Thrombotic and hemorrhagic complications in idiopathic erythrocytosis
2017; Wiley; Volume: 92; Issue: 11 Linguagem: Inglês
10.1002/ajh.24873
ISSN1096-8652
AutoresIrene Bertozzi, Marco Ruggeri, Ilaria Nichele, Giacomo Biagetti, Elisabetta Cosi, Maria Luigia Randi,
Tópico(s)Erythrocyte Function and Pathophysiology
ResumoAmerican Journal of HematologyVolume 92, Issue 11 p. E639-E641 E-ONLY ARTICLEFree Access Thrombotic and hemorrhagic complications in idiopathic erythrocytosis Irene Bertozzi, Irene Bertozzi Department of Medicine, DIMED- University of Padua, Padua, ItalySearch for more papers by this authorMarco Ruggeri, Marco Ruggeri orcid.org/0000-0003-1557-0957 Hematology Department, San Bortolo Hospital, Vicenza, ItalySearch for more papers by this authorIlaria Nichele, Ilaria Nichele Hematology Department, San Bortolo Hospital, Vicenza, ItalySearch for more papers by this authorGiacomo Biagetti, Giacomo Biagetti Department of Medicine, DIMED- University of Padua, Padua, ItalySearch for more papers by this authorElisabetta Cosi, Elisabetta Cosi Department of Medicine, DIMED- University of Padua, Padua, ItalySearch for more papers by this authorMaria Luigia Randi, Corresponding Author Maria Luigia Randi marialuigia.randi@unipd.it orcid.org/0000-0001-7945-1864 Department of Medicine, DIMED- University of Padua, Padua, ItalyCorrespondence Maria Luigia Randi, via Giustiniani 2, 35128 Padova, Italy. Email: marialuigia.randi@unipd.itSearch for more papers by this author Irene Bertozzi, Irene Bertozzi Department of Medicine, DIMED- University of Padua, Padua, ItalySearch for more papers by this authorMarco Ruggeri, Marco Ruggeri orcid.org/0000-0003-1557-0957 Hematology Department, San Bortolo Hospital, Vicenza, ItalySearch for more papers by this authorIlaria Nichele, Ilaria Nichele Hematology Department, San Bortolo Hospital, Vicenza, ItalySearch for more papers by this authorGiacomo Biagetti, Giacomo Biagetti Department of Medicine, DIMED- University of Padua, Padua, ItalySearch for more papers by this authorElisabetta Cosi, Elisabetta Cosi Department of Medicine, DIMED- University of Padua, Padua, ItalySearch for more papers by this authorMaria Luigia Randi, Corresponding Author Maria Luigia Randi marialuigia.randi@unipd.it orcid.org/0000-0001-7945-1864 Department of Medicine, DIMED- University of Padua, Padua, ItalyCorrespondence Maria Luigia Randi, via Giustiniani 2, 35128 Padova, Italy. Email: marialuigia.randi@unipd.itSearch for more papers by this author First published: 01 August 2017 https://doi.org/10.1002/ajh.24873Citations: 6 Funding information: University of Padua DOR AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat To the Editor The diagnosis of idiopathic erythrocytosis (IE) is ruled out when all the known causes of erythrocytosis are excluded after a complete and accurate diagnostic process. The estimated prevalence of IE is 1.1 cases per 1000 persons, for secondary acquired erythrocytosis (SAE), mediated by altere\d production of erythropoietin, is 2.2 per 1000 persons1 and for polycythemia vera (PV), a myeloproliferative neoplasm characterized by a consistent risk of hemorrhagic and thrombotic complications, is 0.3 per 1000 persons. Therefore, the prevalence of IE is four times higher than PV and half than SAE in general population.2 In spite of its relative frequency, few papers have focused on IE and information about thrombotic and haemorrhagic risk in this setting are lacking. We report clinical features of a large cohort of patients with IE compared to a cohort of patients with PV, focusing on the thrombotic and hemorrhagic risk. Between 1980 and 2015, we studied and followed 145 patients with IE in two Centers of Veneto Region, Italy, expert in the field of erythrocytosis. In these patients, all known causes of familial and