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1.
Health Qual Life Outcomes ; 17(1): 162, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31665035

RESUMO

BACKGROUND: When a child undergoes hematopoietic cell transplantation (HCT), the impact extends to the entire family, including siblings. Assessment of the quality of life (QoL) of siblings is challenged by their general lack of availability for regular assessment by clinical providers. Thus, the use of parent proxy reporting may be useful. Our aim was to describe the QoL of siblings of HCT survivors, as reported by their parents, as well as to identify parent and family factors associated with lower sibling QoL. METHODS: A cross-sectional study was utilized to assess parent-reported QoL of the HCT recipient's sibling (Short Form (SF)-10 Health Survey for Children and the Pediatric Symptom Checklist (PSC)-17). Parent QoL was assessed using the SF-12. Multivariable linear regression was used to explore hypothesized predictors of sibling QoL, including parent QoL, family impact/function (Impact on Family Scale, Family Adaptability and Cohesion Evaluation Scales, IV, and a question asking about financial problems) while adjusting for demographic and HCT characteristics. RESULTS: Ninety-seven siblings (55% males) with a mean age of 12 years (standard deviation [SD] 4 years) were assessed, representing HCT survivors, who were an average of 5 years (SD 4 years) post-HCT. Neither sibling psychosocial (mean 49.84, SD 10.70, p = 0.87) nor physical health scores (mean 51.54, SD 8.42, p = 0.08) differed from norms. Parent proxies reported behavioral/emotional problems (PSC-17 total score > 15) in 24% of siblings. While parental ratings of their own physical health (SF-12 were higher than norms (mean 53.04, SD 8.17, p = 0.0005), mental health scores were lower (mean 45.48, SD 10.45, p < 0.0001). In multivariable analysis, lower parent emotional functioning and adverse family function were associated with lower sibling QoL, as reported by parents. CONCLUSIONS: While proxy-reported QoL of siblings did not differ significantly from normative data, both parent QoL and family function were associated with sibling QoL. Future research is needed to understand how siblings themselves perceive their QoL following HCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas/psicologia , Qualidade de Vida/psicologia , Irmãos/psicologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Relações Familiares/psicologia , Feminino , Humanos , Masculino , Transtornos Mentais/epidemiologia , Pessoa de Meia-Idade , Pais/psicologia , Inquéritos e Questionários
3.
Haemophilia ; 25(4): 575-580, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31329369

RESUMO

INTRODUCTION: The major complication of protein replacement therapy for haemophilia A is the development of anti-FVIII antibodies or inhibitors that occur in 25%-30% of persons with severe haemophilia A. Alternative therapeutics such as bypassing agents or immune tolerance induction protocols have additional challenges and are not always effective. AIM: Assemble a National Heart, Lung and Blood Institute (NHLBI) State of the Science (SOS) Workshop to generate a national blueprint for research on inhibitors to solve the problem of FVIII immunogenicity. METHODS: An Executive Steering Committee was formed in October 2017 to establish the scientific focus and Scientific Working Groups for the SOS Workshop in May 2018. Four working groups were assembled to address scientific priorities in basic, translational and clinical research on inhibitors. RESULTS: Working Group 1 was charged with determining the scientific priorities for clinical trials to include the integration of non-intravenous, non-factor therapeutics including gene therapy into the standard of care for people with haemophilia A with inhibitors. Working Group 2 established the scientific priorities for 21st-century data science and biospecimen collection for observational inhibitor cohort studies. The scientific priorities for acquiring an actionable understanding of FVIII immunogenicity and the immunology of the host response and FVIII tolerance were developed by Working Group 3. Working Group 4 designed prospective pregnancy/birth cohorts to study FVIII immunogenicity, inhibitor development and eradication. CONCLUSION: The NHLBI SOS Workshop generated a focused summary of scientific priorities and implementation strategies to overcome the challenges of eradicating and preventing inhibitors in haemophilia A.


