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Background : This study aimed to evaluate the clinical and prognostic associations of the systemic inflammatory index (SII) in polycythemia vera (PV) patients. SII integrates information on absolute neutrophil (ANC), lymphocyte (ALC), and platelet counts into one index (calculated as ANCxALC/platelet count) and was previously shown to predict thrombotic and mortality risks in the general population. Methods : A total of 279 PV patients treated in several hematologic centers in Croatia and Serbia was retrospectively evaluated. Results : The median SII for the overall cohort was 1960. Higher SII stratified at the specific cut-off points was significantly associated with shorter time to thrombosis (TTT; p = 0.004) driven by arterial thrombotic events, and shorter overall survival (OS; p < 0.001). Higher SII was able to refine the European Leukemia Net-defined high-risk patient subgroup for both thrombotic and survival risks, especially in individuals over 60 years of age. SII and all other evaluated CBC components and indices (leukocytes, ANC, ALC, platelets, neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR)) demonstrated low-to-modest prognostic properties, whereas SII outperformed other parameters with respect to TTT and OS prognostications. Discussion : The presented results complement prior studies evaluating the prognostic performance of different CBC components for thrombotic and survival risk predictions and offer more options to personalize PV treatments.

The exact prognostic role of cardiovascular (CV) risk factors in patients with BCR::ABL1 negative chronic myeloproliferative neoplasms (MPNs) remains unknown as it is often masked by other MPN-related features that bear strong prognostic impact on thrombotic risk. Therefore, current MPN treatment is not primarily guided by presence of CV risk factors. Treatment of CV risk factors in MPN patients usually mirrors that from the general population, despite the fact that CV risk factors in MPNs have their own specificities. Moreover, the optimal target levels for different metabolic deflections in MPNs (i.e., low-density lipoprotein, serum uric acid, or glycated hemoglobin levels) have not been defined. In the current review, we separately discuss the most important aspects of every individual CV risk factor (arterial hypertension, hyperlipidemia, chronic kidney disease, smoking, diabetes mellitus, hyperuricemia, and obesity and cachexia) in MPNs, summarize recent advances in the field, and propose future directions and research areas which may be needed to appropriately manage CV risk factors in MPNs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To investigate the prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC), platelet count and their ratios, neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), to thrombotic risk in patients with prefibrotic and overt fibrotic myelofibrosis (MF)., Methods: We retrospectively analyzed a cohort of 256 patients with prefibrotic (85 patients) and overt fibrotic MF (171 patients) treated in six Croatian hematological centers., Results: Prefibrotic compared to overt fibrotic MF patients presented with significantly higher ALC, platelet count and PLR, and experienced longer time to thrombosis (TTT). Among prefibrotic patients, ANC > 8.33 × 10 9 /L (HR 13.08, p = 0.036), ALC > 2.58 × 10 9 /L (HR 20.63, p = 0.049) and platelet count > 752 × 10 9 /L (HR 10.5, p = 0.043) remained independently associated with shorter TTT. Among overt fibrotic patients, ANC > 8.8 × 10 9 /L (HR 4.49, p = 0.004), ALC ≤ 1.43 × 10 9 /L (HR 4.15, p = 0.003), platelet count ≤ 385 × 10 9 /L (HR 4.68, p = 0.004) and chronic kidney disease (HR 9.07, p < 0.001) remained independently associated with shorter TTT., Conclusions: Prognostic properties of ANC, ALC and platelet count are mutually independent and exceed those of NLR and PLR regarding thrombotic risk stratification. ALC and platelet count associate in opposite directions with thrombotic risk in prefibrotic and overt fibrotic MF patients.

