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José J. Fuster
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Bleeding, Thrombosis and Vascular Biology
Parkinson's disease
Blood platelet heterogeneity at a glance: new insights into the relationship between platelet distribution width and neuropsychiatric disorders
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Invited Editorials
2023-05-03
2023-02-27
2023-04-30
2023-06-27
Bleed Thromb Vascul Biol
José J. Fuster
2023/05/03
10.4081/btvb.2023.65
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid
2785-5309
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Parkinson's disease
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Tirozzi A, Quiccione MS, Cerletti C, et al. A multi-trait association analysis of brain disorders and platelet traits identifies novel susceptibility loci for major depression, Alzheimer's and Parkinson's disease. Cells 2023;12:245.
Blood platelet heterogeneity at a glance: new insights into the relationship between platelet distribution width and neuropsychiatric disorders
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                                                                                                         INVITED EDITORIAL

Blood platelet heterogeneity at a glance: new insights into the relationship between
platelet distribution width and neuropsychiatric disorders
Benedetta Izzi, José J. Fuster

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain




    Functional and morphological differences in blood                        century later than the first discovery of blood platelets was
platelet subpopulations, especially in relation to their vol-                made by Giulio Bizzozero in 1882.1 Volume changes in
ume variability, became a target of investigation about a                    blood platelets have been extensively associated with
                                                                             functional changes in numerous in vitro and in vivo stud-
                                                                             ies, and platelet volume indices, such as mean platelet vol-
  Correspondence: Benedetta Izzi, Spanish National Center for Car-           ume (MPV) and platelet distribution width (PDW), have




                                                                                              ly
  diovascular Research Carlos III, C/Melchor Fernández Almagro 3,            often been described to be altered in several pathological
  28029 Madrid, Spain.                                                       human conditions.




                                                                                       on
  E-mail: benedetta.izzi@cnic.es
                                                                                 PDW is an easily measured blood parameter that re-
  Citation: Izzi B, Fuster JJ. Blood platelet heterogeneity at a glance:     flects platelet volume heterogeneity, and it is used in clin-
  new insights into the relationship between platelet distribution           ical practice to diagnose impaired megakaryocyte




                                                                                 e
  width and neuropsychiatric disorders. Bleeding, Thrombosis, and            differentiation and thrombopoiesis.2 PDW should be seen
  Vascular Biology 2023;2:65.

  Key words: platelet distribution width; neuropsychiatric disorders;
                                                                            us
                                                                             as an instant picture of how different circulating blood
                                                                             platelets are in a given individual with respect to their
  Mendelian randomization, Parkinson's disease.
                                                                            al
                                                                             size. Even if platelet size/volume has been long recog-
  Contributions: the authors contributed equally.
                                                                             nized as an important proxy of platelet function in a
                                                         ci

                                                                             plethora of in vitro and ex/in vivo studies,3 the idea of
                                                       er


  Conflict of interest: the authors declare no potential conflict of in-     PDW-dependent platelet heterogeneity as a driver of func-
  terest.                                                                    tional variability was raised only in the last years and still
                                                      m



  Acknowledgments/Funding: BI is supported by the program Atrac-             needs further clarifications.
  ción de Talento of the Comunidad de Madrid (GN:2022-T1/BMD-                    In 2010, PDW was first reported as a marker of
                                          om




  23767). JJF is supported by a Ramon y Cajal award (RYC-2016                platelet anisocytosis, the process that goes side-by-side
  –20026) from the Spanish Ministry of Science and Innovation/
  Agencia Estatal de Investigacion (AEI)/10.13039/501100011033               with platelet activation, during which pseudopods form,
                                                                             increasing platelet diameter and apparent volume.4 In the
                                    -c




  and Fondo Social Europeo El FSE invierte en tu futuro. Research
  work by BI and JJF is supported by grant PLEC2021-008194 from              Moli-family cohort we provided the first evidence of the
  the Spanish Ministry of Science and Innovation (MCIN/AEI/
                           on




