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Postacute COVID-19 sequelae affect millions of individuals, and active research into the pathophysiological mechanisms and potential treatments is underway. The report by Nara and colleagues shows persistent platelet hyperactivity in the chronic phase of the infection, suggesting a possible role of platelets in post-COVID-19 complications and, consequently, a possible therapeutic target. Commentary on: Nara et al. Prolonged platelet hyperactivity after COVID-19 infection. Br J Haematol 2024;204:492-496.
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COVID-19 , Trombosis , Humanos , COVID-19/complicaciones , Plaquetas/fisiología , Trombosis/etiologíaRESUMEN
MYC translocations, a hallmark of Burkitt lymphoma, occur in 5-15% of diffuse large B-cell lymphoma, and have a negative prognostic impact. Numerical aberrations of MYC have also been detected in these patients, but their incidence and prognostic role are still controversial. We analyzed the clinical impact of MYC increased copy number on 385 patients with diffuse large B-cell lymphoma screened at diagnosis for MYC, BCL2, and BCL6 rearrangements. We enumerated the number of MYC copies, defining as amplified those cases with an uncountable number of extra-copies. The prevalence of MYC translocation, increased copy number and amplification was 8.8%, 15%, and 1%, respectively. Patients with 3 or 4 gene copies, accounting for more than 60% of patients with MYC copy number changes, had a more favorable outcome compared to patients with >4 copies or translocation of MYC, and were not influenced by the type of treatment received as first-line. Stratification according to the number of MYC extra-copies showed a negative correlation between an increasing number of copies and survival. Patients with >7 copies or the amplification of MYC had the poorest prognosis. Patients with >4 copies of MYC showed a similar, trending towards worse prognosis compared to patients with MYC translocation. The survival of patients with >4 copies, translocation or amplification of MYC seemed to be superior if intensive treatments were used. Our study underlines the importance of fluorescence in situ hybridization testing at diagnosis of diffuse large B-cell lymphoma to detect the rather frequent and clinically significant numerical aberrations of MYC.
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Linfoma de Células B Grandes Difuso , Proteínas Proto-Oncogénicas c-myc , Linfocitos B , Variaciones en el Número de Copia de ADN , Humanos , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-myc/genética , Translocación GenéticaRESUMEN
Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High-dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate-risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long-term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML-01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high-risk AML (adverse cytogenetic, isolated FLT3-internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19-75), were considered standard-risk and received the NILG AML-01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+-PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1-2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment-related mortality was 3/160 (1.8%). After a median follow-up of 66.4 months, overall survival (OS) and relapse-free survival (RFS) at 5-years were 61.4% and 52.4%, respectively. Twenty-eight selected patients aged >65 had similar outcomes. According to European leukemia net-2010 classification, the OS and RFS at 5-years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate-I, 45.2% and 36.5% in Intermediate-II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Terapia Combinada , Citarabina/efectos adversos , Citarabina/uso terapéutico , Daunorrubicina/efectos adversos , Daunorrubicina/uso terapéutico , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Quimioterapia de Inducción , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiología , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Trasplante Autólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening immune-mediated thrombotic microangiopathy. Daily therapeutic plasma exchange (TPE) and the optimized use of rituximab have strikingly improved the outcome of this disease, however the rate of disease recurrence remains high. Specific predictors of relapse in patients in remission can be relevant for an optimal patient management. In this study, we aimed to identify predictive variables of disease relapse in a multicenter cohort of 74 out of 153 iTTP patients. They were tested at different time points during remission for the levels of ADAMTS-13 activity and autoantibody, and did not receive pre-emptive treatment for ADAMTS-13 activity deficiency during remission. The results showed that the association of ADAMTS13 activity ≤20% with a high anti-ADAMTS-13 titer at remission, and the time to response to first line treatment ≥13 days, were independent predictive factors of disease relapse. In addition, the use of rituximab in patients with exacerbation or refractoriness to TPE was significantly associated with reduced relapse rate. By Cox regression analysis, patients with ADAMTS-13 activity ≤20% plus anti-ADAMTS13 antibody titer ≥15 U/mL at remission had an increased risk of relapse (HR 1.98, CI 95% 1.087-3.614; P < .02). These findings may help to outline more personalized therapeutic strategies in order to provide faster and sustained responses to first-line iTTP treatment and prevent relapses in these patients.
