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Life (Basel, Switzerland) Apr 2024Myeloproliferative neoplasms (MPNs) are often associated with splanchnic vein thrombosis (SVT). Not all the factors involved in the thrombotic tendency are currently...
ADAMTS13, von Willebrand Factor, Platelet Microparticles, Factor VIII, and Impact of Somatic Mutations in the Pathogenesis of Splanchnic Vein Thrombosis Associated with BCR-ABL-Negative Myeloproliferative Neoplasms.
BACKGROUND
Myeloproliferative neoplasms (MPNs) are often associated with splanchnic vein thrombosis (SVT). Not all the factors involved in the thrombotic tendency are currently known.
OBJECTIVES
This study aims to evaluate a possible association between ADAMTS13, von Willebrand factor (VWF), platelet microvesicles (MV), and factor VIII activity (FVIII:C) with thrombotic events in MPN patients.
MATERIALS AND METHODS
In total, 36 consecutive MPN patients with SVT were enrolled. The MPNs were diagnosed based on clinical characteristics and one or more gene mutations among JAK-2, CALR, and MPL. As controls, 50 randomly selected patients with MPN without thrombosis, 50 patients with deep vein thrombosis without MPNs, and 50 healthy blood donors were evaluated. Complete blood count, ADAMTS13, VWF, MV, and FVIII:C in plasma were measured in all the subjects.
RESULTS
The JAK-2 mutation was found in 94% of the patients with SVT, but none were triple-negative for genetic mutations (JAK2 V617F, CALR, MPL, and exon 12). Compared to the normal subjects, in all the MPN patients (with or without SVT), the levels of ADAMTS13 were found to be significantly lower ( < 0.001) and the MV concentrations were significantly higher ( < 0.001). Among the MPN patients, the VWF and FVIII:C levels were significantly higher in the patients with SVT than those without thrombosis ( = 0.007 and = 0.04, respectively). Splenomegaly was present in 78% of MPN patients with SVT and in 30% of those without SVT ( < 0.001). The ADAMTS13/VWF ratio was reduced in all the patients, but not in the healthy blood donors ( < 0.001).
CONCLUSIONS
The significant increase in circulating MV, VWF, and FVIII:C in the MPN patients and in the patients with thrombosis supports the role of endothelium damage in promoting thrombotic events. In particular, a significant increase in VWF and FVIII:C levels was found in the MPN patients with SVT.
PubMed: 38672756
DOI: 10.3390/life14040486 -
Antioxidants (Basel, Switzerland) Apr 2024To date, little is known concerning the circulating levels of biochemically relevant metabolites (antioxidants, oxidative/nitrosative stress biomarkers, purines, and...
Targeted Metabolomics Highlights Dramatic Antioxidant Depletion, Increased Oxidative/Nitrosative Stress and Altered Purine and Pyrimidine Concentrations in Serum of Primary Myelofibrosis Patients.
To date, little is known concerning the circulating levels of biochemically relevant metabolites (antioxidants, oxidative/nitrosative stress biomarkers, purines, and pyrimidines) in patients with primary myelofibrosis (PMF), a rare form of myeloproliferative tumor causing a dramatic decrease in erythropoiesis and angiogenesis. In this study, using a targeted metabolomic approach, serum samples of 22 PMF patients and of 22 control healthy donors were analyzed to quantify the circulating concentrations of hypoxanthine, xanthine, uric acid (as representative purines), uracil, β-pseudouridine, uridine (as representative pyrimidines), reduced glutathione (GSH), ascorbic acid (as two of the main water-soluble antioxidants), malondialdehyde, nitrite, nitrate (as oxidative/nitrosative stress biomarkers) and creatinine, using well-established HPLC method for their determination. Results showed that PMF patients have dramatic depletions of both ascorbic acid and GSH (37.3- and 3.81-times lower circulating concentrations, respectively, than those recorded in healthy controls, < 0.0001), accompanied by significant increases in malondialdehyde (MDA) and nitrite + nitrate (4.73- and 1.66-times higher circulating concentrations, respectively, than those recorded in healthy controls, < 0.0001). Additionally, PMF patients have remarkable alterations of circulating purines, pyrimidines, and creatinine, suggesting potential mitochondrial dysfunctions causing energy metabolism imbalance and consequent increases in these cell energy-related compounds. Overall, these results, besides evidencing previously unknown serum metabolic alterations in PMF patients, suggest that the determination of serum levels of the aforementioned compounds may be useful to evaluate PMF patients on hospital admission for adjunctive therapies aimed at recovering their correct antioxidant status, as well as to monitor patients' status and potential pharmacological treatments.