                                                                             association of PDW with several aspects of platelet func-
  10.13039/501100011033) and the European Union (“NextGener-
  ationEU”/PRTR) and by grant LCF/PR/HR22/00732 from La                      tion in a large general population: PDW specifically and
  Caixa Foundation. The CNIC is supported by the MICIN, the In-              significantly reflected ex vivo and in vitro P-selectin-de-
                     N




  stituto de Salud Carlos III, the Pro-CNIC Foundation, and is a             pendent platelet activation, as well as platelet involvement
  Severo Ochoa Center of Excellence (grant number CEX2020-
  001041-S).                                                                 in in vitro coagulation.5 In the same population, PDW was
                                                                             also significantly associated with DNA methylation of
  Received: 27 February 2023.                                                PEAR1,6 a gene known to modulate platelet activation and
  Accepted: 30 March 2023.
                                                                             whose genetic variability has been associated with differ-
  Publisher’s note: all claims expressed in this article are solely those    ential responses to anti-platelet treatment.
  of the authors and do not necessarily represent those of their affili-         PDW was repeatedly reported as a predictor of prog-
  ated organizations, or those of the publisher, the editors and the re-     nosis of clinically defined inflammation-based conditions
  viewers. Any product that may be evaluated in this article or claim
  that may be made by its manufacturer is not guaranteed or endorsed         (including cardiovascular disease, cancer, metabolic syn-
  by the publisher.                                                          drome, and diabetes). Interestingly, in a very recent study
                                                                             involving 200,453 participants of the UK Biobank study,
  ©
   Copyright: the Author(s), 2023
  Licensee PAGEPress, Italy
                                                                             PDW was also identified as the blood trait most signifi-
  Bleeding, Thrombosis and Vascular Biology 2023; 2:65                       cantly associated with somatic mutations linked to clonal
  doi:10.4081/btvb.2023.65                                                   hematopoiesis of indeterminate potential,7 an emergent
                                                                             risk factor for cardiovascular disease.
  This work is licensed under a Creative Commons Attribution-
  NonCommercial 4.0 International License (CC BY-NC 4.0).                        In the last decade, a growing body of evidence origi-
                                                                             nating from both epidemiological and genetic studies has

                                              Bleeding, Thrombosis and Vascular Biology 2023; 2:65
42                                                       B. Izzi, J.J. Fuster




consistently suggested PDW as a novel marker of neu-                   than the clinical diagnosis is key. The paper by Yang et
ropsychiatric disorders, including Parkinson's disease                 al. sets an important step forward in this quest.
(PD).8 On the contrary, less consistent data have been re-                 Large longitudinal studies, with the possibility of iden-
ported for the other platelet volume-dependent marker                  tifying PD incident cases over time, will clarify and con-
MPV in relation to the same clinical phenotypes.8 The                  firm whether PDW measurement is sufficient to predict
paper by Yang et al. recently published in Cell Genomics               PD risk much earlier than the onset of the disease, opening
further support a possible causal role of PDW in neuropsy-             up new possibilities for population stratification-based
chiatric disorders.9 Therefore, the authors used large-scale           prevention strategies and novel PD/anti-platelet therapeu-
genome-wide association study summary statistics in com-               tic approaches.
bination with blood-based (from eQTLGen) and platelet
(from GeneSTAR) cis-expression quantitative trait loci
(cis-eQTL). Through Mendelian randomization (MR)                       REFERENCES
analysis, they reported, for the first time, a causal effect of
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increased PDW on PD, but not of MPV on any of the neu-
                                                                           search. Front Cardiovasc Med 2019;6:138.
ropsychiatric phenotypes studied. Even if blood platelets
                                                                        2. Borkataky S, Jain R, Gupta R, et al. Role of platelet volume
are known to play a role in thrombo-inflammation, this in-




                                                                                                  ly
                                                                           indices in the differential diagnosis of thrombocytopenia: a
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                                                                                          on
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                                                                                    e
left unchanged the magnitude of the effect. With this ap-                  tion width: a simple, practical and specific marker of acti-
proach, the Authors identified 60 false discovery rate-sig-
nificant functional genes associated with the PDW-PD trait
                                                                                us
                                                                           vation of coagulation. Hippokratia 2010;14:28-32.
                                                                        5. Izzi B, Gialluisi A, Gianfagna F, et al. Platelet distribution
                                                                           width is associated with P-selectin dependent platelet func-
pair, of which 40 showed a consistent direction of effect
                                                                     al
from multiple MR analyses. Worth of note, 11 out of those                  tion: results from the moli-family cohort study. Cells
                                                                           2021;10:2737.
                                                        ci