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Proteína ADAMTS13/sangre , Autoanticuerpos/sangre , Púrpura Trombocitopénica Trombótica/terapia , Femenino , Humanos , Masculino , Púrpura Trombocitopénica Trombótica/patología , RecurrenciaRESUMEN
BACKGROUND: Stopping tyrosine kinase inhibitor (TKI) treatment has become a realistic and safe objective for patients who have chronic myeloid leukemia (CML). Both a sustained deep molecular response (sDMR) and the lack of a molecular recurrence after TKI discontinuation are required to reach a durable treatment-free remission (TFR). METHODS: The potential predictive role of BCR-ABL transcripts in attaining an sDMR and a TFR was analyzed in a strictly consecutive, unselected series of 194 patients who were diagnosed and treated with TKIs at the authors' center. RESULTS: Of 173 fully evaluable patients, 67 (38.7%) had the e13a2 transcript, and 106 (61.3%) had the e14a2 transcript. Complete cytogenetic and major molecular remissions were not affected, whereas the achievement of both a DMR (P = .008) and an sDMR (P = .004) was favored significantly in patients who had the e14a2 transcript. After a median of 68 months, the sDMR rate was 39.6% in those with the e14a2 transcript and 19.4% in those with the e13a2 transcript. In addition to transcript type, both the early achievement of a molecular response and starting treatment with a second-generation TKI positively affected the attainment of an sDMR in multivariate analysis. The use of a second-generation TKI as frontline treatment increased the sDMR rate in both transcript types. However, in patients who had the e13a2 transcript, the probability of attaining an sDMR was 37% after 60 months and did not increase further despite continuing therapy. Among 51 of 60 patients who attained an sDMR after discontinuing TKIs, 24 experienced a molecular relapse, but all regained molecular remission after resuming TKI treatment. Again, transcript type influenced TFR maintenance (P = .005), because only 2 patients (3%) with the e13a2 transcript enjoyed a durable TFR compared with 25 (23.5%) of those with the e14a2 transcript. CONCLUSIONS: The e13a2 transcript hinders the achievement of deep responses and the possibility of stopping TKI treatment in patients with CML.
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Proteínas de Fusión bcr-abl/genética , Regulación Neoplásica de la Expresión Génica , Mesilato de Imatinib/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Centros Médicos Académicos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Análisis Multivariante , Pronóstico , Modelos de Riesgos Proporcionales , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Thrombosis is a major cause of morbidity and mortality in cancer patients. The pathogenesis of blood coagulation activation in oncological patients is complex and involves both clinical and biological factors. Abnormalities in one or more coagulation test are common in cancer patients, even without thrombotic manifestations, indicating an ongoing hypercoagulable condition. Moreover, venous thromboembolism (VTE) can be the first symptom of an occult malignancy in an otherwise healthy individual. The levels of laboratory markers of activation of blood coagulation parallel the development of malignancy, being the coagulant mechanisms important for both thrombogenesis and tumor progression. Besides general clinical risk factors for VTE, also disease-specific clinical factors, i.e., type and stage of the tumor, and anticancer therapies increase the thrombotic risk in these patients. Furthermore, biological factors, including the cancer cell-specific prothrombotic properties together with the host cell inflammatory response to the tumor, are relevant as well as unique players in the pathogenesis of the cancer-associated hypercoagulability. Cancer cells produce and release procoagulant and fibrinolytic proteins, inflammatory cytokines, and procoagulant microparticles. They also express adhesion molecules binding to the receptors of host vascular cells (i.e., endothelial cells, platelets, and leukocytes), thereby stimulating the prothrombotic properties of these normal cells, including the shed of cell-specific microparticles and neutrophil extracellular traps. Of interest, several genes responsible for the cellular neoplastic transformation drive the programs of hemostatic properties expressed by cancer tissues. A better understanding of such mechanisms will help the development of novel strategies to prevent and treat the Trousseau's syndrome (i.e., cancer-associated thrombosis).
