High plateletcrit may be associated with thrombotic risk in polycythemia vera

Dear Editors, Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) characterized by acquired Janus Kinase 2 (JAK2) mutations and an increased blood viscosity. Patients with PV have a substantial cardiovascular burden; the most important predictors of future thrombotic events are age ≥60 (65) years and thrombosis history and patients having any of these two factors are classified as ‘high-risk’. All PV patients are secured with phlebotomies with an aim to keep hematocrit <45% as this intervention has been shown to lower the cardiovascular risk in the CYTO-PV clinical trial; ‘high-risk’ patients are additionally treated with cytoreduction, usually with hydroxycarbamide (HU) or interferons. Nevertheless, despite these treatments, PV patients still suffer from a substantial residual risk of thrombosis. In recent years, therefore, the focus of the scientific community has shifted towards identifying novel disease biomarkers which could help to better identify MPN patients who may have an increased risk for inferior outcomes and to potentially guide treatments. Increased platelet counts and permanent platelet activation with the formation of platelet-leukocyte complexes are typical disease features in MPNs and are strongly associated with the promotion of thrombosis. For this reason, low-dose aspirin is prescribed to all PV patients. However, even though normalization of platelet counts is one of the variables for assessing treatment responses in PV, it does not seem to correlate with lower thrombotic risk. Similarly, MPN patients have higher mean platelet volumes (MPV) than healthy controls, probably due to the presence of larger and activated platelets in the circulation, but higher MPV values also do not seem to correlate with an increased thrombotic risk in MPNs. On the other hand, studies have shown that higherMPV inMPNsmay correlate with the presence of JAK2 mutation; this driver mutation is almost universally present in PV patients and is associated with higher platelet activation and the presence of immature platelets in the circulation. For this reason, we aimed to investigate the potential prognostic role of plateletcrit (PCT), a measure of total circulating platelet mass, in PV patients. This platelet index has been associated with venous thromboembolism and coronary endothelial disfunction in the general population. This multicenter study was conducted at four hospitals in Croatia in the period between April 2002 and May 2021 and included PV patients whose disease diagnosis was reassessed according to 2016 World Health Organization (WHO) criteria. The 2016 WHO major PV diagnostic criteria include hemoglobin >165 g/L for males and >160 g/L for females and/or hematocrit >49% for males and >48% for females, presence of JAK2 mutation, and bone marrow biopsy showing age-adjusted hypercellularity with panmyelosis (erythroid, granulocytic and megakaryocytic proliferation with pleomoprphic megakaryocytes), whereas the minor criterion includes subnormal erythropoietin levels. The PV diagnosis was made if all three major criteria were present or the first two major and the minor criterion. Excluded from participation were subjects with missing baseline MPN values, pregnant women, patients with other concomitant cancers and acute conditions that may have affected MPV (i.e., surgery, traumas, or acute infections). Clinical and laboratory data were retrospectively recorded through the electronic medical chart review. Cardiovascular risk factors considered were arterial hypertension, diabetes mellitus, hyperlipidemia, chronic kidney disease (CKD; defined as estimated glomerular filtration rate < 60 mL/min/1.73 m ≥ 3 months) and smoking. ‘High-risk’ disease was defined according to British Society for Haematology Guideline; this particular definition of disease risk was used as age >65 years was associated with inferior outcomes in this study. All PV patients were phlebotomized in order to maintain the hematocrit <45% and received low-dose aspirin (except in cases of allergies, bleeding diathesis or anticoagulant use). Complete blood counts were analyzed with Siemens Advia 120, 2100, and 2120i (Siemens Medical Solutions Diagnostics Pte Ltd., Swords, Ireland). Baseline PCT was calculated as mean platelet volume (MPV) platelet count/10 000 and expressed as a percentage (normal range 0.22%–0.24%). Statistics were performed with MedCalc Statistical Software (Ostend, Belgium, version 20.211). Categorical variables were compared using the chi-square test and continuous variables were compared using the Mann–Whitney U test or the t test, as appropriate. Receiver operating characteristic curve (ROC) was used for sensitivity and specificity testing. Thrombosis-free survival (TFS) was measured from diagnosis until an arterial/venous event or death. Survival analyses were performed using the Kaplan–Meier and the Cox regression analyses. Arterial events considered were acute myocardial infarction, transitory ischemic attack, ischemic stroke or acute peripheral arterial occlusion, whereas venous events were pulmonary embolism and/or deep vein thrombosis. The study was approved by Ethics Committees from the participating centers. Due to the retrospective design of the study, informed consent was not required. Ninety JAK2-positive PV patients were included in the study; median age was 70 years (range 21–92), 45 (50%) were females, and the median PCT was 0.45% (range 0.09%–1.15%). First, a ROC curve analysis with thrombosis/death as a classification variable was used to find the optimal cut-off value of PCT and it was set at >0.38%. As shown in Table 1. PV patients with higher PCT were older, had higher total leukocytes, granulocytes and platelets, higher MPV and lower hemoglobin levels (p < 0.050 for all analyses), whereas prior Received: 8 February 2023 Accepted: 6 April 2023