Red blood cell alloimmunization is influenced by recipient inflammatory state at time of transfusion in patients with sickle cell disease

Sickle cell disease (SCD) patients are at increased risk of red blood cell (RBC) alloimmunization. Recipient inflammatory state at time of transfusion has been shown to regulate alloimmunization in murine models, but evidence is lacking in SCD patients. We retrospectively studied a cohort of alloimmunized SCD patients to determine the influence of pro‐inflammatory SCD‐related complications at time of transfusion on alloimmunization. For each transfusion, the presence of pro‐inflammatory state, degree of RBC antigen matching, unit age, storage solution and alloantibody detection date were ascertained. Transfusion‐associated pro‐inflammatory events were compared between transfusions resulting and not resulting in new alloantibodies. Univariate analysis and multivariate logistic regression were performed. Fifty‐two patients received 3166 pre‐storage leuco‐reduced transfusions of which 128 resulted in alloantibodies. Transfusions during inflammatory events were associated with increased alloantibody risk on univariate and multivariate analysis; acute chest syndrome and vaso‐occlusive crisis showed strongest associations with alloimmunization. Increased antigen matching demonstrated a protective effect on alloimmunization (univariate and multivariate analysis). Although an association was seen between citrate‐phosphate‐dextrose (adenine) stored units and alloimmunization on univariate analysis, no effect was found on multivariate analysis. Identifying recipient pro‐inflammatory states at time of transfusion that promote alloimmunization can impact RBC unit selection decisions for SCD patients at risk for alloimmunization.     

Alloimmunization is associated with older age of transfused red blood cells in sickle cell disease

Red blood cell (RBC) alloimmunization is a significant clinical complication of sickle cell disease (SCD). It can lead to difficulty with cross‐matching for future transfusions and may sometimes trigger life‐threatening delayed hemolytic transfusion reactions. We conducted a retrospective study to explore the association of clinical complications and age of RBC with alloimmunization in patients with SCD followed at a single institution from 2005 to 2012. One hundred and sixty six patients with a total of 488 RBC transfusions were evaluated. Nineteen patients (11%) developed new alloantibodies following blood transfusions during the period of review. The median age of RBC units was 20 days (interquartile range: 14–27 days). RBC antibody formation was significantly associated with the age of RBC units (P = 0.002), with a hazard ratio of 3.5 (95% CI: 1.71–7.11) for a RBC unit that was 7 days old and 9.8 (95% CI: 2.66–35.97) for a unit that was 35 days old, 28 days after the blood transfusion. No association was observed between RBC alloimmunization and acute vaso‐occlusive complications. Although increased echocardiography‐derived tricuspid regurgitant jet velocity (TRV) was associated with the presence of RBC alloantibodies (P = 0.02), TRV was not significantly associated with alloimmunization when adjusted for patient age and number of transfused RBC units. Our study suggests that RBC antibody formation is significantly associated with older age of RBCs at the time of transfusion. Prospective studies in patients with SCD are required to confirm this finding. Am. J. Hematol. 90:691–695, 2015. © 2015 Wiley Periodicals, Inc.     

Prevalence and risk factors for red blood cell alloimmunization in 175 children with sickle cell disease in a French university hospital reference centre

Patients with sickle cell disease (SCD) show a high prevalence of red blood cell (RBC) alloimmunization, but few studies have focused on children. We aimed to study the prevalence and risk factors of RBC alloimmunization in SCD children. We retrospectively analysed the medical and transfusion files for 245 SCD children hospitalized in our centre in 2014 and included 175 patients who had received at least one RBC unit in their lifetime. The main clinical and immuno‐haematological characteristics of alloimmunized and non‐alloimmunized patients were compared. The prevalence of alloimmunization was 13·7% [95% confidence interval (CI) (8·6–18·6)], and 7·4% [95% CI (3·5–11·3)] after excluding the probable irregular natural antibodies (anti‐M, anti‐Le^a, anti‐Le^b, anti‐Le^x). Main risk factors for alloimmunization were increased number of RBC units received (median of 65 vs. 10 units per patient; P = 0·01) and the presence of one or more red cell autoantibodies (46·2% vs. 4·7%; P < 0·0001). The alloimmunization rate was higher for episodically transfused than chronically transfused patients (1·43 vs. 0·24/100 units received; P < 0·001). The presence of red cell autoantibodies appears to be a major risk factor for alloimmunization in SCD children and could justify specific transfusion guidelines.     