SAE were excluded and JAK2V617F or JAK2 exon 12 mutations were not found. As controls, we used 145 patients with PV, strictly diagnosed in agreement with WHO criteria, studied in the same period and matched for Ht values. We collected in all IE and PV patients' disease-relevant parameters, including blood count at diagnosis, thrombosis, hemorrhages, progression into overt myelofibrosis, leukemic transformation, and death. All patients were treated with phlebotomies, to maintain hematocrit (Ht) below 45% and when appropriate, they received low dose aspirin. Eighty (54.8%) PV patients were treated with hydroxyurea for high platelet count or symptomatic splenomegaly or after vascular complications. The statistical tests adopted were Mann–Whitney U-test, χ2 test or Fisher's exact test as appropriate, Kaplan-Meier method for survivals, Log Rank test, Cox proportional hazard regression model. Main clinical and laboratory data of our patients are summarized in Table 1. Table 1. Main clinical and laboratory data of our patients with erythrocytosis IE PV P Patients, n 145 145 - Males, n (%) 127 (87.6) 83 (57.2) <.001 Median age at diagnosis, years (5th-95th Percentile) 56.5 (21.2–75.8) 61.7 (30.3–81.9) .006 Median follow up, years (5th-95th Percentile) 6.6 (0.3–23.2) 7.4 (0.3–22.1) n.s. Median WBC, × 109/L (5th-95th Percentile) 7.2 (5–11.9) 8.7 (5.7–17.3) <.001 Median Hb, g/L (5th-95th Percentile) 179 (164–195) 175 (149–213) .03 Median Ht, % (5th-95th Percentile) 52.8 (48.3–57.8) 53.1 (46.2–66.2) n.s. Median plts count, × 109/L (5th-95th Percentile) 217 (132–320) 485 (209–882) <.001 Patients with at least a thrombosis, n (%) 21 (14.5) 39 (26.9) .01 Patients with at least a hemorrhage, n (%) 7 (4.8) 22 (15.2%) .005 Patients treated with low-dose aspirin, n (%) 73 (50.3) 118 (81.4) .001 Abbreviations: IE, idiopathic Erythrocytosis; PV, polycythemia vera. Twenty-one (14.5%) patients with IE and 39 (26.9%) with PV (P = .01) experienced at least one thrombotic event. Five IE (3.4%) and 12 PV (8.3%) had a thrombotic event (P = NS) at presentation of erythrocytosis. The thrombotic events were 3 arterial and 2 venous in IE and 3 arterial and 9 venous in PV. During follow-up, 16 patients with IE (11%) and 27 with PV (18.6%) experienced thrombotic complications (P = .047). Venous events were 2 (2 deep vein thrombosis -DVT) in IE and 15 (8 DVT, 3 pulmonary embolism, 4 splanchnic vein thrombosis) in PV (P = .002). Arterial complications occurred in 13 IE (7 myocardial infarction -MI, 4 stroke, 2 transitory ischemic attack -TIA) and in 12 PV (5 MI, 1 stroke, 5 TIA and 1 peripheral arterial thrombosis) with no significant difference. Thrombosis free survival was significantly shorter in PV patients (P = .005) (Supporting Information Fig. 1). The thrombotic incidence rate was 3% patients/year in PV and 1.5% patients/year in IE (IRR = 2). IE displays a significant lower risk of developing thrombosis than PV also in age and sex adjusted multivariable analysis (HR 0.471, 95% CI 0.242–0.915; P = .026). During follow-up, 7 (4.8%) patients with IE (1 gastro-intestinal and 6 minor hemorrhage) and 22 (15.2%) with PV (6 major and 16 minor hemorrhage) suffered for bleedings with a significant difference between the two cohorts (P = .005). In particular, 4 IE (5.4%) bleed compared to 19 PV (16%) (P = .02) during the use of aspirin. Also Hemorrhagic Free survival was dramatically different (P = .002) (Supporting Information Fig. 2). The hemorrhagic incidence rate was 0.57% patients/year in IE and 2.01% patients/year in PV (IRR = 0.28). Low dose aspirin was administered in 81.4% of PV and in 50.3% of IE (P = .001). Cox multivariable analysis, including age, sex, platelet count at diagnosis and low-dose aspirin therapy, confirms the significant lower risk of bleedings in IE compared to