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1.
Am J Hematol ; 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31903617

RESUMO

Although the most common front-line therapies for immune thrombocytopenia (ITP) have been in use for decades, it is still not possible to predict an individual patient's clinical course and response to therapy. Patients are managed with a trial-and-error approach and often suffer side effects of therapies which could have been avoided if response prediction were possible. Corticosteroids are the most frequently used upfront therapy for adults and children with ITP. Our group performed whole exome sequencing on a cohort of pediatric ITP patients, and identified two missense single nucleotide variants (SNV) in Toll-like receptor 4 (TLR4). These coding variants in TLR4 had an increased frequency in Caucasian patients with poor response to upfront steroid therapy. Both TLR4 (D299G; rs4986790) and TLR4 (T399I; rs4986791) had a minor allele frequency (MAF) of 20.7% in those patients unresponsive to steroids, but were present at lower allele frequencies of 2.3% and 3.4% in responders respectively (P < .001). These findings were consistent with the trend identified in an independent cohort of pediatric ITP patients treated with corticosteroids who underwent direct genotyping for both SNVs. This study identified two candidate genetic variants in two unique cohorts of ITP patients which may contribute to steroid response and have prognostic implications for treatment response in ITP.

2.
Hum Mutat ; 41(1): 277-290, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31562665

RESUMO

The heterogeneous manifestations of MYH9-related disorder (MYH9-RD), characterized by macrothrombocytopenia, Döhle-like inclusion bodies in leukocytes, bleeding of variable severity with, in some cases, ear, eye, kidney, and liver involvement, make the diagnosis for these patients still challenging in clinical practice. We collected phenotypic data and analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder. Patients were enrolled in the BRIDGE-BPD and ThromboGenomics Projects and their samples processed by high throughput sequencing (HTS). We identified 50 patients with a rare variant in MYH9. All patients had macrothrombocytes and all except two had thrombocytopenia. Some degree of bleeding diathesis was reported in 41 of the 50 patients. Eleven patients presented hearing impairment, three renal failure and two elevated liver enzymes. Among the 28 rare variants identified in MYH9, 12 were novel. HTS was instrumental in diagnosing 23 patients (46%). Our results confirm the clinical heterogeneity of MYH9-RD and show that, in the presence of an unclassified platelet disorder with macrothrombocytes, MYH9-RD should always be considered. A HTS-based strategy is a reliable method to reach a conclusive diagnosis of MYH9-RD in clinical practice.

4.
J Allergy Clin Immunol ; 144(6): 1660-1673, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31445098

RESUMO

BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. OBJECTIVE: We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. RESULTS: Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.

5.
Hamostaseologie ; 39(3): 266-271, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31167247

RESUMO

Management of immune thrombocytopenia (ITP) is complex requiring communication between patients and caregivers to establish a mutual understanding of the impact of the patient's disease on quality of life, the current symptoms and risk of morbidity/mortality and the goals of therapy. The currently available second-line therapies for ITP provide potential for management of thrombocytopenia and bleeding symptoms with medical therapy or surgical intervention potentially offering long-term remission. All therapies are associated with potential side effects and necessary monitoring or modifications/risks and careful discussion of these is necessary to determine the optimal therapy for each patient. This review covers second-line therapies for ITP and discusses the currently available information on immunomodulatory second-line treatments for ITP.

6.
Hematol Oncol Clin North Am ; 33(3): 471-487, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31030814

RESUMO

The inherited platelet disorders are a heterogeneous group of disorders that can be pleotropic in their clinical presentations. They may present with variable platelet counts and bleeding, making their diagnosis difficult. New diagnostic tools range from flow cytometric platelet function assessments to next-generation sequencing. Several platelet disorders may now be treated with gene therapy or bone marrow transplant. Improved understanding of the molecular and biologic mechanisms of the inherited platelet disorders may lead to novel targeted therapies.