Immunophenotypic parameters and RBC alloimmunization in children with sickle cell disease on chronic transfusion

Alloimmunization against red blood cell (RBC) antigens is a cause of morbidity and mortality in transfused patients with sickle cell disease (SCD). To investigate distinguishing characteristics of patients who develop RBC alloantibodies after transfusion (responders) versus those who do not (non‐responders), a cross‐sectional study of 90 children with SCD on chronic RBC transfusion therapy at a single institution was conducted in which 18 immune parameters (including T and B cell subsets) were tested via flow cytometry, and medical records were reviewed. RBC alloimmunization was present in 26/90 (29%) patients, with anti‐E, K, and C among the most commonly detected alloantibodies despite prophylactic matching for these antigens at the study institution. In addition, RBC autoantibodies had been detected in 18/26 (69%) of alloimmunized versus 7/64 (11%) of non‐alloimmunized patients (P < 0.0001). Alloimmunized patients were significantly older (median 13.0 years vs. 10.7 years, P = 0.010) and had more RBC unit exposures (median 148 U vs. 82 U, P = 0.020) than non‐alloimmunized patients. Sex, age at initiation of chronic transfusion, splenectomy, stroke, and transfusion outside of the study institution were not significantly associated with RBC alloimmunization. Alloimmunized patients had a significantly increased percentage of CD4+ T memory cells compared to non‐alloimmunized patients (57% vs. 49%, P = 0.0047), with no other significant differences in immune cell subsets or laboratory values detected between these groups. Additional research of RBC alloimmunization is needed to optimize transfusion therapy and to develop strategies to prevent alloimmunization. Am. J. Hematol. 90:1135–1141, 2015. © 2015 Wiley Periodicals, Inc.     

Alloimmunization to platelets in heavily transfused patients with sickle cell disease

Bone marrow transplantation (BMT) is now an option for some patients with sickle cell disease (SCD). Many SCD patients are multiply transfused with red blood cells (RBCs), and may be immunized to alloantigens other than erythrocyte antigens. Because platelet refractoriness is a significant complication during BMT, we wished to determine the prevalence of alloimmunization to platelets in transfused SCD patients. Sera collected from 47 transfused and 14 untransfused SCD patients were screened for HLA and platelet-specific antibodies. Transfusion and RBC antibody histories were reviewed. A subset of the patients were rescreened 1 year later. Eighty-five percent of patients with at least 50 RBC transfusions (22 of 26), 48% of patients with less than 50 transfusions (10 of 21), and none of 14 untransfused patients demonstrated platelet alloimmunization (P < .05). Platelet alloimmunization was more prevalent than RBC alloimmunization (20% to 30%). Half of the platelet reactivity was chloroquine-elutable. Eighteen of 22 patients (82%) on chronic RBC transfusion remained platelet-alloimmunized 11 to 22 months after initial testing. In summary, 85% of heavily transfused SCD patients are alloimmunized to HLA and/or platelet-specific antigens. These patients may be refractory to platelet transfusion, a condition that would increase their risk during BMT. Leukodepletion in the transfusion support of SCD patients should be considered to prevent platelet alloimmunization.     

