10.4081/btvb.2023.102
Polycythemia vera (PV) is a chronic Philadelphia-negative myeloproliferative neoplasm caused by JAK2 mutation and characterized predominantly by the overproduction of red blood cells. The current treatment strategies of PV are based on periodic phlebotomies aimed at preventing thrombotic events associated with increased hematocrit levels. Additional therapies to mitigate the thrombotic burden, which represents the most important predictor of reduced survival in PV patients, include cytoreductive therapies, low-dose aspirin, and systemic anticoagulation. This concise review summarizes the current knowledge on the management of the thrombotic risk in PV patients.
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Massimo Franchini
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Bleeding, Thrombosis and Vascular Biology
therapy
Polycythemia vera and management of the thrombotic risk: an update
Text.Serial.Journal
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Bleed Thromb Vascul Biol
Massimo Franchini
2023/12/20
10.4081/btvb.2023.102
Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantua
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Mainoli B, Duarte GS, Costa J, Ferreira J, Caldeira D. Once- versus Twice-Daily Aspirin in Patients at High Risk of Thrombotic Events: Systematic Review and Meta-Analysis. Am J Cardiovasc Drugs 2021;21:63-71.
Polycythemia vera and management of the thrombotic risk: an update
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                                                                                                                     MINI-REVIEW

Polycythemia vera and management of the thrombotic risk: an update
Massimo Franchini

Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantua, Italy



ABSTRACT
     Polycythemia vera (PV) is a chronic Philadelphia-negative myeloproliferative neoplasm caused by JAK2 mutation and characterized
predominantly by the overproduction of red blood cells. The current treatment strategies of PV are based on periodic phlebotomies aimed
at preventing thrombotic events associated with increased hematocrit levels. Additional therapies to mitigate the thrombotic burden, which
represents the most important predictor of reduced survival in PV patients, include cytoreductive therapies, low-dose aspirin, and systemic
anticoagulation. This concise review summarizes the current knowledge on the management of the thrombotic risk in PV patients.


                                                                            PV see the recent update by Tefferi and Barbui).1 The conse-
Introduction                                                                quent overactivation of JAK-pathway leads to an over-prolifer-
                                                                            ation of hematopoietic components, with a predominance of the




                                                                                                      ly
     Polycythemia vera (PV) is a chronic Philadelphia-negative
                                                                            erythroid component in PV compared to the other MPNs (i.e.,
myeloproliferative neoplasm (MPN) with an incidence ranging




                                                                                               on
                                                                            essential thrombocythemia and myelofibrosis).1 Beside the de-
from 2.5 to 10/100,000 inhabitants. The discovery in 2005 of
                                                                            tection of increased hematocrit (49% in men and 48% in
the gain-of-function JAK2V617F mutation on the exon 14 of
                                                                            women) and the positivity for JAK2 mutation, the laboratory
chromosome 9, responsible of the 98% of PV cases (the remain-




                                                                                         e
                                                                            hallmark includes leukocytosis and thrombocytosis in approxi-
ing cases are caused by the exon 12 JAK2 mutation), has repre-
sented a great improvement in PV diagnosis, clearly separating
it from secondary erythrocytosis (for the diagnostic criteria of
                                                                                 us
                                                                            mately half of the patients at diagnosis. The clinical features of
                                                                            PV, which is more commonly diagnosed in people over the age
                                                                            of 60 years (male/female ratio: 1.3), include a wide spectrum of
                                                                            al
                                                                            symptoms ranging from those involving microcirculation abnor-
                                                                            malities (headaches, dizziness, visual disturbances, distal pares-
                                                                  ci

  Correspondence: Massimo Franchini, Department of Hematology               thesia, acrocyanosis and erythromelalgia), aquagenic pruritus,
  and Transfusion Medicine, Carlo Poma Hospital, Mantova, Italy.            asthenia to the more severe arterial or venous thrombosis, which
                                                                er


  Tel.: +39.0376.201234.                                                    are a major cause of morbidity and mortality.2 On the latter issue
  E-mail: massimo.franchini@asst-mantova.it                                 will be dedicated this concise review.
                                                               m