7.
Am J Hematol ; 94(7): 741-750, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30945320

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and hemorrhagic risk. While many children with ITP can be safely observed, treatments are often needed for various reasons, including to decrease bleeding, or to improve health related quality of life (HRQoL). There are a number of available second-line treatments, including rituximab, thrombopoietin-receptor agonists, oral immunosuppressive agents, and splenectomy, but data comparing treatment outcomes are lacking. ICON1 is a prospective, multi-center, observational study of 120 children starting second-line treatments for ITP designed to compare treatment outcomes including platelet count, bleeding, and HRQoL utilizing the Kids ITP Tool (KIT). While all treatments resulted in increased platelet counts, romiplostim had the most pronounced effect at 6 months (P = .04). Only patients on romiplostim and rituximab had a significant reduction in both skin-related (84% to 48%, P = .01 and 81% to 43%, P = .004) and non-skin-related bleeding symptoms (58% to 14%, P = .0001 and 54% to 17%, P = .0006) after 1 month of treatment. HRQoL significantly improved on all treatments. However, only patients treated with eltrombopag had a median improvement in KIT scores at 1 month that met the minimal important difference (MID). Bleeding, platelet count, and HRQoL improved in each treatment group, but the extent and timing of the effect varied among treatments. These results are hypothesis generating and help to improve our understanding of the effect of each treatment on specific patient outcomes. Combined with future randomized trials, these findings will help clinicians select the optimal second-line treatment for an individual child with ITP.

9.
Am J Hematol ; 94(4): 461-466, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30663792

RESUMO

Immune thrombocytopenia (ITP) is the most common autoimmune cytopenia in children. Approximately, 25% of patients develop chronic disease, which may be unpredictable and challenging to treat. It is not currently possible to predict at the time of presentation which patients will have chronic disease or will experience symptoms requiring second-line therapy defined as treatment beyond corticosteroids, intravenous immunoglobulin, or Rh immune globulin. A multi-institutional retrospective review of 311 pediatric patients with ITP was performed with the goal of identifying clinical characteristics associated with disease course. In a cohort of 216 patients tested and for whom disease status was known, a positive direct antiglobulin test (DAT) was associated with chronic ITP vs spontaneous resolution of disease (29.2% vs 8.1%, P < 0.001) as well as the need for treatment with second line agents (38.5% vs 11.4%, P < 0.001) in 241 patients. Controlling for the effect of Evans syndrome, defined as having two immune cytopenias, a positive DAT was independently associated with chronic ITP (OR = 2.7, 95% CI: 1.0-7.2, P = 0.041) and use of second-line agents (OR: 3.6, 95% CI: 1.7-7.7, P = 0.001) by multivariate logistic regression model. These findings demonstrate an association with positive DAT and chronic disease, as well as refractory disease requiring second-line agents.


Assuntos
Corticosteroides/administração & dosagem , Anemia Hemolítica Autoimune , Teste de Coombs , Imunoglobulinas Intravenosas/administração & dosagem , Púrpura Trombocitopênica Idiopática , Imunoglobulina rho(D)/administração & dosagem , Trombocitopenia , Anemia Hemolítica Autoimune/sangue , Anemia Hemolítica Autoimune/tratamento farmacológico , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Masculino , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Trombocitopenia/sangue , Trombocitopenia/tratamento farmacológico
10.
J Allergy Clin Immunol ; 143(1): 258-265, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29935219

RESUMO

BACKGROUND: The lack of pathogen-protective, isotype-switched antibodies in patients with common variable immunodeficiency (CVID) suggests germinal center (GC) hypoplasia, yet a subset of patients with CVID is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy. OBJECTIVE: We sought to compare the physical characteristics and immunologic output of GC responses in patients with CVID with AIC (CVID+AIC) and without AIC (CVID-AIC). METHODS: We analyzed GC size and shape in excisional lymph node biopsy specimens from 14 patients with CVID+AIC and 4 patients with CVID-AIC. Using paired peripheral blood samples, we determined how AICs specifically affected B-and T-cell compartments and antibody responses in patients with CVID. RESULTS: We found that patients with CVID+AIC displayed irregularly shaped hyperplastic GCs, whereas GCs were scarce and small in patients with CVID-AIC. GC hyperplasia was also evidenced by an increase in numbers of circulating follicular helper T cells, which correlated with decreased regulatory T-cell frequencies and function. In addition, patients with CVID+AIC had serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than their counterparts with CVID-AIC. Moreover, IgG+ B cells from patients with CVID+AIC expressed VH4-34-encoded antibodies with unmutated Ala-Val-Tyr and Asn-His-Ser motifs, which recognize both erythrocyte I/i self-antigens and commensal bacteria. CONCLUSIONS: Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG+ B-cell clones that recognize both commensal bacteria and hematopoietic I/i self-antigens.


