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Background: The study aimed to determine the most crucial parameters associated with CVD and employ a novel data ensemble refinement procedure to uncover the optimal pattern of these parameters that can result in a high prediction accuracy., Methods and Results: Data were collected from 369 patients in total, 281 patients with CVD or at risk of developing it, compared to 88 otherwise healthy individuals. Within the group of 281 CVD or at-risk patients, 53 were diagnosed with coronary artery disease (CAD), 16 with end-stage renal disease, 47 newly diagnosed with diabetes mellitus 2 and 92 with chronic inflammatory disorders (21 rheumatoid arthritis, 41 psoriasis, 30 angiitis). The data were analyzed using an artificial intelligence-based algorithm with the primary objective of identifying the optimal pattern of parameters that define CVD. The study highlights the effectiveness of a six-parameter combination in discerning the likelihood of cardiovascular disease using DERGA and Extra Trees algorithms. These parameters, ranked in order of importance, include Platelet-derived Microvesicles (PMV), hypertension, age, smoking, dyslipidemia, and Body Mass Index (BMI). Endothelial and erythrocyte MVs, along with diabetes were the least important predictors. In addition, the highest prediction accuracy achieved is 98.64%. Notably, using PMVs alone yields a 91.32% accuracy, while the optimal model employing all ten parameters, yields a prediction accuracy of 0.9783 (97.83%)., Conclusions: Our research showcases the efficacy of DERGA, an innovative data ensemble refinement greedy algorithm. DERGA accelerates the assessment of an individual's risk of developing CVD, allowing for early diagnosis, significantly reduces the number of required lab tests and optimizes resource utilization. Additionally, it assists in identifying the optimal parameters critical for assessing CVD susceptibility, thereby enhancing our understanding of the underlying mechanisms., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) represents a curative treatment for various blood-related disorders, including hematological malignancies and genetic disorders. The success of this procedure hinges on the efficacy of the conditioning regimen and the graft's ability to engraft and function properly. Microparticles (MPs), small vesicles produced from stimulated, apoptotic, or activated cells, are involved in both physiological and pathological processes. However, the impact of MPs on allo-HCT remains poorly understood., Objectives: This study aimed to investigate the presence of MPs from different cell types in grafts and patient plasma after allo-HCT, as well as their association with various parameters. We measured MPs from CD34+, CD56+, CD3+, CD19+, and CD33+ cells in grafts and patient plasma from day 0 to day 60 after transplantation., Methods: 224 blood samples were collected from 19 consecutive allo -HCT recipients at 0, +4, +14,+30 and + 60 day as well as from their grafts. MPs isolated from the plasma and quantified by flow cytometry analysis., Results: MP levels varied over time. Notably, CD34+ MP levels were linked to both early and late engraftment of neutrophils and platelets. Furthermore, grafts with high CD34+ and CD56+ MP levels in patient plasma on days 0 and + 4 were associated with late engraftment, whereas high CD33+ MP levels in both graft and patient plasma on day +4 were associated with early engraftment. Conditioning regimen affected CD19+ MP levels at day +14, and the number of CD34+, CD56+, and CD19+ MPs 30 days after transplantation was correlated with acute graft-versus-host disease., Conclusion: These findings suggest that MPs derived from hematopoietic cells may play a significant role in the clinical course of patients following allo-HCT., Competing Interests: Conflict of interest statement There are no conflicts of interest to report., (Copyright © 2024. Published by Elsevier B.V.)