Red blood cell transfusions are associated with HLA class I but not H‐Y alloantibodies in children with sickle cell disease

Blood transfusions can induce alloantibodies to antigens on red blood cells (RBCs), white blood cells and platelets, with these alloantibodies affecting transfusion and transplantation. While transfusion‐related alloimmunization against RBC antigens and human leucocyte antigens (HLA) have been studied, transfusion‐related alloimmunization to minor histocompatibility antigens (mHA), such as H‐Y antigens, has not been clinically characterized. We conducted a cross‐sectional study of 114 children with sickle cell disease (SCD) and tested for antibodies to 5 H‐Y antigens and to HLA class I and class II. Few patients had H‐Y antibodies, with no significant differences in the prevalence of any H‐Y antibody observed among transfused females (7%), transfused males (6%) and never transfused females (4%). In contrast, HLA class I, but not HLA class II, antibodies were more prevalent among transfused than never transfused patients (class I: 33% vs. 13%, P = 0·046; class II: 7% vs. 8%, P = 0·67). Among transfused patients, RBC alloantibody history but not amount of transfusion exposure was associated with a high (>25%) HLA class I panel reactive antibody (Odds ratio 6·8, 95% confidence interval 2·1–22·3). These results are consistent with immunological responder and non‐responder phenotypes, wherein a subset of patients with SCD may be at higher risk for transfusion‐related alloimmunization.     

Early occurrence of red blood cell alloimmunization in patients with sickle cell disease

Red blood cell (RBC) alloimmunization is a major complication of transfusion therapy in sickle cell disease (SCD). Identification of high‐risk patients is hampered by lack of studies that take the cumulative transfusion exposure into account. In this retrospective cohort study among previously non‐transfused SCD patients in the Netherlands, we aimed to elucidate the association between the cumulative transfusion exposure, first alloimmunization and independent risk factors. A total of 245 patients received 11 952 RBC units. Alloimmunization occurred in 43 patients (18%), half of them formed their first alloantibody before the 8th unit. In patients with exposure to non‐extended matched transfusions (ABO and RhD) the cumulative alloimmunization risk increased up to 35% after 60 transfused units. This was significantly higher compared to a general transfused population (HR 6.6, CI 4.2–10.6). Receiving the first transfusion after the age of 5 was an independent risk factor for alloimmunization (HR 2.3, CI 1.0–5.1). Incidental, episodic transfusions in comparison to chronic scheme transfusions (HR 2.3, CI 0.9–6.0), and exposure to non‐extended matched units in comparison to extended matching (HR 2.0, CI 0.9–4.6) seemed to confer a higher alloimmunization risk. The majority of first alloantibodies are formed after minor transfusion exposure, substantiating suggestions of a responder phenotype in SCD and stressing the need for risk factor identification. In this study, older age at first transfusion, episodic transfusions and non‐extended matched transfusions appeared to be risk factors for alloimmunization. Am. J. Hematol. 91:763–769, 2016. © 2017 Wiley Periodicals, Inc.     

Red blood cell alloimmunization in sickle cell disease: The influence of racial and antigenic pattern differences between donors and recipients in Brazil

Red blood cell (RBC) transfusions are widely used in the management of patients with sickle cell disease (SCD). However, repeated RBC transfusions are often complicated by RBC alloimmunization. To investigate whether the frequency of RBC alloimmunization could be accounted for by racial and RBC phenotype differences between donors and recipients in Brazil, in this study we compared the RBC phenotype of 100 SCD patients with that observed in 120 randomly selected blood donors. A comparison of the RBC phenotype between the two groups revealed a statistically significant increase in the frequency of the C antigen in the donor population (P < 0.01), but no significant difference was observed for the A, B, D, c, E, e, K, k, Fy^a, M, N, S, s, and Jk^a antigens. Using standard techniques (indirect antiglobulin test, enzyme treatment, and low-ionic-strength solution) we observed an RBC alloimmunization rate of 12.9% (11/85) in the SCD patients. Fifteen alloantibodies were detected in 11 patients, and most (80%) involved antigens in the Rhesus and Kell systems. This observed RBC alloimmunization rate in SCD patients in Brazil is lower than that reported by studies from North America, suggesting that the requirement for extended antigen-matched RBC transfusion for SCD patients in the setting of a RBC phenotype concordant donor-recipient population may not be cost-effective in some countries. © 1996 Wiley-Liss, Inc.     