Secondary polycythemia is commonly observed among patients with chronic pulmonary diseases. However, its significance in the context of Coronavirus disease 2019 (COVID-19) is unknown. We retrospectively evaluated a total of 5872 hospitalized COVID-19 patients with mostly severe and critical symptoms, and without prior or subsequently diagnosed myeloproliferative neoplasm. Patients were stratified based on admission hemoglobin into four subgroups: anemia (hemoglobin <120 g/L for females and 130 g/L for males), normal hemoglobin, mild (hemoglobin 160-165 g/L for females and 165-185 g/L for males) and severe polycythemia (hemoglobin >165 g/L for females and >185 g/L for males). Among 5872 patients, a total of 158 (2.7%) had mild and 25 (0.4%) severe polycythemia. Polycythemia was significantly associated with higher respiratory and functional impairment, reduced plasma volume, higher serum osmolarity and comorbidity burden specific to the degree of polycythemia. Patients presenting with mild (odds ratio (OR) = 1.63, p  = .003) and severe polycythemia (OR = 4.98, p  < .001) had increased risk of death in comparison to patients with normal hemoglobin, whereas no significant associations with venous thromboembolism, arterial thrombosis nor major bleeding were observed. Anemia was associated with higher risk of death (OR = 1.42, p  < .001), venous thromboembolism (OR = 1.34, p  < .006) and major bleeding (OR = 2.27, p  < .001) in comparison to normal hemoglobin. Associations of polycythemia and anemia with mortality diminished, and anemia with venous thromboembolism and major bleeding persisted, after multivariate adjustments for age, sex, comorbidities, COVID-19 severity and functional status. Secondary polycythemia in hospitalized COVID-19 patients without prior of subsequently diagnosed myeloproliferative neoplasm is rare and is associated with high mortality, increasing with degree of polycythemia, but not markedly higher thrombotic risk.

Background: Due to non-consistent reports in the literature, there are uncertainties about the potential benefits and harms of selective serotonin reuptake inhibitors (SSRIs) in patients with Coronavirus disease 2019 (COVID-19)., Aim: To investigate associations of SSRIs with clinical characteristics and unwanted outcomes among real-life severe and critical COVID-19 patients and their relationship with remdesivir (RDV) use., Methods: This retrospective cohort study evaluated a total of 1558 COVID-19 patients of the white race treated in a tertiary center institution, among them 779 patients treated with RDV and 779 1:1 case-matched patients., Results: A total of 78 (5%) patients were exposed to SSRIs during hospitalization, similarly distributed among patients treated with RDV and matched patients (5.1 and 4.9%). No significant associations of SSRI use with age, sex, comorbidity burden, and COVID-19 severity were present in either of the two cohorts ( p  > 0.05 for all analyses). In multivariate analyses adjusted for clinically meaningful variables, SSRI use was significantly associated with higher mortality among RDV (adjusted odds ratio (aOR) 2.0, p  = 0.049) and matched patients (aOR 2.22, p  = 0.044) and with higher risk for mechanical-ventilation (aOR 2.57, p  = 0.006), venous-thromboembolism (aOR 3.69, p  = 0.007), and bacteremia (aOR 2.22, p  = 0.049) among RDV treated patients., Conclusions: Adverse outcomes associated with SSRI use in COVID-19 patients might be potentiated by RDV use, and clinically significant interactions between these two drug classes might exist. Although our findings raise important considerations for clinical practice, they are limited by retrospective nature of the study, lack of ethnic diversity, and the potential for unmeasured confounding factors. Future studies exploring underlying biological mechanisms are needed., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Blood plasma is a large reservoir of circulating mediators of inflammation and its expansion has been associated with unfavorable outcomes in patients with inflammatory and cardiovascular diseases. The aim of this study was to determine clinical and prognostic value of estimated plasma volume status (ePVS) in hospitalized patients with COVID-19. We retrospectively investigated 5871 consecutive COVID-19 patient hospitalized in our tertiary-level institution in period 3/2020-6/2021. ePVS was determined using the Strauss-derived Duarte formula and was correlated with clinical characteristics and unwanted outcomes. Median ePVS was 4.77 dl/g with interquartile range 4.11-5.74. Higher ePVS was significantly associated with older age, female sex, higher comorbidity burden, worse functional status, less severe COVID-19 clinical presentation with lower severity and longer duration of symptoms, but more pronounced inflammatory profile with higher C-reactive protein, interleukin-6 and D-dimer levels (P < 0.05 for all analyses). In the multivariate regression analysis U shaped relationship of ePVS with mortality was revealed, present independently of age, sex, COVID-19 severity and comorbidity burden. In addition, higher ePVS was independently associated with higher tendency for mechanical ventilation, intensive care unit treatment, venous thromboembolism, major bleeding and bacteriemia and lower ePVS was independently associated with tendency for arterial thrombotic events. Higher ePVS, indicative of plasma volume expansion and inflammatory cytokine accumulation, may predispose respiratory deterioration and venous thromboembolism, despite less severe initial clinical presentation. Lower ePVS, indicative of hemoconcentration, may predispose arterial thrombotic events. Both may be associated with higher mortality in hospitalized COVID-19 patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We aimed to investigate the associations of hypo- and hyperosmolarity at hospital admission with clinical characteristics and outcomes in 5645 consecutive hospitalized COVID-19 patients treated at a tertiary-level institution. Serum osmolarity was calculated as 2x Na (mmol/L) + urea (mmol/L) + glucose (mmol/L), with normal range from 275 to 295 mOsm/L. Median serum osmolarity was 292.9 mOsm/L with 51.8% normoosmolar, 5.3% hypoosmolar and 42.9% hyperosmolar patients present at the time of hospital admission. Hypoosmolarity was driven by hyponatremia, and was associated with the presence of chronic liver disease, liver cirrhosis, active malignancy and epilepsy. Hyperosmolarity was driven by an increase in urea and glucose and was associated with the presence of chronic metabolic and cardiovascular comorbidities. Both hypo- and hyperosmolar patients presented with more severe COVID-19 symptoms, higher inflammatory status, and experienced higher mortality in comparison to normoosmolar patients. In multivariate analysis, hypoosmolarity (adjusted odds ratio (aOR)=1.39, p  = 0.024) and hyperosmolarity (aOR = 1.9, p  < 0.001) remained significantly associated with higher mortality independently of older age, male sex, higher Charlson Comorbidity Index and more severe COVID-19. Disruptions in serum osmolarity are frequent in COVID-19 patients, may be easy to detect and target therapeutically, and thus potentially moderate associateds poor prognosis.

