10.4081/btvb.2023.63
Blood platelets are indubitably one of the wonders of the world, whether the first of the eight may be a matter of debate, but they certainly are. Compared with all other cells they are much smaller and, like few others, devoid of a nucleus but despite this, they are extremely complex and provided with multiple functions [...].
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Paolo Gresele
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Bleeding, Thrombosis and Vascular Biology
phylogeny
Blood platelets and Charles Darwin’s natural selection
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Bleed Thromb Vascul Biol
Paolo Gresele
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Section of Internal and Cardiovascular Medicine, Department of Medicine and Surgery, University of Perugia
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Chouldry FA, Bagger FO, Macaulay IC, et al. Transcriptional characterization of human megakaryocyte polyploidization and lineage commitment. J Thromb Haemost2021;19:1236-49.
Blood platelets and Charles Darwin’s natural selection
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                                                                                                                        EDITORIAL

Blood platelets and Charles Darwin’s natural selection
Stefania Momi, Paolo Gresele

Section of Internal and Cardiovascular Medicine, Department of Medicine and Surgery, University of Perugia, Italy




                                                                             the rapid secretion of several molecules crucial for pri-
INTRODUCTION                                                                 mary hemostasis.3-5
    Blood platelets are indubitably one of the wonders of                        In the animal kingdom, platelets are unique to mam-
the world, whether the first of the eight may be a matter                    mals, which include around 6,400 extant species out of
of debate, but they certainly are. Compared with all other                   1.5-1.8 million living species on earth, i.e. only 0.35-
cells they are much smaller and, like few others, devoid                     0.42% of all living organisms.
of a nucleus but despite this, they are extremely complex
and provided with multiple functions.1,2




                                                                                              ly
    Their peculiar shape and dimensions lend them spe-                       WHAT IS KNOWN ABOUT THE PHYLOGENESIS




                                                                                       on
cial skills. The discoid shape allows platelets to have a                    OF MAMMALIAN PLATELETS
much larger surface area compared with a normal glob-
                                                                                 Several aspects of the phylogenesis of mammalian
ular cell of the same size and their small dimensions, by




                                                                                 e
                                                                             platelets have been clarified in the last decades.6 In all mam-
reducing the distance their granules must travel in the
cytoplasm before reaching the plasma membrane, favor                        us
                                                                             malia, platelets have similar functions and structure, as
                                                                             small anucleate secretory cells derived from precursor poly-
                                                                             ploid megakaryocytes. Their ability to exert a wide reper-
                                                                            al
                                                                             toire of complex functions, which span from adhesion and
                                                                             aggregation at a site of vessel wall damage, to chemotaxis,
                                                         ci

  Correspondence: Stefania Momi, Department of Medicine and Sur-
  gery, Section of Internal and Cardiovascular Medicine, University          phagocytosis, antigen presentation, regulation of cell
                                                       er


  of Perugia, Centro didattico - Edificio B piano 1, Strada vicinale         growth and differentiation, participation in atherosclerosis,
  Via delle Corse, 06132, Perugia.
                                                                             etc.,7-9 likely dates back to an era in which all innate host
                                                      m



  Tel.: +39.0755783989.
  E-mail: stefaniamomi@gmail.com                                             defenses were accomplished by one single cell type, or at
                                          om




                                                                             most by a small number of cells, instead than by the exten-
  Citation: Momi S, Gresele P. Blood platelets and Charles Darwin’s          sive and specialized cellular repertoire which has then de-
  natural selection. Bleeding, Thrombosis, and Vascular Biology
  2023;2:63.
                                                                             veloped in mammalians’ blood (Figure 1).
                                    -c




                                                                                 Invertebrates possess an open circulatory system (the
  Key words: platelets; phylogeny.                                           hemolymph) with only one type of circulating cell, the
                           on