PV (HR 0.27, 95% CI 0.091–0.792; P = .017). Being few papers focusing on IE,2-4 we ignore the real outcome of this disease. We know that IE is an indolent form and it does not evolve into myelofibrosis or acute leukemia, unlike PV. IE is frequent in males suggesting that hormonal activity could play a significant role3: increased red blood cell mass is the most common adverse event associated with testosterone therapy in clinical practice and experimental data suggest that testosterone stimulates erythropoiesis by stimulating EPO and increasing iron utilization for erythropoiesis.5 In the present cohort, IE patients have a lower risk of thrombosis (1.5/100 patients/year) than PV (3/100 patients/year) possibly because in PV platelets and WBC are frequently increased while they are normal in IE.3 A significantly poorer thrombosis free survival of PV comparing IE confirms this observation. Interestingly, only 2 out of our IE patients suffered for venous thrombosis during follow-up with a lower incidence compared to PV patients while arterial events are similarly distributed among PV and IE. Recent data6 suggest that red blood cells independently promote arterial thrombosis increasing the rate of platelet deposition and thrombus growth: this may explain the occurrence of arterial thrombosis in IE and not only in PV patients. A bleeding incidence rate in IE about 4 times lower than in PV (2.9/100 patients/year), not increased by the use of low-dose aspirin, has been observed in the present cohort. In agreement, the haemorrhage free survival is longer in IE patients compared to PV. In conclusion, IE has a lower thrombotic and hemorrhagic risk than PV in spite of a stringent program of phlebotomies and a frequent use of low dose aspirin. Prospective, randomized study are needed to reinforce our results. ACKNOWLEDGMENT The study was supported in part by the University of Padua DOR funding. CONFLICT OF INTEREST The authors have no disclosure to declare. AUTHOR CONTRIBUTIONS MLR and MR designed the study, analysed the data and wrote the manuscript, IB performed statistical analysis and contributed clinical information, GB, EC and IN contributed clinical information. All Authors have read and approved the final version and agree to act as guarantor of the work. Supporting Information Additional Supporting Information may be found online in the supporting information tab for this article. Filename Description ajh24873-sup-0001-suppinfo.docx18.2 KB Supporting Information ajh24873-sup-0002-suppinfoFig1.tif127 KB Supporting Information Figure 1 ajh24873-sup-0003-suppinfoFig2.tif28.8 KB Supporting Information Figure 2 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1 Ruggeri M, Tosetto A, Frezzato M, Rodeghiero F. The rate of progression to polycythemia vera or essential thrombocythemia in patients with erythrocytosis or thrombocytosis. Ann Intern Med. 2003; 139: 470– 475. 2 Finazzi G, Gregg XT, Barbui T, Prchal JT. Idiopathic erythrocytosis and other non-clonal polycythemias. Best Pract Res Clin Haematol. 2006; 19: 471– 482. 3 Randi ML, Bertozzi I, Cosi E, Santarossa C, Peroni E, Fabris F. Idiopathic erythrocytosis: a study of a large cohort with a long follow-up. Ann Hematol. 2016; 95: 233– 237. 4 McMullin MF. Diagnosis and management of congenital and idiopathic erythrocytosis. Ther Adv Hematol. 2012; 3: 391– 398. 5 Bachman E, Travison TG, Basaria S, et al. Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. J Gerontol A Biol Sci Med Sci. 2014; 69(6): 725– 735. 6 Walton BL, Lehmann M, Skorczewski T, et al. Elevated Hematocrit enhances platelet accumulation following vascular injury. Blood. 2017; 129: 2537– 2546. Citing Literature Volume92, Issue11November 2017Pages E639-E641 ReferencesRelatedInformation
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