  Key words: polycythemia vera, JAK2, thrombosis, therapy.
                                                    om




  Conflict of interest: the author declares no potential conflict of in-    Pathogenesis and management of thrombotic
  terest.
                                                                            risk in polycythemia vera
                                             -c




  Funding: none.                                                                As previously mentioned, PV patients are at increased risk
                                    on




                                                                            of thrombotic events, including venous thromboembolism
  Informed consent: the manuscript does not contain any individual
  person’s data in any form.                                                (VTE), cardiovascular and cerebrovascular accidents, with an
                                                                            unfavorable impact on overall survival.3 In the prospective RE-
                              N




  Availability of data and material: data and materials are available       VEAL study,4 nearly 20% of patients with PV experienced a
  by the authors.                                                           thrombotic event at the time of enrolment, and in a population-
                                                                            based study the likelihood of thrombotic complications after a
  Received: 17 October 2023.                                                median follow-up of 20 years was estimated at 26%.5 Beside the
  Accepted: 7 December 2023.
                                                                            hematocrit levels, age >60 years and thrombosis history have
                                                                            been identified as the most important risk factors for thrombosis
  Publisher’s note: all claims expressed in this article are solely those
  of the authors and do not necessarily represent those of their affili-    permitting to stratify patients in high-risk (> 60 years or throm-
  ated organizations, or those of the publisher, the editors and the re-    bosis history) and low-risk (absence of both risk factors) cate-
  viewers. Any product that may be evaluated in this article or claim       gories.1 An additional, detrimental effect on thrombotic risk is
  that may be made by its manufacturer is not guaranteed or endorsed        also exerted by the presence of cardiovascular risk factors (i.e.,
  by the publisher.                                                         hypertension, diabetes and hyperlipidemia), leukocytosis (in par-
                                                                            ticular, an increased absolute neutrophil count), microvascular
  ©
   Copyright: the Author(s), 2023                                           symptoms, JAK2 allele burden (i.e., the measurement of mutant
  Licensee PAGEPress, Italy                                                 allele versus wild type allele in hematopoietic cells), and fre-
  Bleeding, Thrombosis and Vascular Biology 2023; 2:102
                                                                            quent phlebotomies.6
  doi:10.4081/btvb.2023.102
                                                                                The management of PV should take into account the throm-
  This work is licensed under a Creative Commons Attribution-               botic risk, which should be tailored to each patient.3 Thus, while
  NonCommercial 4.0 International License (CC BY-NC 4.0).                   phlebotomy, aimed at reaching and maintaining hematocrit lev-
                                                                            els <45%, is considered the mainstay of PV treatment in low-


                                             Bleeding, Thrombosis and Vascular Biology 2023; 2:102
                                 Polycythemia vera and management of the thrombotic risk: an update                                    63



risk patients, it could aggravate the thrombotic tendency in high-     daily low-dose aspirin (more effective than single dose in in-
risk patients. It is well known, indeed, that repeated phle-           hibiting platelet activation) may be necessary in low-risk pa-
botomies decrease body iron stores, which in turn render red           tients at increased risk of arterial thrombosis, including those
blood cells (RBCs) smaller with an increased red cell mass de-         with cardiovascular risk factors, leukocytosis and microvascular
spite a potentially normal hematocrit (RBCs occupy less of the         symptoms and in high-risk patients with history of arterial
space in the hematocrit), resulting in an enhanced thrombotic          thrombosis.10 By contrast, adding long-term prophylactic sys-
risk.1 In addition, the phlebotomy-related reduction in oxygena-       temic anticoagulation [i.e., low-molecular weight heparin, vita-
tion induces the expression of cytokines [i.e., hypoxia-inducible      min K antagonists and direct oral anticoagulants (DOACs)] is
factors 1 and 2 alpha (HIF1a and HIF2a)] that downregulate the         often required in high-risk patients with previous VTE history
expression of hepcidin, the main regulator of iron metabolism,         to prevent VTE recurrence.1 The association, however, between
leading to increased erythropoiesis.1 Thus, in high-risk patients      aspirin and oral anticoagulants is still under investigation due to
phlebotomy alone is not a sufficient therapeutic presidium but         safety concerns regarding their potential increased hemorrhagic
needs to be associated with cytoreductive therapy (i.e., hydrox-       risk. Figure 1 summarizes the current management strategies to
yurea which carries a low risk of leukemic transformation).1 In        minimize the thrombotic risk in PV patients.
as subset analysis of the prospective multicenter ECLAP study,
hydroxyurea demonstrated and advantage over phlebotomy,
nearly halving the incidence of fatal and non-fatal cardiovascular     Conclusions
events (7.9% versus 13.2%).7 There is also a general agreement




