10.4081/btvb.2022.38
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Tiziano Barbui
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Bleeding, Thrombosis and Vascular Biology
Malignancy
Clonal hematopoiesis and inflammation: a link with thrombosis and malignancy
Text.Serial.Journal
https://www.btvb.org/btvb
1
Invited Editorials
2022-07-21
2022-05-09
2022-05-23
2022-07-21
Bleed Thromb Vascul Biol
Tiziano Barbui
2022/07/21
10.4081/btvb.2022.38
FROM Research Foundation, Papa Giovanni XXIII Hospital, Bergamo
2785-5309
2
Malignancy
en
Farrukh F, Guglielmelli P, Loscocco GG, et al. Deciphering the individual contribution of absolute neutrophil and monocyte counts to thrombosis risk in polycythemia vera and essential thrombocythemia. Am J Hematol 2022;97:E35-7.
Clonal hematopoiesis and inflammation: a link with thrombosis and malignancy
https://www.btvb.org/btvb/article/download/38/34
1
                                                                                                       INVITED EDITORIAL

Clonal hematopoiesis and inflammation: a link with thrombosis and malignancy
Tiziano Barbui

FROM Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy




                                                                                Thrombotic complications are the major cause of mor-
INTRODUCTION                                                                bidity and mortality in PV and ET and are mechanistically
    The discovery of driver somatic mutations in JAK2                       associated with the mutation status;3 in around 20% of pa-
(V617F), CALR, or MPL in patients with polycythemia                         tients, thrombosis may occur years before the MPN diag-
vera (PV), essential thrombocythemia (ET), and myelofi-                     nosis.4,5 After diagnosis, the thrombotic risk persists and
brosis (MF) has opened a new era in the understanding of                    accounts for an incident rate of 3.5% person-year in PV
the pathobiology of these myeloproliferative neoplasms                      while it is slightly lower in patients with ET and primary
(MPN) and has contributed to the knowledge on MPN-as-                       myelofibrosis (PMF) (2.5 and 2% person-year, respec-




                                                                                                     ly
sociated arterial and venous thrombosis.1,2 Several addi-                   tively).4,5 These estimates are three or more-fold greater




                                                                                             on
tional mutations, most of them affecting genes involved in                  than in the normal population with or without generic risk
epigenetic regulation (TET2, ASXL1, EZH2, IDH1,                             factors for cardiovascular events such as diabetes, hyper-
DNMT3A) and RNA splicing (SRSF2) have also been                             tension, smoking obesity.4,5




                                                                                        e
identified in MPNs. These mutations can either precede, or                      In a population-based study carried out in Sweden, re-
accumulate on, a JAK2V617F mutated clone and cooperate
with JAK2V617F to favor clonal dominance, modify dis-
                                                                                 us
                                                                            cruiting 9429 patients with MPNs and 35,820 matched
                                                                            controls from 1987 to 2009, the hazard ratios (HRs) for
ease phenotype, or promote leukemic transformation.3
                                                                            al
                                                                            arterial thrombosis in MPNs compared with controls were
                                                                            3.0, 2.0, and 1.5 at 3 months, 1 and 5 years, respectively.
                                                                  ci

                                                                            The corresponding HRs for venous thrombosis were 9.7,
                                                                er


                                                                            4.7, and 3.2, respectively.6
  Correspondence: Tiziano Barbui, FROM Research Foundation,
                                                               m



  Papa Giovanni XXIII Hospital, Piazza OMS 1, 24127 Bergamo
  (BG), Italy.                                                              CLONAL HEMATOPOIESIS
                                                    om




  Tel. +39.0352675134 or +39.0352674436.
  E-mail: tbarbui@fondazionefrom.it                                         OF INDETERMINATE POTENTIAL

  Key words: Clonal hematopoiesis of indetermined potential; In-
                                                                                In 2014, seminal studies identified somatic mutations
                                             -c




  flammation; Myeloproliferative neoplasms; Thrombosis; Malig-              of TET2, ASXL1, EZH2, IDH1, DNMT3A e
  nancy.                                                                    JAK2V617F, in individuals without hematological ab-
                                    on




