low expression of HNA-2 (P = 0.031 and P = 0.004). Atypical antigen expression was observed in 5.9% (8/135) of the individuals, three nonpregnant women and five men. In these cases, the cDNA sequences revealed three SNPs (A134T, G156A and G1333A) strongly related to this atypical HNA-2 expression (P = 0.004, P = 0.006 and P < 0.0001, respectively). CONCLUSIONS: Our data show that polymorphisms in the CD177 are associated with variations in the HNA-2 expression and may be the cause of atypical expressions.

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Human neutrophil reactive antibodies may cause clinical disorders such as transfusion-related acute lung injury, febrile transfusion reactions, alloimmune neonatal neutropenia, immune neutropenia after stem cell transplantation, refractoriness to granulocyte transfusion, drug-induced neutropenia and autoimmune neutropenia. Using the granulocyte immunofluorescence test by flow cytometry, the phenotypic frequencies of the human neutrophil alloantigens (HNA)-1a, -1b, -2, -3a and -4a were determined in 100 healthy Brazilian persons. Neutrophils were separated from blood samples by sedimentation, centrifugated and incubated with HNA-specific alloantibody plus fluorescein isothiocyanate-labeled F(ab')(2) fragments of anti-human IgG. The results showed that the phenotype frequencies of HNA-1a, -1b, -2a, -3a and -4a were 65%, 83%, 97%, 95% and 94%, respectively. We detected that neutrophils from 17% of Brazilians typed positive only with anti-HNA-1a (HNA-1a/a), 35% only with anti-HNA-1b (HNA-1b/b) and 48% reacted with both antibodies (HNA-1a/b). The frequencies found for HNA-1a and -1b were quite similar to that reported among Africans and American-Africans, but different from those found in Japanese and Chinese. In addition, our data showed that the frequencies of HNA-2, -3a and -4a in Brazilians were comparable with those observed in Caucasians. The determination of HNAs frequencies among populations with distinct racial backgrounds is important not only for anthropological reasons, but also for neonatal typing in suspected cases of alloimmune neutropenia or when patients are severely neutropenic.

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We sought to assess clinical, epidemiological, biochemical, serological and histological characteristics of anti-hepatitis C virus (HCV)-positive female blood donors and compare them with men. As women are frequently the minority among blood donors, studies evaluating this population usually reflect characteristics of male gender. This retrospective study included 380 blood donors with confirmed positive anti-HCV. The mean age was 36.9 +/- 11.3 years and 33.2% were women. Compared with men, female donors showed higher prevalence of prior transfusion of blood products (P = 0.031) and lower prevalence of intravenous drug use (P = 0.001) and alcohol abuse (P < 0.001). Women exhibited lower medians of alanine aminotransferase (P < 0.001) and gamma-glutamyltransferase (P < 0.001). They also showed higher platelet count (P < 0.001) and prothrombin activity (P = 0.049), and a lower frequency of antibody against core antigen of hepatitis B virus (anti-HBc) positivity (P = 0.032). A higher proportion of spontaneous viral clearance (P = 0.001) and a lower frequency of viraemia (P < 0.001) were observed among women. On liver biopsy, women had lower prevalence of fibrosis stage > or = 2. Multivariate analysis identified age (OR = 1.050, 95% CI: 1.019-1.081, P = 0.001) and anti-HBc positivity (OR = 2.184, 95% CI: 1.010-4.722, P = 0.047) as independent predictors of significant fibrosis. Female blood donors presented higher prevalence of spontaneous viral clearance as well as biochemical and histological evidence of less advanced liver disease. These findings could be because of intrinsic characteristics of female gender or secondary to associated factors such as younger age or anti-HBc positivity.

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BACKGROUND AND OBJECTIVES: Benefits of adopting restrictive guidelines for erythrocyte transfusions are still controversial. The objective of this study was to verify if a very strict guideline could reduce erythrocyte transfusions in preterm infants without adverse outcomes. MATERIALS AND METHODS: Two prospective cohorts of neonates with gestational age < 37 weeks and birth weight < 1500 g were studied. Neonates born in Period 1 were submitted to a strict guideline for erythrocyte transfusions. In Period 2, a new stricter protocol was introduced. Infants of both periods were compared regarding number of transfusions and clinical outcome. RESULTS: The median number of transfusions decreased from 2 (1 to 14) in Period 1 to 1 (1-9), P = 0.001, in Period 2. The linear regression multivariate analysis showed that the implementation of the stricter guideline was associated with a reduction in the number of transfusions received by patients by 0.55 (95% confidence interval: -0.08; -1.02) units/patients. Number of apnea episodes, weight at 28 days of life and days of hospital stay were similar in both periods. Intra-hospital death was lower in Period 2. CONCLUSION: A very strict guideline reduced the number of erythrocyte transfusions in preterm infants, without threatening their clinical course.

