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1.
Br J Haematol ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31674662

RESUMO

The relevance of donor-specific human leukocyte antigen (HLA) antibodies in HLA-mismatched haematopoietic cell transplant (HCT) is known, but the importance of HLA antibodies in HLA-matched HCT is unclear. We hypothesized that HLA antibodies detected before HCT would cause platelet transfusion refractoriness during HCT and investigated this in a multi-centre study. Pre-HCT samples from 45 paediatric patients with sickle cell disease (SCD) undergoing HLA-matched HCT were tested for HLA class I antibodies. The number of platelet transfusions received before day +45 was compared between those with and without antibodies. Thirteen of 45 (29%) patients had a positive HLA class I antibody screen, and these patients received significantly more platelet transfusions than patients without antibodies (median 19 vs. 7·5, P = 0·028). This platelet transfusion association remained significant when controlling for conditioning regimen. Among alloimmunized patients, there was no association between the panel-reactive antibody and the number of platelet transfusions. Patients with HLA class I antibodies also had a higher incidence of acute graft-versus-host disease (GVHD): 6/13 (46%) vs. 3/32 (9%), P = 0·011. Pre-HCT HLA class I alloimmunization is associated with increased platelet transfusion support and acute GVHD in paediatric HLA-matched HCT for SCD. Further studies are needed to investigate the pathobiology of this association.

2.
Crit Care Med ; 47(12): 1766-1772, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31567407

RESUMO

OBJECTIVE: Although bleeding frequently occurs in critical illness, no published definition to date describes the severity of bleeding accurately in critically ill children. We sought to develop diagnostic criteria for bleeding severity in critically ill children. DESIGN: Delphi consensus process of multidisciplinary experts in bleeding/hemostasis in critically ill children, followed by prospective cohort study to test internal validity. SETTING: PICU. PATIENTS: Children at risk of bleeding in PICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-four physicians worldwide (10 on a steering committee and 14 on an expert committee) from disciplines related to bleeding participated in development of a definition for clinically relevant bleeding. A provisional definition was created from 35 descriptors of bleeding. Using a modified online Delphi process and conference calls, the final definition resulted after seven rounds of voting. The Bleeding Assessment Scale in Critically Ill Children definition categorizes bleeding into severe, moderate, and minimal, using organ dysfunction, proportional changes in vital signs, anemia, and quantifiable bleeding. The criteria do not include treatments such as red cell transfusion or surgical interventions performed in response to the bleed. The definition was prospectively applied to 40 critically ill children with 46 distinct bleeding episodes. The kappa statistic between the two observers was 0.74 (95% CI, 0.57-0.91) representing substantial inter-rater reliability. CONCLUSIONS: The Bleeding Assessment Scale in Critically Ill Children definition of clinically relevant bleeding severity is the first physician-driven definition applicable for bleeding in critically ill children derived via international expert consensus. The Bleeding Assessment Scale in Critically Ill Children definition includes clear criteria for bleeding severity in critically ill children. We anticipate that it will facilitate clinical communication among pediatric intensivists pertaining to bleeding and serve in the design of future epidemiologic studies if it is validated with patient outcomes.

3.
Hematol Oncol Clin North Am ; 33(3): 507-520, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31030816

RESUMO

Blood transfusions are frequently lifesaving, but there is growing awareness of their associated infectious and noninfectious adverse events. Patient blood management advocates for judicious use of transfusions and considerations of alternatives to correct anemia or achieve hemostasis. Several transfusion practices, either already implemented or under investigation, aim to further improve the safety of transfusions. An enduring challenge in pediatric and neonatal transfusion practice is that studies typically focus on adults, and findings are extrapolated to younger patients. This article aims to summarize some of the newer developments in transfusion medicine with a focus on the neonatal and pediatric population.