                                                                            normality.7-9 These genetic events allow to identify a
  Conflict of interest: The author declares no potential conflict of in-
                                                                            new entity called “clonal hematopoiesis of indeterminate
                              N




  terest.
                                                                            potential” (CHIP) as it was uncertain whether it could
  Funding: None.                                                            evolve towards hematological malignancies. The fre-
  Received for publication: 9 May 2022.
                                                                            quency of CHIP was age-related and found in up to 50%
  Accepted for publication: 4 July 2022.                                    of elderly persons and associated with an excess of mor-
                                                                            tality.10 Interestingly, arterial thrombosis (myocardial in-
  Publisher’s note: All claims expressed in this article are solely those   farction, stroke) and heart failure were frequently
  of the authors and do not necessarily represent those of their affili-
                                                                            reported in these individuals and attributed to systemic
  ated organizations, or those of the publisher, the editors and the re-
  viewers. Any product that may be evaluated in this article or claim       chronic inflammation driven by the genetic mutation
  that may be made by its manufacturer is not guaranteed or endorsed        particularly.11,12 The link between the JAK2V617F-mu-
  by the publisher.                                                         tation and chronic inflammation, revealed by elevation
  ©
                                                                            of inflammatory biomarkers, is now explained by the
   Copyright: the Author(s), 2022
  Licensee PAGEPress, Italy                                                 fact that the JAK2617F-mutation per se is a generator of
  Bleeding, Thrombosis and Vascular Biology 2022; 1:38                      reactive oxygen species (ROS)13-15 activating cells car-
  doi:10.4081/btvb.2022.38                                                  rying this mutation (e.g., granulocytes, monocytes, B-
  This work is licensed under a Creative Commons Attribution-
                                                                            cells, T cells, platelets) and explaining the increased risk
  NonCommercial 4.0 International License (CC BY-NC 4.0).                   of atherosclerosis and thrombosis.16 In addition, the
                                                                            same mechanism involving inflammation in the bone

                                              Bleeding, Thrombosis and Vascular Biology 2022; 1:38
                          Clonal hematopoiesis and inflammation: a link with thrombosis and malignancy                        41



marrow compartment is considered a driving force of                should be considered an additional contributor to enhance
clonal evolution and transition to more advanced phases            the inflammatory status.22,23
of MPN.17,18                                                            Two inflammatory biomarkers, high-sensitivity (hs)-
                                                                   CRP and PTX3 belonging to the superfamily of pentraxins
                                                                   were found markers of thrombosis in ET and PV and were
CHIP, THROMBOSIS AND RISK OF EVOLUTION                             correlated with JAK2V617F allele burden (p=0.003).24 In-
TO MYELOPROLIFERATIVE NEOPLASMS                                    terestingly, hs-CRP was confirmed as a marker of inflam-
    In the general population, CHIP-associated mortality           mation in CHIP supporting the link between inflammation
is due to an increased risk of atherosclerotic cardiovas-          and coronary artery disease in the CHIP stage as well. The
cular disease (CVD), particularly in subjects with CHIP            relationship between leukocytosis and thrombosis has been
clones characterized by a high variant allele fraction             extensively investigated in several experimental studies,25,26
(VAF).13-16 Conversely, the risk of developing a hemato-           based on the notion that in MPNs, chronic and subclinical
logical neoplasm including MPN, from CHIP status, is               systemic inflammation has a critical role in the pathogene-
relatively modest, 0.5% to 1% per year, and most indi-             sis of vascular events. However, strong evidence in support
viduals will remain asymptomatic with normal blood                 of leukocytosis as an inflammatory biomarker potentially
                                                                   contributing to differentiate prognostic categories in PV is




                                                                                    ly
counts.17,18
    However, the transition towards clonal myeloid disor-          still missing. In a very recent meta-analysis,27 the associa-




