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1.
J Allergy Clin Immunol ; 146(5): 1194-1200.e1, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32853638

RESUMO

BACKGROUND: We studied 2 unrelated patients with immune thrombocytopenia and autoimmune hemolytic anemia in the setting of acute infections. One patient developed multisystem inflammatory syndrome in children in the setting of a severe acute respiratory syndrome coronavirus 2 infection. OBJECTIVES: We sought to identify the mechanisms underlying the development of infection-driven autoimmune cytopenias. METHODS: Whole-exome sequencing was performed on both patients, and the impact of the identified variants was validated by functional assays using the patients' PBMCs. RESULTS: Each patient was found to have a unique heterozygous truncation variant in suppressor of cytokine signaling 1 (SOCS1). SOCS1 is an essential negative regulator of type I and type II IFN signaling. The patients' PBMCs showed increased levels of signal transducer and activator of transcription 1 phosphorylation and a transcriptional signature characterized by increased expression of type I and type II IFN-stimulated genes and proapoptotic genes. The enhanced IFN signature exhibited by the patients' unstimulated PBMCs parallels the hyperinflammatory state associated with multisystem inflammatory syndrome in children, suggesting the contributions of SOCS1 in regulating the inflammatory response characteristic of multisystem inflammatory syndrome in children. CONCLUSIONS: Heterozygous loss-of-function SOCS1 mutations are associated with enhanced IFN signaling and increased immune cell activation, thereby predisposing to infection-associated autoimmune cytopenias.


Assuntos
Anemia Hemolítica Autoimune/imunologia , Anemia Hemolítica Autoimune/virologia , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/virologia , Trombocitopenia/imunologia , Trombocitopenia/virologia , Adolescente , Anemia Hemolítica Autoimune/genética , Betacoronavirus , Pré-Escolar , Infecções por Coronavirus/imunologia , Haploinsuficiência , Humanos , Masculino , Mutação , Pandemias , Pneumonia Viral/imunologia , Proteína 1 Supressora da Sinalização de Citocina/genética , Trombocitopenia/genética
4.
Blood ; 135(15): 1270-1280, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32077913

RESUMO

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by complexes between platelet factor 4 (PF4) and heparin or other polyanions, but the risk of thrombosis extends beyond exposure to heparin implicating other PF4 partners. We recently reported that peri-thrombus endothelium is targeted by HIT antibodies, but the binding site(s) has not been identified. We now show that PF4 binds at multiple discrete sites along the surface of extended strings of von Willebrand factor (VWF) released from the endothelium following photochemical injury in an endothelialized microfluidic system under flow. The HIT-like monoclonal antibody KKO and HIT patient antibodies recognize PF4-VWF complexes, promoting platelet adhesion and enlargement of thrombi within the microfluidic channels. Platelet adhesion to the PF4-VWF-HIT antibody complexes is inhibited by antibodies that block FcγRIIA or the glycoprotein Ib-IX complex on platelets. Disruption of PF4-VWF-HIT antibody complexes by drugs that prevent or block VWF oligomerization attenuate thrombus formation in a murine model of HIT. Together, these studies demonstrate assembly of HIT immune complexes along VWF strings released by injured endothelium that might propagate the risk of thrombosis in HIT. Disruption of PF4-VWF complex formation may provide a new therapeutic approach to HIT.


Assuntos
Anticorpos/imunologia , Anticoagulantes/efeitos adversos , Heparina/efeitos adversos , Fator Plaquetário 4/imunologia , Trombocitopenia/induzido quimicamente , Trombose/etiologia , Fator de von Willebrand/imunologia , Animais , Anticoagulantes/imunologia , Heparina/imunologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Adesividade Plaquetária , Trombocitopenia/complicações , Trombocitopenia/imunologia , Trombocitopenia/patologia , Trombose/imunologia , Trombose/patologia
5.
Biol Pharm Bull ; 43(4): 669-674, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32037352