Cardiovascular (CV) risk factors are important contributors to thrombotic risk in the general population and in patients with chronic myeloproliferative neoplasms (MPNs). However, the role of CV risk factors is often masked by other disease features that have a strong prognostic impact regarding thrombotic risk in MPN patients. This review summarizes the contemporary knowledge and aspects that have not been addressed or lack consensus in the medical community. We propose multidisciplinary care for MPN patients with CV comorbidities and provide future directions that may be needed to appropriately manage CV risk factors in MPNs.

Competing Interests: Both authors declare no conflict of interest.

Competing Interests: Disclosures: Authors have reported no disclosures of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L23-0164.

Introduction: Blood plasma represents a large reservoir of cytokines and other mediators of inflammation. Higher estimated plasma volume status (ePVS) has been shown to correlate with increased thrombotic risk in polycythemia vera patients, but its clinical and prognostic associations in patients with myelofibrosis are unknown which we aim to evaluate in this study., Materials and Methods: We retrospectively analysed a multicentric cohort of 238 patients with primary (PMF) and secondary myelofibrosis (SMF). Estimated plasma volume status was calculated using the Strauss-derived Duarte formula. Overall survival (OS) and time to thrombosis (TTT) considering both arterial and venous thromboses were primary endpoints of interest., Results: Median ePVS was 5.8 dL/g and it did not significantly differ between PMF and SMF patients. Patients with more advanced disease features, more pronounced inflammation and higher comorbidity burden had higher ePVS. Higher ePVS (> 5.6 dL/g) was associated with shorter OS in PMF (unadjusted hazard ratio, HR = 2.8, 95% confidence interval, CI (1.79-4.41), P < 0.001) and SMF (unadjusted HR = 2.55, 95% CI (1.1-5.71), P =0.025) and with shorter TTT in PMF (> 7 dL/g, unadjusted HR = 4.1, 95% CI (1.44-11.59), P = 0.009) patients. Associations with OS diminished in multivariate analyses after adjustments for the dynamic-international-prognostic-scoring-system (DIPSS) and myelofibrosis-secondary-to-PV-and ET-prognostic-model (MYSEC-PM), respectively. Association with TTT remained significant independently of JAK2 mutation, white blood cell count and chronic kidney disease., Conclusions: Myelofibrosis patients with more advanced disease features and more pronounced inflammation have higher ePVS, indicative of expanded plasma volume. Higher ePVS is associated with impaired survival in PMF and SMF and higher thrombotic risk in PMF patients., Competing Interests: Potential conflict of interest None declared., (Croatian Society of Medical Biochemistry and Laboratory Medicine.)