4.
Transfusion ; 58(11): 2564-2571, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30265742

RESUMO

BACKGROUND: Hemolysis is a reported side effect of intravenous immunoglobulin (IVIG) therapy in adults, but pediatric data are scarce. We determined the frequency of IVIG-associated hemolysis in patients with Kawasaki disease (KD) and characterized risk factors for hemolysis. We hypothesized that hemolysis is more common in children with KD than adults with other disorders, and hemolysis risk is related to IVIG dose and degree of inflammation. STUDY DESIGN AND METHODS: This was an 8-year, single-center, retrospective cohort study. A total of 419 KD patients were identified; 123 had pre- and post-treatment complete blood counts allowing for assessment of anemia. Hemolytic anemia was defined as decrease in hemoglobin after IVIG greater than 1 g/dL with immunohematologic or biochemical studies supporting hemolysis. RESULTS: 123 patients were stratified as having hemolysis (n = 18, 15%) or nonhemolysis (n = 105, 85%). Patients with hemolysis were more likely to have complete versus incomplete KD (65% vs. 39%, p = 0.04) and refractory versus nonrefractory course (78% vs. 16%, p < 0.001). Patients receiving 4 g/kg versus 2 g/kg IVIG were more likely to hemolyze (89% vs. 34%, p < 0.001). Patients with hemolysis had mostly non-O blood group (94%), positive direct antiglobulin tests (89%), and positive eluates (72%). Two-thirds of patients with hemolysis required RBC transfusion. CONCLUSIONS: Hemolysis occurred in 15% of KD patients evaluated for anemia and is strongly associated with high-dose (4 g/kg) IVIG. KD patients receiving high-dose IVIG should have close hematologic monitoring to identify hemolysis.


Assuntos
Anemia Hemolítica/etiologia , Imunoglobulinas Intravenosas/efeitos adversos , Imunoglobulinas Intravenosas/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Pré-Escolar , Feminino , Hemólise , Humanos , Masculino , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , Estudos Retrospectivos
5.
Pediatr Crit Care Med ; 19(9): 884-898, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30180125

RESUMO

OBJECTIVES: To date, there are no published guidelines to direct RBC transfusion decision-making specifically for critically ill children. We present the recommendations from the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. DESIGN: Consensus conference series of multidisciplinary, international experts in RBC transfusion management of critically ill children. SETTING: Not applicable. INTERVENTION: None. SUBJECTS: Children with, or children at risk for, critical illness who receive or are at risk for receiving a RBC transfusion. METHODS: A panel of 38 content and four methodology experts met over the course of 2 years to develop evidence-based, and when evidence lacking, expert consensus-based recommendations regarding decision-making for RBC transfusion management and research priorities for transfusion in critically ill children. The experts focused on nine specific populations of critically ill children: general, respiratory failure, nonhemorrhagic shock, nonlife-threatening bleeding or hemorrhagic shock, acute brain injury, acquired/congenital heart disease, sickle cell/oncology/transplant, extracorporeal membrane oxygenation/ventricular assist/ renal replacement support, and alternative processing. Data to formulate evidence-based and expert consensus recommendations were selected based on searches of PubMed, EMBASE, and Cochrane Library from 1980 to May 2017. Agreement was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. MEASUREMENTS AND RESULTS: The Transfusion and Anemia Expertise Initiative consensus conference developed and reached consensus on a total of 102 recommendations (57 clinical [20 evidence based, 37 expert consensus], 45 research recommendations). All final recommendations met agreement, defined a priori as greater than 80%. A decision tree to aid clinicians was created based on the clinical recommendations. CONCLUSIONS: The Transfusion and Anemia Expertise Initiative recommendations provide important clinical guidance and applicable tools to avoid unnecessary RBC transfusions. Research recommendations identify areas of focus for future investigation to improve outcomes and safety for RBC transfusion.