RESUMO

Despite in vivo studies suggesting that obesity increases carboplatin (CBDCA) bone marrow toxicity, the American Society of Clinical Oncology recommends that full weight-based cytotoxic chemotherapy doses be used to treat obese patients with cancer. Accordingly, the present study retrospectively investigated the effect of body mass index (BMI) on bone marrow toxicity in patients with gynecological cancer who underwent paclitaxel and carboplatin (TC) therapy after eliminating the effect of the target area under the curve (AUC). Risk factors for CBDCA bone marrow toxicity were also identified. A total of 110 patients with primary gynecological cancer or gynecological cancer of unknown primary origin who underwent TC therapy with a target AUC of 5-6 were included herein. Patients with a BMI of ≥25 and <25 kg/m2 were assigned to the obesity and control groups, respectively, and evaluated according to changes in hematological test values (platelet, white blood cell, and hemoglobin counts) starting from initial TC therapy administration until 21 d after the second treatment course. The obesity group had a significantly higher thrombocytopenia rate than the control group. Risk factors for thrombocytopenia ≥ grade 2 included BMI ≥25 kg/m2. Among patients with primary gynecological cancer or gynecological cancer of unknown primary origin who had a BMI of ≥25 kg/m2, those receiving CBDCA may be at increased risk for thrombocytopenia ≥ grade 2 when the dosage is calculated using the Calvert formula with the creatinine clearance level.


Assuntos
Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Neoplasias dos Genitais Femininos/tratamento farmacológico , Obesidade/complicações , Paclitaxel/efeitos adversos , Trombocitopenia/induzido quimicamente , Idoso , Índice de Massa Corporal , Feminino , Hemoglobinas/análise , Humanos , Contagem de Leucócitos , Pessoa de Meia-Idade , Obesidade/imunologia , Contagem de Plaquetas , Fatores de Risco , Trombocitopenia/imunologia
7.
Int Immunopharmacol ; 80: 106127, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978798

RESUMO

BACKGROUND: The increased differentiation of T helper 17 cells (Th17) accelerates the development of immune thrombocytopenia (ITP), which is a common autoimmune disease with limited therapeutic methods. Recent studies have revealed that long non-coding RNAs (lncRNAs) play a critical role in autoimmune diseases, thus this study aims to investigate the effect of lncRNA GAS5 on the differentiation of Th17 cells in ITP. METHODS: The expression of GAS5 in peripheral blood mononuclear cells (PBMCs) of ITP patients and spleen tissues of ITP mice was measured by qRT-PCR. The percentage of Th17 cells in CD4+ cells was measured by flow cytometry. The combination between GAS5 and STAT3 was confirmed by RNA pull-down assay and RNA Binding Protein Immunoprecipitation (RIP). The ubiquitination of STAT3 was detected by ubiquitination assay and the interaction between STAT3 and TRAF6 was measured by Co-Immunoprecipitation (Co-IP). Finally, the effect of GAS5 on Th17 differentiation was investigated in vitro and in vivo using lentivirus (lenti)-GAS5. RESULTS: GAS5 expression was downregulated both in PBMCs of ITP patients and spleen tissues of ITP mice. Overexpression of GAS5 suppressed Th17 differentiation while had no effect on Treg differentiation in naïve CD4+ cells. RNA pull-down and RNA immunoprecipitation assays confirmed the interaction between GAS5 and STAT3. Further studies showed GAS5 accelerated the degradation of STAT3 via promoting TRAF6-mediated ubiquitination. Overexpressing GAS5 suppressed Th17 differentiation in vitro and alleviated ITP in vivo via reducing STAT3. CONCLUSION: LncRNA GAS5 inhibited Th17 differentiation through promoting the TRAF6-mediated ubiquitination of STAT3, thus relieving ITP.