Introduction: Interferons (IFNs) have been used for decades to treat polycythemia vera (PV). Single-arm clinical trials assessing IFN in PV patients demonstrated high hematological and molecular response rates, indicating potential disease-modifying activity of IFN. However, discontinuation rates of IFNs have been rather high due to frequent treatment-related side-effects., Areas Covered: Ropeginterferon alfa-2b (ROPEG) is a monopegylated IFN consisting of a single isoform, which differentiates it from previous IFNs with respect to tolerability and dosing frequency. ROPEG has improved pharmacokinetic and pharmacodynamic properties, which allow extended dosing every 2 weeks and monthly administration during maintenance phase. This review covers ROPEG's pharmacokinetic and pharmacodynamic properties, presents results of randomized clinical trials (RCT) that evaluated ROPEG in the treatment of PV patients, and discusses contemporary findings regarding the potential disease-modifying activity of ROPEG., Expert Opinion: RCT have demonstrated high rates of hematological and molecular responses in PV patients treated with ROPEG, irrespective of thrombotic risk. Drug discontinuation rates were generally low. However, even though RCT captured the most important surrogate endpoints of thrombotic risk and disease progression in PV, they were not statistically powered to fully determine whether therapeutic intervention with ROPEG indeed has a direct positive effect on these important clinical outcomes.

Purpose of Review: Estimating and modifying thrombotic risk is currently the mainstay of care for patients with polycythemia vera (PV) and essential thrombocythemia (ET). In recent years, however, increased attention has shifted towards quality of life and disease modification. In this review, we discuss recent advances in risk stratification, present updated results for ruxolitinib and interferon randomized clinical trials, discuss new approaches in antiplatelet and anticoagulant treatment, and summarize early phase trials of novel agents and emerging therapeutic concepts for the treatment of PV and ET., Recent Findings: International collaborations and novel technologies, i.e., next-generation sequencing and machine learning techniques, have demonstrated excellent abilities to improve thrombotic risk stratification in PV and ET. Updated results from ruxolitinib and interferon randomized clinical trials have confirmed excellent efficacy and safety of these agents, both as first- and second-line treatments. Early trials of novel agents (histone deacetylase inhibitors, telomerase inhibitors, lysine-specific demethylase-1 inhibitors, human double-minute 2 inhibitors, and hepcidin mimetics) have shown encouraging efficacy and safety in blood count control, reduction of splenomegaly, and alleviation of disease-related symptoms. Finally, accumulating evidence suggested that direct oral anticoagulants may be a valid therapeutic alternative to warfarin for prolonged thromboprophylaxis. International collaborations ("big data") with the help of new technologies represent an exciting new approach to analyze rare outcomes in rare diseases, especially for identifying novel prognostic biomarkers in PV and ET. Randomized clinical trials are also needed to fully elucidate whether novel agents may establish new standards of care., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Serum uric acid (SUA) can promote inflammation and is associated with increased cardiovascular morbidity. Primary (PMF) and secondary myelofibrosis (SMF) are myeloproliferative neoplasms characterized by high cellular turnover and substantial risk of thrombosis and death., Methods: We have retrospectively investigated SUA in 173 patients with myelofibrosis (125 PMF; 48 SMF) and 30 controls., Results: The PMF patients had significantly higher SUA in comparison to SMF and controls. In both PMF and SMF higher SUA was significantly associated with arterial hypertension and decreased renal function. Among PMF patients, higher SUA was significantly associated with older age, larger spleen, higher white blood cell counts, higher lactate dehydrogenase, lower immunoglobulin G levels, allopurinol use and non-smoking. Among SMF patients, higher SUA was associated with male sex (P < 0.05 for all analyses). In PMF higher SUA was univariately associated with inferior survival (> 427 μmol/L hazard ratio (HR) = 2.22; P = 0.006) and shorter time to thrombosis (> 444 μmol/L HR = 5.05; P = 0.006), which could be shown separately for arterial (> 380 μmol/L; HR = 4.9; P = 0.013) and venous thromboses (> 530 μmol/L; HR = 17.9; P < 0.001). In multivariate analyses, SUA remained significantly associated with inferior survival independent of the Dynamic International Prognostic Staging System and with shorter time to thrombosis independent of age in PMF patients; however, the prognostic significance of SUA was diminished after including serum creatinine in the models. SUA was not prognostic in SMF patients., Conclusion: The PMF patients present with higher SUA levels, which are associated with features of more advanced disease and higher risks of arterial and venous thrombosis and death., (© 2021. Springer-Verlag GmbH, AT part of Springer Nature.)