Glucose‐6‐phosphate‐dehydrogenase deficient red blood cell units are associated with decreased posttransfusion red blood cell survival in children with sickle cell disease

Chronic transfusion therapy (CTT) for sickle cell disease (SCD) reduces disease morbidity by suppressing the amount of circulating hemoglobin S (HbS)‐containing red blood cells (RBC). The effectiveness of CTT depends on the rate of RBC clearance. Glucose‐6‐phosphate dehydrogenase (G6PD) deficient donor RBC may exhibit increased hemolysis, but it is unknown if transfusion of these units results in less effective transfusion outcomes in SCD. Children with SCD on CTT were followed prospectively for multiple transfusions. G6PD activity of transfused units was measured prior to expiration date. HbA clearance (ΔHbA) was calculated as the difference of estimated posttransfusion HbA to the pretransfusion HbA of the subsequent transfusion episode. Sixty‐two patients received 388 transfusions. Of 755 RBC units, 687 (91%) had normal G6PD (>60% activity), 38 (5%) had moderately low G6PD (10‐60% activity), and 30 (4%) had severely low G6PD (<10% activity). Of 358 evaluable transfusions, 54 (15%) included ≥1 G6PD deficient units, and 22 (6%) had ≥1 severely deficient units. The proportion of the transfusion episode consisting of G6PD deficient units was associated with increased ΔHbA for all G6PD deficient units (P = .05) and for severely G6PD deficient units (P = .0070). In multivariate mixed effects modeling, ΔHbA was positively associated with severely G6PD deficient units (P = .0074) and RBC alloimmunization (P = .03) and negatively associated with recipient splenectomy (P = .015). Higher ΔHbA was associated with higher HbS and reticulocyte counts at the subsequent transfusion episode. In conclusion, G6PD deficient RBC transfusions may have shorter in vivo survival and adversely affect the suppression of sickle erythropoiesis.     

Prevalence and specificities of red blood cell alloantibodies in transfused Ugandans with different diseases

Background and Objectives Alloantibody formation against red blood cell (RBC) antigens is a common complication of transfusion therapy. However, the prevalence of RBC alloimmunization is hardly known in Black Africans. In Uganda, the practice is to transfuse ABO/D compatible blood without screening for immune antibodies. The aim of this study was to determine the prevalence and specificities of RBC alloantibodies in transfused Ugandans. Materials and Methods Using a cross‐sectional design, transfused patients at Mulago Hospital in Kampala, Uganda were investigated. Demographic characteristics and transfusion histories were recorded. EDTA blood samples were obtained from consenting patients and RBC alloimmunization was demonstrated using immunohaematological tests. Results A total of 214 transfused patients (mean age, 30·3 years; F/M ratio, 1·0) were investigated. Thirteen patients (6·1%) possessed RBC alloantibodies whose specificities were six anti‐E; three anti‐S; one each of anti‐D, ‐K and ‐Le^a; and two samples were pan‐reactive. Eleven (84·6%) of the alloimmunized patients had experienced up to 10 transfusion episodes. The number of units of blood transfused and the transfusion episodes were significantly associated with the RBC alloimmunization rate (P = 0·01). Conclusions The prevalence of RBC alloimmunization in transfused Ugandans was 6·1% and was associated with the number of donor exposures. This immunization rate is similar to that observed in transfused Caucasians despite differences in RBC antigen distributions. Patients with malaria were less likely to develop RBC alloantibodies. Alloantibodies were mainly against E and S antigens. We recommend the introduction of pretransfusion antibody tests in Uganda depending on the recipient’s diagnosis.     

