RESUMEN
Immune thrombocytopenia (ITP) is a highly heterogeneous autoimmune bleeding disorder characterized by low platelet counts due to an immune-mediated platelet destruction and impaired platelet production. The pathophysiology is multifactorial and remains to be fully unravelled. Consequently, disease trajectories and responses to therapeutics, despite the availability of multiple agents, can be unpredictable and differing between patients. There is an urgent need for the identification of diagnostic and therapeutic biomarkers, but this has proven to be challenging to achieve. To shed light on this, two studies in this issue of the British Journal of Haematology have recognized the opportunity of using high-throughput Omics technologies in ITP. Sun et al. performed proteomics, and Li et al. metabolomics, on bone marrow biopsy samples of patients with ITP. This was conducted using mass spectrometry and, due to the generation of large datasets, in combination with machine learning. These studies set the stage for further investigations exploring the high potential of multi-omics technologies in order to shed light on the heterogeneity in ITP, accelerating the path towards a much needed personalized medicine approach. Commentary on: Li et al. Metabolomics profile and machine learning prediction of treatment responses in immune thrombocytopenia: A prospective cohort study. Br J Haematol 2024;204:2405-2417. Commentary on: Sun et al. Proteomics landscape and machine learning prediction of long-term response to splenectomy in primary immune thrombocytopenia. Br J Haematol 2024;204:2418-2428.
Asunto(s)
Metabolómica , Proteómica , Púrpura Trombocitopénica Idiopática , Humanos , Púrpura Trombocitopénica Idiopática/terapia , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/genética , Púrpura Trombocitopénica Idiopática/sangre , Proteómica/métodos , Metabolómica/métodos , Biomarcadores , Aprendizaje AutomáticoRESUMEN
Chronic refractory primary immune thrombocytopenia (CRITP) is currently defined as refractory to multiple therapeutic of second-line agents with or without splenectomy, faced with the threat of severe bleeding and challenging to obtain effective treatment. Although stable and effective drug therapy is needed, it is tough to find one. Daratumumab (Dara), an anti-CD38 monoclonal antibody presented the target cloned plasma cells in multiple myeloma, has also been reported to be effective in refractory autoimmune cytopenia in some case or series reports and ongoing clinical trials for adult patients with CRITP. Here, we report the early and durable response of Dara combination with avatrombopag in three CRITP patients (2 male and 1 female aged 12, 5 and 7 years, respectively) in our centre, with a follow-up period of more than 25 weeks. Before Dara, the duration of immune thrombocytopenia was 9, 1.4 and 4 years, respectively, a baseline platelet count of 4, 6, 9 × 109/L, the bleeding score was all above level 2 and the number of previous drugs was >3. The time to response (R: Plt ≥30 × 109/L with at least a twofold increase in the baseline count) of Dara was on Day 45, 6 and 4 and achieved complete response (CR: Plt ≥100 × 109/L) on Day 51, 6 and 8, the sustained response (SR: Plt >30 × 109/L following Dara at ≥75% of the platelet count assessment at follow-up end-point since the patient achieved response) was 48, 175 and 204 days with the follow-up time of 39.1, 25.9 and 29.7 weeks. The bleeding score decreased from grade 3 to grade 0 during follow-up. No significant treatment-related adverse events were found during follow-up. Dara combination with avatrombopag may be a safe and efficacious therapy for children with CRITP, but it needs to be further explored.
Asunto(s)
Anticuerpos Monoclonales , Púrpura Trombocitopénica Idiopática , Humanos , Masculino , Femenino , Niño , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/sangre , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , China , Preescolar , Enfermedad Crónica , Resultado del Tratamiento , Recuento de PlaquetasRESUMEN
This study aimed to identify key proteomic analytes correlated with response to splenectomy in primary immune thrombocytopenia (ITP). Thirty-four patients were retrospectively collected in the training cohort and 26 were prospectively enrolled as validation cohort. Bone marrow biopsy samples of all participants were collected prior to the splenectomy. A total of 12 modules of proteins were identified by weighted gene co-expression network analysis (WGCNA) method in the developed cohort. The tan module positively correlated with megakaryocyte counts before splenectomy (r = 0.38, p = 0.027), and time to peak platelet level after splenectomy (r = 0.47, p = 0.005). The blue module significantly correlated with response to splenectomy (r = 0.37, p = 0.0031). KEGG pathways analysis found that the PI3K-Akt signalling pathway was predominantly enriched in the tan module, while ribosomal and spliceosome pathways were enriched in the blue module. Machine learning algorithm identified the optimal combination of biomarkers from the blue module in the training cohort, and importantly, cofilin-1 (CFL1) was independently confirmed in the validation cohort. The C-index of CFL1 was >0.7 in both cohorts. Our results highlight the use of bone marrow proteomics analysis for deriving key analytes that predict the response to splenectomy, warranting further exploration of plasma proteomics in this patient population.