Assuntos
Educação/organização & administração , Fator VIII/antagonistas & inibidores , National Institutes of Health (U.S.) , Pesquisa/educação , Ensaios Clínicos como Assunto , Hemofilia A/tratamento farmacológico , Humanos , Estados Unidos
4.
J Clin Immunol ; 39(1): 81-89, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30607663

RESUMO

The association of immunodeficiency-related vaccine-derived rubella virus (iVDRV) with cutaneous and visceral granulomatous disease has been reported in patients with primary immunodeficiency disorders (PIDs). The majority of these PID patients with rubella-positive granulomas had DNA repair disorders. To support this line of inquiry, we provide additional descriptive data on seven previously reported patients with Nijmegen breakage syndrome (NBS) (n = 3) and ataxia telangiectasia (AT) (n = 4) as well as eight previously unreported patients with iVDRV-induced cutaneous granulomas and DNA repair disorders including NBS (n = 1), AT (n = 5), DNA ligase 4 deficiency (n = 1), and Artemis deficiency (n = 1). We also provide descriptive data on several previously unreported PID patients with iVDRV-induced cutaneous granulomas including cartilage hair hypoplasia (n = 1), warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome (n = 1), MHC class II deficiency (n = 1), Coronin-1A deficiency (n = 1), X-linked severe combined immunodeficiency (X-SCID) (n = 1), and combined immunodeficiency without a molecular diagnosis (n = 1). At the time of this report, the median age of the patients with skin granulomas and DNA repair disorders was 9 years (range 3-18). Cutaneous granulomas have been documented in all, while visceral granulomas were observed in six cases (40%). All patients had received rubella virus vaccine. The median duration of time elapsed from vaccination to the development of cutaneous granulomas was 48 months (range 2-152). Hematopoietic cell transplantation was reported to result in scarring resolution of cutaneous granulomas in two patients with NBS, one patient with AT, one patient with Artemis deficiency, one patient with DNA Ligase 4 deficiency, one patient with MHC class II deficiency, and one patient with combined immunodeficiency without a known molecular etiology. Of the previously reported and unreported cases, the majority share the diagnosis of a DNA repair disorder. Analysis of additional patients with this complication may clarify determinants of rubella pathogenesis, identify specific immune defects resulting in chronic infection, and may lead to defect-specific therapies.


Assuntos
Reparo do DNA/genética , Granuloma/complicações , Granuloma/virologia , Síndromes de Imunodeficiência/complicações , Vírus da Rubéola/patogenicidade , Dermatopatias/etiologia , Dermatopatias/virologia , Adolescente , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/virologia , Criança , Pré-Escolar , Feminino , Granuloma/genética , Cabelo/anormalidades , Cabelo/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hirschsprung/genética , Doença de Hirschsprung/virologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/virologia , Masculino , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/virologia , Osteocondrodisplasias/congênito , Osteocondrodisplasias/genética , Osteocondrodisplasias/virologia , Rubéola (Sarampo Alemão)/genética , Rubéola (Sarampo Alemão)/virologia , Pele/virologia , Dermatopatias/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/virologia
5.
J Blood Med ; 9: 185-192, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464668

RESUMO

Background: Noonan syndrome (NS) is an autosomal dominant genetic condition that has a number of clinical features, including bleeding diathesis and a number of hematological abnormalities including clotting factor deficiencies, von Willebrand disease and abnormal platelet count/function. Methods: We evaluated the frequency/types of bleeding disorders, and associated hematological laboratory findings, in patients with NS, using published data from 1965 to 2014. Results: Of 45 studies identified, 31 included data for 428 patients with NS. Of these patients, 43% had reported bleeding, 26% had no reported bleeding and no bleed data was reported for 31%. Most patients (90%) had bleeding-related laboratory test abnormalities, but only 194 (45%) had a confirmed diagnosis of a specific bleeding disorder. Abnormal laboratory tests included: prolonged prothrombin time, activated partial thromboplastin time, and other platelet-related disorders. Of the 194 patients with a confirmed diagnosis of a specific bleeding disorder, 153 (79%) had single clotting factor deficiencies, von Willebrand disease or platelet-related disorders, and 41 (21%) had multiple deficiencies including platelet-related disorders. Conclusion: As patients with NS can experience multiple bleeding disorders, including abnormal platelet function, clinical evaluations should be performed at diagnosis, after diagnosis, before any surgery is undertaken, and if patients become symptomatic.