We have attempted to explore further the involvement of complement components in the host COVID-19 (Coronavirus disease-19) immune responses by targeted genotyping of COVID-19 adult patients and analysis for missense coding Single Nucleotide Polymorphisms (coding SNPs) of genes encoding Alternative pathway (AP) components. We have identified a small group of common coding SNPs in Survivors and Deceased individuals, present in either relatively similar frequencies (CFH and CFI SNPs) or with stark differences in their relative abundance (C3 and CFB SNPs). In addition, we have identified several sporadic, potentially protective, coding SNPs of C3, CFB, CFD, CFH, CFHR1 and CFI in Survivors. No coding SNPs were detected for CD46 and CD55. Our demographic analysis indicated that the C3 rs1047286 or rs2230199 coding SNPs were present in 60 % of all the Deceased patients (n = 25) (the rs2230199 in 67 % of all Deceased Males) and in 31 % of all the Survivors (n = 105, p = 0.012) (the rs2230199 in 25 % of all Survivor Males). When we analysed these two major study groups using the presence of the C3 rs1047286 or rs2230199 SNPs as potential biomarkers, we noticed the complete absence of the protective CFB rs12614 and rs641153 coding SNPs from Deceased Males compared to Females (p = 0.0023). We propose that in these individuals, C3 carrying the R102G and CFB lacking the R32W or the R32Q amino acid substitutions, may contribute to enhanced association dynamics of the C3bBb AP pre-convertase complex assembly, thus enabling the exploitation of the activation of the Complement Alternative pathway (AP) by SARS-CoV-2., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Complement is an elaborate system of innate immunity. Genetic variants and autoantibodies leading to excessive complement activation are implicated in a variety of human diseases. Among them, the hematologic disease paroxysmal nocturnal hemoglobinuria (PNH) remains the prototypic model of complement activation and inhibition. Eculizumab, the first-in-class complement inhibitor, was approved for PNH in 2007. Addressing some of the unmet needs, a long-acting C5 inhibitor, ravulizumab, and a C3 inhibitor, pegcetacoplan, have also now been approved for PNH. Novel agents, such as factor B and factor D inhibitors, are under study, with very promising results. In this era of several approved targeted complement therapeutics, selection of the proper drug must be based on a personalized approach. Beyond PNH, complement inhibition has also shown efficacy and safety in cold agglutinin disease, primarily with the C1s inhibitor of the classical complement pathway sutimlimab, as well as with pegcetacoplan. Furthermore, C5 inhibition with eculizumab and ravulizumab, as well as inhibition of the lectin pathway with narsoplimab, is being investigated in transplantation-associated thrombotic microangiopathy. With this revolution of next-generation complement therapeutics, additional hematologic entities, such as delayed hemolytic transfusion reaction or immune thrombocytopenia, might also benefit from complement inhibitors. Therefore, this review aims to describe state-of-the-art knowledge of targeting complement in hematologic diseases, focusing on (1) complement biology for the clinician, (2) complement activation and therapeutic inhibition in prototypic complement-mediated hematologic diseases, (3) hematologic entities under investigation for complement inhibition, and (4) other complement-related disorders of potential interest to hematologists., (© 2022 by The American Society of Hematology.)

Therapy related acute myeloid leukemia (tAML) and secondary AML after an antecedent hematologic disorder (sAML-AHD) are often addressed together, blurring any clinical and prognostic differences. Among 516 AML patients, we compared characteristics and outcomes of 149 patients with "sAML" (sAML-AHD: 104, tAML: 45), uniformly and intensively treated during the last 2 decades at 1 center. Clinical outcomes of the whole "sAML" cohort were significantly inferior compared to de novo AML and in both intermediate and poor cytogenetic risk groups. Adverse karyotype had no effect on survival in tAML, while it was a negative predictor in sAML-AHD. Both groups showed similarly dismal outcome, with low complete remission rates (CR 44% vs. 41%) and median overall survival (OS 7 vs. 10.5 months). Allogeneic hematopoietic cell transplantation (alloHCT) recipients in CR1 had superior median OS (24 vs. 8 months). By multivariate analysis, alloHCT was an independent predictor of outcome, while karyotype was for sAML-AHD only. In conclusion, both "sAML" groups have inferior outcomes after chemotherapy, with adverse karyotype affecting primarily sAML-AHD. Until new treatment approaches are available, only alloHCT offers a survival advantage., (Copyright © 2021. Published by Elsevier Inc.)

Sickle cell disease (SCD) is a common inherited clinical syndrome, characterized by the presence of hemoglobin S. Anemia, susceptibility to infections and episodes of vaso-occlusive crisis (VOC) are among its features. Since SCD complications (VOC or delayed hemolytic transfusion reaction/DHTR) lead to significant morbidity and mortality, a number of studies have addressed their pathophysiology Although SCD pathophysiology has been mainly attributed to the interaction between sickle cells and neutrophils, platelets or endothelial cells in small vessels leading to hemolysis, the role of complement activation has been increasingly investigated. Importantly, complement inhibition with eculizumab has shown beneficial effects in DHTR. Given the unmet clinical need of novel therapeutics in SCD, our review summarizes current understanding of (a) complement system for the clinician, (b) complement activation in SCD both in asymptomatic state and severe clinical manifestations, (c) probable underlying mechanisms of complement activation in SCD, and (d) new therapeutic perspective of complement inhibition., (Copyright © 2021. Published by Elsevier Ltd.)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare life-threatening disease resulting from clonal hematopoietic stem cell evolution. There is a strong link between PNH and other acquired bone marrow failure syndromes, including myelodysplastic syndrome (MDS). Cytogenetic, morphological abnormalities or both are observed in the range of MDS/PNH diagnosis. Herein, we investigate cytogenetic abnormalities in PNH patients. We found two patients with PNH clones and MDS-associated abnormalities that later disappeared. The first patient, originally diagnosed with MDS and Trisomy 6, developed a large PNH clone. At the time of PNH diagnosis, the abnormal cytogenetic clone was no longer detectable despite persistent trilineage dysplasia. In the second patient, a large PNH clone and MDS-defining abnormality were detected at diagnosis, without evidence of dysplasia. No cytogenetic abnormalities were evident after complement inhibition. Our report adds significant information on the complex link between MDS and PNH, suggesting that distinction between these entities may be difficult in some cases. Especially in transplant eligible patients, the clinical phenotype may be the leading feature for treatment decisions in the era of complement inhibition. Lastly, the transient presence of cytogenetic abnormalities is a unique characteristic of our patients' course that needs to be further elucidated in larger studies., Competing Interests: Declaration of Competing Interest Nothing to disclose., (Copyright © 2020. Published by Elsevier Inc.)