PubMed: 38671937
DOI: 10.3390/antiox13040490 -
Journal of Fungi (Basel, Switzerland) Mar 2024Ruxolitinib, a selective inhibitor of Janus kinases, is a standard treatment for intermediate/high-risk myelofibrosis (MF) but is associated with a predisposition to... (Review)
Review
Disseminated Histoplasmosis in a Patient with Myelofibrosis on Ruxolitinib: A Case Report and Review of the Literature on Ruxolitinib-Associated Invasive Fungal Infections.
Ruxolitinib, a selective inhibitor of Janus kinases, is a standard treatment for intermediate/high-risk myelofibrosis (MF) but is associated with a predisposition to opportunistic infections, especially herpes zoster. However, the incidence and characteristics of invasive fungal infections (IFIs) in these patients remain uncertain. In this report, we present the case of a 59-year-old woman with MF who developed disseminated histoplasmosis after seven months of ruxolitinib use. The patient clinically improved after ten weeks of combined amphotericin B and azole therapy, and ruxolitinib was discontinued. Later, the patient received fedratinib, a relatively JAK2-selective inhibitor, without relapse of histoplasmosis. We also reviewed the literature on published cases of proven IFIs in patients with MF who received ruxolitinib. Including ours, we identified 28 such cases, most commonly due to species (46%). IFIs were most commonly disseminated (39%), followed by localized lung (21%) infections. Although uncommon, a high index of suspicion for opportunistic IFIs is needed in patients receiving JAK inhibitors. Furthermore, the paucity of data regarding the optimal management of IFIs in patients treated with JAK inhibitors underscore the need for well-designed studies to evaluate the epidemiology, pathobiology, early diagnosis, and multimodal therapy of IFIs in patients with hematological malignancies receiving targeted therapies.
PubMed: 38667935
DOI: 10.3390/jof10040264 -
Polish Archives of Internal Medicine Jun 2024
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Polycythemia Vera; Primary Myelofibrosis; Male; Disease Progression; Aged; Myelodysplastic Syndromes; Middle Aged
PubMed: 38656083
DOI: 10.20452/pamw.16735 -
Annals of Hematology Jun 2024
Triple a score (AAA: age, absolute neutrophil count and absolute lymphocyte count) and its prognostic utility in patients with overt fibrotic and prefibrotic myelofibrosis.