Assuntos
Estado Terminal/terapia , Transfusão de Eritrócitos/normas , Adolescente , Criança , Pré-Escolar , Consenso , Transfusão de Eritrócitos/métodos , Humanos , Lactente , Recém-Nascido
6.
Pediatr Crit Care Med ; 19(9S Suppl 1): S149-S156, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30161070

RESUMO

OBJECTIVES: To present the recommendations and supporting evidence for RBC transfusions in critically ill children with hematologic and oncologic disease from the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. DESIGN: Consensus conference series of international, multidisciplinary experts in RBC transfusion management of critically ill children. METHODS: The panel of 38 experts developed evidence-based and, when evidence was lacking, expert-based clinical recommendations and research priorities for RBC transfusions in critically ill children. The hematologic/oncologic subgroup included seven experts. Electronic searches were conducted using PubMed, EMBASE, and Cochrane Library databases from 1980 to May 2017. Agreement was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. RESULTS: The hematologic/oncologic subgroup developed 14 recommendations (seven clinical, seven research); all achieved greater than 80% agreement. In patients with sickle cell disease, Transfusion and Anemia Expertise Initiative recommends: 1) RBC transfusion to achieve a target hemoglobin concentration of 10 g/dL rather than hemoglobin of less than 30% prior to surgical procedures requiring general anesthesia and 2) exchange transfusion over simple (nonexchange) transfusion if the child's condition is deteriorating (based on clinical judgment), otherwise a simple, nonexchange RBC transfusion is recommended. There is insufficient evidence to make recommendations on transfusion thresholds for patients with sickle cell disease prior to minor procedures, with acute stroke or with pulmonary hypertension. For patients with oncologic disease or undergoing hematopoietic stem cell transplant, a hemoglobin concentration of 7-8 g/dL is recommended. Due to lack of evidence, research is needed to clarify the appropriate transfusion thresholds in these patients. CONCLUSIONS: Transfusion and Anemia Expertise Initiative developed specific pediatric recommendations regarding RBC transfusion management in critically ill children with sickle cell disease, oncologic disease, and hematopoietic stem cell transplant and recommendations to help guide future research priorities.


Assuntos
Anemia Hemolítica/terapia , Anemia Falciforme/terapia , Transfusão de Eritrócitos/normas , Neoplasias/terapia , Talassemia/terapia , Anemia Hemolítica/sangue , Anemia Falciforme/sangue , Criança , Cuidados Críticos/normas , Estado Terminal/terapia , Contagem de Eritrócitos/classificação , Medicina Baseada em Evidências/métodos , Humanos , Neoplasias/sangue , Transplante de Células-Tronco/efeitos adversos , Talassemia/sangue
7.
Transfusion ; 58(6): 1363-1371, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29664198

RESUMO

BACKGROUND: Chronic transfusion therapy for sickle cell anemia reduces disease complications by diluting sickle-erythrocytes with hemoglobin A (HbA)-containing erythrocytes and suppressing erythropoiesis. Minor antigen mismatches may result in alloimmunization, but it is unknown if antigen mismatches or recipient characteristics influence HbA clearance posttransfusion. STUDY DESIGN AND METHODS: Children with sickle cell anemia on chronic transfusion therapy were followed prospectively for 12 months. All patients received units serologically matched for C/c, E/e, and K; patients with prior red blood cell (RBC) antibodies had additional matching for Fya , Jkb , and any previous alloantibodies. Patients' RBC antigen genotypes, determined by multiplexed molecular assays (PreciseType Human Erythrocyte Antigen, and RHCE and RHD BeadChip, Immucor) were compared to genotypes of transfused RBC units to assess for antigen mismatches. Decline in hbA (ΔHbA) from posttransfusion to the next transfusion was calculated for each transfusion episode. RESULTS: Sixty patients received 789 transfusions, 740 with ΔHbA estimations, and 630 with donor Human Erythrocyte Antigen genotyping. In univariate mixed-model analysis, ΔHbA was higher in patients with past RBC antibodies or splenomegaly and lower in patients with splenectomy. RBC antigen mismatches were not associated with ΔHbA. In multivariate linear mixed-effects modeling, ΔHbA was associated with RBC antibodies (2.70 vs. 2.45 g/dL/28 d, p = 0.0028), splenomegaly (2.87 vs. 2.28 g/dL/28 d, p = 0.019), and negatively associated with splenectomy (2.46 vs. 2.70 g/dL/28 d, p = 0.011). CONCLUSIONS: HbA decline was increased among patients with sickle cell anemia with prior immunologic response to RBC antigens and decreased among those with prior splenectomy, demonstrating that recipient immunologic characteristics influenced the clearance of transfused RBCs.