Assuntos
RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/metabolismo , Células Th17/imunologia , Trombocitopenia/genética , Adulto , Animais , Estudos de Casos e Controles , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Proteólise , Baço/imunologia , Baço/patologia , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Trombocitopenia/sangue , Trombocitopenia/imunologia , Trombocitopenia/patologia , Ubiquitinação/genética
8.
Mod Rheumatol ; 30(1): 116-124, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30557100

RESUMO

Objectives: Thrombocytopenia is frequently observed in antiphospholipid antibody (aPL) carriers. Due to the paradoxical risks of thrombosis and hemorrhage, the management of aPL-associated thrombocytopenia (APAT) is often deductive. We aimed to investigate the efficacy and safety of therapeutic approaches for APAT through a systematic review.Methods: Four therapeutic approaches for APAT, including antiplatelet agents, glucocorticoids, splenectomy and thrombopoietin receptor agonists, were selected. Clinical trials evaluating therapeutic outcomes including the remission, complications, mortality and relapse, were searched in MEDLINE, EMBASE and CENTRAL from the inception dates to 28 November 2016. A meta-analysis was performed to calculate risk ratios (RRs) and 95% confidence intervals (CIs) using random-effects models.Results: Out of 1407 papers, eight controlled clinical trials were included. In patients with APAT, the remission rates were higher in patients on glucocorticoids (RR 8.33 [95% CI 3.07-22.6]) or splenectomy (RR 8.37 [95% CI 1.61-43.7]) than in patients without those treatments. There was no significant association between glucocorticoids and thrombosis (RR 1.57 [95% CI, 0.17-14.9]) or between splenectomy and hemorrhage (RR 0.17 [95% CI 0.02-1.28]). The extracted data of mortality and relapse rate were not available for synthesis.Conclusion: Glucocorticoids or splenectomy seemed suitable therapeutic approaches for APAT.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Glucocorticoides/uso terapêutico , Hemorragia/prevenção & controle , Inibidores da Agregação de Plaquetas/uso terapêutico , Esplenectomia/métodos , Trombocitopenia/terapia , Trombose/prevenção & controle , Anticorpos Antifosfolipídeos/sangue , Hemorragia/etiologia , Humanos , Receptores de Trombopoetina/agonistas , Trombocitopenia/sangue , Trombocitopenia/imunologia , Trombose/etiologia
10.
Sci Rep ; 9(1): 17497, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767905

RESUMO

Thrombocytopenia is usually associated with liver injury, elevated plasma aspartate aminotransferase and alanine aminotransferase levels, and high antiplatelet immunoglobulin (Ig) titers, although the mechanism behind these effects remains elusive. Deciphering the mechanism behind acute liver disease-associated thrombocytopenia may help solve difficulties in routine patient care, such as liver biopsy, antiviral therapy, and surgery. To determine whether liver damage is sufficient per se to elicit thrombocytopenia, thioacetamide (TAA)-induced hepatitis rodent models were employed. The analysis results indicated that TAA treatment transiently induced an elevation of antiplatelet antibody titer in both rats and mice. B-cell-deficient (BCD) mice, which have loss of antibody expression, exhibited markedly less thrombocytopenia and liver damage than wild-type controls. Because TAA still induces liver damage in BCD mice, this suggests that antiplatelet Ig is one of the pathogenic factors, which play exacerbating role in the acute phase of TAA-induced hepatitis. TNF-α was differentially regulated in wild-type versus BCD mice during TAA treatment, and anti-TNF treatment drastically ameliorated antiplatelet Ig induction, thrombocytopenia, and liver injury, suggesting that the TNF pathway plays a critical role in the disease progression.


Assuntos
Antígenos de Plaquetas Humanas/imunologia , Autoanticorpos/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Tioacetamida/efeitos adversos , Trombocitopenia/imunologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/complicações , Modelos Animais de Doenças , Progressão da Doença , Humanos , Masculino , Camundongos , Ratos , Trombocitopenia/induzido quimicamente , Fator de Necrose Tumoral alfa/metabolismo
11.
J Clin Immunol ; 39(8): 786-794, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31620947