Assuntos
Autoanticorpos/imunologia , Linfócitos B/imunologia , Imunodeficiência de Variável Comum/imunologia , Centro Germinativo/imunologia , Imunoglobulina G/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Linfócitos B/patologia , Biópsia , Criança , Imunodeficiência de Variável Comum/patologia , Feminino , Centro Germinativo/patologia , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Linfócitos T/patologia
11.
J Allergy Clin Immunol ; 143(4): 1482-1495, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30170123

RESUMO

BACKGROUND: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing. OBJECTIVES: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles. METHODS: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants. RESULTS: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein. CONCLUSION: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.

13.
Am J Med Genet A ; 176(10): 2058-2069, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30380191

RESUMO

22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by recurrent, chromosome-specific, low copy repeat (LCR)-mediated copy-number losses of chromosome 22q11. The Children's Hospital of Philadelphia has been involved in the clinical care of individuals with what is now known as 22q11.2DS since our initial report of the association with DiGeorge syndrome in 1982. We reviewed the medical records on our continuously growing longitudinal cohort of 1,421 patients with molecularly confirmed 22q11.2DS from 1992 to 2018. Most individuals are Caucasian and older than 8 years. The mean age at diagnosis was 3.9 years. The majority of patients (85%) had typical LCR22A-LCR22D deletions, and only 7% of these typical deletions were inherited from a parent harboring the deletion constitutionally. However, 6% of individuals harbored other nested deletions that would not be identified by traditional 22q11.2 FISH, thus requiring an orthogonal technology to diagnose. Major medical problems included immune dysfunction or allergies (77%), palatal abnormalities (67%), congenital heart disease (64%), gastrointestinal difficulties (65%), endocrine dysfunction (>50%), scoliosis (50%), renal anomalies (16%), and airway abnormalities. Median full-scale intelligence quotient was 76, with no significant difference between individuals with and without congenital heart disease or hypocalcemia. Characteristic dysmorphic facial features were present in most individuals, but dermatoglyphic patterns of our cohort are similar to normal controls. This is the largest longitudinal study of patients with 22q11.2DS, helping to further describe the condition and aid in diagnosis and management. Further surveillance will likely elucidate additional clinically relevant findings as they age.


Assuntos
Síndrome de DiGeorge/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 22 , Comorbidade , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/epidemiologia , Feminino , Gastroenteropatias/etiologia , Cardiopatias Congênitas/etiologia , Humanos , Estudos Longitudinais , Masculino , Mortalidade , Philadelphia/epidemiologia , Transição para Assistência do Adulto
14.
JCI Insight ; 3(18)2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30232279

RESUMO

Heparin-induced thrombocytopenia (HIT) is an immune-mediated thrombocytopenic disorder associated with a severe prothrombotic state. We investigated whether neutrophils and neutrophil extracellular traps (NETs) contribute to the development of thrombosis in HIT. Using an endothelialized microfluidic system and a murine passive immunization model, we show that HIT induction leads to increased neutrophil adherence to venous endothelium. In HIT mice, endothelial adherence is enhanced immediately downstream of nascent venous thrombi, after which neutrophils undergo retrograde migration via a CXCR2-dependent mechanism to accumulate into the thrombi. Using a microfluidic system, we found that PF4 binds to NETs, leading them to become compact and DNase resistant. PF4-NET complexes selectively bind HIT antibodies, which further protect them from nuclease digestion. In HIT mice, inhibition of NET formation through Padi4 gene disruption or DNase treatment limited venous thrombus size. PAD4 inactivation did affect arterial thrombi or severity of thrombocytopenia in HIT. Thus, neutrophil activation contributes to the development of venous thrombosis in HIT by enhancing neutrophil-endothelial adhesion and neutrophil clot infiltration, where incorporated PF4-NET-HIT antibody complexes lead to thrombosis propagation. Inhibition of neutrophil endothelial adhesion, prevention of neutrophil chemokine-dependent recruitment of neutrophils to thrombi, or suppression of NET release should be explored as strategies to prevent venous thrombosis in HIT.


Assuntos
Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , Trombocitopenia/imunologia , Trombose/imunologia , Animais , Doenças Autoimunes/imunologia , Movimento Celular , Células Endoteliais , Humanos , Leucócitos , Vasos Linfáticos , Masculino , Camundongos , Camundongos Knockout , Ativação de Neutrófilo , Fator Plaquetário 4/genética , Desiminases de Arginina em Proteínas/genética , Receptores de Interleucina-8B/metabolismo
15.
Am J Med Genet A ; 176(10): 2203-2214, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30244528