Asunto(s)
Aprendizaje Automático , Proteómica , Púrpura Trombocitopénica Idiopática , Esplenectomía , Humanos , Masculino , Femenino , Proteómica/métodos , Púrpura Trombocitopénica Idiopática/cirugía , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/genética , Adulto , Persona de Mediana Edad , Biomarcadores/sangre , Anciano , Estudios RetrospectivosRESUMEN
Avatrombopag (AVA) is a novel thrombopoietin receptor agonist (TPO-RA) that has been recently approved as a second-line therapy for immune thrombocytopenia (ITP) in adults; however, its safety and efficacy data in children are lacking. Here, we demonstrated the efficacy and safety of AVA as second-line therapy in children with ITP. A multicentre, retrospective, observational study was conducted in children with persistent or chronic ITP who did not respond to or relapsed from previous treatment and were treated with AVA for at least 12 weeks between August 2020 and December 2022. The outcomes were the responses (defined as achieving a platelet count ≥30 × 109/L, twofold increase in platelet count from baseline and absence of bleeding), including rapid response within 4 weeks, sustained response at weeks 12 and 24, bleeding control and adverse events (AEs). Thirty-four (18 males) patients with a mean age of 6.3 (range: 1.9-15.3) years were enrolled. The median number of previous treatment types was four (range: 1-6), and 41.2% patients switched from other TPO-RAs. Within 4 weeks, overall response (OR) was achieved in 79.4% patients and complete response (CR, defined as a platelet count ≥100 × 109/L and the absence of bleeding) in 67.7% patients with a median response time of 7 (range: 1-27) days. At 12 weeks, OR was achieved in 88.2%, CR in 76.5% and sustained response in 44% of patients. At 24 weeks, 22/34 (64.7%) patients who achieved a response and were followed up for 24 weeks were evaluated; 12/22 (54.55%) achieved a sustained response. During AVA therapy, median platelet counts increased by week 1 and were maintained throughout the treatment period. The proportion of patients with grade 1-3 bleeding decreased from 52.95% at baseline to 2.94% at 12 weeks, while concomitant ITP medications decreased from 36.47% at baseline to 8.82% at 12 weeks, with only 9 (26.47%) patients receiving rescue therapy 23 times within 12 weeks. There were 61.8% patients with 59 AEs: 29.8% with Common Terminology Criteria for Adverse Events grade 1 and the rest with grade 2. These findings show that AVA could achieve a rapid and sustained response in children with persistent or chronic ITP as a second-line treatment, with good clinical bleeding control and reduction of concomitant ITP therapy, without significant AEs.
Asunto(s)
Púrpura Trombocitopénica Idiopática , Humanos , Niño , Masculino , Femenino , Estudios Retrospectivos , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/sangre , Preescolar , Adolescente , Lactante , China , Enfermedad Crónica , Resultado del Tratamiento , Recuento de Plaquetas , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Hemorragia/inducido químicamente , Receptores de Trombopoyetina/agonistas , Pueblos del Este de Asia , Tiazoles , TiofenosRESUMEN
Immune thrombocytopenia (ITP) is an autoimmune disease characterized by antibody-mediated platelet destruction and impaired platelet production. The mechanisms underlying ITP and biomarkers predicting the response of drug treatments are elusive. We performed a metabolomic profiling of bone marrow biopsy samples collected from ITP patients admission in a prospective study of the National Longitudinal Cohort of Hematological Diseases. Machine learning algorithms were conducted to discover novel biomarkers to predict ITP patient treatment responses. From the bone marrow biopsies of 91 ITP patients, we quantified a total of 4494 metabolites, including 1456 metabolites in the positive mode and 3038 metabolites in the negative mode. Metabolic patterns varied significantly between groups of newly diagnosed and chronic ITP, with a total of 876 differential metabolites involved in 181 unique metabolic pathways. Enrichment factors and p-values revealed the top metabolically enriched pathways to be sphingolipid metabolism, the sphingolipid signalling pathway, ubiquinone and other terpenoid-quinone biosynthesis, thiamine metabolism, tryptophan metabolism and cofactors biosynthesis, the phospholipase D signalling pathway and the phosphatidylinositol signalling system. Based on patient responses to five treatment options, we screened several metabolites using the Boruta algorithm and ranked their importance using the random forest algorithm. Lipids and their metabolism, including long-chain fatty acids, oxidized lipids, glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine biosynthesis, helped differentiate drug treatment responses. In conclusion, this study revealed metabolic alterations associated with ITP in bone marrow supernatants and a potential biomarker predicting the response to ITP.