We retrospectively investigated C reactive protein to albumin ratio (CAR) in a cohort of 142 patients with myelofibrosis [101 primary (PMF); 41 secondary (SMF)] and compared it to hematological and clinical parameters. Among other associations, higher CAR was significantly associated with higher grade of bone marrow fibrosis, lower frequency of Calreticulin (CALR) mutations, presence of constitutional symptoms, massive splenomegaly, transfusion dependency, blast phase disease, lower hemoglobin, lower platelets, higher ferritin and higher lactate dehydrogenase (LDH) ( p  < .05 for all analyses). Higher CAR was able to predict inferior survival in PMF independently of DIPSS [hazard ratio (HR)=2.17; p  = .015 for high CAR and HR = 2.05; p  < .001 for DIPSS] and in SMF independently of Mysec-PM (HR = 6.48; p  = .022 for high CAR and HR = 2.63; p  = .013 for Mysec-PM) demonstrating its good prognostic potential. CAR seems to be an independent and prognostically relevant parameter, both in PMF and SMF, and might aid in timely recognition of most vulnerable patients.

We retrospectively investigated a cohort of 176 myelofibrosis patients (128 primary-PMF; 48 secondary-SMF) from five hematology centers. The presence of chronic kidney disease (CKD) was determined in addition to other clinical characteristics. CKD was present in 26.1% of MF patients and was significantly associated with older age (P < 0.001), higher WBC (P = 0.015), and its subsets (neutrophil, monocyte, and basophil counts), higher platelets (P = 0.001), lower albumin (P = 0.018), higher serum uric acid (P = 0.001), higher LDH (P = 0.022), and the presence of CV risk factors (P = 0.011). There was no significant association with driver mutations, degree of bone marrow fibrosis, PMF/SMF, or DIPSS risk categories (P > 0.05 for all analyses). The presence of CKD was significantly associated with shorter time to arterial (HR = 3.49; P = 0.041) and venous thrombosis (HR = 7.08; P = 0.030) as well as with shorter overall survival (HR 2.08; P = 0.009). In multivariate analyses, CKD (HR = 1.8; P = 0.014) was associated with shorter survival independently of the DIPSS (HR = 2.7; P < 0.001); its effect being more pronounced in lower (HR = 3.56; P = 0.036) than higher DIPSS categories (HR = 2.07; P = 0.023). MF patients with CKD should be candidates for active management aimed at the improvement of renal function. Prospective studies defining the optimal therapeutic approach are highly needed.

Objectives: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare autoimmune disorder characterized by auto-antibodies to Willebrand factor (vWF) cleaving enzyme (ADAMTS13), resulting in unusually large vWF multimers that lead to platelet aggregation, microthrombi formation and microangiopathic hemolytic anemia. Hemolysis in aTTP is mechanical; thus, direct antiglobulin test (Coombs test) is usually negative. Multiple autoimmune conditions and various auto-antibodies have been described in the context of chronic myelomonocytic leukemia (CMML). In this paper, we describe the first case of CMML with auto-antibodies to ADAMTS13, presenting initially as plasmapheresis-refractory Coombs-positive aTTP. Results: Although our patient was not treated for CMML, a complete remission of aTTP was eventually achieved with rituximab. Conclusion; We propose that aTTP should be in the differential diagnosis of CMML patients with thrombocytopenia and anemia (Coombs positive or not) who develop signs of thrombotic microangiopathy. Further studies are much needed to decipher the immune-mediated processes in CMML.

Objectives: Serum chitotriosidase activity (CHIT1) is a biomarker of macrophage activation with an important role in inflammation-induced tissue remodeling and fibrosis. Macrophages have been described to play a crucial role in regulating pathological erythropoiesis in polycythemia vera (PV). The aim of this study was to evaluate CHIT1 in patients diagnosed with Philadelphia-negative myeloproliferative neoplasms (MPNs)., Methods: Using fluorometric assay, we measured CHIT1 in 28 PV, 27 essential thrombocythemia (ET), 17 primary myelofibrosis (PMF), 19 patients with secondary myelofibrosis and in 25 healthy controls., Results: CHIT1 was significantly higher in PV (p < .001) and post-PV myelofibrosis (MF) transformation (post-PV MF) (p = .020), but not in ET (p = .080), post-ET MF transformation (p = .086), and PMF patients (p = .287), when compared to healthy controls. CHIT1 in PV was positively correlated with hemoglobin (p = .026), hematocrit (p = .012), absolute basophil count (p = .030) and the presence of reticulin fibrosis in the bone marrow (p = .023)., Discussion: A positive correlation between CHIT1 and these distinct laboratory PV features might imply macrophages closely related to clonal erythropoiesis as cells of CHIT1 origin. In addition, a positive association between CHIT1 and reticulin fibrosis might indicate its potential role in PV progression., Conclusion: CHIT1 might be considered as a circulating biomarker in PV. Additional studies are needed to clarify the role of CHIT1 in promoting disease progression and bone marrow fibrosis in PV.