10.4081/btvb.2022.48
The aim of this essay is to re-consider the peculiar type of thrombogenesis observed in severe cases of COVID-19 infection, focusing on the multiple interconnected networks involved, such as inflammation, blood coagulation, fibrinolysis, and immune responses. These linked mechanisms can be assimilated to the “Complex Systems” (CS), that play a capital role in various domains: from physics to chemistry, biology and medicine, to social and behavioral sciences. CS are characterized by eliciting variable responses: their final results can be contradictory and often unpredictable. In fact, in severe COVID-19 various outcomes can occur, such as macro- and micro-thrombosis, vasculitis, hemorrhage, hyper and hypo fibrinolysis, distorted inflammatory and immune response, and others. The insight supplied by the CS theory in understanding thrombogenesis in COVID-19 can be useful in several ways. It recalls the importance of a “holistic” view of multiple patterns of signs, symptoms and biomarkers; stresses the added value of global versus mechanistic tests, particularly in coagulation and fibrinolysis; suggests building up small trials of selected patients in a perspective of precision medicine; discourages passive transfer of therapeutic choices from non-COVID to COVID patients; and finally indicates that some treatments, as the anti-inflammatory and the anti-coagulant ones, should be initiated as early as possible, so to avoid worsening of the condition by repetitive feedback and shortcut mechanisms.
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Sergio Coccheri
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Bleeding, Thrombosis and Vascular Biology
Thrombogenesis
A re-appraisal of thrombogenesis in COVID-19, seen as a multiple "Complex system"
Text.Serial.Journal
https://www.btvb.org/btvb
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Narrative Reviews
2022-10-24
2022-07-27
2022-10-17
2022-10-25
Bleed Thromb Vascul Biol
Sergio Coccheri
2022/10/24
10.4081/btvb.2022.48
University of Bologna, School of Medicine, Bologna, Italy; Arianna Foundation for Anticoagulation, Bologna
2785-5309
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Thrombogenesis
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Perico N, Cortinovis M, Suter F, et al. Home as the new frontier for the treatment of COVID-19: the case for antiinflammatory agents. Lancet Infect Dis 2022:S1473- 3099:00433-9.
A re-appraisal of thrombogenesis in COVID-19, seen as a multiple "Complex system"
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                                                                                        INVITED NARRATIVE REVIEW

A re-appraisal of thrombogenesis in COVID-19, seen as a multiple Complex System
Sergio Coccheri

University of Bologna, School of Medicine, Bologna, Italy; Arianna Foundation for Anticoagulation, Bologna, Italy



ABSTRACT
    The aim of this essay is to re-consider the peculiar type of thrombogenesis observed in severe cases of COVID-19 infection, focusing
on the multiple interconnected networks involved, such as inflammation, blood coagulation, fibrinolysis, and immune responses. These
linked mechanisms can be assimilated to the “Complex Systems” (CS), that play a capital role in various domains: from physics to
chemistry, biology and medicine, to social and behavioral sciences. CS are characterized by eliciting variable responses: their final
results can be contradictory and often unpredictable. In fact, in severe COVID-19 various outcomes can occur, such as macro- and
micro-thrombosis, vasculitis, hemorrhage, hyper and hypo fibrinolysis, distorted inflammatory and immune response, and others. The
insight supplied by the CS theory in understanding thrombogenesis in COVID-19 can be useful in several ways. It recalls the importance
of a “holistic” view of multiple patterns of signs, symptoms and biomarkers; stresses the added value of global versus mechanistic tests,
particularly in coagulation and fibrinolysis; suggests building up small trials of selected patients in a perspective of precision medicine;
discourages passive transfer of therapeutic choices from no- COVID to COVID patients; and finally indicates that some treatments, as




                                                                                                     ly
the anti-inflammatory and the anti-coagulant ones, should be initiated as early as possible, so to avoid worsening of the condition by




                                                                                             on
repetitive feedback and shortcut mechanisms.




                                                                                        e
                                                                            years a committed supporter of the theory of the so-called
INTRODUCTION                                                                “Complex Systems” (CS), applied to many domains of
   The outstanding scientist Giorgio Parisi, recently
awarded the 2021 Nobel Prize for Physics, has been for
                                                                                 us
                                                                            science.1,2 CS possess peculiar properties due to the in-
                                                                            volvement of a great number of interconnected factors. In
                                                                            al
                                                                            fact, they display high variability, randomness, disorder,
                                                                            and hence unpredictable effects bound to the contradic-
                                                                  ci

                                                                            tory nature of the crosstalk among multiple factors, thus
                                                                er


  Correspondence: Sergio Coccheri, Via Ugo Bassi, 13, 40121                 leading to the non-linearity of responses. Although the
  Bologna (BO), Italy.
                                                                            terms “complex” and “complexity” have often been mis-
                                                               m



  E-mail: sergio.coccheri@gmail.com
                                                                            used and seem to be in some cases repetitive and worn
  Key words: Thrombogenesis; COVID-19; Complex Systems.
                                                    om




                                                                            out, they can regain their full meaning provided they cor-
  Acknowledgments: The author expresses high appreciation and               respond to precise scientific criteria.
  gratitude to Dr Donatella Orlando, scientific secretary, for her in-          In biological and medical science, we are confronted
                                             -c




  valuable help in the selection and evaluation of the literature and       with many CS of different degrees. Thrombogenesis can
  the building-up of the manuscript.
                                                                            be defined as a complex system, as it recruits activators
                                    on