Asunto(s)
Aprendizaje Automático , Metabolómica , Púrpura Trombocitopénica Idiopática , Humanos , Púrpura Trombocitopénica Idiopática/metabolismo , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/sangre , Estudios Prospectivos , Masculino , Femenino , Persona de Mediana Edad , Metabolómica/métodos , Adulto , Anciano , Biomarcadores , Metaboloma , Redes y Vías Metabólicas , Resultado del Tratamiento , Médula Ósea/metabolismo , Médula Ósea/patologíaRESUMEN
Cases of de novo immune thrombocytopenia (ITP), including a fatality, following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in preexisting ITP. In this study, 4 data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a 10-center retrospective study of adults with preexisting ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] ×109/L approximately 1 week postvaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 117 patients with preexisting ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30 × 109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK patients with ITP, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in preexisting ITP or be identified de novo post-SARS-CoV2 vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those postsplenectomy and with more refractory disease, is indicated.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Púrpura Trombocitopénica Idiopática , SARS-CoV-2 , Anciano , Anciano de 80 o más Años , Plaquetas/inmunología , Plaquetas/metabolismo , COVID-19/sangre , COVID-19/epidemiología , COVID-19/inmunología , COVID-19/prevención & control , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/inducido químicamente , Púrpura Trombocitopénica Idiopática/epidemiología , Púrpura Trombocitopénica Idiopática/inmunología , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2/inmunología , SARS-CoV-2/metabolismo , Esplenectomía , Reino Unido/epidemiologíaRESUMEN
As a versatile element for maintaining homeostasis, the chemokine system has been reported to be implicated in the pathogenesis of immune thrombocytopenia (ITP). However, research pertaining to chemokine receptors and related ligands in adult ITP is still limited. The states of several typical chemokine receptors and cognate ligands in the circulation were comparatively assessed through various methodologies. Multiple variable analyses of correlation matrixes were conducted to characterize the correlation signatures of various chemokine receptors or candidate ligands with platelet counts. Our data illustrated a significant decrease in relative CXCR3 expression and elevated plasma levels of CXCL4, 9-11, 13, and CCL3 chemokines in ITP patients with varied platelet counts. Flow cytometry assays revealed eminently diminished CXCR3 levels on T and B lymphocytes and increased CXCR5 on cytotoxic T cell (Tc) subsets in ITP patients with certain platelet counts. Meanwhile, circulating CX3CR1 levels were markedly higher on T cells with a concomitant increase in plasma CX3CL1 level in ITP patients, highlighting the importance of aberrant alterations of the CX3CR1-CX3CL1 axis in ITP pathogenesis. Spearman's correlation analyses revealed a strong positive association of peripheral CXCL4 mRNA level, and negative correlations of plasma CXCL4 concentration and certain chemokine receptors with platelet counts, which might serve as a potential biomarker of platelet destruction in ITP development. Overall, these results indicate that the differential expression patterns and distinct activation states of peripheral chemokine network, and the subsequent expansion of circulating CXCR5+ Tc cells and CX3CR1+ T cells, may be a hallmark during ITP progression, which ultimately contributes to thrombocytopenia in ITP patients.
Asunto(s)
Receptor 1 de Quimiocinas CX3C , Púrpura Trombocitopénica Idiopática , Receptores CXCR3 , Receptores CXCR5 , Humanos , Receptores CXCR3/metabolismo , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/inmunología , Receptor 1 de Quimiocinas CX3C/metabolismo , Masculino , Receptores CXCR5/metabolismo , Femenino , Adulto , Persona de Mediana Edad , Recuento de Plaquetas , Factor Plaquetario 4/sangre , Factor Plaquetario 4/metabolismo , Anciano , Linfocitos B/inmunología , Linfocitos B/metabolismoRESUMEN
Immune thrombocytopenia (ITP) is the most common autoimmune disorder characterized by decreased platelet counts and impaired platelet production. Eltrombopag has been demonstrated to be safe and effective for children with ITP. It is reported eltrombopag can achieve a sustained response off treatment. However, data on its overall efficacy and safety profile are scarce in children. This study aimed to investigate the long-term efficacy of eltrombopag in children with ITP. Treatment overall response (OR), complete response (CR), response (R), durable response (DR), no response (NR), treatment free remission (TFR), and relapse rate, were assessed in 103 children with ITP during eltrombopag therapy. The OR rate, CR rate, R rate, DR rate, NR rate, TFR rate, and relapse rate were 67.0%, 55.3%, 11.7%, 56.3%, 33.0%, 60%, 36.2%, respectively. Importantly, we discovered that newly diagnosed ITP patients showed a higher DR rate, TFR rate and lower relapse rate compared to persistent and chronic ITP patients. Furthermore, the CR rate, DR rate, and TFR rate of 5 patients under six months were 100%. None of them suffered relapse. The most common adverse event (AEs) was hepatotoxicity (7.77%). Our study highlighted the critical role of eltrombopag as the second-line treatment in children with ITP who were intolerant to first-line therapy.