                                                                             hemocyte, that among others also plays the hemostatic
  Conflicts of interest: the authors declare no potential conflict of in-
                                                                             role being able to aggregate and seal wounds. Coelomo-
                     N




  terest.
                                                                             cytes, the primary immune cells of earthworms, have
  Funding: none.                                                             many functions resembling mammalian platelets, includ-
                                                                             ing chemotaxis, and phagocytosis,10 and express Toll-like
  Received: 7 February 2023.
  Accepted: 1 March 2023.                                                    receptors and favor the formation of extracellular traps.11
                                                                             The hemolymph of many insects contains coagulocytes
  Publisher’s note: all claims expressed in this article are solely those    which, upon contact with a foreign surface, extrude long
  of the authors and do not necessarily represent those of their affili-
                                                                             processes containing cytoplasmic granules able to create
  ated organizations, or those of the publisher, the editors and the re-
  viewers. Any product that may be evaluated in this article or claim        a hemostatic plug.12 In Drosophila melanogaster more
  that may be made by its manufacturer is not guaranteed or endorsed         than 90% of all hemocytes are plasmatocytes,13 which per-
  by the publisher.                                                          form important functions during animal development and,
                                                                             in the response to infection and tissue damage. Sea urchin
  ©
   Copyright: the Author(s), 2023
  Licensee PAGEPress, Italy                                                  coelomocytes accumulate at sites of injury in response to
  Bleeding, Thrombosis and Vascular Biology 2023; 2:63                       chemotactic stimuli, generate sealing and encapsulating
  doi:10.4081/btvb.2023.63                                                   clots that are dependent on cell-cell adhesion, and have
                                                                             secretory and phagocytic functions.14 In Arthropoda,
  This work is licensed under a Creative Commons Attribution-
  NonCommercial 4.0 International License (CC BY-NC 4.0).                    amoebocytes are responsible for hemostasis. In the Limu-
                                                                             lus polyphemus, the American horseshoe crab, the major

                                              Bleeding, Thrombosis and Vascular Biology 2023; 2:63
36                                                     S. Momi and P. Gresele




defense systems in hemolymph are carried out by the so-               thrombocytes that differ from one another for cytoplas-
called amoebocyte/granulocyte,15 which has primitive                  mic granules. The cytoplasm in reptiles contains actin-
wound sealing functions and is able to aggregate in re-               like filaments in the perinuclear area and a smooth
sponse to lipopolysaccharide (LPS) and to release a cas-              endoplasmic reticulum throughout the peripheral cyto-
cade of antimicrobial substances, such as the anti-LPS                plasm.21 An extensive ultrastructural study of six domes-
factor, lectins, protease inhibitors (including trypsin in-           tic species of birds showed that their thrombocytes are
hibitor and α2-macroglobulin), and also coagulation fac-              similar in size to lymphocytes but have a denser nucleus,
tors (Factor C, Factor B, Factor G, proclotting enzymes,              a very highly vacuolated cytoplasm and a membrane sur-
coagulogen) involved in the engulfing and killing of in-              face-connected canalicular system similar to mammalian
vading microbes and in preventing hemolymph leakage.16                platelets. Thrombocytes are the most common blood cell
     Except for mammalia, in all other classes of the ani-            in the chicken after erythrocytes, contain 5-hydrox-
mal kingdom cells involved in hemostasis are nucleated.               ytryptamine,22 and release proteins including a fraction
Non-mammalian vertebrates have nucleated, often spin-                 that seems to correspond to β-thromboglobulin.23 Bird
dle-shaped, thrombocytes, that represent the first cells              thrombocytes do not form vaso-occlusive thrombi after
that specialized in haemostasis during evolution.17 Ze-               arterial vessel wall injury in vivo and indeed birds have
brafish (Danio rerio) and other fish species have nucle-              more prolonged bleeding.24 A recent study comparing




                                                                                                ly
ated thrombocytes that, although broadly similar to                   the hemostatic cells of five mammals with 48 bird




                                                                                         on
platelets in terms of function,18 do not aggregate in re-             species across the avian phylogeny, 12 reptiles, three
sponse to adenosine diphosphate and epinephrine,19 but                amphibian and three fish species, showed that the cyto-
still play a role in the development of arterial thrombi.20           plasmic domain of GPIbα is lacking in birds and this




