Evaluation of Absolute Neutrophil, Lymphocyte and Platelet Count and Their Ratios as Predictors of Thrombotic Risk in Patients with Prefibrotic and Overt Myelofibrosis.

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 × 109/L (HR 13.08, p = 0.036), ALC > 2.58 × 109/L (HR 20.63, p = 0.049) and platelet count > 752 × 109/L (HR 10.5, p = 0.043) remained independently associated with shorter TTT. Among overt fibrotic patients, ANC > 8.8 × 109/L (HR 4.49, p = 0.004), ALC ≤ 1.43 × 109/L (HR 4.15, p = 0.003), platelet count ≤ 385 × 109/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 in acutely ill COVID-19 patients is associated with higher mortality but not markedly higher thrombotic risk.

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.

Estimated plasma volume status in COVID-19 patients and its relation to comorbidities and clinical outcomes.

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.

Higher estimated plasma volume status is associated with increased thrombotic risk and impaired survival in patients with primary myelofibrosis.

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.

Is Better Standardization of Therapeutic Antibody Quality in Emerging Diseases Epidemics Possible?

During the ongoing COVID-19 epidemic many efforts have gone into the investigation of the SARS-CoV-2-specific antibodies as possible therapeutics. Currently, conclusions cannot be drawn due to the lack of standardization in antibody assessments. Here we describe an approach of establishing antibody characterisation in emergent times which would, if followed, enable comparison of results from different studies. The key component is a reliable and reproducible assay of wild-type SARS-CoV-2 neutralisation based on a banking system of its biological components - a challenge virus, cells and an anti-SARS-CoV-2 antibody in-house standard, calibrated to the First WHO International Standard immediately upon its availability. Consequently, all collected serological data were retrospectively expressed in an internationally comparable way. The neutralising antibodies (NAbs) among convalescents ranged from 4 to 2869 IU mL-1 in a significant positive correlation to the disease severity. Their decline in convalescents was on average 1.4-fold in a one-month period. Heat-inactivation resulted in 2.3-fold decrease of NAb titres in comparison to the native sera, implying significant complement activating properties of SARS-CoV-2 specific antibodies. The monitoring of NAb titres in the sera of immunocompromised COVID-19 patients that lacked their own antibodies evidenced the successful transfusion of antibodies by the COVID-19 convalescent plasma units with NAb titres of 35 IU mL-1 or higher.

Red cell distribution width is a potent prognostic parameter for in-hospital and post-discharge mortality in hospitalized coronavirus disease 2019 patients: a registry-based cohort study on 3941 patients.

AIM: To investigate clinical and prognostic associations of red cell distribution width (RDW) in hospitalized coronavirus disease 2019 (COVID-19) patients. METHODS: We retrospectively analyzed the records of 3941 consecutive COVID-19 patients admitted to a tertiary-level institution from March 2020 to March 2021 who had available RDW on admission. RESULTS: The median age was 74 years. The median Charlson comorbidity index (CCI) was 4. The majority of patients (84.1%) on admission presented with severe or critical COVID-19. Patients with higher RDW were significantly more likely to be older and female, to present earlier during infection, and to have higher comorbidity burden, worse functional status, and critical presentation of COVID-19 on admission. RDW was not significantly associated with C-reactive protein, occurrence of pneumonia, or need for oxygen supplementation on admission. During hospital stay, patients with higher RDW were significantly more likely to require high-flow oxygen therapy, mechanical ventilation, intensive care unit, and to experience prolonged immobilization, venous thromboembolism, bleeding, and bacterial sepsis. Thirty-day and post-hospital discharge mortality gradually increased with each rising RDW percent-point. In a series of multivariate Cox-regression models, RDW demonstrated robust prognostic properties at >14% cut-off level. This cut-off was associated with inferior 30-day and post-discharge survival independently of COVID-19 severity, age, and CCI; and with 30-day survival independently of COVID severity and established prognostic scores (CURB-65, 4C-mortality, COVID-gram and VACO-index). CONCLUSION: RDW has a complex relationship with COVID-19-associated inflammatory state and is affected by prior comorbidities. RDW can improve the prognostication in hospitalized COVID-19 patients.

C reactive protein to albumin ratio as prognostic marker in primary and secondary myelofibrosis.

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.

Elevated Neutrophil-to-Lymphocyte-ratio and Platelet-to-Lymphocyte Ratio in Myelofibrosis: Inflammatory Biomarkers or Representatives of Myeloproliferation Itself?

BACKGROUND/AIM: We aimed to investigate clinical associations of inflammatory biomarkers neutrophil-to-lymphocyte-ratio (NLR) and platelet-to-lymphocyte-ratio (PLR) in patients with myelofibrosis, myeloproliferative neoplasm with inflammatory background. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 102 myelofibrosis patients. NLR and PLR were assessed in addition to other disease-specific parameters. RESULTS: NLR and PLR were significantly higher in myelofibrosis than in healthy controls. Higher NLR was significantly associated with Janus-kinase-2 (JAK2)-mutation, wild-type-Calreticulin (CALR), older age and parameters reflecting increased proliferative potential of disease (higher leukocytes, higher hemoglobin, larger spleen-size), whereas there was no significant association with C-reactive-protein (CRP). Higher PLR was significantly associated with absence of blast-phase-disease, absence of constitutional-symptoms, lower percentage-of-circulatory-blasts, smaller spleen-size and lower CRP. In the Cox-regression-model, higher-NLR (HR=2.76; p=0.004), lower-PLR (HR=1.99; p=0.042) and Dynamic-International-Prognostic-System (DIPSS) (HR=3.26; p<0.001) predicted inferior survival independently of each other. CONCLUSION: In the context of myelofibrosis, elevated NLR and PLR are more likely to represent myeloproliferation itself and not necessary the extent of inflammation.