                                                                             on
ders can be higher in some subgroups of patients with ar-          tion of leukocytosis with thrombosis was stronger in ET
terial thrombosis who subsequently may develop MPN.                than in PV and exclusively related to arterial events, as
As alluded to before, 20% of MPN patients do experience            shown in our previous analysis of ECLAP patients where




                                                                        e
thrombosis before the onset of this disease, particularly          time-dependent and not baseline leukocytosis was associ-
in arterial sites. This finding suggests that PV, ET and
PMF have a long period which, with current diagnostic
                                                                 usated with myocardial infarction.28 Other Authors found that
                                                                   the persistent leukocytosis in PV is linked to hematologic
                                                                   evolution rather than thrombosis.29
                                                            al
criteria, escapes the diagnosis of MPN. However, the
pathogenesis of both CHIP and overt MPN is similar and                  While by definition there is no pathological elevation
                                               ci

involves genetic mutations and inflammation; in addition,          of blood counts in CHIP, in a large population study, a sig-
                                                                   nificant increase of white cell, hemoglobin and platelet
                                             er


the characteristics that mark the risk of vascular events
and evolution to MPN, could be operating in the CHIP               counts compared to the controls, was documented to be
                                            m



stage, as well. Besides these genetic alterations, further         JAK2V617F VAF dependent and associated with an in-
factors, including cytokine-driven inflammation by the             creased venous thrombosis risk.30
                                   om




malignant clone and non-malignant cells of the bone mar-                Interestingly, new data are emerging on the role of
row microenvironment, may deteriorate the hematological            non-myeloid inflammatory cells, such as T lymphocytes
disease course.19,20 Moreover, CHIP is likely to contribute        and monocytes in the process of immune thrombosis; in
                             -c




to the whole thrombotic risk together with other generic           particular, experimental work has consistently shown that
                      on




risk factors for cardiovascular events.18,21                       T-reg lymphocytes are involved in the regulation of the
    It follows that recognizing which of these patients may        prothrombotic action of activated neutrophils in the
                                                                   process of fibrin formation and dissolution.31,32 Based on
                 N




be at greater risk of future hematological developments
in MPN and thrombotic events, could help with appropri-            this knowledge, the ratio between neutrophils-to-lympho-
ate monitoring and early intervention proposals. Future            cytes (NLR) was considered to represent a synthesis of
studies should address the question of screening for CHIP          these two opposed actions in the thrombotic events and
in patients with premature or unexplained coronary artery          was tested in PV and ET. It was found that elevated value
diseases or stroke in the absence of traditional risk factors.     of NLR was a prognostic factor of venous and not arterial
Moreover, obtaining results from NGS mutation may be               thrombosis as it was the JAK2 V617F VAF superior to
appropriate in young people with thrombotic events oc-             50%.33-35 This is a new area of research that deserves new
curring in unusual sites, such as splanchnic or cerebral           investigations also in the stage of CHIP.
vein thrombosis, who often present blood counts within                  In conclusion, the tight association between clonal
the normal range and no other signs of myeloproliferative          hematopoiesis and chronic inflammation has brought out
disease such as splenomegaly. In addition to evaluating            the notion that CHIP and MPNs are unique models to elu-
the VAF for CHIP mutations, in particular for                      cidate common mechanisms of genetic damage initially
JAK2V617F it could also be useful to search for biomark-           not associated with obvious diseases, but which represent
ers of inflammation that are linked to both the cardiovas-         a risk of developing frank diseases. Thrombosis, in the
cular complications and the risk of hematological                  setting of either CHIP and MPN, may reflect the effects
transformation. Furthermore, it should be highlighted that         of inflammation and mark a transition state from latency
thrombosis is a multifactorial event, in which CHIP                to more frank disease.