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It is well established that interleukin-6 (IL-6) is an essential growth factor for multiple myeloma (MM) and patients with increased IL-6 levels have a poor prognosis. In healthy subjects, the presence of the C allele at a polymorphic site (-174 G/C) of the IL-6 gene is related to low IL-6 levels. In view of the potential association of this particular polymorphism with IL-6 concentration, and the relevance of IL-6 in MM pathogenesis, the objective of the present study was to investigate the prevalence of IL-6 (-174 G/C) promoter polymorphism and its association with development of MM in Brazilian individuals. We investigated the prevalence of these alleles in 52 patients and 60 healthy subjects (matched by age, sex, and race) of a Brazilian population. Thirty patients were male (42.4%), 24 (46.2%) were white and the median age at diagnosis was 58.5 years (range: 28 to 84 years). To determine the IL-6 (-174 G/C) polymorphism, molecular analysis was performed by polymerase chain reaction followed by endonuclease restriction digestion. The genotype distributions observed in the group of patients were 4% CC, 42% GC and 54% GG. The C allele frequency was 0.25. These results were similar to the control group, suggesting no impact of this polymorphism on the susceptibility to MM.

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It is well established that interleukin-6 (IL-6) is an essential growth factor for multiple myeloma (MM) and patients with increased IL-6 levels have a poor prognosis. In healthy subjects, the presence of the C allele at a polymorphic site (-174 G/C) of the IL-6 gene is related to low IL-6 levels. In view of the potential association of this particular polymorphism with IL-6 concentration, and the relevance of IL-6 in MM pathogenesis, the objective of the present study was to investigate the prevalence of IL-6 (-174 G/C) promoter polymorphism and its association with development of MM in Brazilian individuals. We investigated the prevalence of these alleles in 52 patients and 60 healthy subjects (matched by age, sex, and race) of a Brazilian population. Thirty patients were male (42.4 percent), 24 (46.2 percent) were white and the median age at diagnosis was 58.5 years (range: 28 to 84 years). To determine the IL-6 (-174 G/C) polymorphism, molecular analysis was performed by polymerase chain reaction followed by endonuclease restriction digestion. The genotype distributions observed in the group of patients were 4 percent CC, 42 percent GC and 54 percent GG. The C allele frequency was 0.25. These results were similar to the control group, suggesting no impact of this polymorphism on the susceptibility to MM.

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The goal of this research was to study the safety and the efficacy of transfusing citrate-phosphate-adenine anticoagulant-preservative (CPDA-1) RBC stored for up to 28 days to reduce donor exposures in premature infants. A prospective randomized two-group study was conducted with very low-birth-weight premature infants that received at least one RBC transfusion during hospital stay. Neonates randomly assigned to Group 1 (26 infants) were transfused with CPDA-1 RBC stored for up to 28 days; those assigned to Group 2 (26 infants) received CPDA-1 RBC stored for up to 3 days. Demographic and transfusion-related data were collected. Neonates from both groups showed similar demographics and clinical characteristics. The number of transfusions per infant transfused was 4.4 +/- 4.0 in Group 1 and 4.2 +/- 3.1 in Group 2, and the number of donors per infant transfused was 1.5 +/- 0.8 (Group 1) and 4.3 +/- 3.4 (Group 2), P < 0.001. RBC transfusions containing 29.7 +/- 18.3 mmol L(-1) of potassium (RBC stored for up to 28 days) did not cause clinical or biochemical changes and reduced donor exposures by 70.2%, compared to transfusions containing 19.8 +/- 12.3 mmol L(-1) of potassium (RBC stored for up to 3 days), P < 0.001. In conclusion, RBC stored for up to 28 days safely reduced donor exposures in premature infants.