6.
Cancer Genet ; 211: 9-17, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28279309

RESUMO

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder where an oncogenic TP53 germline mutation is passed from parent to child. Tumor protein p53 is a key tumor suppressor regulating cell cycle arrest in response to DNA damage. Paradoxically, some mutant TP53 carriers remain unaffected, while their children develop cancer within the first few years of life. To address this paradox, response to UV stress was compared in dermal fibroblasts (dFb) from an affected LFS patient vs. their unaffected carrier parent. UV induction of CDKN1A/p21, a regulatory target of p53, in LFS patient dFb was significantly reduced compared to the unaffected parent. UV exposure also induced significantly greater p53[Ser15]-phosphorylation in LFS patient dFb, a reported property of some mutant p53 variants. Taken together, these results suggested that unaffected parental dFb may express an increased proportion of wild-type vs. mutant p53. Indeed, a significantly increased ratio of wild-type to mutant TP53 allele-specific expression in the unaffected parent dFb was confirmed by RT-PCR-RFLP and RNA-seq analysis. Hence, allele-specific expression of wild-type TP53 may allow an unaffected parent to mount a response to genotoxic stress more characteristic of homozygous wild-type TP53 individuals than their affected offspring, providing protection from the oncogenesis associated with LFS.


Assuntos
Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/genética , Alelos , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Síndrome de Li-Fraumeni/metabolismo , Masculino , Pais
7.
Patient Prefer Adherence ; 9: 1549-60, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26604708

RESUMO

INTRODUCTION: Severe hemophilia and subsequent hemophilic arthropathy result in joint pain and impaired health-related quality of life (HRQoL). Assessment of HRQoL in persons with hemophilia (PWH), including underlying factors that drive HRQoL differences, is important in determining health care resource allocation and in making individualized clinical decisions. AIM: To examine potential associations between HRQoL, pain interference, and self-reported arthritis and age, employment, activity, bleed frequency, and hemophilia treatment center and health care professional utilization. METHODS: PWH (age ≥18 years) from ten countries completed a 5-point Likert scale on pain interference over the previous 4 weeks, the EQ-5D-3L scale (mobility, usual activities, self-care, pain/discomfort, anxiety/depression) including a health-related visual analog scale (0-100, coded as an 11-point categorical response). RESULTS: Pain interference (extreme/a lot) was higher in PWH aged >40 years (31%) compared to those aged 31-40 years (27%) or ≤30 years (21%). In an analysis of eight countries with home treatment, PWH who reported EQ-5D mobility issues were less likely to be employed (53% vs 79%, with no mobility issues). Median annual bleed frequency increased with worsening EQ-5D pain or discomfort. The percentage of PWH with inhibitors reporting visual analog scale scores of 80-90-100 was lower (20%) than those without inhibitors (34%). Median bleed frequency increased with pain. Globally, nurse and social worker involvement increased with disability and pain; physiotherapist utilization was moderate regardless of the extent of disability or pain. CONCLUSION: Increased disability and pain were associated with increased age, lower employment, higher reported bleed frequency, and lower HRQoL.

9.
Transfusion ; 55(1): 45-50, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25070582

RESUMO

BACKGROUND: Patients with congenital Factor XIII (FXIII) deficiency have impaired fibrin stabilization and are at high risk for surgical bleeding. Data regarding the use of FXIII concentrates before and during surgery are lacking. The objective of this study was to report the use of plasma-derived FXIII concentrate (Corifact in the United States; Fibrogammin P in other countries) in patients with congenital FXIII deficiency undergoing surgical procedures. STUDY DESIGN AND METHODS: FXIII concentrate at preoperative doses ranging from 25 to 40 U/kg was administered to six patients with congenital FXIII deficiency undergoing major or minor surgeries. RESULTS: FXIII concentrate was administered immediately before surgery for five surgical cases; three of these patients achieved excellent hemostasis during and after surgery, while two had intraoperative bleeding. In one surgical case, a regular prophylactic dose of FXIII concentrate was administered to the patient 1 week before minor surgery. FXIII concentrate provided rapid replacement of FXIII activity. In all but one of the patients given a dose of FXIII designed to increase FXIII levels more than 50%, there was satisfactory intraoperative and postoperative hemostasis. One patient undergoing aortic valve replacement on cardiopulmonary bypass (CPB) was the exception. Intraoperative bleeding in this patient was associated with lower-than-expected blood levels of FXIII. CONCLUSION: Preoperative plasma-derived FXIII concentrate allowed for sufficient hemostasis in most patients with FXIII deficiencies. Additional doses were necessary to achieve hemostasis in one patient who underwent a CPB procedure.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Deficiência do Fator XIII/terapia , Fator XIII/uso terapêutico , Hemorragia Pós-Operatória/prevenção & controle , Cuidados Pré-Operatórios/métodos , Adolescente , Adulto , Idoso , Anticoagulantes/uso terapêutico , Deficiência do Fator XIII/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hemorragia Bucal/prevenção & controle , Trombose/prevenção & controle , Varfarina/uso terapêutico
10.
Pediatr Transplant ; 18(7): E252-4, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25118016