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Neoplasias/fisiopatología , Trombosis/fisiopatología , Coagulación Sanguínea/fisiología , Humanos , Neoplasias/complicaciones , Trombosis/etiologíaRESUMEN
Thrombosis is a major cause of morbidity and mortality in cancer patients. Many clinical factors contribute to the high thrombotic risk of this condition, including the type of malignancy, its disease stage, anticancer therapies, and comorbidities. However, the cancer cell-specific prothrombotic properties together with the host cell inflammatory response are important players in the pathogenesis of the cancer-associated hypercoagulability. Tissue factor (TF) is the most important procoagulant protein expressed by cancer cells, and with other cancer tissue procoagulant properties highly contributes to the procoagulant phenotype of malignant cells. Recent discoveries indicate that oncogenes determine the procoagulant protein expression, including TF, in cancer tissues. In addition, in malignancy, TF is also overexpressed by host normal blood cells triggered by cancer-derived inflammatory stimuli. As a consequence, a subclinical activation of blood coagulation is typically present in cancer patients, as demonstrated by abnormalities of circulating thrombotic biomarkers. The relevance of measuring these biomarkers to determine the patient thrombotic risk level is under active investigation. The goal is to identify the high-risk subgroups to establish more accurate and targeted anticoagulation strategies to prevent thrombosis in cancer patients. Ultimately, the clarification of specific molecular mechanisms triggering blood coagulation in specific cancer types may also indicate alternative ways to inhibit clotting activation in these conditions.
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Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/biosíntesis , Neoplasias/sangre , Trombofilia/sangre , Tromboplastina/biosíntesis , Trombosis/sangre , Humanos , Neoplasias/mortalidad , Neoplasias/patología , Neoplasias/terapia , Trombofilia/mortalidad , Trombofilia/patología , Trombofilia/prevención & control , Trombosis/mortalidad , Trombosis/patología , Trombosis/prevención & controlRESUMEN
Acute leukemia (AL) patients may experience more than one episode of bloodstream infection (BSI) caused by the same pathogen during the entire chemotherapy program. In order to identify factors influencing BSI recurrence (R-BSI) during subsequent phases of treatment, we analyzed all BSIs occurring to consecutively treated AL patients during a period of active epidemiologic surveillance at our institution between 2004 and 2011. Two hundred and fifty BSIs were observed in 138 patients receiving more than 1 cycle of chemotherapy. BSI due to the same pathogen recurred in 39/138 (28.3 %) patients. Gram-negative rods (GNRs) accounted for 59.6 % and Gram-positive cocci (GPCs) for 34.4 % of BSI. Four pathogens were involved in R-BSI: Escherichia coli, Pseudomonas aeruginosa, coagulase-negative staphylococci, and Streptococcus viridans. GNRs were significantly more frequent among R-BSI compared to non-relapsing BSI (nR-BSI) [69/94 (73.4 %) vs 70/156 (50.6 %), p < 0.0001]; in particular, E. coli accounted for 67 % of R-BSI vs 32.1 % of nR-BSI (p < 0.0001). Receiving more than four chemotherapy courses and having an extended spectrum ß-lactamase (ESBL)-producing E. coli BSI at any time of treatment were significantly associated to R-BSI. A trend toward a higher mortality among R-BSI patients in comparison with nR-BSI was observed (17.9 and 7.1 %, respectively, p = 0.12). Among AL patients, R-BSI is a frequent phenomenon, which may contribute to the shift of epidemiology toward GNR and to a higher mortality. This should significantly impact the strategies of antibiotic prophylaxis and treatment in patients with AL.