Topics: Humans; Primary Myelofibrosis; Neutrophils; Lymphocyte Count; Male; Female; Aged; Middle Aged; Leukocyte Count; Prognosis; Age Factors; Aged, 80 and over; Adult
PubMed: 38652241
DOI: 10.1007/s00277-024-05751-7 -
Annals of Hematology Jun 2024Janus kinase 2 (JAK2) V617F mutation is present in most patients with polycythemia vera (PV). One persistently puzzling aspect unresolved is the association between... (Meta-Analysis)
Meta-Analysis
Janus kinase 2 (JAK2) V617F mutation is present in most patients with polycythemia vera (PV). One persistently puzzling aspect unresolved is the association between JAK2V617F allele burden (also known as variant allele frequency) and the relevant clinical characteristics. Numerous studies have reported associations between allele burden and both hematologic and clinical features. While there are strong indications linking high allele burden in PV patients with symptoms and clinical characteristics, not all associations are definitive, and disparate and contradictory findings have been reported. Hence, this study aimed to synthesize existing data from the literature to better understand the association between JAK2V617F allele burden and relevant clinical correlates. Out of the 1,851 studies identified, 39 studies provided evidence related to the association between JAK2V617F allele burden and clinical correlates, and 21 studies were included in meta-analyses. Meta-analyses of correlation demonstrated that leucocyte and erythrocyte counts were significantly and positively correlated with JAK2V617F allele burden, whereas platelet count was not. Meta-analyses of standardized mean difference demonstrated that leucocyte and hematocrit were significantly higher in patients with higher JAK2V617F allele burden, whereas platelet count was significantly lower. Meta-analyses of odds ratio demonstrated that patients who had higher JAK2V617F allele burden had a significantly greater odds ratio for developing pruritus, splenomegaly, thrombosis, myelofibrosis, and acute myeloid leukemia. Our study integrates data from approximately 5,462 patients, contributing insights into the association between JAK2V617F allele burden and various hematological parameters, symptomatic manifestations, and complications. However, varied methods of data presentation and statistical analyses prevented the execution of high-quality meta-analyses.
Topics: Polycythemia Vera; Janus Kinase 2; Humans; Alleles; Gene Frequency; Amino Acid Substitution; Mutation, Missense
PubMed: 38652240
DOI: 10.1007/s00277-024-05754-4 -
Cytometry. Part B, Clinical Cytometry Apr 2024Thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), prefibrotic/early (pre-PMF), and overt fibrotic PMF (overt PMF) are classical...
Thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), prefibrotic/early (pre-PMF), and overt fibrotic PMF (overt PMF) are classical Philadelphia-Negative (Ph-negative) myeloproliferative neoplasms (MPNs). Differentiating between these types based on morphology and molecular markers is challenging. This study aims to clarify the application of flow cytometry in the diagnosis and differential diagnosis of classical MPNs. This study retrospectively analyzed the immunophenotypes, clinical characteristics, and laboratory findings of 211 Ph-negative MPN patients, including ET, PV, pre-PMF, overt PMF, and 47 controls. Compared to ET and PV, PMF differed in white blood cells, hemoglobin, blast cells in the peripheral blood, abnormal karyotype, and WT1 gene expression. PMF also differed from controls in CD34 cells, granulocyte phenotype, monocyte phenotype, percentage of plasma cells, and dendritic cells. Notably, the PMF group had a significantly lower plasma cell percentage compared with other groups. A lasso and random forest model select five variables (CD34CD19cells and CD34CD38 cells on CD34cells, CD13CD11b cells in granulocytes, CD38CD19plasma, and CD123HLA-DRbasophils), which identify PMF with a sensitivity and specificity of 90%. Simultaneously, a classification and regression tree model was constructed using the percentage of CD34CD38 on CD34 cells and platelet counts to distinguish between ET and pre-PMF, with accuracies of 94.3% and 83.9%, respectively. Flow immunophenotyping aids in diagnosing PMF and differentiating between ET and PV. It also helps distinguish pre-PMF from ET and guides treatment decisions.
PubMed: 38647185
DOI: 10.1002/cyto.b.22173 -
American Journal of Hematology Jul 2024Emerging evidence shows the crucial role of inflammation (particularly NF-κB pathway) in the development and progression of myelofibrosis (MF), becoming a promising...