                                                                                          ly
in the fundamental therapeutic role of low-dose aspirin (100               Since the discovery of the JAK2 mutation causative of PV




                                                                                  on
mg/die) as antithrombotic prophylaxis in all PV patients. In a         in 2005, several studies have been conducted in PV patients
double-blind randomized controlled trial enrolling 518 PV pa-          aimed at the identification of those risk factors influencing their
tients, low-dose aspirin compared to placebo reduced the risk of       outcome. Among them, thrombosis is considered, along with
                                                                       age, the most important determinant of worse prognosis and




                                                                            e
death from cardiovascular causes without increasing the bleed-
ing risk.8 In addition, it was more effective than cytoreduction       studies in this field have permitted to stratify patients in low-
in protecting against cardiovascular events.9 However, twice         usand high-risk and thus to set up adequate preventive counter-
                                                                al
                                                  ci
                                                er
                                               m
                                     om
                               -c
                        on
                  N




Figure 1. Management strategies for patients with polycythemia vera.
Consider twice daily low-dose aspirin in low-risk patients with cardiovascular risk factors, leukocytosis, or inadequate control of mi-
crovascular symptoms and in high-risk patients with history of arterial thrombosis. Consider adding pegylated IFN-α in low-risk patients
in the presence of frequent phlebotomies, severe and protracted pruritus, symptomatic splenomegaly, and persistent symptoms and in
high-risk younger patients or in those with intolerance or resistance to hydroxyurea. Systemic anticoagulation is required in high-risk
patients with venous thromboembolism history.


                                        Bleeding, Thrombosis and Vascular Biology 2023; 2:102
64                                                             M. Franchini




measures. While the management of PV patients according to                    polycythemia vera in the United States. Clin Lymphoma
their thrombotic risk profile is nowadays well consolidated,                  Myeloma Leuk 2018;18:788-95.
some grey areas still persist and are object of intense investiga-       5.   Szuber N, Mudireddy M, Nicolosi M, et al. 3023 Mayo
tion from researchers. They include the role of DOACs and the                 Clinic patients with myeloproliferative neoplasms: risk-
risk-benefit ratio of prophylactic long-term systemic anticoag-               stratified comparison of survival and outcomes data among
ulation associated with aspirin in high-risk patients with previ-             disease subgroups. Mayo Clin Proc 2019;94:599-610.
ous VTE. Future clinical trials in this setting will help to             6.   Carobbio A, Ferrari A, Masciulli A, et al. Leukocytosis and
optimize the anti-thrombotic management of PV patients.                       thrombosis in essential thrombocythemia and polycythemia
                                                                              vera: a systematic review and meta-analysis. Blood Adv
                                                                              2019;3:1729-37.
References                                                               7.   Barbui T, Vannucchi AM, Finazzi G, et al. A reappraisal of
                                                                              the benefit-risk profile of hydroxyurea in polycythemia vera:
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    bocythemia: 2021 update on diagnosis, risk-stratification                 A propensity-matched study. Am J Hematol 2017;92:1131-6.
    and management. Am J Hematol 2024;98:1465-87.                        8.   Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety
 2. Tefferi A, Vannucchi AM, Barbui T. Polycythemia vera: his-                of low-dose aspirin in polycythemia vera. N Engl J Med
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 3. Guglielmelli P, Vannucchi AM. Current management strate-                  plastic risk in a large cohort of patients with polycythemia
                                                                              vera. J Clin Oncol 2005;23:2224-32.




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