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Antineoplásicos/uso terapéutico , Bacteriemia/microbiología , Infecciones por Bacterias Gramnegativas/microbiología , Infecciones por Bacterias Grampositivas/microbiología , Leucemia/tratamiento farmacológico , Leucemia/microbiología , Enfermedad Aguda , Adulto , Bacteriemia/complicaciones , Esquema de Medicación , Escherichia coli/efectos de los fármacos , Escherichia coli/aislamiento & purificación , Escherichia coli/fisiología , Femenino , Infecciones por Bacterias Gramnegativas/complicaciones , Infecciones por Bacterias Grampositivas/complicaciones , Humanos , Leucemia/complicaciones , Masculino , Persona de Mediana Edad , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/aislamiento & purificación , Pseudomonas aeruginosa/fisiología , Recurrencia , Staphylococcus/efectos de los fármacos , Staphylococcus/aislamiento & purificación , Staphylococcus/fisiología , Estreptococos Viridans/efectos de los fármacos , Estreptococos Viridans/aislamiento & purificación , Estreptococos Viridans/fisiología , beta-Lactamasas/metabolismoAsunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/metabolismo , Cocaína/toxicidad , Elastasa de Leucocito/metabolismo , Neutropenia/inducido químicamente , Adulto , Agranulocitosis/inducido químicamente , Agranulocitosis/tratamiento farmacológico , Femenino , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Persona de Mediana Edad , Unión Proteica/efectos de los fármacosRESUMEN
Background and aim: High-grade B cell lymphomas with concomitant MYC and BCL2 and/or BCL6 rearrangements (HGBCL-DH/TH) have a poor prognosis when treated with the standard R-CHOP-like chemoimmunotherapy protocol. Whether this can be improved using intensified regimens is still under debate. However, due to the rarity of HGBCL-DH/TH there are no prospective, randomized controlled trials (RCT) available. Thus, with this systematic review and meta-analysis we attempted to compare survival in HGBCL-DH/TH patients receiving intensified vs. R-CHOP(-like) regimens. Methods: The PubMed and Web of Science databases were searched for original studies reporting on first-line treatment in HGBCL-DH/TH patients from 08/2014 until 04/2022. Studies with only localized stage disease, ≤10 patients, single-arm, non-full peer-reviewed publications, and preclinical studies were excluded. The quality of literature and the risk of bias was assessed using the Methodological Index for Non-Randomized Studies (MINORS) and National Heart, Lung, and Blood Institute (NHLBI) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Random-effect models were used to compare R-CHOP-(like) and intensified regimens regarding 2-year overall survival (2y-OS) and 2-year progression-free survival (2y-PFS). Results: Altogether, 11 retrospective studies, but no RCT, with 891 patients were included. Only four studies were of good quality based on aforementioned criteria. Intensified treatment could improve 2y-OS (hazard ratio [HR]=0.78 [95% confidence interval [CI] 0.63-0.96]; p=0.02) as well as 2y-PFS (HR=0.66 [95% CI 0.44-0.99]; p=0.045). Conclusions: This meta-analysis indicates that intensified regimens could possibly improve 2y-OS and 2y-PFS in HGBCL-DH/TH patients. However, the significance of these results is mainly limited by data quality, data robustness, and its retrospective nature. There is still a need for innovative controlled clinical trials in this difficult to treat patient population. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022313234.
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INTRODUCTION: Coronavirus disease is a clinical challenge for patients with autoimmune conditions. Patients affected by immune thrombotic thrombocytopenic purpura (iTTP) are particularly vulnerable to SARS-CoV-2 infection. Protecting these patients with vaccination is therefore mandatory, although concerns may exist on a possible increased thrombotic risk or risk of disease relapse after vaccine exposure. So far, there is no information on serological response and hemostatic activation in iTTP patients after SARS-CoV-2 vaccination. MATERIALS AND METHODS: In this study, in April 2021, we enrolled iTTP patients in clinical remission and on regular outpatient follow-up to receive the first and second dose BNT162b2 vaccine as a part of a prospective trial aimed at monitoring for 6 months after vaccination the occurrence of subclinical laboratory signs of clotting activation, as well as overt thrombotic complications or disease relapse. The seroconversion response was monitored in parallel. The results were compared with those of control non-iTTP subjects. RESULTS: A moderate decrease of ADAMTS-13 activity was recorded at 3 and 6 months in five patients with normal values at baseline, while an ADAMTS-13 relapse occurred at 6 months in one patient. Abnormalities in the endothelium activation biomarkers postvaccination were observed in iTTP patients compared with controls. The immunological response to vaccine was overall positive. No clinical iTTP relapses or thrombotic events manifested in the 6 month-follow-up after vaccination. CONCLUSION: The results of this study are in favor of efficacy and safety of mRNA vaccines in patients with iTTP, and highlight the importance of long-term monitoring of iTTP patients.