                                      Bleeding, Thrombosis and Vascular Biology 2022; 1:38
42                                                                T. Barbui




                                                                                brosis: is chronic inflammation a trigger and driver of clonal
REFERENCES                                                                      evolution and development of accelerated atherosclerosis
                                                                                and second cancer? Blood 2012;119:3219-25.
 1. Nangalia J, Mitchell E, Green AR. Clonal approaches to un-
                                                                          19.   Fleischman AG, Aichberger KJ, Luty SB, et al. TNFα Fa-
    derstanding the impact of mutations on hematologic disease
                                                                                cilitates Clonal Expansion of JAK2V617F Positive Cells in
    development. Blood 2019;133:1436-45.
                                                                                Myeloproliferative Neoplasms. Blood 2011;118:6392-8.
 2. Lee J, Godfrey AL, Nangalia J. Genomic heterogeneity in
    myeloproliferative neoplasms and applications to clinical             20.   Tefferi A, Vaidya R, Caramazza D, et al. Circulating Inter-
    practice. Blood Rev 2020;42:100708.                                         leukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independ-
 3. Grinfeld J, Nangalia J, Green AR. Molecular determinants                    ently prognostic in primary myelofibrosis: a comprehensive
    of pathogenesis and clinical phenotype in myeloproliferative                cytokine profiling study. J Clin Oncol 2011;29:1356–1363.
    neoplasms. Haematologica 2017;102:7-17.                               21.   Jaiswal S, Ebert BL. Clonal hematopoiesis in human aging
 4. Barbui T, Carobbio A, De Stefano V. Thrombosis in myelo-                    and disease. Science 2019;366:eaan4673.
    proliferative neoplasms during cytoreductive and antithrom-           22.   Rohm TV, Meier DT, Olefsky JM, Donath MY. Inflamma-
    botic drug treatment. Res Pract Thromb Haemost                              tion in obesity, diabetes, and related disorders. Immunity
    2022;6:e12657.                                                              2022;55:31-55.
 5. Tefferi A, Vannucchi AM, Barbui T. Polycythemia vera: his-            23.   Leiva O, Hobbs G, Ravid K, Libby P. Cardiovascular Dis-
    torical oversights, diagnostic details, and therapeutic views.              ease in Myeloproliferative Neoplasms: JACC: CardioOn-




                                                                                                      ly
    Leukemia 2021;35:3339-51.                                                   cology State-of-the-Art Review. J Am Coll Cardiol Cardio
 6. Hultcrantz, M, Björkholm M, Dickman PW, et al. Risk for                     Onc 2022;4:166-82.




                                                                                              on
    arterial and venous thrombosis in patients with myelopro-             24.   Barbui T, Carobbio A, Finazzi G, et al. Inflammation and
    liferative neoplasms: a population-based cohort study. Ann                  thrombosis in essential thrombocythemia and polycythemia
    Intern Med 2018;168:317-25.                                                 vera: different role of C-reactive protein and pentraxin 3.




                                                                                         e
 7. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal             Haematologica 2011;96:315-8.
    hematopoiesis associated with adverse outcomes. N Engl J
    Med 2014;371:2488-98.
 8. Genovese G, Kahler AK, Handsaker RE, et al. Clonal
                                                                          25.
                                                                                 us
                                                                                Carobbio A, Finazzi G, Guerini V, et al. Leukocytosis is a
                                                                                risk factor for thrombosis in essential thrombocythemia: in-
                                                                                teraction with treatment, standard risk factors, and Jak2 mu-
                                                                        al
    hematopoiesis and blood-cancer risk inferred from blood                     tation status. Blood 2007;109:2310-3.
    DNA sequence. N Engl J Med 2014;371:2477-87.                          26.   Carobbio A, Antonioli E, Guglielmelli P, et al. Leukocytosis
                                                           ci

 9. Xie M, Lu C, Wang J, et al. Age-related mutations associated                and risk stratification assessment in essential thrombo-
                                                                                cythemia. J Clin Oncol 2008;26:2732-6.
                                                         er


    with clonal hematopoietic expansion and malignancies. Nat
    Med 2014;20:1472-8.                                                   27.   Carobbio A, Ferrari A, Masciulli A, et al. Leukocytosis and
                                                                                thrombosis in essential thrombocythemia and polycythemia
                                                        m