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The biologic basis of the negative prognosis of plasmablastic myeloma is not fully understood. To determine whether histologically aggressive multiple myeloma (MM) is associated with a more angiogenic marrow environment, bone marrow samples from 50 recently diagnosed MM patients were evaluated. Twelve percent (6/50) of patients presented plasmablastic MM, and this feature correlated with moderate/strong intensity of vascular endothelial growth factor staining of plasma cells (P = 0.036). Although plasmablastic MM was not associated with increasing of microvessel density, this new evidence of increased expression of vascular endothelial growth factor on plasmablasts suggests that the adverse prognosis conferred by plasmablastic disease may be due, at least in part, to secretion of this angiogenic cytokine, also suggesting that the subset of MM patients with plasmablastic features may derive particular benefit from antiangiogenic therapies.

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The biologic basis of the negative prognosis of plasmablastic myeloma is not fully understood. To determine whether histologically aggressive multiple myeloma (MM) is associated with a more angiogenic marrow environment, bone marrow samples from 50 recently diagnosed MM patients were evaluated. Twelve percent (6/50) of patients presented plasmablastic MM, and this feature correlated with moderate/strong intensity of vascular endothelial growth factor staining of plasma cells (P = 0.036). Although plasmablastic MM was not associated with increasing of microvessel density, this new evidence of increased expression of vascular endothelial growth factor on plasmablasts suggests that the adverse prognosis conferred by plasmablastic disease may be due, at least in part, to secretion of this angiogenic cytokine, also suggesting that the subset of MM patients with plasmablastic features may derive particular benefit from antiangiogenic therapies.

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The HPA-15 (Gov) alloantigen is a biallelic co-dominant system on human platelets, and its allele HPA-15a and HPA-15b differ by an A-->C single nucleotide polymorphism at nucleotide 2108 of the coding sequence resulting in a Tyr682Ser substitution in the mature CD109 glycoprotein. Employing the polymerase chain reaction-restriction fragment length polymorphism technique, we determined the HPA-15 gene frequencies among 276 subjects of distinct Brazilian ethnic groups including, 15 Caucasians, 15 African Brazilians, 15 Orientals, 106 Amazon Xikrin Indians, 31 Amazon Gavioes Indians and 94 blood donors. The calculated HPA-15a and HPA-15b allele frequencies found in Caucasians (0.53/0.47), African Brazilians (0.57/0.43), Orientals (0.57/0.43) and Brazilian blood donors (0.52/0.48) did not differ significantly. However, the HPA-15a and HPA-15b gene frequencies of Xikrin Indians (0.78/0.22) were significantly different from that of all other groups (P < 0.01). The HPA-15a/a, HPA-15a/b and HPA-15b/b genotype frequencies observed in Gavioes Indians were significantly different from those seen in African Brazilians (P = 0.04) and blood donors (P = 0.017). The present data showed that the distribution of the HPA-15 (Gov) system alleles observed among the Brazilian population is quite similar to the distributions already reported among Asian, Canadian and European populations. Moreover, the data indicated differences in the frequency of the HPA-15 system between Amazon Indians and other distinct Brazilian ethnic groups suggesting that Amerindians would be at higher risk of HPA-15 alloimmunization in the need of receiving blood components collected from blood donors of other ethnic groups.

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Primary bone lymphoma (PBL) is a rare entity and comprises about 5% of all extranodal non-Hodgkin's lymphomas (NHL) and 7% of all primary bone tumors. To date there is no consensus about the optimal treatment for PBL. We retrospectively reviewed all cases of PBL treated at Hospital São Paulo, Brazil, over a 10-year-period (January 1992-January 2002). Medical records of 7 patients with PBL were reviewed and information on age at diagnosis, sex, NHL clinical staging (CS), treatment and response to treatment were retrieved. Five patients (72%) received combined-modality therapy (CMT) and all of them are in complete remission (CR) with a median follow up of 19 months (ranging from 12 to 144 months). We conclude that PBL is a potentially curable malignancy and treatment should be undertaken in a multiprofessional approach, in order to provide the best support which probably has to include chemotherapy, radiotherapy and, for patients with IPI higher than 2, consolidation with stem-cell transplantation.