Prevalence and clinical significances of red cell alloimmunization and red cell bound immunoglobulin G in polytransfused patients with thalassemias

The study was to determine the prevalence and clinical significances of red blood cell (RBC)-bound IgG as detected by flow cytometry in polytransfused patients with thalassemias. Relationship of the presence of RBC-bound IgG with RBC alloimmunization was also evaluated. This study included 59 polytransfused patients with β-thalassemia disease. We studied the frequency of RBC autoantibodies and alloimmunization. Direct Coombs test and flow cytometry were performed to detect the presence of RBC autoantibodies while RBC alloantibodies were detected by antibody screening and identification assays.

Eight (13.6%) and 34 (57.6%) patients were found a positive direct Coombs test and flow cytometry, respectively. Twenty (33.9%) patients developed RBC alloantibodies. The four most frequent RBC alloantibodies were anti-E (55%), anti-Mia (40%), anti-Di(a) (25%) and anti-c (15%), respectively. There was no significant difference in the presence of RBC-bound IgG between polytransfused with thalassemia patients who developed RBC alloimmunization (13 of 20; 65%) and those without RBC alloantibodies (21 of 39; 53.8%), p?=?0.412. Splenectomy and increased transfusion requirement were significantly associated with the presence of RBC-bound IgG but not with RBC alloantibody formation.

The overall frequency of RBC alloantibody formation in polytransfused patients with thalassemias was 33.9%. The most common RBC alloantibody was anti-E. RBC autoantibody formation was more frequently detected by flow cytometry (57.6%) than by direct Coombs test (13.6%). Splenectomy was significantly associated with the development of autoreactive RBC-bound IgG antibodies in the polytransfused patients with thalassemias. The presence of the anti-RBC autoantibodies may cause an increase of transfusion requirement.     

Partial dysfunction of Treg activation in sickle cell disease

Sickle cell disease (SCD) is a chronic inflammatory disease associated with multiple organ damage, chronic anemia, and infections. SCD patients have a high rate of alloimmunization against red blood cells (RBCs) following transfusion and may develop autoimmune diseases. Studies in mouse models have suggested that regulatory T cells (Treg) play a role in alloimmunization against RBC antigens. We characterized the phenotype and function of the Treg cell population in a homogeneous cohort of transfused SCD patients. We found that the distribution of Treg subpopulations differed significantly between SCD patients and healthy blood donors. SCD patients have a particular Treg phenotype, with strong CTLA‐4 and CD39 expression and weak HLA‐DR and CCR7 expression. Finally, we show that this particular phenotype is related to SCD rather than alloimmunization status. Indeed, we observed no difference in Treg phenotype or function in vitro using autologous feeder cells between strong and weak responders to alloimmunization. Am. J. Hematol. 89:261–266, 2014. © 2013 Wiley Periodicals, Inc.     

Red‐blood‐cell alloimmunization and female sex predict the presence of HLA antibodies in patients undergoing liver transplant

Background Refractoriness to platelet transfusion because of HLA antibodies can jeopardize the outcome of patients who require platelet support during surgery. As routine screening for HLA antibodies would pose a huge burden on presurgical work‐ups, a stratification of patients according to the risk of having HLA antibodies is warranted. Study design and methods Clinical and laboratory data from 1351 patients submitted to liver transplant were analyzed to determine the accuracy of RBC alloimmunization and other patient features to predict the concomitant presence of HLA antibodies. Predictive variables were selected through binary logistic regression and their accuracy to prognosticate HLA alloimmunization was calculated by contingent table methods. Results RBC and HLA antibodies were detected in 70 (5·2%) and 71 (5·3%) patients, respectively. Female sex and RBC alloimmunization were the only patient features associated with HLA aloimmunization. Risk of being HLA immunized increased from male patients without RBC antibodies (n = 842; 1·5% with HLA antibodies) to female patients with RBC alloimmunization (n = 36, 36·2% with HLA antibodies), being of 9·7% in the remaining 473 patients. In women, the positive and negative predictive values of RBC alloimmunization to prognosticate HLA alloimmunization were 36% and 90%, respectively. In male patients, such values were 12% and 99%, respectively. The incidence of HLA immunization decreased after the introduction of universal leukoreduction in 2002. Conclusions RBC alloimmunized female patients that may require platelet support during liver transplant should be preoperatively evaluated for HLA antibodies. Such evaluation is unnecessary in male patients without detectable RBC antibodies. Decision‐making in the remaining patients must be individualized.     