RESUMO

BACKGROUND: We undertook a study to determine the impact of Wiskott Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT) and their therapies upon the health-related quality of life (HRQOL) of patients and their families. MATERIALS AND METHODS: We undertook a survey of patients and their families, who self-identified as having either WAS or XLT. We assessed the PedsQL™ 4.0, the parent proxy form, and the family impact module. These results were compared with normative data from previously published reports. RESULTS: Sixty-eight patients (29 patients completed both the PedsQL™ 4.0 and the parent proxy form; 21 completed only the PedsQL™ 4.0; and 18 completed only the parent proxy form) were included. In contrast to patient-reported outcomes, parents of patients who had a bone marrow transplant (BMT) reported that their children had better QOL scores compared with those who did not (82.6 vs. 73.3, p = 0.023). The QOL of patients vs. previously published normative data showed decreases in patient scores for psychosocial health (72.62 vs. 86.58, p = < 0.001), emotional functioning (69.91 vs. 82.64, p = < 0.001), social functioning (77.55 vs. 91.56, p = < 0.001), and school functioning (70.46 vs. 85.67, p = < 0.001). The family impact study revealed deficits in emotional, social, and cognitive functioning, communication, and worry. CONCLUSION: These results show that patients with WAS/XLT are significantly impacted with respect to QOL. BMT offered a better QOL for patients according to parents, but not as reported by the patients. Future studies should incorporate QOL to provide more data and a better understanding of outcomes for long-term survivors and decision-making regarding BMT.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/psicologia , Pais/psicologia , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Trombocitopenia/psicologia , Síndrome de Wiskott-Aldrich/psicologia , Adolescente , Transplante de Medula Óssea , Cuidadores/psicologia , Criança , Pré-Escolar , Tomada de Decisões , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Masculino , Inquéritos e Questionários/estatística & dados numéricos , Sobreviventes/psicologia , Trombocitopenia/complicações , Trombocitopenia/imunologia , Trombocitopenia/terapia , Síndrome de Wiskott-Aldrich/complicações , Síndrome de Wiskott-Aldrich/imunologia , Síndrome de Wiskott-Aldrich/terapia , Adulto Jovem
12.
BMC Res Notes ; 12(1): 604, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547852

RESUMO

OBJECTIVE: Objective of the study is to evaluate the on-admission day symptoms and signs, clinical, hematological parameters and liver transaminases of the dengue NS1 positive patients who got admitted on different clinical phases [Febrile phase (day 1-3) and Critical phase(day 4-5)] of dengue at medical wards of Jaffna Teaching Hospital. RESULTS: Blood samples were collected from 150 suspected dengue patients from day 1 to 5 of the illness. Seventy-eight patients were positive for dengue NS1, according to the WHO proposed dengue clinical phase framework 37 patients were from febrile phase and 41 patients from critical phase. Patients who admitted on critical phase framework suffered from leukopenia and thrombocytopenia. Nine patients had the evidence of leakage with fever and the leakers had significant rise in hemoglobin, hematocrit and liver transaminase levels which are considered as severe form of the disease.


Assuntos
Vírus da Dengue/patogenicidade , Febre/diagnóstico , Hospitais de Ensino , Leucopenia/diagnóstico , Dengue Grave/diagnóstico , Trombocitopenia/diagnóstico , Proteínas não Estruturais Virais/sangue , Adolescente , Adulto , Vírus da Dengue/imunologia , Progressão da Doença , Feminino , Febre/sangue , Febre/imunologia , Febre/virologia , Hospitalização , Humanos , Leucopenia/sangue , Leucopenia/imunologia , Leucopenia/virologia , Fígado/patologia , Fígado/virologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Dengue Grave/sangue , Dengue Grave/imunologia , Dengue Grave/virologia , Sri Lanka , Trombocitopenia/sangue , Trombocitopenia/imunologia , Trombocitopenia/virologia , Transaminases/sangue , Proteínas não Estruturais Virais/imunologia
14.
BMJ Case Rep ; 12(9)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31488440

RESUMO

We present a case of a 47-year-old man with severe thrombocytopenia. The differential diagnosis for thrombocytopenia is wide. The assessment includes an evaluation for falsely low platelet counts (pseudothrombocytopenia), immune-mediated platelet destruction, bone marrow dysfunction, or increased consumption and sequestration. After extensive and systematic workup, we found a relationship of his thrombocytopenia with haemodialysis. Although not widely recognised by clinicians, partly due to an incomplete understanding of its pathophysiology, haemodialysis is also a potential cause of thrombocytopenia. His platelet counts completely normalised after the substitution of his haemodialysis membrane. We concluded that our patient had haemodialysis-induced thrombocytopenia, most likely secondary to electron-beam sterilisation.