Asunto(s)
Benzoatos , Hidrazinas , Púrpura Trombocitopénica Idiopática , Pirazoles , Humanos , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Hidrazinas/uso terapéutico , Hidrazinas/efectos adversos , Hidrazinas/administración & dosificación , Benzoatos/uso terapéutico , Benzoatos/efectos adversos , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/sangre , Niño , Masculino , Femenino , Preescolar , Adolescente , Lactante , Resultado del Tratamiento , Estudios Retrospectivos , Inducción de Remisión , RecurrenciaRESUMEN
While studies have explored the feasibility of switching between various thrombopoietin receptor agonists in treating immune thrombocytopenia (ITP), data on the switching from eltrombopag to hetrombopag remains scarce. This post-hoc analysis of a phase III hetrombopag trial aimed to assess the outcomes of ITP patients who switched from eltrombopag to hetrombopag. In the original phase III trial, patients initially randomized to the placebo group were switched to eltrombopag. Those who completed this 14-week eltrombopag were eligible to switch to a 24-week hetrombopag. Treatment response, defined as a platelet count of ≥ 50 × 109/L, and safety were evaluated before and after the switch. Sixty-three patients who completed the 14-week eltrombopag and switched to hetrombopag were included in this post-hoc analysis. Response rates before and after the switch were 66.7% and 88.9%, respectively. Among those with pre-switching platelet counts below 30 × 109/L, eight out of 12 patients (66.7%) responded, while eight out of nine patients (88.9%) with pre-switching platelet counts between 30 × 109/L and 50 × 109/L responded post-switching. Treatment-related adverse events were observed in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment. No severe adverse events were noted during hetrombopag treatment. Switching from eltrombopag to hetrombopag in ITP management appears to be effective and well-tolerated. Notably, hetrombopag yielded high response rates, even among patients who had previously shown limited response to eltrombopag. However, these observations need to be confirmed in future trials.
Asunto(s)
Benzoatos , Hidrazinas , Púrpura Trombocitopénica Idiopática , Pirazoles , Pirazolonas , Receptores de Trombopoyetina , Humanos , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/administración & dosificación , Masculino , Femenino , Benzoatos/uso terapéutico , Benzoatos/efectos adversos , Benzoatos/administración & dosificación , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/sangre , Persona de Mediana Edad , Adulto , Anciano , Hidrazinas/uso terapéutico , Hidrazinas/efectos adversos , Hidrazinas/administración & dosificación , Receptores de Trombopoyetina/agonistas , Pirazolonas/uso terapéutico , Sustitución de Medicamentos , Recuento de Plaquetas , Resultado del Tratamiento , HidrazonasRESUMEN
We aimed to observe the effects of adipose-derived mesenchymal stem cells (ADSCs) on T helper 17 (Th17)/regulatory T cells (Treg) and T-box transcription factor (T-bet)/GATA-binding protein 3 (GATA-3) in model mice with primary immune thrombocytopenia (ITP). 32 BALB/C mice were selected. ADSCs were isolated from 2 mice and cultured. The other 30 mice were randomly divided into the normal control group, the ITP model control group, and the ITP experimental group. Platelet count (PLT), Th17/Treg cells, related serum cytokines [interleukin-6 (IL-6), IL-17A, IL-10, and transforming growth factor ß1 (TGF-ß1)], T-bet and GATA-3 mRNA levels in peripheral blood mononuclear cells (PBMCs) in the 3 groups were detected. PLT and Treg in the ITP experimental group were significantly lower than those in the normal control group (P<0.05), but significantly higher than those in the ITP model control group (P<0.05). Th17 and Th17/Treg in the ITP experimental group were significantly higher than those in the normal control group (P<0.05), but significantly lower than those in the ITP model control group (P<0.05). Serum IL-6 and IL-17A levels, and T-bet mRNA levels in the ITP experimental group were significantly higher than those in the normal control group (P<0.05), but significantly lower than those in the ITP model control group (P<0.05). Serum IL-10 and TGF-ß levels, and GATA-3 mRNA levels in the ITP experimental group were significantly lower than those in the normal control group (P<0.05), but significantly higher than those in the ITP model control group (P<0.05). ADSCs can effectively regulate Th17/Treg balance and improve T-bet/GATA-3 mRNA expression levels in ITP model mice.