RESUMO

Thrombocytopenia is a frequent complication following HSCT in pediatric patients. Romiplostim is a TPO receptor agonist that has been utilized successfully in the treatment of pediatric patients with immune thrombocytopenia. We describe a three-yr-old male with X-linked CGD treated with an unrelated donor bone marrow transplant. His course was complicated by the development of symptomatic thrombocytopenia. He was started on romiplostim with prompt improvement in his thrombocytopenia. We found the use of romiplostim to be an effective and safe alternative to the potential complications as well as morbidity and mortality associated with the use of immunosuppressive agents such as corticosteroids.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombocitopenia/etiologia , Trombopoetina/uso terapêutico , Corticosteroides/uso terapêutico , Pré-Escolar , Humanos , Imunossupressores/uso terapêutico , Masculino , Complicações Pós-Operatórias , Transplante Homólogo
11.
Appl Clin Genet ; 7: 55-66, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24817816

RESUMO

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder characterized by the triad of eczema, thrombocytopenia, and severe and often recurrent infections. Despite the rarity of this disorder, our understanding of the molecular and cellular pathogenesis of WAS has continued to increase. Advances in the use of diagnostic tools, the provision of supportive care, and improvements in allogeneic hematopoietic stem cell transplantation have significantly reduced the morbidity and mortality associated with this disorder. Exciting advancements in the care of patients with WAS have also occurred, including the successful application of autologous gene-modified hematopoietic stem cell transplantation.

12.
J Inherit Metab Dis ; 37(5): 791-9, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24619150

RESUMO

OBJECTIVE: Acyl-CoA oxidase (ACOX1) deficiency is a rare disorder of peroxisomal very-long chain fatty acid oxidation. No reports detailing attempted treatment, longitudinal imaging, or neuropathology exist. We describe the natural history of clinical symptoms and brain imaging in two siblings with ACOX1 deficiency, including the younger sibling's response to allogeneic unrelated donor hematopoietic stem cell transplantation (HSCT). METHODS: We conducted retrospective chart review to obtain clinical history, neuro-imaging, and neuropathology data. ACOX1 genotyping were performed to confirm the disease. In vitro fibroblast and neural stem cell fatty acid oxidation assays were also performed. RESULTS: Both patients experienced a fatal neurodegenerative course, with late-stage cerebellar and cerebral gray matter atrophy. Serial brain magnetic resonance imaging in the younger sibling indicated demyelination began in the medulla and progressed rostrally to include the white matter of the cerebellum, pons, midbrain, and eventually subcortical white matter. The successfully engrafted younger sibling had less brain inflammation, cortical atrophy, and neuronal loss on neuro-imaging and neuropathology compared to the untreated older sister. Fibroblasts and stem cells demonstrated deficient very long chain fatty acid oxidation. INTERPRETATION: Although HSCT did not halt the course of ACOX1 deficiency, it reduced the extent of white matter inflammation in the brain. Demyelination continued because of ongoing neuronal loss, which may be due to inability of transplant to prevent progression of gray matter disease, adverse effects of chronic corticosteroid use to control graft-versus-host disease, or intervention occurring beyond a critical point for therapeutic efficacy.


Assuntos
Acil-CoA Oxidase/deficiência , Encefalopatias Metabólicas Congênitas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Encéfalo/patologia , Encefalopatias Metabólicas Congênitas/enzimologia , Encefalopatias Metabólicas Congênitas/patologia , Pré-Escolar , Evolução Fatal , Feminino , Movimentos da Cabeça/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Hipotonia Muscular/etiologia , Células-Tronco Neurais/transplante , Irmãos , Resultado do Tratamento
13.
Inflamm Res ; 63(4): 299-308, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24385191