The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies, including anti-β2-glycoprotein-I (anti-β2GPI), that are considered central to APS pathogenesis. Based on animal studies showing a role of complement in APS-related clinical events, we used the modified Ham (mHam) assay (complement-dependent cell killing) and cell-surface deposition of C5b-9 to test the hypothesis that complement activation is associated with thrombotic events in APS. A positive mHam (and corresponding C5b-9 deposition) were present in 85.7% of catastrophic APS (CAPS), 35.6% of APS (and 68.5% of samples collected within 1 year of thrombosis), and only 6.8% of systemic lupus erythematosus (SLE) sera. A positive mHam assay was associated with triple positivity (for lupus anticoagulant, anticardiolipin, and anti-β2GPI antibodies) and recurrent thrombosis. Patient-derived anti-β2GPI antibodies also induced C5b-9 deposition, which was blocked completely by an anti-C5 monoclonal antibody, but not by a factor D inhibitor, indicating that complement activation by anti-β2GPI antibodies occurs primarily through the classical complement pathway. Finally, patients with CAPS have high rates of rare germline variants in complement regulatory genes (60%), compared with patients with APS (21.8%) or SLE (28.6%) or normal controls (23.3%), and have mutations at a rate similar to that of patients with atypical hemolytic uremic syndrome (51.5%). Taken together, our data suggest that anti-β2GPI antibodies activate complement and contribute to thrombosis in APS, whereas patients with CAPS have underlying mutations in complement regulatory genes that serve as a "second hit," leading to uncontrolled complement activation and a more severe thrombotic phenotype., (© 2020 by The American Society of Hematology.)

Blood pressure levels are directly associated with cardiovascular and cerebrovascular morbidity and mortality, rendering arterial hypertension a major public health problem affecting almost 1 billion people worldwide. Several models have been used for cardiovascular risk prediction based on traditional cardiovascular risk factors. Among them, hypertension represents a factor that may be triggered by distinct pathogenetic mechanisms in specific disease populations. Accumulating evidence points towards an increased incidence of hypertension in patients with hematologic malignancies and recipients of hematopoietic cell transplantation. However, the role of hypertension in these entities remains under-reported in the relevant literature. In the complex setting of life-threatening conditions that need immediate and aggressive treatment, conditions that are common and easy to diagnose such as hypertension, may be neglected by treating physicians. However, hypertension may represent a key diagnostic and prognostic clinical finding in acute syndromes, such as thrombotic microangiopathy. Furthermore, hypertension may arise as a late effect of long-term survivors leading to increased morbidity and mortality across all age groups. Our concise review focuses on incidence, pathophysiology and management of hypertension in patients following hematopoietic cell transplantation and treatment for hematologic malignancies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We investigated whether aldosterone concurrently mediates microvascular and macrovascular impairment, in a population of treatment-naïve young- to middle-aged individuals free from cardiovascular comorbidities. Newly diagnosed, never-treated essential hypertensive patients and normotensive individuals participated in the study. Pulse wave velocity (PWV) and augmentation index were estimated with applanation tonometry. Microalbuminuria was determined from 24-hour urine collections. Laboratory tests included measurement of plasma renin activity, serum aldosterone, and high-sensitivity C-reactive protein. In 221 individuals aged 42.0 ± 12.3 years, classification in the highest aldosterone tertile was associated with the highest levels of blood pressure (BP), PWV, and high-sensitivity C-reactive protein (P < .05 for all). These individuals also exhibited twice the prevalence of microalbuminuria, compared to the first tertile (P = .081). Multivariate analysis showed that the positive association between PWV and increasing aldosterone tertiles remained significant after adjustment for BP and other parameters (P = .035). Likewise, aldosterone independently predicted microalbuminuria (P = .026) in the logistic regression analysis. In treatment-naïve individuals whose BP ranges from normal to early-stage hypertension, significant interactions exist between aldosterone and indices of microvascular and macrovascular damage. These findings suggest that aldosterone concurrently modulates microvascular and macrovascular function from the very early stages of essential hypertension and is dynamically implicated in the pathogenesis of hypertensive vascular