Asunto(s)
Modelos Animales de Enfermedad , Factor de Transcripción GATA3 , Células Madre Mesenquimatosas , Ratones Endogámicos BALB C , Proteínas de Dominio T Box , Linfocitos T Reguladores , Células Th17 , Animales , Femenino , Masculino , Ratones , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Citocinas/metabolismo , Citocinas/sangre , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/metabolismo , Interleucina-10/genética , Interleucina-10/sangre , Interleucina-10/metabolismo , Interleucina-17/sangre , Interleucina-17/metabolismo , Interleucina-17/genética , Interleucina-6/sangre , Interleucina-6/metabolismo , Interleucina-6/genética , Células Madre Mesenquimatosas/metabolismo , Recuento de Plaquetas , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/inmunología , Células Th17/metabolismo , Células Th17/inmunología , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/sangreRESUMEN
Thrombopoietin (TPO) is the critical regulator of platelet production. However, the role of TPO in pediatric patients with thrombocytopenic disorders has not been fully elucidated. In the present study, we attempted to investigate serum TPO levels in patients with acquired aplastic anemia (aAA) and immune thrombocytopenia (ITP). We analyzed the endogenous plasma concentration of TPO and platelet count at the time of TPO measurement in 166 patients with aAA and 280 patients with ITP retrospectively. We further observed a correlation between platelet counts and TPO. Serum TPO levels were significantly higher in aAA compared with ITP (1142 vs. 77.99 pg/mL, P <0.001). In patients with aAA, an elevation for TPO levels in very severe AA (VSAA) was seen when compared with non-severe AA (NSAA) (1360 vs. 984.4 pg/mL, P <0.05). In contrast, the circulating TPO levels with chronic ITP (CITP) showed a decrease than newly diagnosed ITP (NITP) and persistent ITP (PITP) (62.28 vs. 81.56 pg/mL, P <0.01, 62.28 vs. 87.82 pg/mL, P <0.05, respectively). There was a negative correlation between platelet counts and TPO levels in aAA (r s =-0.3325, P <0.001) as well as ITP (r s =-0.2570, P <0.001). Especially, TPO levels were inversely correlated with platelet counts in NSAA (r s =-0.3672, P <0.001) and NITP (r s =-0.3316, P <0.001). After grouping by age or sex, there were no statistical differences in aAA or ITP. Serum TPO levels were markedly elevated in pediatric patients with aAA compared with ITP. It was higher in VSAA and lower in CITP, suggesting that serum TPO level could play a role in classifying disease severity or clinical course in aAA and ITP.
Asunto(s)
Anemia Aplásica , Púrpura Trombocitopénica Idiopática , Trombopoyetina , Humanos , Trombopoyetina/sangre , Femenino , Masculino , Anemia Aplásica/sangre , Niño , Púrpura Trombocitopénica Idiopática/sangre , Preescolar , Adolescente , Estudios Retrospectivos , Recuento de Plaquetas , LactanteRESUMEN
BACKGROUND: Since Imbach [1] first reported the use of high-dose intravenous immunoglobulin (IVIg) in the treatment of idiopathic thrombocytopenic purpura (ITP) in children, indications for IVIg therapy have been increaseing. At present, IVIg infusion has become an important means of clinical treatment. The phenomenon of anti-HBs and anti-HBc elevation caused by IVIg infusion in patients has been reported in journals, but similar reports in journals related to laboratory diagnosis are rare. METHODS: We reported a case of a patient with immune thrombocytopenia (ITP) which interfered with hepatitis B virus (HBV) serological detection after receiving intravenous IVIg. We used chemiluminescence immunoassay to detect serological markers of HBV. IU/mL was used to represent the detection data of HBsAg and HBsAb and cutoff value was used to represent the detection HBeAg, HBeAb, and HbcAb. RESULTS: The serological markers of HBV were all negative before IVIg infusion. One week after IVIG infusion, the item was tested again, and the results of HBsAb, HBeAb, and HBcAb were positive. As the time increased after infusion, HBsAb, HBeAb, and HBcAb in the patient gradually decreased. CONCLUSIONS: After IVIg infusion, the sudden positive change of HBsAb, HBeAb, and HbcAb in the patient's body was not caused by HBV infection, but caused by the infusion of foreign antibody. This case study shows that physicians should be particularly careful when interpreting results in patients treated with intravenous IVIg involving viral hepatitis B.
Asunto(s)
Anticuerpos contra la Hepatitis B , Virus de la Hepatitis B , Hepatitis B , Inmunoglobulinas Intravenosas , Púrpura Trombocitopénica Idiopática , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunoglobulinas Intravenosas/administración & dosificación , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/inmunología , Hepatitis B/diagnóstico , Hepatitis B/inmunología , Hepatitis B/sangre , Anticuerpos contra la Hepatitis B/sangre , Virus de la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/inmunología , Pruebas Serológicas/métodos , Masculino , FemeninoRESUMEN
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse effect of ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria) and Janssen Ad26.COV2.S COVID-19 vaccine, and it is associated with unusual thrombosis. VITT is caused by anti-platelet factor 4 (PF4) antibodies activating platelets through their FcγRIIa receptors. Antibodies that activate platelets through FcγRIIa receptors have also been identified in patients with COVID-19. These findings raise concern that vaccination-induced antibodies against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4. Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared using in silico prediction tools and 3D modeling. The SARS-CoV-2 spike protein and PF4 share at least 1 similar epitope. Reactivity of purified anti-PF4 antibodies from patients with VITT was tested against recombinant SARS-CoV-2 spike protein. However, none of the affinity-purified anti-PF4 antibodies from 14 patients with VITT cross-reacted with SARS-CoV-2 spike protein. Sera from 222 polymerase chain reaction-confirmed patients with COVID-19 from 5 European centers were tested by PF4-heparin enzyme-linked immunosorbent assays and PF4-dependent platelet activation assays. We found anti-PF4 antibodies in sera from 19 (8.6%) of 222 patients with COVID-19. However, only 4 showed weak to moderate platelet activation in the presence of PF4, and none of those patients developed thrombotic complications. Among 10 (4.5%) of 222 patients who had COVID-19 with thrombosis, none showed PF4-dependent platelet-activating antibodies. In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT. PF4-reactive antibodies found in patients with COVID-19 in this study were not associated with thrombotic complications.