Predictors of Red Cell Alloimmunization in Kurdish Multi Transfused Patients with Hemoglobinopathies in Iraq

Abstract

Hemoglobinopathies are significant health problems in Iraq, including its Northern Kurdistan region. One of the essential components of management of these disorders is regular lifelong blood transfusions. The latter is associated with several complications including red cell alloimmunization. No study has looked at the frequency of alloimmunization and its associations in the country. To address the latter issue, 401 multi transfused patients [311 with β-thalassemia (β-thal) syndrome and 90 with sickle cell disease], registered at a large thalassemia care center in Iraqi Kurdistan had their records reviewed, and their sera tested for atypical antibodies using screening and extended red cell panels. Red cell alloimmunization was detected in 18 patients (4.5%) with a total of 20 alloantibodies, while no autoantibodies were detected. The most frequent alloantibody was anti-E, followed by anti-D, anti-K, anti-C^w, anti-C, anti-c and anti-Le^a. Ethnicity was an important predictor of alloimmunization, while age at start of transfusion (>2 vs. ≤2 years) (p?=?0.005), Rhesus D (RhD) negative status (p?=?0.0017) and history of previous transfusion reactions (p?=?0.007) showed a statistically significant higher rate of alloimmunization. However, patients’ age, gender, number of units transfused, underlying diagnosis and splenectomy were not significantly associated with alloimmunization. Based on our observations, measures to reduce alloimmunization rates may include extended matching for Rhesus and Kell antigens and early initiation of blood transfusions.     

Red blood cell alloimmunization in sickle cell disease and in thalassaemia: current status,future perspectives and potential role of molecular typing

Red blood cell (RBC) transfusions are a milestone in the treatment for sickle cell anaemia (SSA) and for thalassaemia. RBC alloimmunization remains a major challenge of chronic transfusion therapy, and it can lead to adverse life‐threatening events. The alloimmunization risk could depend on multiple factors such as the number of transfusions and, most of all, the genetic background. Different ethnic groups are predisposed to immunization because of a significant degree of RBC antigenic mismatch between donor and recipient. There is no universal agreement and standards for the most appropriate selection of RBC units in chronically transfused subjects. Current practice only deals with compatibility of ABO, Rh and K antigens. Molecular RBC antigenic matching extended to other blood group systems is an innovative strategy to ensure a better quality and effectiveness of transfusion therapy.     

Investigation of T-cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) polymorphisms in essential thrombocythaemia (ET)

Objectives: T-cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) is preferentially expressed on terminally differentiated Th1 cells and inhibits their IFN-γ production. It has been reported that chronic inflammation may be an important driving force for myeloproliferative neoplasms (MPNs). Therefore, we hypothesized that as an important inflammation regulator, TIM-3 may be involved in essential thrombocythaemia (ET). The goal of this study was to investigate whether the ?1516G?>?T, ?574G?>?T and +4259T?>?G single-nucleotide polymorphisms (SNPs) within the TIM-3 gene contribute to the genetic susceptibility of individuals to ET.

Methods: Genotyping of the TIM-3 ?1516G?>?T, ?574G?>?T and?+?4259T?>?G SNPs was performed in 175 patients with ET and in 151 controls via a polymerase chain reaction-restriction fragment length polymorphism assay. We also investigated the relationships between the genotypes of each SNP and the risk factors of ET such as routine blood indexes, age and JAK2 V617F mutation.