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Intracranial haemorrhage (ICH) is a common cause of morbidity and mortality in haemophilic patients. The overall incidence of ICH has been reported to range from 2.2% to 7.5% in patients with haemophilia. From 1987 to 2001, 401 haemophilic patients from the Serviço de Hemofilia, Disciplina de Hematologia e Hemoterapia, Universidade Federal de São Paulo were evaluated. The episodes of ICH were documented by CT scan and the anatomic location, clinical presentation, relationship to trauma and clinical factors, including the presence of HIV infection and the presence of inhibitor, were reviewed. Among 401 haemophilic patients, 45 ICH episodes in 35 (8.7%) patients with age ranging from 4 days to 49 years (mean 10.6 years) were observed. A history of recent trauma was documented in 24 (53.3%) cases. Seventeen (37.8%) episodes occurred in more than one site of bleeding, 12 (26.7%) were subdural, seven (15.5%) subarachnoid, four (8.9%) epidural, two (4.4%) intracerebral and one (2.2%) intraventricular. The most frequent symptoms were headache and drowsiness. All patients were submitted to replacement therapy and neurosurgical intervention was performed in eight (17.8%) patients. Despite the treatment, three (8.6%) haemophilia A patients died due to the ICH event and three presented late sequelae. The most important aspect of ICH management is the early replacement therapy in haemophilic patients. This prompt treatment will increase the chances of a better prognosis. Another impact measure consists in the administration of the deficient coagulation factor after every head trauma, even when considered minor.

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BACKGROUND AND OBJECTIVES: Immunophenotyping is an essential method for diagnosis and classification of acute myeloid leukemias (AML), and its extensive use could identify blast cell subpopulations with aberrant phenotypes rarely seen in normal myelopoiesis. The aberrant phenotypes have been correlated with clinical, morphological and prognostic features but their occurrence in AML differs in the various studies. DESIGN AND METHODS: In this study, we analyzed 35 cases of AML, examining them for aberrant phenotypes by multiparametric flow cytometry. Co-expression of lymphoid-associated markers in myeloblasts and asynchronous antigen expression were correlated with clinical features. RESULTS: Aberrant phenotypes were found in 88.6% of the cases studied. In this group, cross-lineage antigen expression was present in 34.3% and asynchronous expression in 82.4% of the cases. CD7 was the most frequent lymphoid-associated antigen. Among the cases of asynchronous antigen expression, the most frequent phenotype was CD117(+) and/or CD34(+) in association with CD11c(+), followed by CD15(+) and CD65(+), corresponding to 67.6%, 61.7 and 50.0% of the cases, respectively. Twenty out of 33 patients were available for complete remission assessment. The CD117(+) CD15(+) phenotype correlated significantly with complete remission achievement and with the lack of unfavorable chromosome associations. INTERPRETATION AND CONCLUSIONS: We conclude that aberrant phenotypes, as they are described here, are present in the great majority of cases of AML, asynchronous antigen expression being the most frequent example; and that CD117(+) CD15(+) phenotype shows a relevant association with clinical prognosis.

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BACKGROUND: The FcgammaRIIA gene is expressed in two polymorphic forms, R131 and H131, which differ by the replacement of histidine by arginine at position 131. The FCGR3B (FcgammaRIIIB) gene exists in two allelic isoforms, known as FCGR3B1 (FcgammaRIIIB-NA1) and FCGR3B2 (FcgammaRIIIB-NA2), which differ in nucleotides 141, 147, 227, 277, and 349. An additional polymorphism is the SH antigen that is associated with the FCGR3B3 (FcgammaRIIIB-SH) allele. STUDY DESIGN AND METHODS: By use of a PCR with allele-specific primers, the allelic polymorphisms of FcgammaRIIA and FcgammaRIIIB were determined among 263 unrelated Brazilian subjects, including Amazon Indians (n = 92), blood donors (n = 85), and patients with sickle cell disease (SCD) (n = 86). RESULTS: Amazon Indians had a significantly higher frequency of the R131 allele than did blood donors and SCD patients (0.91 vs. 0.55 vs. 0.55; p<0.001). NA1 and NA2 gene frequencies were found to be 0.67 and 0.21 for Amazon Indians, 0.58 and 0.42 for blood donors, and 0.61 and 0.39 for SCD patients, respectively. The FcgammaRIIIB-SH allele was absent from the Amazon Indians, but 9 (10.6%) blood donors and 10 (11.6%) SCD patients expressed this allele. CONCLUSION: Overall, the data indicate that the distribution of the FcgammaRIIIB alleles is significantly different in Amazon Indians from the distribution in Brazilian blood donors or African Brazilian patients with SCD, but that it is similar to the distributions reported in Asian populations. Moreover, the distribution of the FcgammaRIIA and FcgammaRIIIB alleles among Brazilian blood donors and SCD patients is comparable to the distributions reported in whites from the United States and Europe.

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