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COVID-19 , Hemostáticos , Púrpura Trombocitopénica Idiopática , Púrpura Trombocitopénica Trombótica , Vacunas , Humanos , Estudios Prospectivos , Proteína ADAMTS13 , Vacuna BNT162 , Vacunas contra la COVID-19/efectos adversos , SARS-CoV-2 , RecurrenciaRESUMEN
Patients with chronic Myeloproliferative Neoplasms (MPN) including polycythemia vera (PV) and essential thrombocythemia (ET) exhibit unique clinical features, such as a tendency toward thrombosis and hemorrhage, and risk of disease progression to secondary bone marrow fibrosis and/or acute leukemia. Although an increase in blood cell lineage counts (quantitative features) contribute to these morbid sequelae, the significant qualitative abnormalities of myeloid cells that contribute to vascular risk are not well understood. Here, we address this critical knowledge gap via a comprehensive and untargeted profiling of the platelet proteome in a large (n= 140) cohort of patients (from two independent sites) with an established diagnosis of PV and ET (and complement prior work on the MPN platelet transcriptome from a third site). We discover distinct MPN platelet protein expression and confirm key molecular impairments associated with proteostasis and thrombosis mechanisms of potential relevance to MPN pathology. Specifically, we validate expression of high-priority candidate markers from the platelet transcriptome at the platelet proteome (e.g., calreticulin (CALR), Fc gamma receptor (FcγRIIA) and galectin-1 (LGALS1) pointing to their likely significance in the proinflammatory, prothrombotic and profibrotic phenotypes in patients with MPN. Together, our proteo-transcriptomic study identifies the peripherally-derived platelet molecular profile as a potential window into MPN pathophysiology and demonstrates the value of integrative multi-omic approaches in gaining a better understanding of the complex molecular dynamics of disease.
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(1) Background: Venous thromboembolism (VTE) is a frequent complication in ambulatory lung cancer patients during chemotherapy and is associated with increased mortality. (2) Methods: We analyzed 568 newly diagnosed metastatic lung cancer patients prospectively enrolled in the HYPERCAN study. Blood samples collected before chemotherapy were tested for thrombin generation (TG) and a panel of hemostatic biomarkers. The Khorana risk score (KRS), new-Vienna CATS, PROTECHT, and CONKO risk assessment models (RAMs) were applied. (3) Results: Within 6 months, the cumulative incidences of VTE and mortality were 12% and 29%, respectively. Patients with VTE showed significantly increased levels of D-dimer, FVIII, prothrombin fragment 1 + 2, and TG. D-dimer and ECOG performance status were identified as independent risk factors for VTE and mortality by multivariable analysis and utilized to generate a risk score that provided a cumulative incidence of VTE of 6% vs. 25%, death of 19% vs. 55%, and in the low- vs. high-risk group, respectively (p < 0.001). While all published RAMs significantly stratified patients for risk of death, only the CATS and CONKO were able to stratify patients for VTE. (4) Conclusions: A new prediction model was generated to stratify lung cancer patients for VTE and mortality risk, where other published RAMs failed.
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BACKGROUND: Risk assessment models (RAMs) are relevant approaches to identify cancer outpatients at high risk of venous thromboembolism (VTE). Among the proposed RAMs, the Khorana (KRS) and the new-Vienna CATS risk scores have been externally validated in ambulatory patients with cancer. OBJECTIVES: To test KRS and new-Vienna CATS scores in 6-month VTE prediction and mortality in a large prospective cohort of metastatic cancer outpatients during chemotherapy. PATIENTS/METHODS: Newly diagnosed patients with metastatic non-small cell lung, colorectal, gastric, or breast cancers were analyzed (n = 1286). The cumulative incidence of objectively confirmed VTE was estimated with death as a competing risk and multivariate Fine and Gray regression. RESULTS: Within 6 months, 120 VTE events (9.7%) occurred. The KRS and the new-Vienna CATS scores showed comparable c-stat. Stratification by KRS provided VTE cumulative incidences of 6.2%, 11.4%, and 11.5% in the low-, intermediate-, and high-risk categories, respectively (p = ns), and of 8.5% vs. 11.8% (p = ns) in the low- vs. high-risk group by the single 2-point cut-off value stratification. Using a pre-defined 60-point cut-off by the new-Vienna CATS score, 6.6% and 12.2% cumulative incidences were obtained in the low- and high-risk groups, respectively (p < 0.001). Furthermore, having a KRS ≥2 = or a new-Vienna CATS score >60 points was also an independent risk factor for mortality. CONCLUSION: In our cohort, the 2 RAMs showed a comparable discriminating potential; however, after the application of cut-off values, the new-Vienna CATS score provided statistically significant stratification for VTE. Both RAMs proved to be effective in identifying patients at increased risk of mortality.