Assuntos
Anemia Falciforme/terapia , Transfusão de Eritrócitos/métodos , Hemoglobina A/metabolismo , Criança , Hemoglobina A/análise , Humanos , Isoanticorpos/imunologia , Isoantígenos/imunologia , Esplenectomia/efeitos adversos , Esplenomegalia
8.
Am J Hematol ; 93(5): 630-634, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29377292

RESUMO

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.


Assuntos
Anemia Falciforme/sangue , Transfusão de Eritrócitos/efeitos adversos , Eritrócitos/citologia , Glucose-6-Fosfato/sangue , Deficiência de Glucosefosfato Desidrogenase/sangue , Adolescente , Preservação de Sangue , Sobrevivência Celular , Criança , Pré-Escolar , Eritrócitos/enzimologia , Eritropoese , Feminino , Hemoglobina A/análise , Humanos , Masculino , Estudos Prospectivos , Adulto Jovem
9.
Transfusion ; 57(11): 2799-2803, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28884825

RESUMO

BACKGROUND: Directed donation is associated with a higher prevalence of donations that are positive for infectious disease markers; however, little is known about the positive rates among parental-directed, non-parental-directed, and allogeneic donations. STUDY DESIGN AND METHODS: We reviewed blood-collection records from January 1997 through December 2008, including infectious disease results, among parental, non-parental, and community donations. Infectious disease rates were compared by Mann-Whitney U test. RESULTS: In total, 1532 parental, 4910 non-parental, and 17,423 community donations were examined. Among parental donors, the median rate of positive infectious disease testing was 8.66% (interquartile range (IQR), 4.49%) for first-time donors and 1.26% (IQR, 5.86%) for repeat donors; among non-parental donors, the rate was 1.09% (IQR, 0.98%) for first-time donors and 0% (IQR, 0.83%) for repeat donors; and, among community donors, the rate was 2.95% (IQR, 1.50%) for first-time donors and 0.45% (IQR, 0.82%) for repeat donors. The mean rate of positive infectious disease testing for first-time parental donors was significantly higher (7.63%), whereas all repeat donors had similar rates. However, the rate of positive infectious disease testing among first-time non-parental donors was significantly lower than that in the other groups, especially for the period from 2001 through 2008. CONCLUSION: First-time non-parental and community donors had significantly higher infectious disease risk than the respective repeat donors. First-time parental donors had the highest rates of positive infectious disease testing. We suggest that first-time parental blood donation should be discouraged. Repeat community donors or first-time non-parental donors provide a safer alternative. These findings can foster better patient education, donor selection, and possibly a reduced risk of infectious disease.


Assuntos
Doadores de Sangue , Doenças Transmissíveis/transmissão , Seleção do Doador/métodos , Reação Transfusional , Transfusão de Sangue/normas , Controle de Doenças Transmissíveis/métodos , Feminino , Humanos , Masculino , Pais , Características de Residência , Centros de Atenção Terciária
10.
Transfusion ; 57(11): 2738-2746, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28840600