Results: The genotype and allele frequencies of the ?1516G?>?T SNP (p?=?0.016 and 0.019, respectively), the ?574G?>?T SNP (p?=?0.035 and 0.038, respectively) and the +4259T?>?G SNP (p?=?0.036 and 0.038, respectively) of the ET patients and the controls were significantly different. A haplotype analysis found that the GGT and TGT haplotypes had significantly different distributions between ET and controls (p?=?0.041 and 0.041, respectively). However, no significant differences were detected between the genotypes of all SNPs and routine blood indexes, age and JAK2V617F mutation.

Conclusion: The ?1516G?>?T, ?574G?>?T and +4259T?>?G SNPs within TIM-3 gene might play an important role as a genetic risk factor in the pathogenesis of ET.     

How we treat delayed haemolytic transfusion reactions in patients with sickle cell disease

Transfusion therapy is effective in the prevention and treatment of many complications of sickle cell disease (SCD). However, its benefits must be balanced against its risks, including delayed haemolytic transfusion reactions (DHTR). Not only is the relative rate of alloimmunization higher in patients with SCD than in other patient populations, but attendant risks associated with DHTR are even greater in SCD. Clinicians' awareness of DHTR events is poor because symptoms of DHTR mimic acute vaso‐occlusive pain and immunohaematology findings are often negative. Transfusions delivered in the acute rather than elective setting appear to confer a higher risk of DHTR. Management of DHTR in SCD depends on the clinical severity, ranging from supportive care to immunosuppression, and optimization of erythropoiesis. DHTR must be considered in any recently transfused patient presenting with acute sickle cell pain. Meticulous documentation of transfusion and immunohaematology history is key. We anticipate an increase in DHTR events in SCD patients with the increasing use of red blood cell transfusion therapy.     

Stochastic modeling of human RBC alloimmunization: evidence for a distinct population of immunologic responders

Red blood cell (RBC) transfusion is unique as a common large-scale intravenous introduction of foreign tissue and provides a valuable opportunity to study human immunologic response to intravenous foreign antigen. Patients receiving RBC transfusions are at risk of forming alloantibodies against donor RBC antigens, and valid estimates of alloimmunization risk are clinically important, but little is known about the factors governing this risk or, more generally, about determinants of human response to intravenous antigen. Here, we mine large electronic patient databases enabling us to model RBC alloimmunization as a stochastic process. We identify a subgroup of transfusion recipients that has a dramatically increased risk of alloimmunization that appears to be genetically determined because it is independent of common disease states, patient age, or the number of alloantibodies already formed, and only weakly dependent on transfusion count.     

The contribution of CYP2C gene subfamily involved in epoxygenase pathway of arachidonic acids metabolism to hypertension susceptibility in Russian population

Numerous studies demonstrated an importance of cytochrome P-450 epoxygenase pathway of arachidonic acids metabolism for the pathogenesis of essential hypertension (EH). The present study was designed to investigate whether common single-nucleotide polymorphisms (SNP) of CYP2C gene subfamily such as CYP2C8 (rs7909236 and rs1934953), CYP2C9 (rs9332242), and CYP2C19 (rs4244285) are associated with susceptibility to EH in Russian population. A total of 816 unrelated Russian individuals comprising 425 EH patients and 391 normotensive controls were included into the study. Genotyping of SNPs was performed using the MassARRAY 4 system. SNP rs7909236 of CYP2C8 was significantly associated with increased risk of EH (OR adjusted for sex and age was 2.99 95% CI 1.39-6.44, P = 0.005). SNPs rs1934953 CYP2C8 and rs4244285 of CYP2C19 showed association with EH risk but at a borderline statistical significance (P ≤ 0.04). Combination of genotypes CYP2C8 rs7909236 TT and CYP2C19 rs4244285 GG was associated with increased EH risk (OR 3.34 95%CI 1.48-7.51, P = 0.004). Genotype–phenotype correlation analysis showed that the levels of CYP2C8 mRNA were significantly correlated with SNP rs7909236 (P = 0.01). in silico functional prediction analysis revealed the functionality of majority of investigated SNPs. Thus, genes of CYP2C subfamily are important genetic determinants of susceptibility to essential hypertension in Russians.