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Neoplasias , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiología , Estudios Prospectivos , Estudios Retrospectivos , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/complicaciones , Factores de Riesgo , Medición de RiesgoRESUMEN
Introduction: In a prospective cohort of hospitalized COVID-19 patients, an extensive characterization of hemostatic alterations by both global and specific assays was performed to clarify mechanisms underlying the coagulopathy and identify predictive factors for thrombotic and hemorrhagic events during hospitalization. Materials and Methods: Intensive care unit (ICU; n = 46) and non-ICU (n = 55) patients were enrolled, and the occurrence of thrombotic and hemorrhagic events was prospectively monitored. At study inclusion, thromboelastometry together with the measurement of specific coagulation proteins and hypercoagulation markers was performed. Results: Patients (median age 67 years) showed significantly shorter clot formation time together with greater maximum clot firmness by thromboelastometry, increased levels of F1 + 2 and D-dimer, as biomarkers of hypercoagulability, and of procoagulant factors V, VIII, IX, XI, and fibrinogen, while FXIII was significantly reduced. The concentration of fibrinolytic proteins, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were elevated in the overall cohort of patients. Many of these hemostatic alterations were significantly greater in ICU compared to non-ICU subjects and, furthermore, they were associated with inflammatory biomarker elevation [i.e., interleukin 6 (IL-6), C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), and procalcitonin]. After enrollment, 7 thrombosis and 14 major bleedings occurred. Analysis of clinical and biological data identified increased t-PA, PAI-1, and NLR values as independent predictive factors for thrombosis, while lower FXIII levels were associated with bleeding. Conclusion: This study demonstrates alterations in all different hemostatic compartments analyzed, particularly in severe COVID-19 conditions, that strongly correlated with the inflammatory status. A potential role of fibrinolytic proteins together with NLR and of FXIII as predictors of thrombotic and hemorrhagic complications, respectively, is highlighted.
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Background: the tight and reciprocal interaction between cancer and hemostasis has stimulated investigations on the possible role of hemostatic biomarkers in predicting specific cancer outcomes, such as disease progression (DP) and overall survival (OS). In a prospective cohort of newly diagnosed metastatic gastrointestinal (GI) cancer patients from the HYPERCAN study, we aimed to assess whether the hemostatic biomarker levels measured before starting any anticancer therapy may specifically predict for 6-months DP (6m-DP) and for 1-year OS (1y OS). Methods: plasma samples were collected and tested for thrombin generation (TG) as global hemostatic assay, and for D-dimer, fibrinogen, and prothrombin fragment 1 + 2 as hypercoagulation biomarkers. DP and mortality were monitored during follow-up. Results: A prospective cohort of 462 colorectal and 164 gastric cancer patients was available for analysis. After 6 months, DP occurred in 148 patients, providing a cumulative incidence of 24.8% (21.4−28.4). D-dimer and TG endogenous thrombin potential (ETP) were identified as independent risk factors for 6m-DP by multivariate Fine−Gray proportional hazard regression model corrected for age, cancer site, and >1 metastatic site. After 1 year, we observed an OS of 75.7% (71.9−79.0). Multivariate Cox regression analysis corrected for age, site of cancer, and performance status identified D-dimer and ETP as independent risk factors for 1y OS. Patients with one or both hemostatic parameters above the dichotomizing threshold were at higher risk for both 6m-DP and 1-year mortality. Conclusion.: in newly diagnosed metastatic GI cancer patients, pretreatment ETP and D-dimer appear promising candidate biomarkers for predicting 6m-DP and 1y OS. In this setting, for the first time, the role of TG as a prognostic biomarker emerges in a large prospective cohort.