RESUMO

BACKGROUND: Red blood cell (RBC) alloimmunization occurs at a high frequency in sickle cell anemia (SCA) despite serologic matching for Rh (C/c, E/e) and K antigens. RBC minor antigen genotyping allows for prediction of antigens and RH variants that may lead to alloimmunization. STUDY DESIGN AND METHODS: RBC antigen genotyping was performed on chronically transfused pediatric SCA patients, using PreciseType human erythrocyte antigen (HEA), RHCE, and RHD BeadChip arrays. All patients received C/c, E/e, and K serologically matched units (Category 1); patients with prior RBC antibodies were also matched for Fya , Jkb , and any antibodies (Category 2). The RBC genotypes of all leukoreduced (LR) units transfused over a 12-month period were determined by the prototype HEA-LR BeadChip assay. RESULTS: There were 2320 RBC units transfused to 90 patients in 1135 transfusion episodes. Thirty-five (38.9%) patients had homozygous or compound heterozygous RH variants. Seven new alloantibodies were detected, with alloantibody incidence of 0.706 in 100 units for Category 2 transfusions and 0.068 in 100 units for Category 1 (p = 0.02). Three patients on Category 2 transfusions formed new anti-Jsa and had a higher rate of exposure to Jsa than those who did not form anti-Jsa (20.4 vs. 8.33 exposures/100 units, p = 0.02). The most frequent mismatches were S (43.9%), Doa (43.9%), Fya (29.2%), M (28.4%), and Jkb (28.1%). CONCLUSIONS: Alloimmunization incidence was higher in those with prior RBC antibodies, suggesting that past immunologic responders are at higher risk for future alloimmunization and therefore may benefit from more extensive antigen matching beyond C/c, E/e, K, Fya , and Jkb .


Assuntos
Anemia Falciforme/terapia , Incompatibilidade de Grupos Sanguíneos/diagnóstico , Tipagem e Reações Cruzadas Sanguíneas/métodos , Transfusão de Eritrócitos/efeitos adversos , Eritrócitos/imunologia , Adolescente , Anemia Falciforme/sangue , Anemia Falciforme/complicações , Tipagem e Reações Cruzadas Sanguíneas/normas , Criança , Pré-Escolar , Genótipo , Humanos , Isoanticorpos/sangue
12.
Blood Adv ; 1(18): 1414-1422, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-29296782

RESUMO

RH genes are highly polymorphic and encode the most complex of the 35 human blood group systems. This genetic diversity contributes to Rh alloimmunization in patients with sickle cell anemia (SCA) and is not avoided by serologic Rh-matched red cell transfusions. Standard serologic testing does not distinguish variant Rh antigens. Single nucleotide polymorphism (SNP)-based DNA arrays detect many RHD and RHCE variants, but the number of alleles tested is limited. We explored a next-generation sequencing (NGS) approach using whole-exome sequencing (WES) in 27 Rh alloimmunized and 27 matched non-alloimmunized patients with SCA who received chronic red cell transfusions and were enrolled in a multicenter study. We demonstrate that WES provides a comprehensive RH genotype, identifies SNPs not interrogated by DNA array, and accurately determines RHD zygosity. Among this multicenter cohort, we demonstrate an association between an altered RH genotype and Rh alloimmunization: 52% of Rh immunized vs 19% of non-immunized patients expressed variant Rh without co-expression of the conventional protein. Our findings suggest that RH allele variation in patients with SCA is clinically relevant, and NGS technology can offer a comprehensive alternative to targeted SNP-based testing. This is particularly relevant as NGS data becomes more widely available and could provide the means for reducing Rh alloimmunization in children with SCA.