Asunto(s)
Anticuerpos/efectos adversos , Vacunas contra la COVID-19/efectos adversos , Reacciones Cruzadas/inmunología , Factor Plaquetario 4/inmunología , Púrpura Trombocitopénica Idiopática/etiología , Púrpura Trombocitopénica Idiopática/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Plaquetas/inmunología , COVID-19/inmunología , Estudios de Cohortes , Epítopos/inmunología , Femenino , Heparina/metabolismo , Humanos , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Unión Proteica , Dominios Proteicos , Púrpura Trombocitopénica Idiopática/sangre , Glicoproteína de la Espiga del Coronavirus/química , Adulto JovenRESUMEN
SARS-CoV-2 vaccine ChAdOx1 nCoV-19 (AstraZeneca) causes a thromboembolic complication termed vaccine-induced immune thrombotic thrombocytopenia (VITT). Using biophysical techniques, mouse models, and analysis of VITT patient samples, we identified determinants of this vaccine-induced adverse reaction. Super-resolution microscopy visualized vaccine components forming antigenic complexes with platelet factor 4 (PF4) on platelet surfaces to which anti-PF4 antibodies obtained from VITT patients bound. PF4/vaccine complex formation was charge-driven and increased by addition of DNA. Proteomics identified substantial amounts of virus production-derived T-REx HEK293 proteins in the ethylenediaminetetraacetic acid (EDTA)-containing vaccine. Injected vaccine increased vascular leakage in mice, leading to systemic dissemination of vaccine components known to stimulate immune responses. Together, PF4/vaccine complex formation and the vaccine-stimulated proinflammatory milieu trigger a pronounced B-cell response that results in the formation of high-avidity anti-PF4 antibodies in VITT patients. The resulting high-titer anti-PF4 antibodies potently activated platelets in the presence of PF4 or DNA and polyphosphate polyanions. Anti-PF4 VITT patient antibodies also stimulated neutrophils to release neutrophil extracellular traps (NETs) in a platelet PF4-dependent manner. Biomarkers of procoagulant NETs were elevated in VITT patient serum, and NETs were visualized in abundance by immunohistochemistry in cerebral vein thrombi obtained from VITT patients. Together, vaccine-induced PF4/adenovirus aggregates and proinflammatory reactions stimulate pathologic anti-PF4 antibody production that drives thrombosis in VITT. The data support a 2-step mechanism underlying VITT that resembles the pathogenesis of (autoimmune) heparin-induced thrombocytopenia.
Asunto(s)
Complejo Antígeno-Anticuerpo/inmunología , Autoanticuerpos/inmunología , COVID-19/prevención & control , Proteínas de la Cápside/efectos adversos , ChAdOx1 nCoV-19/efectos adversos , Contaminación de Medicamentos , Vectores Genéticos/efectos adversos , Células HEK293/inmunología , Inmunoglobulina G/inmunología , Factor Plaquetario 4/inmunología , Púrpura Trombocitopénica Idiopática/etiología , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/efectos adversos , Adenoviridae/inmunología , Animales , Complejo Antígeno-Anticuerpo/ultraestructura , Autoanticuerpos/biosíntesis , Síndrome de Fuga Capilar/etiología , Proteínas de la Cápside/inmunología , Línea Celular Transformada , ChAdOx1 nCoV-19/química , ChAdOx1 nCoV-19/inmunología , ChAdOx1 nCoV-19/toxicidad , Dispersión Dinámica de Luz , Epítopos/química , Epítopos/inmunología , Trampas Extracelulares/inmunología , Extravasación de Materiales Terapéuticos y Diagnósticos/etiología , Vectores Genéticos/inmunología , Células HEK293/química , Humanos , Imagenología Tridimensional , Inmunoglobulina G/biosíntesis , Inflamación , Ratones , Microscopía/métodos , Activación Plaquetaria , Proteómica , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/inmunología , Trombosis de los Senos Intracraneales/diagnóstico por imagen , Trombosis de los Senos Intracraneales/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Cultivo de VirusRESUMEN
A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) is a multidomain metalloprotease for which until now only a single substrate has been identified. ADAMTS13 cleaves the polymeric force-sensor von Willebrand factor (VWF) that unfolds under shear stress and recruits platelets to sites of vascular injury. Shear force-dependent cleavage at a single Tyr-Met peptide bond in the unfolded VWF A2 domain serves to reduce the size of VWF polymers in circulation. In patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP), a rare life-threatening disease, ADAMTS13 is targeted by autoantibodies that inhibit its activity or promote its clearance. In the absence of ADAMTS13, VWF polymers are not adequately processed, resulting in spontaneous adhesion of blood platelets, which presents as severe, life-threatening microvascular thrombosis. In healthy individuals, ADAMTS13-VWF interactions are guided by controlled conversion of ADAMTS13 from a closed, inactive to an open, active conformation through a series of interdomain contacts that are now beginning to be defined. Recently, it has been shown that ADAMTS13 adopts an open conformation in the acute phase and during subclinical disease in iTTP patients, making open ADAMTS13 a novel biomarker for iTTP. In this review, we summarize our current knowledge on ADAMTS13 conformation and speculate on potential triggers inducing conformational changes of ADAMTS13 and how these relate to the pathogenesis of iTTP.