Assuntos
Membranas Artificiais , Diálise Renal/efeitos adversos , Trombocitopenia/etiologia , Materiais Biocompatíveis/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Polímeros/uso terapêutico , Diálise Renal/instrumentação , Esterilização , Sulfonas/uso terapêutico , Trombocitopenia/imunologia
15.
Autoimmun Rev ; 18(11): 102395, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520800

RESUMO

BACKGROUND: According to criteria for the classification of Systemic Lupus Erythematosus (SLE), thrombocytopenia is one of the disease-defining hematologic disorders. Since the recognition of Antiphospholipid Syndrome (APS), thrombocytopenia was frequently reported but several studies yielded contradictory results on the association between aPL-positivity and thrombocytopenia. METHODS: We evaluated the role of antiphospholipid antibodies (aPL) and different aPL profiles on the risk of thrombocytopenia in SLE patients by conducting a systematic review and meta-analysis of available literature from 1987 to 2018. MEDLINE, EMBASE, Cochrane Library, congress abstracts, and reference lists of eligible studies were searched. Studies were selected if they included SLE patients with descriptions of the exposure to aPL and the outcomes (thrombocytopenia). Two reviewers extracted study characteristics and outcome data from published reports. Estimates were pooled using random effects models and sensitivity analyses. We followed the PRISMA guidelines for all stages of the meta-analysis. PROSPERO registration number: CRD42015027378. RESULTS: From 3278 articles identified, 53 studies met inclusion criteria amounting to 9019 SLE patients. Twenty-nine percent of aPL-positive SLE patients had thrombocytopenia compared to 15.1% in aPL-negative SLE patients. The overall pooled Odds Ratio (OR) for thrombocytopenia in aPL positive patients was 2.48 (95% CI; 2.10-2.93). Among aPL subtypes, the risk of thrombocytopenia was highest for lupus anticoagulant (OR = 3.56 [95% CI, 2.57-5.25]), IgM anti-ß2-GP1(OR = 2.87 [95% CI; 2.57-5.25]), IgG and IgM anticardiolipin antibodies (OR = 1.87 [95% CI; 1.52-2.31] and OR = 1.73 [95% CI; 1.36-2.19] respectively). CONCLUSIONS: The occurrence of thrombocytopenia was strongly determined by various aPL profiles in SLE patients. While the association between IgM antibodies and other APS manifestations including thrombosis is debated, IgM isotypes are helpful in the risk stratification of thrombocytopenia in SLE.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Lúpus Eritematoso Sistêmico/epidemiologia , Trombocitopenia/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Estudos Transversais , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Fatores de Risco , Trombocitopenia/imunologia
16.
Biomater Sci ; 7(11): 4568-4577, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31414106

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune disorder in which platelet-reactive autoantibodies accelerate the destruction of platelets. Macrophages play an important role in ITP through Fc receptor (FcR)-mediated antigen presenting and platelet clearance. In this study, a novel drug delivery system of vincristine-loaded platelets coated with anti-CD41 mAbs (CD41-VCR-PLT, CD41-VLP) was successfully established. The therapeutic effects and safety of CD41-VLP in vitro and in vivo were evaluated, and the possible mechanism was also explored. The results showed that PLT-CD41 could load VCR with high drug loading (DL) and encapsulation efficiency (EE), which were up to 41.16 ± 1.92% and 60.73 ± 2.79%, respectively, where platelets had no obvious morphological or functional changes. CD41-VLP could facilitate vincristine accumulation in macrophages, where the intracellular VCR concentration was 30.72 ± 3.11% at 72 h, which was significantly increased compared with the other groups (P < 0.01), thus inhibiting macrophage cell viability and inducing apoptosis. The cell viability inhibition rate and total apoptosis rate were 73.06 ± 5.26% and 69.70 ± 4.26%, respectively, both much higher than those of the other groups (P < 0.05). In the ITP mouse model, CD41-VLP increased the platelet count in peripheral blood, which was 720 ± 197.98 × 109 L-1, and significantly improved the platelet count compared with that in the VCR group (P < 0.05); moreover, it reduced the systemic toxicity and peripheral neurotoxicity of vincristine. The possible mechanism was that CD41-VLP could precisely target M1 macrophages in spleen and liver tissues through FcγR, thus reducing the platelet destruction caused by M1 macrophages. Therefore, CD41-VLP provides a new targeted therapy for ITP treatment.