13.
Arch Dis Child Fetal Neonatal Ed ; 102(1): F79-F84, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27178714

RESUMO

OBJECTIVE: To develop normative ranges for citrate-modified and heparinase-modified thromboelastography (TEG) in term neonates. DESIGN: Prospective observational study. SETTING: An outborn neonatal and cardiac intensive care unit in a free-standing academic children's hospital. PATIENTS: Thirty term neonates were enrolled as control subjects. Seventeen infants with clinically documented bleeding requiring blood transfusion were enrolled in the comparison group. MAIN OUTCOME MEASURES: Citrate-modified and heparinase-modified TEG parameters were calculated from blood specimens drawn via peripheral arterial stick or arterial line. RESULTS: TEG in neonates differs from older children and adults; clotting time (R) and clot kinetics (K) values are generally lower while fibrinolysis or rate of clot breakdown (LY30) and coagulation index (CI) are often higher in neonates. TEG values in term neonates calculated as median (Q1-Q3) are as follows: R 4.150 (3.200-6.200), K 1.550 (1.200-1.800), α angle (α) 70.100 (66.000-72.900), maximum amplitude (MA) 61.850 (59.400-66.000), LY30 1.050 (0.100-1.600) and CI 1.950 (0.100 to 2.900). Cut points selected for optimal predictive value for bleeding using receiver operating curve analyses were R>6.3 (sensitivity 82.4%, specificity 80%); K>2.5 (sensitivity 82.4%, specificity 96.7%); α<59 (sensitivity 82.4%, specificity 96.7%); MA<57 (sensitivity 82.4%, specificity 86.7%); CI<-0.15 (sensitivity 88.2%, specificity 83.3%). CONCLUSIONS: The reference ranges and cut points for citrate-modified and heparinase-modified TEG can be used to diagnose and evaluate coagulopathy in term neonates.


Assuntos
Transtornos da Coagulação Sanguínea/diagnóstico , Coagulação Sanguínea , Nascimento a Termo/sangue , Tromboelastografia/métodos , Transtornos da Coagulação Sanguínea/sangue , Testes de Coagulação Sanguínea , Feminino , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Estudos Prospectivos
15.
PLoS One ; 11(4): e0153244, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27116614

RESUMO

Sickle cell anemia (SCA) is an inherited hemolytic anemia with compensatory reticulocytosis. Recent studies have shown that increased levels of reticulocytosis during infancy are associated with increased hospitalizations for SCA sequelae as well as cerebrovascular pathologies. In this study, absolute reticulocyte counts (ARC) measured prior to transfusion were analysed among a cohort of 29 pediatric SCA patients receiving chronic transfusion therapy (CTT) for primary and secondary stroke prevention. A cross-sectional flow cytometric analysis of the reticulocyte phenotype was also performed. Mean duration of CTT was 3.1 ± 2.6 years. Fifteen subjects with magnetic resonance angiography (MRA) -vasculopathy had significantly higher mean ARC prior to initiating CTT compared to 14 subjects without MRA-vasculopathy (427.6 ± 109.0 K/µl vs. 324.8 ± 109.2 K/µl, p<0.05). No significant differences in hemoglobin or percentage sickle hemoglobin (HbS) were noted between the two groups at baseline. Reticulocyte phenotyping further demonstrated that the percentages of circulating immature [CD36(+), CD71(+)] reticulocytes positively correlated with ARC in both groups. During the first year of CTT, neither group had significant reductions in ARC. Among this group of children with SCA, cerebrovasculopathy on MRA at initiation of CTT was associated with increased reticulocytosis, which was not reduced after 12 months of transfusions.


Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/terapia , Transfusão de Sangue , Reticulocitose , Adolescente , Anemia Falciforme/complicações , Transfusão de Sangue/métodos , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Angiografia por Ressonância Magnética , Masculino , Contagem de Reticulócitos , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Adulto Jovem
16.
Transfusion ; 56(7): 1707-15, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26997031