Asunto(s)
Proteína ADAMTS13/inmunología , Autoanticuerpos/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Factor de von Willebrand/inmunología , Proteína ADAMTS13/sangre , Animales , Autoanticuerpos/sangre , Biomarcadores/sangre , Humanos , Púrpura Trombocitopénica Idiopática/sangre , Factor de von Willebrand/metabolismoRESUMEN
Recently, we showed that ADAMTS13 circulates in an open conformation during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP). Although the cause of this conformational change remains elusive, ADAMTS13 is primarily closed in iTTP patients in remission with ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, as well as after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, immunoglobulin G from 18 acute iTTP patients was purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14 of 18 (78%) samples, proving that anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n = 197) that also included plasma samples from iTTP patients in remission in whom ADAMTS13 activity was <50%. The open ADAMTS13 conformation was found during acute iTTP, as well as in patients in remission with ADAMTS13 activity <50% and in half of the patients with ADAMTS13 activity >50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus, open ADAMTS13 is a hallmark of acute iTTP, as well as a novel biomarker that can be used to detect subclinical iTTP in patients in remission. Finally, a long-term follow-up study in 1 iTTP patient showed that the open conformation precedes a substantial drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management.
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Proteína ADAMTS13/sangre , Autoanticuerpos/sangre , Púrpura Trombocitopénica Idiopática/sangre , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Conformación Proteica , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Rituximab/administración & dosificaciónRESUMEN
Polyclonal anti-D is a first-line therapy for immune thrombocytopenia (ITP). Monoclonal antibodies are desirable alternatives, but none have yet proven successful despite their ability to opsonize erythrocytes (or red blood cells, RBCs) and cause anemia. Here, we examined 12 murine erythrocyte-specific antibodies of different specificity and subtypes and found that 8 of these antibodies could induce anemia in antigen-positive mice. Of these 8 antibodies, only 5 ameliorated ITP. All antibodies were examined for their in vitro ability to support macrophage-mediated phagocytosis of erythrocytes. Antibodies which supported erythrocyte phagocytosis in vitro successfully ameliorated ITP in vivo. To examine the ability of each antibody to inhibit phagocytosis of platelets, the antibodies were used to sensitize erythrocytes in vitro and these were added to a platelet phagocytosis assay. Antibodies that inhibited platelet phagocytosis in vitro also all ameliorated ITP in vivo. We conclude that inducing anemia is not a sufficient condition for amelioration of ITP but that the antibody's ability to prevent platelet phagocytosis in vitro predicted its ability to ameliorate ITP. We suggest that inhibition of in vitro platelet phagocytosis may prove to be a valuable tool for determining which erythrocyte antibodies would likely be candidates for clinical use in ITP.