Assuntos
Anticorpos Monoclonais/imunologia , Macrófagos/efeitos dos fármacos , Glicoproteína IIb da Membrana de Plaquetas/imunologia , Trombocitopenia/tratamento farmacológico , Vincristina/farmacologia , Animais , Anticorpos Monoclonais/química , Apoptose/efeitos dos fármacos , Plaquetas/química , Plaquetas/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Glicoproteína IIb da Membrana de Plaquetas/química , Células THP-1 , Trombocitopenia/imunologia , Células Tumorais Cultivadas , Vincristina/química
17.
BMJ Case Rep ; 12(7)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371330

RESUMO

Thrombocytopaenia can be associated with an autoimmune mechanism. Immune thrombocytopaenia can be associated with thyroid autoimmune disease. The authors present a case of a teenager with a history of thrombocytopaenia who complained of tiredness. Laboratory investigation showed thyroid autoantibodies. The co-existence of thrombocytopaenia and thyroiditis lead to further investigation and antibodies against platelet glycoprotein IIbIIIa were found. This case illustrates the association of the overlap aspects between thyroid and platelet autoimmunity.


Assuntos
Autoanticorpos/imunologia , Trombocitopenia/imunologia , Tireoidite Autoimune/imunologia , Adolescente , Autoanticorpos/sangue , Feminino , Humanos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/imunologia , Trombocitopenia/sangue , Tireoidite Autoimune/sangue
18.
Hematology ; 24(1): 588-595, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31392938

RESUMO

Objective: To explore the activity of B subsets from Autoimmune Hemolytic Anemia/Evans syndrome (AIHA/ES) patients. Methods: The expression of Bruton's tyrosine kinase (BTK) and phosphorylated BTK (p-BTK) on CD5+CD19+B and CD5-CD19+B lymphocytes were detected using flow cytometry in AIHA/ES patients with different disease states, healthy controls (HCs) and chronic lymphocytic leukemia (CLL) patients. The correlations of expressed BTK and p-BTK with clinical variables were analyzed. Results: Thirty six AIHA/ES patients (16 hemolytic, 20 remission), 11 CLL patients, and 15 HCs were enrolled. The expression levels of BTK and p-BTK on CD5+B lymphocytes in AIHA/ES patients were higher than those in HCs and CLL patients. The latter two groups had no significant difference, and were positively correlated with the quantity of IgE. The ratio of p-BTK to BTK on CD5+B lymphocytes of the hemolytic and remission groups was obviously higher than that on CD5-B lymphocytes (74.62 ± 6.42% and 29.63 ± 10.19%, respectively; P = 0.001 versus 77.95 ± 9.57% and 26.29 ± 6.86%, respectively; P = 0.006). The ratio of p-BTK to BTK on CD5+B lymphocytes (54.89 ± 9.56%) and CD5-B lymphocytes (30.86 ± 12.47%) did not differ significantly in HCs (P = 0.109). BTK did not differ significantly between CD5+ and CD5-B lymphocytes in AIHA/ES, but p-BTK on CD5+B lymphocytes was significantly higher than that on CD5-B lymphocytes in AIHA/ES patients. Conclusions: CD5+B lymphocytes are the major B subtype that is activated in AIHA/ES patients and it positively correlates with IgE.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Anemia Hemolítica Autoimune/imunologia , Linfócitos B/metabolismo , Trombocitopenia/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
J Thromb Haemost ; 17(12): 2123-2130, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31420903