RESUMO

BACKGROUND: Chronic transfusion therapy (CTT) is indicated for stroke prevention in children with sickle cell anemia (SCA) and is complicated by iron overload and alloimmunization. CTT is performed by simple transfusion (ST), partial manual exchange (PME), or erythrocytapheresis (RCE). Although small case series have demonstrated RCE in combination with iron chelation therapy stabilizes and/or decreases ferritin, there are no reports comparing the effect of ST, PME, and RCE on liver iron concentration (LIC). CTT modality effect on serum ferritin and LIC were compared in SCA patients on iron chelation, with hemoglobin (Hb)S goal of 30%. STUDY DESIGN AND METHODS: Medical records of SCA patients on CTT and deferasirox (≥25 mg/kg/day) were retrospectively reviewed. Mean HbS%, change in ferritin and LIC, and alloimmunization rate were determined for each CTT group. RESULTS: Twenty-eight patients were included; six crossed over (one from ST to PME, one from ST to PME then to RCE, three from ST to RCE, and one from PME to RCE) to include 36 transfusion modality intervals. Median pretransfusion HbS% levels were 32.7% (ST), 36.2% (PME), and 34.7% (RCE; p = 0.732). Median ferritin changes were +15 (-17 to +45), +38 (+24 to +105), and -91 (-141 to -48) ng/mL/month (p = 0.003), and median LIC changes (available in 22 patient transfusion modality intervals) were +1.3 (-1.6 to +4.3), +2.3 (-6.5 to +8.9), and -5.7 (-10.7 to -0.5) mg/g/year (p = 0.024) in ST, PME, and RCE, respectively. There was no significant difference in alloimmunization rate between ST/PME and RCE groups. CONCLUSION: We recommend RCE plus chelation as an effective method for reducing iron overload, while maintaining HbS at 30% to 35%.


Assuntos
Anemia Falciforme/terapia , Terapia por Quelação/métodos , Transfusão de Eritrócitos/métodos , Transfusão Total/métodos , Adolescente , Criança , Terapia Combinada , Feminino , Ferritinas/sangue , Humanos , Ferro/isolamento & purificação , Sobrecarga de Ferro/prevenção & controle , Sobrecarga de Ferro/terapia , Masculino , Estudos Retrospectivos
17.
Lancet ; 387(10019): 661-70, 2016 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-26670617

RESUMO

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Transfusão de Sangue/métodos , Hidroxiureia/uso terapêutico , Adolescente , Anemia Falciforme/fisiopatologia , Velocidade do Fluxo Sanguíneo , Circulação Cerebrovascular/fisiologia , Criança , Pré-Escolar , Terapia Combinada , Substituição de Medicamentos , Feminino , Humanos , Masculino , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento , Ultrassonografia Doppler Transcraniana
18.
Hum Immunol ; 77(1): 35-40, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26476208

RESUMO

BACKGROUND: Alloimmunization or the development of alloantibodies to Red Blood Cell (RBC) antigens is considered one of the major complications after RBC transfusions in patients with sickle cell disease (SCD) and can lead to both acute and delayed hemolytic reactions. It has been suggested that polymorphisms in HLA genes, may play a role in alloimmunization. We conducted a retrospective study analyzing the influence of HLA-DRB1 and DQB1 genetic diversity on RBC-alloimmunization. STUDY DESIGN: Two-hundred four multi-transfused SCD patients with and without RBC-alloimmunization were typed at low/medium resolution by PCR-SSO, using IMGT-HLA Database. HLA-DRB1 and DQB1 allele frequencies were analyzed using logistic regression models, and global p-value was calculated using multiple logistic regression. RESULTS: While only trends towards associations between HLA-DR diversity and alloimmunization were observed, analysis of HLA-DQ showed that HLA-DQ2 (p=0.02), -DQ3 (p=0.02) and -DQ5 (p=0.01) alleles were significantly higher in non-alloimmunized patients, likely behaving as protective alleles. In addition, multiple logistic regression analysis showed both HLA-DQ2/6 (p=0.01) and HLA-DQ5/5 (p=0.03) combinations constitute additional predictor of protective status. CONCLUSION: Our data suggest that particular HLA-DQ alleles influence the clinical course of RBC transfusion in patients with SCD, which could pave the way towards predictive strategies.