RESUMO

OBJECTIVE AND DESIGN: Variable tissue factor (TF) expression by human microvascular endothelial cells (HMVEC) may be regulated by two promoter haplotypes, distinguished by an 18-basepair deletion (D) or insertion (I) at -1,208. We sought to determine the relationship between these haplotypes and interleukin-1α (IL-1α)-induced TF expression in neonatal versus adult HMVEC. RESULTS: IL-1-stimulated TF mRNA, protein, and activity were significantly higher in neonatal compared to adult D/D donors. IL-1-stimulated HMVEC from neonatal D/D donors expressed threefold higher levels of TF mRNA, twofold higher TF protein, and fourfold increased TF activity compared to HMVEC from adult D/D donors. These results indicate that homozygosity for the D haplotype is characterized by increased response to IL-1 in neonates, but not adults. IL-1 induced increased phosphorylation of p38 mitogen-activated protein kinase (MAPK), which was significantly greater in neonatal compared to adult HMVEC. Moreover, inhibition of the p38 MAPK pathway reduced IL-1-stimulated TF mRNA expression in D/D neonatal but not adult HMVEC. CONCLUSIONS: Upregulation of D/D neonatal HMVEC TF expression by IL-1 is mediated through the p38 MAPK pathway. This heightened response of D/D neonatal HMVEC to inflammatory stimuli may contribute to increased microvascular coagulopathies in susceptible newborn infants.


Assuntos
Células Endoteliais/metabolismo , Tromboplastina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adulto , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Genótipo , Humanos , Recém-Nascido , Interleucina-1alfa/farmacologia , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Tromboplastina/genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
14.
PLoS One ; 8(1): e55094, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23359821

RESUMO

We have engineered a transgenic mouse on a C57BL/6 background that bears a floxed Itga2 gene. The crossing of this mouse strain to transgenic mice expressing Cre recombinase driven by the megakaryocyte (MK)-specific Pf4 promoter permits the conditional knockout of Itga2 in the MK/platelet lineage. Mice lacking MK α2ß1 develop normally, are fertile, and like their systemic α2ß1 knockout counterparts, exhibit defective adhesion to and aggregation induced by soluble type I collagen and a delayed onset to low dose fibrillar collagen-induced aggregation, results consistent with blockade or loss of platelet α2ß1. At the same time, we observed a significant reduction in mean platelet volume, which is consistent with the reported role of α2ß1 in MK maturation and proplatelet formation in vivo. This transgenic mouse strain bearing a floxed Itga2 gene will prove valuable to distinguish in vivo the temporal and spatial contributions of α2 integrin in selected cell types.


Assuntos
Integrina alfa2beta1/fisiologia , Megacariócitos/metabolismo , Contagem de Plaquetas , Animais , Sequência de Bases , Western Blotting , Adesão Celular , Colágeno Tipo I/metabolismo , Primers do DNA , Técnicas de Inativação de Genes , Integrina alfa2beta1/genética , Megacariócitos/citologia , Camundongos , Reação em Cadeia da Polimerase
15.
Curr Opin Hematol ; 19(5): 371-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22872156

RESUMO

PURPOSE OF REVIEW: This review summarizes our current knowledge of common gene variants (polymorphisms) that have small individual effects on platelet function in humans, but can cumulatively lead to hyperreactive platelets and increase risk for negative outcomes in thrombotic disorders. RECENT FINDINGS: Candidate gene association and genome-wide association studies (GWAS) have identified loci that include single nucleotide polymorphisms, which exert a cumulative effect on platelet function by modifying basic platelet parameters, such as mean platelet volume (MPV) or platelet count, by altering the expression or activity of key platelet receptors, or by influencing downstream effector pathways utilized by these receptors. SUMMARY: Variation in MPV between normal individuals is responsible for roughly a two-fold range in platelet protein content, including key surface receptors and reactive granule constituents, the association of ADRA2, GP1BA, GP6, ITGA2 and P2Y12 variants with platelet reactivity, initially identified by candidate gene analyses, has now been validated by genome-wide approaches in much larger individual cohorts, and GWAS have identified novel gene variants, most notably PEAR1, that participate in variation in platelet reactivity among normal individuals, all of which contribute to a genetic basis for differences in platelet reactivty among normal individuals.


Assuntos
Plaquetas/fisiologia , Trombose/genética , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Contagem de Plaquetas , Testes de Função Plaquetária , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/metabolismo , Trombose/metabolismo
16.
Biol Blood Marrow Transplant ; 18(12): 1776-84, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22863842

