key: cord-0765980-elp7wq34 authors: Liu, Dan; Li, Bing; Xu, Zefeng; Zhang, Peihong; Qin, Tiejun; Qu, Shiqiang; Pan, Lijuan; Sun, Xiujuan; Shi, Zhongxun; Huang, Huijun; Wang, Huijun; Gale, Robert Peter; Xiao, Zhijian title: RBC distribution width predicts thrombosis risk in polycythemia vera date: 2021-09-08 journal: Leukemia DOI: 10.1038/s41375-021-01410-2 sha: ded746d0f1266577c89c43953fa3155049c8167f doc_id: 765980 cord_uid: elp7wq34 nan 274 subjects (32%) had ≥1 thrombotic event pre-diagnosis (Supplementary Table S2 ), 262 (96%) of which were arterial and 20 (7%), venous. These frequencies are higher than those reported in persons of predominately European descent (Fig. 1A ) [2] . 25 of 539 subjects (5%) had abnormal cytogenetics at diagnosis. 99 subjects had 112-gene panel next generation sequencing at diagnosis, 47 of whom (47%) had ≥ 1 mutated gene in addition to JAK2 (Fig. S1 ). The most common mutations were in TET2 (n = 18) and DNMT3A (n = 8). Phlebotomy is recommended as initial therapy for low-risk PV [6] . However, only RBC apheresis is approved in China. Consequently, phlebotomy is used in few Chinese with PV. In our study, 837 (93%) subjects received cytoreductive treatment. 455 (50%), 155 (17%) and 213 (24%) initially received hydroxyurea, nonpegylated interferon or combination of hydroxyurea with nonpegylated interferon. 14 (2%) subjects received therapy(ies) other than hydroxyurea or interferon. 54 (6%) subjects underwent watching and waiting and 11 died without treatment details. [2] . The proportion of patients with post-diagnosis thrombosis was much lower in our study than reported in Barbui study (5% vs 19%, p < 0.001; Fig. 1B ) [2] . The 5-and 10-year commutative incidences of thrombosis were 5.3% (4.4, 6.2%) and 11.0% (9.0, 13.0%) in our study, also lower than reported in Barbui study (Fig. 1B) [2] . In low-risk cohort, the proportion of patient with post-diagnosis thrombosis in our study was lower than reported in persons treated with phlebotomy in Barbui study (4% vs 12%, p < 0.001; Fig. 1C [10] . Previous studies reported that PV receiving phlebotomy had higher thrombosis rate than those treated by chlorambucil, P32 or hydroxyurea [11] [12] [13] . The thrombosis rate post-diagnosis in our study was lower than that reported in Barbui study [2, 10] , which might partly related to significantly less phlebotomies in Chinese than Western cohort. Uni-and multi-variable analyses of TFS are displayed in Supplementary Table S3 Table S3 ). These data differ from prior studies [1, 2, 5] . A lower RDW correlated with worse TFS in subjects defined as high-risk using standard risk criteria (HR Table S3 and Supplementary Fig. S1D) . Higher RDW has been recognized as a biomarker of ineffective erythropoiesis and inflammation [7] , and was reported to have association with increased mortality in patients with COVID-19 infection [14] . Krecǎk et al. reported higher RDW was associated [2] , median follow-up 6.9 years (range, 0-39 years; n = 1545). Barbui et al. [10] , median follow-up 4.9 years (range, 0-34 years) in low-risk subjects treated by phlebotomy (n = 604). CI cumulative incidence, TFS thrombosis-free survival; **p < 0.01; *** p < 0.001. with inferior TFS in 92 patients with myeloproliterative neoplasms (51 essential thrombosis and 41 PV) [7] , which is opposite to our study. Higher RDW corelates with older age, female sex, palpable splenomegaly, higher concentrations of WBC, RBC, hemoglobin and JAK2 V617F allele burden, but lower concentrations of epoetin, serum iron and serum ferritin in our study (Supplementary Table S4 ). However, the underlying mechanism of lower RDW corelated with worse TFS remains unknown. A machine learning study reported that lymphocytes percentage <19.3% and RDW < 14.05% were associated with higher thrombosis rate in the first year treatment of hydroxyurea for PV without history of thrombosis [8] . We found lymphocytes <1.2 × 10 E + 9/L was associated with worse TFS in subjects without prior thrombosis (HR = 2.8 [1.2, 4.9] ; p = 0.01; Supplementary Fig. S2H ). Lymphocytes ≥ 2.2 × 10 E + 9/L tend to associated with worse TFS in subjects with thrombosis history (HR = 2.6 [0.9, 4.4]; p = 0.06; Supplementary Fig. S2I) . We found no significant correlations between age >60 years (Hazard Ratio [HR] =1.5 [0.8, 2.6]; p = 0.17) or prior thrombosis (HR = 1.1, [0.6, 2.0]; p = 0.74) and TFS, but standard thrombosis risk stratification still could predict thrombosis risk in our subjects ( Supplementary Fig. S1G -I) [6] . As multivariable analysis yielded HR of 3 Supplementary Fig. S1I ) by multivariable logistic regression model, suggesting a better prognostic value of the new model in our subjects. Our study has limitations. It is retrospective, from one center and with relatively brief follow-up. As such our conclusions need external validation. In summary, we found thrombosis rate post-diagnosis was lower in Chinese with PV compared with persons of predominately European descent [2, 10] . This could reflect a different phenotype, different therapy(ies), both or other factors [2, 10] . RDW < 14.5% at diagnosis was associated with worse TFS, especially for arterial thrombosis and subjects ≥50 years or with prior thrombosis. Risk factors for arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients In contemporary patients with polycythemia vera, rates of thrombosis and risk factors delineate a new clinical epidemiology Efficacy and safety of low-dose aspirin in polycythemia vera Hydroxyurea prevents arterial and late venous thrombotic recurrences in patients with myeloproliferative neoplasms but fails in the splanchnic venous district. Pooled analysis of 1500 cases Prospective identification of high-risk polycythemia vera patients based on JAK2V617F allele burden Guideline of myeloproliferative neoplasms on National Comprehensive Cancer Network (NCCN) (Version 2020) High red blood cell distribution width might predict thrombosis in essential thrombocythemia and polycythemia vera Interactions of key hematological parameters with red cell distribution width (RDW) are associated with incidence of thromboembolic events (TEs) in polycythemia vera (PV) patients: a machine learning study (PV-AIM) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia The effect of arterial hypertension on thrombosis in low-risk polycythemia vera Therapeutic recommendations in polycythemia vera based on polycythemia Vera Study Group protocols A reappraisal of the benefit-risk profile of hydroxyurea in polycythemia vera: a propensity-matched study Different effect of hydroxyurea and phlebotomy on prevention of arterial and venous thrombosis in polycythemia vera Association of red blood cell distribution width with mortality risk in hospitalized adults with SARS-CoV-2 infection ZJX designed the study. DL and ZFX collected and analyzed the data. PHZ analyzed the bone marrow histology. TJQ, SQQ, LJP and XJS recruited subjects and collected the data. DL prepared the typescript with contributions from ZJX, ZFX, BL, RPG, ZXS, HJH and HJW. All authors reviewed the typescript, approved this version and agreed to submit for publication. Correspondence and requests for materials should be addressed to Zhijian Xiao. Reprints and permission information is available at http://www.nature.com/ reprintsPublisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.