disease., (Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Introduction: Anti-thymocyte globulin (ATG)-based immunosuppressive therapy is often used in allogeneic hematopoietic cell transplantation to reduce incidence and severity of graft-versus-host disease (GVHD)., Patients and Methods: In our observational study, ATG (rabbit, Thymoglobulin; Sanofi, 5 mg/kg) was administered as a standardized part of the conditioning in 97 patients with a median age of 34 years (range, 14-58 years), allotransplanted for hematologic malignancies from matched (8/8; n = 52) and allele or antigen mismatched (7/8; n = 43 and 6/8; n = 2) unrelated donors., Results: Five-year overall survival (OS) was 46.9%, disease-free survival was 46.5%, and treatment-related mortality was 20.6%, with a median follow-up of 29 months (range, 1-145 months). Acute GVHD (grade ≥ II) cumulative incidence was 26.9% in matched versus 50.5% in mismatched patients (P = .060), whereas extensive chronic GVHD was 45.6% versus 50%, respectively (P = .310). Five-year OS was 62.2% for the matched patients and 27.9% for the mismatched patients (P = .003) owing to a higher treatment-related mortality rate in mismatched patients (P = .032). In multivariate analysis including age, gender, time until transplantation, disease phase, mismatched donor, ABO mismatch, number of CD34+ infused, acute and chronic GVHD, the significant unfavorable factors for OS were HLA mismatch and advanced disease phase., Conclusion: A relatively low-dose ATG is effective in acute GVHD prophylaxis, leading to promising survival rates in matched transplants. Further comparative studies with adjusted ATG dose depending on Human leukocyte antigen disparity or alternative donors are warranted., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by excessive activation of the alternative pathway of complement (APC). Atypical HUS is frequently a diagnosis of exclusion. Differentiating aHUS from other TMAs, especially thrombotic thrombocytopenic purpura (TTP), is difficult due to overlapping clinical manifestations. We sought to develop a novel assay to distinguish aHUS from other TMAs based on the hypothesis that paroxysmal nocturnal hemoglobinuria cells are more sensitive to APC-activated serum due to deficiency of glycosylphosphatidylinositol- anchored complement regulatory proteins (GPI-AP). Here, we demonstrate that phosphatidylinositol-specific phospholipase C-treated EA.hy926 cells and PIGA-mutant TF-1 cells are more susceptible to serum from aHUS patients than parental EA.hy926 and TF-1 cells. We next studied 31 samples from 25 patients with TMAs, including 9 with aHUS and 12 with TTP. Increased C5b-9 deposition was evident by confocal microscopy and flow cytometry on GPI-AP-deficient cells incubated with aHUS serum compared with heat-inactivated control, TTP, and normal serum. Differences in cell viability were observed in biochemically GPI-AP-deficient cells and were further increased in PIGA-deficient cells. Serum from patients with aHUS resulted in a significant increase of nonviable PIGA-deficient TF-1 cells compared with serum from healthy controls (P < .001) and other TMAs (P < .001). The cell viability assay showed high reproducibility, sensitivity, and specificity in detecting aHUS. In conclusion, we developed a simple, rapid, and serum-based assay that helps to differentiate aHUS from other TMAs., (© 2015 by The American Society of Hematology.)

Early identification of hypertensive target organ damage (TOD) emerges as important for global cardiovascular risk assessment. Retinal vascular alterations, capillary rarefaction, and microalbuminuria represent different forms of microvascular TOD. However, data regarding their concomitant presence in the early stages of hypertension, the association of the number of affected organs with cardiovascular risk, and aldosterone effect on multiple TOD are lacking. We studied naïve, never-treated patients with recent duration of hypertension and healthy volunteers. Innovative software was developed to estimate retinal vascular diameters and capillary density. Biochemical parameters including microalbuminuria and serum aldosterone were derived. Framingham Risk Score was used to determine cardiovascular risk. In total 103 subjects, 66 hypertensives and 37 normotensives, were included. Hypertensive patients exhibited a greater number of affected target organs compared with normotensives (P = .014), with retinopathy and capillary rarefaction (40.9%) representing the most common TOD among hypertensives. The number of affected organs was linearly correlated with increased Framingham score and serum aldosterone, analyzed with univariate (P < .001 and P = .002) and multivariate analysis (P = .025 and P = .004), respectively. Physicians dealing with hypertensive patients should be aware of the possibility of diffuse microvascular impairment and seek multiple TOD even in the early stages of hypertension., (Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)