10. Khetarpal SA, Qamar A, Bick AG, et al. Clonal
    Hematopoiesis of Indeterminate Potential Reshapes Age-                      vera: a systematic review and meta-analysis. Blood Adv
                                              om




    Related CVD: JACC Review Topic of the Week. J Am Coll                       2019;3:1729-37.
    Cardiol 2019;74:578-86.                                               28.   Landolfi R, Di Gennaro L, Barbui T, et al. Leukocytosis as
11. Busque L, Sun M, Buscarlet M, et al. High-sensitivity C-re-                 a major thrombotic risk factor in patients with polycythemia
                                        -c




    active protein is associated with clonal hematopoiesis of in-               vera. Blood 2007;109:2446-52.
    determinate potential. Blood Adv 2020;4:2430-8.                       29.   Ronner L, Podoltsev N, Gotlib J, et al. Persistent leukocy-
                                on




12. Abegunde SO, Buckstein R, Wells RA, Rauh MJ. An in-                         tosis in polycythemia vera is associated with disease evolu-
    flammatory environment containing TNFa favors Tet2-mu-                      tion but not thrombosis. Blood 2020;135:1696-703.
    tant clonal hematopoiesis. Exp Hematol 2018;59:60-65.                 30.   Cordua S, Kjaer L, Skov V, et al. Prevalence and phenotypes
                           N




13. Bjørn ME, Hasselbalch HC. The Role of Reactive Oxygen                       of JAK2 V617F and calreticulin mutations in a Danish gen-
    Species in Myelofibrosis and Related Neoplasms. Mediators                   eral population. Blood 2019;134:469-79.
    Inflamm 2015;2015:648090.                                             31.   Shahneh F, Grill A, Klein M, et al. Specialized regulatory T
14. Vener C, Novembrino FB, Bamonti Catena F, et al. Oxida-                     cells control venous blood clot resolution through SPARC.
    tive stress is increased in primary and post-polycythemia                   Blood 2021;137:1517-26.
    vera myelofibrosis. Exp Hematol 2010;38:1058-65.                      32.   van Os B, Lutgens E. SPARCing the clot. Blood
15. Marty C, Lacout C, Droin N, et al. A role for reactive oxygen               2021;137:1441-2.
    species in JAK2V617F myeloproliferative neoplasm pro-                 33.   Carobbio A, Vannucchi AM, De Stefano V, et al. Neutrophil-
    gression. Leukemia 2013;27:2187-95.                                         to-lymphocyte ratio is a novel predictor of venous thrombo-
16. Menendez-Gonzalez JB, Rodrigues NP. Exploring the asso-                     sis in polycythemia vera. Blood Cancer J 2022;12:28.
    ciations between clonal hematopoiesis of indeterminate po-            34.   Guglielmelli P, Loscocco GG, Mannarelli C, et al.
    tential, myeloid malignancy, and atherosclerosis. Methods                   JAK2V617F variant allele frequency >50% identifies pa-
    Mol Biol 2022;2419:73-88.                                                   tients with polycythemia vera at high risk for venous throm-
17. Baumeister J, Chatain N, Sofias AM, et al. Progression of                   bosis. Blood Cancer J 2021;11:199.
    Myeloproliferative Neoplasms (MPN): diagnostic and ther-              35.   Farrukh F, Guglielmelli P, Loscocco GG, et al. Deciphering
    apeutic perspectives. Cells 2021;10:3551.                                   the individual contribution of absolute neutrophil and mono-
18. Hasselbalch HC. Perspectives on chronic inflammation in                     cyte counts to thrombosis risk in polycythemia vera and es-
    essential thrombocythemia, polycythemia vera, and myelofi-                  sential thrombocythemia. Am J Hematol 2022;97:E35-7.



                                         Bleeding, Thrombosis and Vascular Biology 2022; 1:38