RESUMO

22q11.2 deletion syndrome (DS) is the most frequent copy number variant (CNV) affecting ~1/1,000 fetuses and ~1/2,000-4,000 children, resulting in recognizable but variable findings across multiple organ systems. Patients with atypical features should prompt consideration of coexisting diagnoses due to additional genome-wide mutations, CNVs, or mutations/CNVs on the other allele, unmasking autosomal recessive conditions. Importantly, a dual diagnosis compounds symptoms and impacts management. We previously reported seven patients with 22q11.2DS and: SCID, Trisomy 8 mosaicism, Bernard-Soulier, and CEDNIK syndromes. Here we present six additional unreported patients with 22q11.2DS and concurrent diagnoses. Records on 1,422 patients with 22q11.2DS, identified via FISH, microarray, or MLPA, followed in our 22q and You Center at the Children's Hospital of Philadelphia (CHOP) were reviewed to identify a dual diagnosis. In addition to our seven previously reported cases, we identified an additional six with 22q11.2DS and another coexisting condition identified via: molecular/cytogenetic studies, newborn screening, coagulation factor studies, or enzyme testing; these include CHARGE syndrome (CHD7 mutation), cystic fibrosis, a maternally inherited 17q12 deletion, G6PD deficiency, von Willebrand disease, and 1q21.1 deletion, resulting in an incidence of dual diagnoses at our center of 0.9%. The range of dual diagnoses identified in our cohort is notable, medically actionable, and may alter long-term outcome and recurrence risk counseling. Thus, our findings may support testing patients with 22q11.2DS using a combination of microarray, mutational analysis of the other allele/WES, to ensure appropriate personalized care, as formulating medical management decisions hinges on establishing the correct diagnoses in their entirety.


Assuntos
Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/genética , Adolescente , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
16.
Transfusion ; 58(12): 2836-2840, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30264395

RESUMO

BACKGROUND: Oncology patients are frequent recipients of prophylactic platelet transfusions. Recent studies have demonstrated that lower prophylactic doses of platelets were not associated with a higher incidence of bleeding. At our institution, we found wide variation in platelet dosing due to lack of guidance and support for standardized dosing. STUDY DESIGN AND METHODS: A collaborative process improvement project between oncology, hematology, intensivists, and the transfusion service established guidelines for dosing of prophylactic platelet transfusions in nonbleeding oncology patients: 10 mL/kg or less of apheresis platelets for patients weighing up to 20 kg and 1 unit of apheresis platelets patients weighing 20 kg or more, with our stated goal of standardizing transfusion practice. A graphic data display tool that draws on the electronic medical record to monitor platelet ordering was created, with a target goal of greater than 80% compliance with the dosing guidelines. We implemented decision support for dosing consistent with the guideline, and provided educational materials to prescribers at various levels of training within oncology over multiple plan-do-study-act cycles. RESULTS: We were able to consistently achieve between 85 and 90% compliance of prophylactic platelet transfusion orders without an increase in the number of emergency department visits for bleeding or platelet transfusions or changing the time between platelet transfusions after guideline implementation. CONCLUSION: This project demonstrates that reducing the volume of prophylactic platelet transfusions to doses consistent with published studies was safe and that a process of guideline consensus based on published studies, well-designed decision support for computerized physician order entry, and targeted educational efforts, were effective in changing practice at a large academic hospital.


Assuntos
Fidelidade a Diretrizes/normas , Hemorragia/prevenção & controle , Neoplasias/terapia , Transfusão de Plaquetas/normas , Melhoria de Qualidade , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
18.
Mol Ther Methods Clin Dev ; 10: 291-302, 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30155509

RESUMO

Under intravenous delivery, recombinant adeno-associated vectors (rAAVs) interact with blood-borne components in ways that can critically alter their therapeutic efficiencies. We have previously shown that interaction with human galectin 3 binding protein dramatically reduces rAAV-6 efficacy, whereas binding of mouse C-reactive protein improves rAAV-1 and rAAV-6 transduction effectiveness. Herein we have assessed, through qualitative and quantitative studies, the proteins from mouse and human sera that bind with rAAV-8 and rAAV-9, two vectors that are being considered for clinical trials for patients with neuromuscular disorders. We show that, in contrast to rAAV-1 and rAAV-6, there was a substantial similarity in protein binding patterns between mouse and human sera for these vector serotypes. To establish an in vivo role for the vector binding of these sera proteins, we chose to study platelet factor 4 (PF4), which interacts with both vectors in both mouse and human sera. Experiments using PF4-knockout mice showed that a complete lack of PF4 did not alter skeletal muscle transduction for these vectors, whereas heart transduction was moderately improved. Our results strongly support our position that the impact of serum proteins on the transduction properties of rAAV-8 and rAAV-9, already observed in mouse models, should be similar in human preclinical trials.