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Myeloproliferative neoplasms (MPNs) are clonal disorders of the hematopoietic stem cell. Classical BCR/ABL-negative MPNs include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Thrombotic events are a major cause of morbidity and mortality in these patients. Pathogenesis of blood clotting activation involves various abnormalities of platelets, erythrocytes, and leukocytes, as well as dysfunctions of endothelial cells. Patients with MPN can be stratified in "high risk" or "low risk" of thrombosis according to established risk factors. ET and PV clinical management is highly dependent on the patient's thrombotic risk, and a risk-oriented management strategy to treat these diseases is strongly recommended. In this review, we give an overview of risk factors, pathogenesis, and thrombosis prevention and treatment in MPN.
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Trastornos Mieloproliferativos/complicaciones , Trombosis/prevención & control , Trombosis/terapia , Humanos , Incidencia , Factores de RiesgoRESUMEN
Introduction Endothelial damage and hypercoagulability are major players behind the hemostatic derangement of SARS-CoV-2 infection. Aim In this prospective study we assessed endothelial and inflammatory biomarkers in a cohort of COVID-19 patients, aiming to identify predictive factors of in-hospital mortality. Methods COVID-19 patients hospitalized in intensive care (ICU) and non-ICU units at 2 Bergamo (Italy) hospitals from March 23 to May 30, 2020, were enrolled. Markers of endothelium activation including von-Willebrand factor (vWF), soluble thrombomodulin (sTM), and fibrinolytic proteins (t-PA and PAI-1) were measured. Additionally, D-dimer, Fibrinogen, FVIII, nucleosomes, C reactive protein (CRP) and procalcitonin were assessed. Results Sixty-three (45 ICU, and 18 non-ICU) patients, with a median age of 62 years were analyzed. Increased plasma levels of D-dimer, FVIII, fibrinogen, nucleosomes, CRP, and procalcitonin were observed in the whole cohort. Extremely elevated vWF levels characterized all patients (highest values in ICU-subjects). After a median time of 30 days, death occurred in 13 (21%) patients. By multivariable analysis, vWF-activity, neutrophil-count and PaO2/FiO2 were significantly associated with death. Using these variables, a linear score with 3-risk groups was generated that provided a cumulative incidence of death of 0% in the low-, 32% in the intermediate-, and 78% in the high-risk group. Conclusions COVID-19-induced hemostatic abnormalities are exacerbated by the severity of the disease and strongly correlate with the inflammatory status, underlying the link between coagulation, endothelial activation, and inflammation. Our study provides evidence for a role of vWF, together with neutrophils and PaO2/FiO2, as a significant predictor of in-hospital mortality by SARSCoV-2 infection.
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BACKGROUND: The identification of germline mutations in familial leukemia predisposition genes by next generation sequencing is of pivotal importance. Lately, some "blend pedigrees" characterized by both solid and hematologic malignancies have been described. Some genes were recognized as related to this double predisposition, while the involvement of others is still a matter of debate. ETV6 was associated with hematologic malignancies, in particular myeloid malignancies, and recently described as mutated also in oncologic patients. No clear evidences in its involvement in blend pedigrees are known. Case Presentation. We present our recent experience in the identification of an ETV6 was associated with hematologic malignancies, in particular myeloid malignancies, and recently described as mutated also in oncologic patients. No clear evidences in its involvement in blend pedigrees are known. ETV6 was associated with hematologic malignancies, in particular myeloid malignancies, and recently described as mutated also in oncologic patients. No clear evidences in its involvement in blend pedigrees are known. ETV6 was associated with hematologic malignancies, in particular myeloid malignancies, and recently described as mutated also in oncologic patients. No clear evidences in its involvement in blend pedigrees are known. CONCLUSION: This evidence supports the involvement of ETV6 in the predisposition to both solid and hematologic neoplasia and the importance of the investigation of the noncoding regions of the genes as recently suggested by different expert groups.ETV6 was associated with hematologic malignancies, in particular myeloid malignancies, and recently described as mutated also in oncologic patients. No clear evidences in its involvement in blend pedigrees are known.