Prolonged Proton Pump Inhibitor Use and Thrombohemorrhagic Risk in Essential Thrombocythemia and Polycythemia Vera Patients Treated with Long-Term Aspirin: A Pilot Study.

INTRODUCTION: Proton pump inhibitors (PPIs) are known to decrease the risk of gastrointestinal (GI) bleeding. However, concerns have been raised regarding the potential pharmacodynamic interactions of PPIs and antiplatelet drugs with respect to cardiovascular risk. Patients with BCR::ABL1-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET), and polycythemia vera (PV) often suffer from peptic ulcer disease (PUD) and frequently receive low-dose aspirin due to an intrinsically high thrombotic risk. METHOD: This retrospective multicenter study from a community setting investigated whether continuous PPI use may affect thrombohemorrhagic risk in ET and PV patients treated with long-term aspirin. RESULTS: Ninety-four aspirin-treated MPN patients (ET = 36, PV = 58) were included; median age was 69.5 years (range 21-92) and 40 (42.6%) were males. Nineteen (20.2%) patients continuously received PPIs and pantoprazole (n = 15, 78.9%) was the most frequently received PPI. PV phenotype (p = 0.085), male sex (p = 0.011), and prior thrombosis (p = 0.005) were associated with PPI use, whereas no correlations were found with respect to age, disease risk, splenomegaly, mutational status, constitutional symptoms, cardiovascular risk factors, cytoreductive treatment, or any of the blood cell counts (p > 0.050 for all analyses). The median follow-up time was 55.5 months; 19 (20.2%) thrombotic and 13 (13.8%) bleeding events occurred during this time. The use of PPIs was not associated with an increased risk of thrombosis (p = 0.158) or overall bleeding (p = 0.229) and none of the patients treated with PPIs experienced GI bleeding. CONCLUSIONS: Considering that Helicobacter pylori infection and PUD are quite frequent in ET and PV patients, these preliminary results may provide some reassurance to physicians regarding the absence of thrombohemorrhagic risk associated with prolonged PPI use in MPN patients treated with long-term aspirin. Our observations may be even more important in the light of recent evidence suggesting suboptimal platelet inhibition in ET with once-daily when compared to twice- or triple-daily aspirin which may also cause more abdominal discomfort. Limitations of this study are its retrospective design, limited number of patients included, and the lack of pharmacodynamic and pharmacokinetic assessments.

Reduced renal function strongly affects survival and thrombosis in patients with myelofibrosis.

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.

Systemic Inflammatory Index in Polycythemia Vera and Its Prognostic Implications.

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.

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.

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.

High platelet-to-lymphocyte ratio may differentiate polycythemia vera from secondary polycythemia.

Discriminating polycythemia vera (PV) from secondary polycythemia (SP) is crucial due to the inherent risk of thrombosis in PV and different treatment approaches. The majority of PV patients have subnormal serum erythropoietin levels and harbor Janus kinase 2 (JAK2) mutations; however, serum erythropoietin levels may be normal in approximately one third of PV patients and mutational analysis is costly and requires access to specialized laboratories. Recently, neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR) emerged as rapidly available biomarkers to identify PV patients under an increased risk of thrombosis and death. This multicenter retrospective study investigated whether these two biomarkers may also be used to differentiate PV from SP. A total of 207 subjects were included (103 PV and 104 SP) with both baseline NLR (median 4.33 vs. 1.89) and PLR (median 259.12 vs. 81.11) being significantly higher in PV than in SP (p < 0.001 for both analyses). According to the receiver operating curve analysis, PLR (area under the curve, AUC 0.936, the optimal cut-off value of > 138.1 had 82.5% sensitivity and 91.67% specificity for the detection of PV) outperformed other tested variables (NLR, total leukocytes, neutrophils, lymphocytes and platelets) and its cut-off values with 100% specificity and sensitivity were able to confirm (PLR > 224.56; 31% patients) and to exclude (PLR < 68.8; 13% patients) the highest proportions of PV patients. Therefore, PLR may represent a cheap and a rapidly available biomarker with valuable diagnostic and prognostic properties. This information may be particularly useful in resource-limited settings; however, our results need validation on larger datasets.

Hematocrit to hemoglobin ratio as a prognostic marker in polycythemia vera.