RESUMO

BACKGROUND: Accurate diagnosis of heparin-induced thrombocytopenia (HIT) is essential to ensure timely treatment and prevent complications. Current diagnostic assays include enzyme-linked immunosorbent assays (ELISAs) and rapid immunoassays (RIs). RIs offer fast turnaround times but were not significantly represented in previous external proficiency testing challenges. OBJECTIVES: To use external proficiency testing to assess qualitative concordance for heparin/PF4 antibody detection. METHODS: From 2013 to 2017, the External Quality Control for Assays and Tests (ECAT) Foundation distributed 10 samples internationally. RESULTS: In total, 437 laboratories submitted 3149 results. ELISAs accounted for 1484 (47%) responses with RIs accounting for 1665 (53%) responses. RI use increased over the 5-year period. ELISAs classified 96% of both consensus positive and consensus negative samples concordantly. The coefficient of variation (CV) for positive sample optical densities (ODs) ranged from 35% to 50% when combining ELISA assay methods together. Quantitative RIs classified 97% of consensus-positive and 98% of consensus-negative samples concordantly. Qualitative RIs had a higher proportion of discordant responses and classified 88% of consensus-positive samples and 73% of consensus-negative samples concordantly. Of RIs only latex immunoassays and IgG specific chemiluminescent assays identified > 95% of samples concordantly with consensus. CONCLUSION: Quantitative RIs and ELISAs classify > 95% of samples concordantly. The ODs from different ELISA methods vary considerably and are not interchangeable. Qualitative RI use is increasing despite a greater proportion of discordant classifications. This includes a higher than expected number of negative classifications for consensus-positive samples among many RIs, challenging their use as "rule out" tests.


Assuntos
Anticorpos/sangue , Anticoagulantes/efeitos adversos , Ensaio de Imunoadsorção Enzimática/normas , Heparina/efeitos adversos , Ensaio de Proficiência Laboratorial , Fator Plaquetário 4/imunologia , Radioimunoensaio/normas , Testes Sorológicos/normas , Trombocitopenia/diagnóstico , Anticoagulantes/imunologia , Austrália , Biomarcadores/sangue , Europa (Continente) , Heparina/imunologia , Humanos , Israel , América do Norte , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente , Trombocitopenia/imunologia
20.
Arthritis Res Ther ; 21(1): 161, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262358

RESUMO

BACKGROUND: Thrombocytopenia is a manifestation associated with primary antiphospholipid syndrome (PAPS), and many studies have stressed the leading role played by platelets in the pathogenesis of antiphospholipid syndrome (APS). Platelets are highly specialized cells, and their activation involves a series of rapid rearrangements of the actin cytoskeleton. Recently, we described the presence of autoantibodies against D4GDI (Rho GDP dissociation inhibitor beta, ARHGDIB) in the serum of a large subset of SLE patients, and we observed that anti-D4GDI antibodies activated the cytoskeleton remodeling of lymphocytes by inhibiting D4GDI and allowing the upregulation of Rho GTPases, such as Rac1. Proteomic and transcriptomic studies indicate that D4GDI is very abundant in platelets, and small GTPases of the RHO family are critical regulators of actin dynamics in platelets. METHODS: We enrolled 38 PAPS patients, 15 patients carrying only antiphospholipid antibodies without clinical criteria of APS (aPL carriers) and 20 normal healthy subjects. Sera were stored at - 20 °C to perform an ELISA test to evaluate the presence of anti-D4GDI antibodies. Then, we purified autoantibodies anti-D4GDI from patient sera. These antibodies were used to conduct in vitro studies on platelet activation. RESULTS: We identified anti-D4GDI antibodies in sera from 18/38 (47%) patients with PAPS, in sera from 2/15(13%) aPL carriers, but in no sera from normal healthy subjects. Our in vitro results showed a significant 30% increase in the activation of integrin αIIbß3 upon stimulation of platelets from healthy donors preincubated with the antibody anti-D4GDI purified from the serum of APS patients. CONCLUSIONS: In conclusion, we show here that antibodies anti-D4GDI are present in the sera of PAPS patients and can prime platelet activation, explaining, at least in part, the pro-thrombotic state and the thrombocytopenia of PAPS patients. These findings may lead to improved diagnosis and treatment of APS.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Autoanticorpos/sangue , Plaquetas/imunologia , Ativação Plaquetária/imunologia , Trombocitopenia/etiologia , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/complicações , Autoanticorpos/imunologia , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Seguimentos , Humanos , Proteômica , Estudos Retrospectivos , Trombocitopenia/sangue , Trombocitopenia/imunologia
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