RESUMO

With improvements in hematopoietic cell transplant (HCT) outcomes for severe aplastic anemia (SAA), there is a growing population of SAA survivors after HCT. However, there is a paucity of information regarding late effects that occur after HCT in SAA survivors. This study describes the malignant and nonmalignant late effects in survivors with SAA after HCT. A descriptive analysis was conducted of 1718 patients post-HCT for acquired SAA between 1995 and 2006 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The prevalence and cumulative incidence estimates of late effects are reported for 1-year HCT survivors with SAA. Of the HCT recipients, 1176 (68.5%) and 542 (31.5%) patients underwent a matched sibling donor (MSD) or unrelated donor (URD) HCT, respectively. The median age at the time of HCT was 20 years. The median interval from diagnosis to transplantation was 3 months for MSD HCT and 14 months for URD HCT. The median follow-up was 70 months and 67 months for MSD and URD HCT survivors, respectively. Overall survival at 1 year, 2 years, and 5 years for the entire cohort was 76% (95% confidence interval [CI]: 74-78), 73% (95% CI: 71-75), and 70% (95% CI: 68-72). Among 1-year survivors of MSD HCT, 6% had 1 late effect and 1% had multiple late effects. For 1-year survivors of URD HCT, 13% had 1 late effect and 2% had multiple late effects. Among survivors of MSD HCT, the cumulative incidence estimates of developing late effects were all <3% and did not increase over time. In contrast, for recipients of URD HCT, the cumulative incidence of developing several late effects exceeded 3% by 5 years: gonadal dysfunction 10.5% (95% CI: 7.3-14.3), growth disturbance 7.2% (95% CI: 4.4-10.7), avascular necrosis 6.3% (95% CI: 3.6-9.7), hypothyroidism 5.5% (95% CI: 2.8-9.0), and cataracts 5.1% (95% CI: 2.9-8.0). Our results indicated that all patients undergoing HCT for SAA remain at risk for late effects, must be counseled about, and should be monitored for late effects for the remainder of their lives.


Assuntos
Anemia Aplástica/cirurgia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Gravidez , Análise de Sobrevida , Sobreviventes , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/estatística & dados numéricos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
17.
Haematologica ; 97(5): 692-5, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22133774

RESUMO

A single nucleotide polymorphism in the integrin α2 gene ITGA2 (rs1801106; G1600A) creates the non-conservative amino acid substitution E534K, the basis of the human platelet alloantigen system HPA-5. Yet HPA-5 alleles do not influence binding of α2ß1 to its primary ligand collagen I, and the effect of HPA-5 on platelet function has not been determined. We used a direct platelet adhesion assay to evaluate whether differential inheritance of HPA-5 alleles influences platelet adhesion to collagen I or an alternative ligand, decorin. Platelets from donors bearing one or more minor allele HPA-5b showed attenuated adhesion to purified decorin but not collagen I. Adhesion to decorin was significantly inhibited by human alloantibodies specific for HPA-5a but not by the collagen I sequence GFOGER or α2-specific inhibitory monoclonal antibodies. The minor allele 534K attenuates platelet adhesion to decorin but not collagen I, providing the first evidence of a functional effect of HPA-5 alleles.


Assuntos
Antígenos de Plaquetas Humanas/genética , Colágeno Tipo I/metabolismo , Decorina/metabolismo , Integrina alfa2/genética , Adesividade Plaquetária/genética , Polimorfismo Genético/genética , Adulto , Antígenos de Plaquetas Humanas/imunologia , Antígenos de Plaquetas Humanas/metabolismo , Plaquetas/fisiologia , Feminino , Genótipo , Humanos , Integrina alfa2/imunologia , Integrina alfa2/metabolismo , Masculino , Reação em Cadeia da Polimerase
18.
Arterioscler Thromb Vasc Biol ; 32(1): 147-52, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22015659

RESUMO

OBJECTIVE: The interindividual variation in platelet α(2)ß(1) exceeds a 2-fold variance in platelet α(IIb)ß(3) level. Our objective was to parse the contribution of mean platelet volume (MPV) and integrin gene alleles to this variation in large cohorts of patients with acute coronary syndrome (ACS) and normal subjects. METHODS AND RESULTS: Platelet α(IIb)ß(3) and α(2)ß(1) levels were measured by flow cytometry in whole blood from 320 ACS patients and 128 normal subjects and compared with MPV, platelet count, ITGA2 rs1126643, and ITGB3 rs5918 alleles. In all subjects, a strong direct correlation was found between MPV and α(IIb)ß(3) level (P<0.001). Neither MPV nor α(IIb)ß(3) level correlated with ITGB3 rs5918 alleles. In the case of α(2)ß(1) level, MPV contributed modestly, whereas ITGA2 rs1126643 exerted a greater effect. An inverse correlation was found between MPV and the rs1126643 minor allele. CONCLUSIONS: MPV is the major effector of platelet α(IIb)ß(3) level, whereas the ITGA2 rs1126643 alleles influence α(2)ß(1) level more than MPV does. The rs1126643 minor allele, associated with lower MPV, likely exerts this effect via the influence of α(2)ß(1) on megakaryocyte maturation. Because of the hyperactivity of larger platelets, MPV is an accurate metric of risk for adverse outcome in ACS.