Assuntos
Anemia Falciforme/imunologia , Transfusão de Eritrócitos , Cadeias beta de HLA-DQ/genética , Adolescente , Anemia Falciforme/genética , Anemia Falciforme/terapia , Criança , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Humanos , Imunização , Isoanticorpos/metabolismo , Isoantígenos/imunologia , Masculino , Polimorfismo Genético , Estudos Retrospectivos , Adulto Jovem
19.
J Pediatr ; 169: 227-31.e1, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26593107

RESUMO

OBJECTIVE: To improve prediction of sickle cell anemia severity at an early age, we evaluated whether absolute reticulocyte count (ARC) or hemoglobin (Hb) levels during early infancy (2-6 months of age) in patients with sickle cell anemia predict the risk of later developing an abnormal (abTCD) or conditional (cdTCD) Transcranial Doppler (TCD). STUDY DESIGN: We used chart review to identify 121 consecutive patients who underwent TCD screening and had steady state ARC and Hb levels recorded between 2 and 6 months of age. Cox regression analysis was used to determine the relationship between ARC, Hb levels, and risk of developing cdTCD/abTCD over time. RESULTS: Mean ARC in early infancy was highest and mean Hb lowest in those children with abTCDs and cdTCDs. Cox regression analysis revealed that those subjects with an ARC ≥200 K/µL in early infancy had nearly 3 times the risk of having an abTCD/cdTCD than the group with an ARC <200 K/µL, and patients with a Hb <8.5 g/dL had 2.7 times the risk of having an abTCD/cdTCD. CONCLUSIONS: These data suggest that both elevated ARC and low baseline Hb during early infancy are associated with an increased risk of developing a cdTCD or abTCD later in childhood.


Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/complicações , Anemia/etiologia , Reticulocitose , Ultrassonografia Doppler Transcraniana , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Prognóstico , Contagem de Reticulócitos , Fatores de Tempo
20.
Sci Rep ; 5: 18369, 2015 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-26670709

RESUMO

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency. The purpose of this study is to determine if functional single nucleotide polymorphisms (SNPs) in immune-modulating genes pre-dispose infants to NEC. After Institutional Review Board approval and parental consent, buccal swabs were collected for DNA extraction. TaqMan allelic discrimination assays and BglII endonuclease digestion were used to genotype specific inflammatory cytokines and TRIM21. Statistical analysis was completed using logistic regression. 184 neonates were analyzed in the study. Caucasian neonates with IL-6 (rs1800795) were over 6 times more likely to have NEC (p = 0.013; OR = 6.61, 95% CI 1.48-29.39), and over 7 times more likely to have Stage III disease (p = 0.011; OR = 7.13, (95% CI 1.56-32.52). Neonates with TGFß-1 (rs2241712) had a decreased incidence of NEC-related perforation (p = 0.044; OR = 0.28, 95% CI: 0.08-0.97) and an increased incidence of mortality (p = 0.049; OR = 2.99, 95% CI: 1.01 - 8.86). TRIM21 (rs660) was associated with NEC-related intestinal perforation (p = 0.038; OR = 4.65, 95% CI 1.09-19.78). In premature Caucasian neonates, the functional SNP IL-6 (rs1800795) is associated with both the development and increased severity of NEC. TRIM21 (rs660) and TGFß-1 (rs2241712) were associated with NEC- related perforation in all neonates in the cohort. These findings suggest a possible genetic role in the development of NEC.


Assuntos
Enterocolite Necrosante , Interleucina-6 , Polimorfismo de Nucleotídeo Único/imunologia , Ribonucleoproteínas , Fator de Crescimento Transformador beta1 , Enterocolite Necrosante/genética , Enterocolite Necrosante/imunologia , Feminino , Humanos , Recém-Nascido , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Ribonucleoproteínas/genética , Ribonucleoproteínas/imunologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia
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