BACKGROUND: The hematocrit to hemoglobin ratio (HHR) is frequently used in everyday practice to measure hemoconcentration; however, clinical associations of HHR in the context of polycythemia vera (PV) have not been investigated so far. PATIENTS AND METHODS: We retrospectively assessed HHR at the time of diagnosis in 107 PV and 40 secondary polycythemia (SP) patients from three community hospitals. RESULTS: Median HHR was higher in PV than in SP patients (3.131 vs. 2.975, p = 0.041). Among PV patients, higher HHR correlated with splenomegaly, higher total leukocyte and absolute granulocyte counts, higher red blood cell counts, lower hemoglobin, higher red blood cell distribution width, lower mean corpuscular hemoglobin and lower ferritin levels, whereas in SP patients higher HHR correlated with older age, female sex and lower hemoglobin (p < 0.050 for all analyses). Using the receiver operating curve analysis-defined cut-off points, higher HHR in PV was associated with a shorter time to thrombosis (hazard ratio-HR 5.20, p = 0.022) independently of high-risk disease status (HR 4.48, p = 0.034) and shorter overall survival (HR 6.69, p = 0.009) independently of leukocytosis (HR 4.48, P = 0.034) and the absence of aspirin use (HR 15.53, p < 0.001). CONCLUSION: Higher HHR may represent iron deficiency and a stronger clonal myeloproliferation in PV and could provide additional prognostic information to the classical risk assessment.

Higher serum uric acid is associated with higher risks of thrombosis and death in patients with primary myelofibrosis.

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.

Beneficial effect of ACE inhibitors on kidney function in polycythemia vera.

BACKGROUND: Reduced kidney function has been associated with worse clinical outcomes in patients with myeloproliferative neoplasms (MPN). Statins and angiotensin-converting enzyme inhibitors (ACE-i) have renoprotective properties and their pleiotropic effects might also affect the malignant MPN clone; however, whether concomitant use of statins and ACE­i has a positive effect on estimated glomerular filtration rate (eGFR) in polycythemia vera (PV) patients is currently unknown. METHODS: This multicenter retrospective study investigated effects of statins and ACE­i on 12-month eGFR dynamics in 75 PV patients. RESULTS: Of the patients 25 (33.3%) had a 10% or more increase in eGFR at 12 months. Univariately, statins (55.5% vs. 16.3%; p = 0.022), ACE­i (61% vs. 24.6%; p = 0.004), male sex (54.3%, vs. 15%; p < 0.001) and the absence of chronic kidney disease (CKD, 45.5% vs. 16.1%; p = 0.008) were statistically significantly associated with an improvement in eGFR. ACE­i (p = 0.008), CKD (p < 0.001), male sex (p = 0.004) and higher baseline eGFR (p = 0.007) remained statistically significantly associated with an improvement in eGFR in the multivariate logistic regression model also including statins, hydroxyurea, high-risk disease, cardiovascular risk factors, chronic heart failure and baseline hematocrit. CONCLUSION: The ACE­i might have renoprotective properties in PV. Further studies are needed to elucidate whether the use of these drugs could also affect other MPN-related outcomes.

Chronic kidney disease could be a risk factor for thrombosis in essential thrombocythemia and polycythemia vera.

Chronic kidney disease (CKD) is a well-known risk factor for venous thromboembolism and cardiovascular (CV) disease development in the general population, but its role in thrombotic risk in essential thrombocythemia (ET) and polycythemia vera (PV) remains poorly understood. This retrospective multicenter study analyzed clinical correlations and the potential impact of CKD on thrombosis development in ET and PV patients. We included 167 patients (76 ET and 91 PV); 25.7% had CKD at diagnosis, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 for ≥ 3 months. Lower eGFR correlated with advanced age, female sex, higher granulocytes, higher serum C-reactive protein, history of thrombosis, CV risk factors, and the presence of palpable splenomegaly. CKD was univariately associated with inferior thrombosis-free survival in the entire cohort, as well as in both ET and PV patients. These results remained significant in the multivariate Cox regression models when adjusted to disease-specific risk models. Therefore, CKD could be a risk factor for thrombosis in ET and PV patients. Additional studies on a larger number of patients are needed to confirm our findings and to elucidate whether the addition of CKD to the current risk stratification models might improve prognostication in ET and PV 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.