Assuntos
Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/genética , Plaquetas/patologia , Integrina alfa2beta1/genética , Integrina alfa2beta1/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Adulto , Alelos , Estudos de Casos e Controles , Tamanho Celular , Estudos de Coortes , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade
19.
Pediatr Blood Cancer ; 58(2): 221-5, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21674758

RESUMO

BACKGROUND: Treatment choice in pediatric immune thrombocytopenia (ITP) is arbitrary, because few studies are powered to identify predictors of therapy response. Increasingly, rituximab is becoming a treatment of choice in those refractory to other therapies. METHODS: The objective of this study was to evaluate univariate and multivariable predictors of platelet count response to rituximab. After local IRB approval, 565 patients with chronic ITP enrolled and met criteria for this study in the longitudinal, North American Chronic ITP Registry (NACIR) between January 2004 and October 2010. Treatment response was defined as a post-treatment platelet count ≥ 50,000/µl within 16 weeks of rituximab and 14 days of steroids. Treatment response data were captured both retrospectively at enrollment and then prospectively. RESULTS: Eighty (14.2%) patients were treated with rituximab with an overall response rate of 63.8% (51/80). Univariate correlates of response to rituximab included the presence of secondary ITP and a positive response to steroids. In multivariable analysis, response to steroids remained a strong correlate of response to rituximab, OR 6.8 (95% CI 2.0-23.0, P = 0.002). Secondary ITP also remained a strong predictor of response to rituximab, OR 5.6 (95% CI 1.1-28.6, P = 0.04). Although 87.5% of patients who responded to steroids responded to rituximab, 48% with a negative response to steroids did respond to rituximab. CONCLUSION: In the NACIR, response to steroids and presence of secondary ITP were strong correlates of response to rituximab, a finding not previously reported in children or adults.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Prednisona/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombocitopenia/imunologia , Adolescente , Criança , Pré-Escolar , Doença Crônica , Estudos de Coortes , Feminino , Seguimentos , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Contagem de Plaquetas , Estudos Prospectivos , Estudos Retrospectivos , Rituximab , Resultado do Tratamento
20.
Blood ; 118(1): 28-36, 2011 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-21502541

RESUMO

Romiplostim, a thrombopoietin-mimetic peptibody, increases and maintains platelet counts in adults with immune thrombocytopenia (ITP). In this first study of a thrombopoietic agent in children, patients with ITP of ≥ 6 months' duration were stratified by age 1:2:2 (12 months-< 3 years; 3-< 12 years; 12-< 18 years). Children received subcutaneous injections of romiplostim (n = 17) or placebo (n = 5) weekly for 12 weeks, with dose adjustments to maintain platelet counts between 50 × 10(9)/L and 250 × 10(9)/L. A platelet count ≥ 50 × 10(9)/L for 2 consecutive weeks was achieved by 15/17 (88%) patients in the romiplostim group and no patients in the placebo group (P = .0008). Platelet counts ≥ 50 × 10(9)/L were maintained for a median of 7 (range, 0-11) weeks in romiplostim patients and 0 (0-0) weeks in placebo patients (P = .0019). The median weekly dose of romiplostim at 12 weeks was 5 µg/kg. Fourteen responders received romiplostim for 4 additional weeks for assessment of pharmacokinetics. No patients discontinued the study. There were no treatment-related, serious adverse events. The most commonly reported adverse events in children, as in adults, were headache and epistaxis. In this short-term study, romiplostim increased platelet counts in 88% of children with ITP and was well-tolerated and apparently safe. The trial was registered with http://www.clinicaltrials.gov as NCT00515203.


Assuntos
Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores Fc/administração & dosagem , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/administração & dosagem , Trombopoese/efeitos dos fármacos , Trombopoetina/administração & dosagem , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Lactente , Injeções Subcutâneas , Masculino , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética , Trombopoetina/efeitos adversos , Trombopoetina/farmacocinética , Resultado do Tratamento
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