40 genes are also known drug targets, opening up to drug
                                                                        6. Izzi B, Gianfagna F, Yang WY, et al. Variation of PEAR1
re-purposing strategies to reduce PD risk.
                                                      er


                                                                           DNA methylation influences platelet and leukocyte function.
    This paper stems from recent studies investigating the                 Clin Epigenetics 2019;11:151.
genetic correlation of platelet traits and brain disorders and
                                                     m



                                                                        7. Kar SP, Quiros PM, Gu M, et al. Genome-wide analyses of
the tentative identification of a causal link through MR ap-               200,453 individuals yield new insights into the causes and
                                           om




proaches. These studies were focused originally on major                   consequences of clonal hematopoiesis. Nat Genet
depressive disorders,8 but expanded the spectrum of neu-                   2022;54:1155-66.
ropsychiatric disorders by including other neurodegener-                8. Izzi B, Tirozzi A, Cerletti C, et al. Beyond haemostasis and
                                      -c




ative phenotypes like PD or Alzheimer's disease (AD).10-12                 thrombosis: platelets in depression and its co-morbidities.
    Prior to the publication by Yang et al.,9 the first evi-               Int J Mol Sci 2020;21:8817.
                              on




dence of significant genomic overlap between PDW and                    9. Yang Y, Zhou Y, Nyholt DR, et al. The shared genetic land-
                                                                           scape of blood cell traits and risk of neurological and psy-
PD was observed by Tirozzi et al.,13 through linkage dise-
                         N




                                                                           chiatric disorders. Cell Genom 2023;3:100249.
quilibrium score regression and polygenic risk score analy-
                                                                       10. Astle WJ, Elding H, Jiang T, et al. The allelic landscape of
ses. The same group, almost simultaneously to the paper                    human blood cell trait variation and links to common com-
by Yang et al., additionally applied multi-trait association               plex disease. Cell 2016;167:1415-29.e19.
analysis to exploit genetic correlations and overlap of ge-            11. Nalls MA, Blauwendraat C, Vallerga CL, et al. Identification
netic features of platelet count test, MPV, and PDW with                   of novel risk loci, causal insights, and heritable risk for
PD, AD, and major depressive disorders.14 Also in this                     Parkinson's disease: a meta-analysis of genome-wide asso-
case, the authors identified 70 genome-wide significant                    ciation studies. Lancet Neurol 2019;18:1091-102.
multi-trait LD-independent associations (P<5×10-8) for                 12. Gialluisi A, Izzi B, Di Castelnuovo A, et al. Revisiting the
PD, of which 34 were never reported before.                                link between platelets and depression through genetic epi-
    Overall, this evidence points to the characterization of               demiology: new insights from platelet distribution width.
                                                                           Haematologica 2020;105:e246-8.
PDW as a promising marker of PD risk in the general pop-
                                                                       13. Tirozzi A, Izzi B, Noro F, et al. Assessing genetic overlap
ulation, being in line with the already accepted idea that
                                                                           between platelet parameters and neurodegenerative disor-
platelets can be considered a circulating mirror of neu-                   ders. Front Immunol 2020;11:02127.
rons.15 PD, like AD, is a neurodegenerative disorder oc-               14. Tirozzi A, Quiccione MS, Cerletti C, et al. A multi-trait as-
curring after the long-lasting accumulation of neurotoxic                  sociation analysis of brain disorders and platelet traits iden-
protein aggregates. Identifying easy-to-measure circulat-                  tifies novel susceptibility loci for major depression,
ing biomarkers that can predict disease risk much earlier                  Alzheimer's and Parkinson's disease. Cells 2023;12:245.


                                       Bleeding, Thrombosis and Vascular Biology 2023; 2:65