Asunto(s)
Plaquetas , Eritrocitos/inmunología , Inmunoglobulina G/uso terapéutico , Fagocitosis , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/terapia , Anemia/etiología , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Femenino , Inmunoglobulina G/efectos adversos , Inmunoglobulina G/inmunología , Técnicas In Vitro , Ratones , Ratones Endogámicos C57BL , Fagocitosis/inmunología , Células RAW 264.7 , Ratas , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/uso terapéuticoRESUMEN
Management of symptoms and prevention of life-threatening hemorrhage in immune thrombocytopenia (ITP) must be balanced against adverse effects of therapies. Because current treatment guidelines based on platelet count are confounded by variable bleeding phenotypes, there is a need to identify new objective markers of disease severity for treatment stratification. In this cross-sectional prospective study of 49 patients with ITP and nadir platelet counts <30 × 109/L and 18 aged-matched healthy controls, we used susceptibility-weighted magnetic resonance imaging to detect cerebral microbleeds (CMBs) as a marker of occult hemorrhage. CMBs were detected using a semiautomated method and correlated with clinical metadata using multivariate regression analysis. No CMBs were detected in health controls. In contrast, lobar CMBs were identified in 43% (21 of 49) of patients with ITP; prevalence increased with decreasing nadir platelet count (0/4, ≥15 × 109/L; 2/9, 10-14 × 109/L; 4/11, 5-9 × 109/L; 15/25 <5 × 109/L) and was associated with longer disease duration (P = 7 × 10-6), lower nadir platelet count (P = .005), lower platelet count at time of neuroimaging (P = .029), and higher organ bleeding scores (P = .028). Mucosal and skin bleeding scores, number of previous treatments, age, and sex were not associated with CMBs. Occult cerebral microhemorrhage is common in patients with moderate to severe ITP. Strong associations with ITP duration may reflect CMB accrual over time or more refractory disease. Further longitudinal studies in children and adults will allow greater understanding of the natural history and clinical and prognostic significance of CMBs.
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Hemorragia Cerebral , Imagen por Resonancia Magnética , Neuroimagen , Púrpura Trombocitopénica Idiopática , Adulto , Anciano , Anciano de 80 o más Años , Hemorragia Cerebral/sangre , Hemorragia Cerebral/diagnóstico por imagen , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Estudios Prospectivos , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/diagnóstico por imagenRESUMEN
INTRODUCTION: The absence of high quality evidence for basic clinical dilemmas in immune thrombocytopenic purpura (ITP) underlines the need for contemporary guidelines relevant to the local treatment context. ITP is diagnosed by exclusions, with a hallmark laboratory finding of isolated thrombocytopenia. MAIN RECOMMENDATIONS: Bleeding, family and medication histories and a review of historical investigations are required to gauge the bleeding risk and possible hereditary syndromes. Beyond the platelet count, the decision to treat is affected by individual bleeding risk, disease stage, side effects of treatment, concomitant medications, and patient preference. Treatment is aimed at achieving a platelet count > 20 × 109 /L, and avoidance of severe bleeding. Steroids are the standard first line treatment, with either 6-week courses of tapering prednisone or repeated courses of high dose dexamethasone providing equivalent efficacy. Intravenous immunoglobulin can be used periprocedurally or as first line therapy in combination with steroids. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: There is no consensus on choice of second line treatments. Options with the most robust evidence include splenectomy, rituximab and thrombopoietin receptor agonists. Other therapies include azathioprine, mycophenolate mofetil, dapsone and vinca alkaloids. Given that up to one-third of patients achieve a satisfactory haemostatic response, splenectomy should be delayed for at least 12 months if possible. In life-threatening bleeding, we recommend platelet transfusions to achieve haemostasis, along with intravenous immunoglobulin and high dose steroids.
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Transfusión de Plaquetas/normas , Guías de Práctica Clínica como Asunto , Púrpura Trombocitopénica Idiopática/terapia , Esplenectomía/normas , Adulto , Australia , Consenso , Quimioterapia Combinada/normas , Glucocorticoides/uso terapéutico , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Nueva Zelanda , Prioridad del Paciente , Recuento de Plaquetas , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/diagnóstico , Rituximab/uso terapéuticoRESUMEN
BACKGROUND: The glycosylation alterations of serum and IgG are involved in a variety of autoimmune and inflammatory diseases and have shown great potential in biomarker field. The diagnosis of immune thrombocytopenia (ITP) is exclusive. Our study aimed to discover the potential glyco-biomarkers for auxiliary diagnosis of ITP. METHODS: The serum samples were obtained from 61 ITP patients and 35 healthy controls, and IgG samples were purified from 34 out of 61 ITP patients and 35 healthy controls. DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis (DSA-FACE) was used to analyze serum and IgG N-glycan profiling. RESULTS: 6 of 12 serum N-glycan peaks, 6 of 7 IgG N-glycan peaks, serum fucosylation, and IgG galactosylation were significantly different between ITP patients and healthy controls (p < 0.05). IgG peak 7 showed good diagnostic efficacy for discriminating ITP patients from healthy individuals (AUC 0.967). ITP patients with severe thrombocytopenia had a significantly lower serum fucosylation than ITP patients with mild and moderate thrombocytopenia (p < 0.05). Serum fucosylation and serum peak 5 were correlated with platelet counts in ITP patients with severe thrombocytopenia, and the absolute values of correlation coefficient were both over 0.5. CONCLUSIONS: The specific N-glycan patterns of serum and IgG were observed in ITP patients. IgG peak 7 was a potential biomarker for auxiliary diagnosis of ITP.