19.
Blood Adv ; 2(7): 797-806, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29632235

RESUMO

Patients with RUNX1 haplodeficiency have thrombocytopenia, platelet dysfunction, and deficiencies of α-granules and dense granules. Platelet expression profiling of a patient with a heterozygous RUNX1 mutation (c.969-323G>T) revealed decreased RAB1B, which encodes a small G protein. RAB GTPases regulate vesicle trafficking, and RAB1B is implicated in endoplasmic reticulum (ER)-to-Golgi transport in nonhematopoietic cells, but its role in megakaryocytes (MK) is unknown. We addressed the hypothesis that RAB1B is a transcriptional target of RUNX1 and that RAB1B regulates ER-to-Golgi transport in MK cells. Chromatin immunoprecipitation studies and electrophoretic mobility shift assay using phorbol 12-myristate 13-acetate (PMA)-treated human erythroleukemia cells revealed RUNX1 binding to RAB1B promoter region RUNX1 consensus sites, and their mutation reduced the promoter activity. RAB1B promoter activity and protein expression were inhibited by RUNX1 siRNA and enhanced by RUNX1 overexpression. These indicate that RAB1B is a direct RUNX1 target, providing a mechanism for decreased RAB1B in patient platelets. Vesicle trafficking from ER to Golgi in PMA-treated human erythroleukemia cells was impaired along with Golgi disruption on siRNA downregulation of RUNX1 or RAB1B. The effects of RUNX1 knockdown were reversed by RAB1B reconstitution. Trafficking of von Willebrand factor (vWF), an α-granule MK synthesized protein, was impaired with RUNX1 or RAB1B downregulation and reconstituted by ectopic RAB1B expression. Platelet vWF was decreased in patients with RUNX1 mutations. Thus, ER-to-Golgi transport, an early critical step in protein trafficking to granules, is impaired in megakaryocytic cells on RUNX1 downregulation, secondary to decreased RAB1B expression. Impaired RAB1B mediated ER-to-Golgi transport contributes to platelet α-granule defects in RUNX1 haplodeficiency.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/deficiência , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Megacariócitos/química , Proteínas rab1 de Ligação ao GTP/metabolismo , Plaquetas/química , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Retículo Endoplasmático/metabolismo , Feminino , Complexo de Golgi/metabolismo , Humanos , Leucemia Eritroblástica Aguda/patologia , Masculino , Regiões Promotoras Genéticas , Ligação Proteica , Transporte Proteico , Proteínas rab1 de Ligação ao GTP/genética , Fator de von Willebrand/metabolismo
20.
Am J Hematol ; 93(7): 882-888, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29659042

RESUMO

Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder which presents with isolated thrombocytopenia and risk of hemorrhage. While most children with ITP promptly recover with or without drug therapy, ITP is persistent or chronic in others. When needed, how to select second-line therapies is not clear. ICON1, conducted within the Pediatric ITP Consortium of North America (ICON), is a prospective, observational, longitudinal cohort study of 120 children from 21 centers starting second-line treatments for ITP which examined treatment decisions. Treating physicians reported reasons for selecting therapies, ranking the top three. In a propensity weighted model, the most important factors were patient/parental preference (53%) and treatment-related factors: side effect profile (58%), long-term toxicity (54%), ease of administration (46%), possibility of remission (45%), and perceived efficacy (30%). Physician, health system, and clinical factors rarely influenced decision-making. Patient/parent preferences were selected as reasons more often in chronic ITP (85.7%) than in newly diagnosed (0%) or persistent ITP (14.3%, P = .003). Splenectomy and rituximab were chosen for the possibility of inducing long-term remission (P < .001). Oral agents, such as eltrombopag and immunosuppressants, were chosen for ease of administration and expected adherence (P < .001). Physicians chose rituximab in patients with lower expected adherence (P = .017). Treatment choice showed some physician and treatment center bias. This study illustrates the complexity and many factors involved in decision-making in selecting second-line ITP treatments, given the absence of comparative trials. It highlights shared decision-making and the need for well-conducted, comparative effectiveness studies to allow for informed discussion between patients and clinicians.


Assuntos
Tomada de Decisão Clínica , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Criança , Tomada de Decisões , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Médicos/psicologia , Rituximab/uso terapêutico , Esplenectomia
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