                                                                                   e
Reptiles, birds, and amphibians also have nucleated                   might help to explain why, unlike mammalian platelets,
                                                                            us
                                                                     al
                                                        ci
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                                                     m
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                                      -c
                              on
                          N




Figure 1. Simplified phylogenetic tree showing the evolutionary relationship between animal species and the relative evolution of
multifunctional innate defensive and hemostatic cells to mammalian blood platelets. The hypothesized gene mutation event at the origin
of mammalian platelets is shown. Created with BioRender.com.


                                       Bleeding, Thrombosis and Vascular Biology 2023; 2:63
                                     Blood platelets and Charles Darwin’s natural selection                                     37



avian thrombocytes take longer to produce a clot able to           shear forces than mammalian platelets,24 and that experi-
control bleeding.25                                                mental cell fragmentation generated by the application of
    Non-nucleated platelets, and presumably their poly-            physical forces gives rise to a collection of particles which
ploid precursor bone marrow megakaryocytes, are present            follow a log Gaussian volume distribution30 are in agree-
only in mammals, suggesting that this unique mechanism             ment with this hypothesis. Given that the new character-
producing an unprecedented, highly specialized anucleated          istics of platelets favoured a more efficient arrest of
cell from the cytoplasm of a larger cell, allows to provide        bleeding, the progeny of the animal in which the gene mu-
them with a highly efficient hemostatic function. Although         tation initially occurred would have had an evolutionary
platelets from different mammalian species show some dis-          advantage through natural selection, representing a key
similarities in their biochemistry, physiology and morphol-        step in the evolution of mammals.29 Subsequent further
ogy, their main functions are conserved.26                         adaptive evolutionary events would have then brought to
    The evolutionary events that resulted in the appear-           nowadays mammalian megakaryocytes and platelets.
ance of mammalian megakaryocytes and platelets, as well
as the potential biological advantage of this system, re-
main to be further clarified.                                      CONCLUSIONS




                                                                                     ly
                                                                       Insight into the structure, function and role of platelets
                                                                   in health and disease continues to expand and from the




                                                                              on
WHAT A NEW INTRIGUING HYPOTHESIS
SUGGESTS                                                           initial belief that they were rudimentary cytoplasmic frag-
                                                                   ments we have now arrived to see that platelets are highly
    A recent fascinating new hypothesis, based on a series         complex, multitasking cells provided with fundamental



                                                                        e
of new but scattered information on the structure and gen-         roles in hemostasis, immunity, inflammation, angiogene-
eration of platelets acquired over the last decade, places a
gene mutation occurred around 220 million years ago at
                                                                 ussis, cancer, etc.31 This complexity is probably the conse-
                                                                   quence of the increased number of genes (over 5000)
the origin of current mammalian platelets.
                                                          al
                                                                   present in megakaryocytes32 thanks to polyploidy2,33 with
    This hypothesis puts emphasis on two distinctive char-         the related increased protein production (over 3000 func-
                                              ci

acteristics of blood platelets: the polyploidy of their bone       tional proteins). Blood platelets, thus, might represent a
marrow precursor cells, megakaryocytes, and the log
                                            er


                                                                   paradigmatic example of the way species adapt to the en-
Gaussian cell volume distribution of platelets. Indeed,            vironment and change thanks to advantageous random ge-
                                           m



megakaryocytes are one among the very few non-patho-               netic mutations, providing one further proof of Charles
logic polyploid mammalian cells and all mammalian cells            Darwin’s theory on the origin of species and of the events
                                  om




generated by a mitotic event have a Gaussian volume dis-           that have led to the evolution of mammalians, a tiny group
tribution.                                                         of animals within the animal kingdom, and ultimately to
    An increase in ploidy is always associated with an in-         the appearance of man.
                            -c




crease in cell size, and in fact megakaryocytes are gigantic
                     on




cells. An old theory of thrombopoiesis, recently revital-
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                 N




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