Emerging evidence shows the crucial role of inflammation (particularly NF-κB pathway) in the development and progression of myelofibrosis (MF), becoming a promising therapeutic target. Furthermore, tailoring treatment with currently available JAK inhibitors (such as ruxolitinib or fedratinib) does not modify the natural history of the disease and has important limitations, including cytopenias. Since recent studies have highlighted the role of miR-146a, a negative regulator of the NF-κB pathway, in the pathogenesis of MF; here we used miR-146a (KO) mice, a MF-like model lacking driver mutations, to investigate whether pharmacological inhibition of JAK/STAT and/or NF-κB pathways may reverse the myelofibrotic phenotype of these mice. Specifically, we tested the JAK1/2 inhibitor, ruxolitinib; the NF-κB inhibitor via IKKα/β, BMS-345541; both inhibitors in combination; or a dual inhibitor of both pathways (JAK2/IRAK1), pacritinib. Although all treatments decreased spleen size and partially recovered its architecture, only NF-κB inhibition, either using BMS-345541 (alone or in combination) or pacritinib, resulted in a reduction of extramedullary hematopoiesis, bone marrow (BM) fibrosis and osteosclerosis, along with an attenuation of the exacerbated inflammatory state (via IL-1β and TNFα). However, although dual inhibitor improved anemia and reversed thrombocytopenia, the combined therapy worsened anemia by inducing BM hypoplasia. Both therapeutic options reduced NF-κB and JAK/STAT signaling in a context of JAK2V617F-driven clonal hematopoiesis. Additionally, combined treatment reduced both COL1A1 and IL-6 production in an in vitro model mimicking JAK2-driven fibrosis. In conclusion, NF-κB inhibition reduces, in vitro and in vivo, disease burden and BM fibrosis, which could provide benefits in myelofibrosis patients.
Topics: Animals; Primary Myelofibrosis; MicroRNAs; Mice; NF-kappa B; Nitriles; Pyrimidines; Pyrazoles; Mice, Knockout; Signal Transduction; Disease Models, Animal; Hematopoiesis, Extramedullary
PubMed: 38646919
DOI: 10.1002/ajh.27322 -
Cureus Mar 2024Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by elevated platelet counts and fibrous tissues in the bone marrow. The JAK1/2 inhibitor...
Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by elevated platelet counts and fibrous tissues in the bone marrow. The JAK1/2 inhibitor (JAKi), ruxolitinib, has demonstrated efficacy in reducing splenic size, alleviating myelofibrosis-related symptoms, and improving overall survival. While an increased risk of lymphoproliferative disease (LPD) is suggested in patients with PMF, particularly those treated with JAKi, the involvement of Epstein-Barr virus (EBV) in such cases remains poorly documented. Here, we present the case of a 69-year-old woman with PMF who developed multiple lymphadenopathies and elevated soluble interleukin-2 receptor (sIL-2R) levels. Ruxolitinib and steroid therapy improved the symptoms for a short period; however, the lymphadenopathies and ascites eventually worsened. A biopsy confirmed EBV-positive diffuse large B-cell lymphoma, but the patient died of severe tumor lysis syndrome. Additionally, we conducted a literature review on EBV-related LPD in patients with primary and secondary myelofibrosis. Our report and literature review shed light on the occurrence of EBV-related LPD in MF, especially in those treated with JAKi, emphasizing the need to consider lymphoma as a potential diagnosis and monitor the EBV-DNA viral load in patients displaying lymphadenopathies or increased sIL-2R levels.
PubMed: 38646256
DOI: 10.7759/cureus.56586 -
Indian Journal of Nephrology 2024Proliferative glomerulonephritis in myelofibrosis is a very rare. Mesangial proliferation and sclerosis with changes of chronic thrombotic microangiopathy have been...
Proliferative glomerulonephritis in myelofibrosis is a very rare. Mesangial proliferation and sclerosis with changes of chronic thrombotic microangiopathy have been reported, but pauci-immune focal crescentic glomerulonephritis has not been described so far. Herein, we present a 68-year-old male who was a known case of myelofibrosis and presented with rapidly progressive glomerulonephritis and nephrotic range proteinuria. He was diagnosed as anti-neutrophil cytoplasmic antibody (ANCA)-negative focal crescentic glomerulonephritis, and he responded well to a course of intravenous methylprednisolone and cyclophosphamide. Pauci-immune focal crescentic glomerulonephritis may occur in myelofibrosis without ANCA and may be related to unknown pathogenetic mechanisms in myeloproliferative disorders or suggest any superimposed pathology that might respond well to immunosuppressants.
PubMed: 38645909
DOI: 10.4103/ijn.ijn_218_22