  Conflict of interest: The author declares no potential conflict of in-    and inhibitors of blood coagulation, platelet function and
  terest.
                                                                            fibrinolysis, leading to an unstable balance between pro-
                              N




  Funding: None.                                                            thrombotic, anti-thrombotic, and pro-hemorrhagic states.
                                                                            What is more, in a context of heavy inflammatory and im-
  Availability of data and materials: All data generated or analyzed
  during this study are included in this published article.                 mune activation, as occurring in severe COVID-19, the
                                                                            mechanisms of thrombogenesis are implemented by fac-
  Received for publication: 27 July 2022.                                   tors that include unusual pathways of activation, giving
  Accepted for publication: 5 September 2022.
                                                                            rise to different phenotypes of vascular and thrombotic
  Publisher’s note: All claims expressed in this article are solely those   response. This condition deserves the definition of “mul-
  of the authors and do not necessarily represent those of their affili-
  ated organizations, or those of the publisher, the editors and the re-
                                                                            tiple complex system” (MCS).
  viewers. Any product that may be evaluated in this article or claim           This paper aims to make the mechanisms of interac-
  that may be made by its manufacturer is not guaranteed or endorsed        tions between coagulation, inflammation and immune re-
  by the publisher.
                                                                            sponses as clear as possible for readers involved in clinical
  ©
   Copyright: the Author(s), 2022                                           and research activities.
  Licensee PAGEPress, Italy                                                     The various systems recruited in COVID-19-induced
  Bleeding, Thrombosis and Vascular Biology 2022; 1:48
  doi:10.4081/btvb.2022.48                                                  thrombogenesis are described, with special regard to their
                                                                            mutual interconnections, that may cause “collective ef-
  This work is licensed under a Creative Commons Attribution-
  NonCommercial 4.0 International License (CC BY-NC 4.0).
                                                                            fects” not predictable by any of the single factors in-
                                                                            volved. Finally, the problems of transmission to wider

                                              Bleeding, Thrombosis and Vascular Biology 2022; 1:48
                                A re-appraisal of thrombogenesis in COVID-19 as a multiple complex system                                           25



audiences (medical and non-medical) of concepts of com-                                 Pre-kallikrein opens a further way towards coagula-
plexity are introduced.                                                             tion, by involving coagulation Factor XII and other Fac-
                                                                                    tors as IX, X, and XI.
Entry of the virus and binding to the receptor                                          Thus, a “common contact pathway” of inflammation
                                                                                    and coagulation is established, with variable and unsta-
    At first entry into the organism along proximal and distal
airways, the “spike” protein of the SARS-COV2 virus                                 ble effects of vasodilation, vasoconstriction, endothelial
makes use of a receptor that otherwise binds angiotensin 2                          damage and permeability with stimulation of blood
(ACE2), an enzyme that down-regulates effects of the renin-                         clotting.
angiotensin-aldosterone system (RAAS) and particularly the
balance between vasoconstriction and vasodilation.3 This                            Immune and auto-immune responses
receptor is ubiquitous, but mainly concentrated in airways,                             Besides inflammation, the virus induces a marked im-
lungs, kidneys, and in platelets and other blood cells.                             mune reaction by the host, through innate and adaptive im-
    The binding of the spike protein of the virus to the                            munity. The excessive and disordered immune response of
ACE2 receptor is driven by a proteolytic chain potentiated                          the host is a capital factor for severe disease courses, often
by heparan sulphate (HS), a precursor of endogenous he-                             more dangerous than the viral burden itself.9




                                                                                                     ly
parin,4 responsible for the synthesis of the endothelium pro-                           The main factor of the immune system involved in
tecting layer known as glycocalyx. Impoverishment in HS




                                                                                                 on
                                                                                    thrombogenesis of COVID-19 is the complement com-
in fact contributes to damage of endothelial and blood cells.                       plex.10 Complements are proteins produced and stored
    Occupancy of the receptor by the SARS-COV2 virus                                in the liver. Within the innate host defense, complement




                                                                                         e
results in a distorted hyper-production of angiotensin II,                          components (C2-C5) undergo cleavage and activation,11
which has marked vaso-constrictive and endothelial dam-
aging properties,3 and is linked to thrombogenesis through
the release of the potent inhibitor of fibrinolysis PAI I by
                                                                                 us giving rise to highly thrombogenic fragments. Multiple
                                                                                    links between fractions of complement and various fac-
                                                                                    tors of coagulation and fibrinolysis have been described:
                                                                        al
endothelial and blood cells (Table 1).                                              Factors XIa, X, IXa, as well as thrombin and plasmin
                                                        ci

                                                                                    can in fact be activated by this pathway. The final prod-
Hyper-inflammation                                                                  uct of activated complement, MAC (membrane attack
                                                      er


     The mentioned loss of function of angiotensin, re-                             complex)11 fosters thrombogenesis through multiple
                                                                                    mechanisms such as up-regulation of tissue factor,
                                                     m



placed by the more harmful angiotensin II, is responsible
for acute damage of pulmonary microcirculation, and in-                             platelet activation, increase of fibrinogen, and of PAI-I,
                                          om




duces endothelial injury and vasculitis.5 The disordered                            with consequent hyper-coagulation and hypo-fibrinoly-
RAAS system also combines with the cellular release of                              sis. The rise of von Willebrandt factor (VWF) also oc-
cytokines, a family of endogenous inflammatory agents                               curs with production of ultra-large multimers
                                   -c




that become massively activated (the cytokine storm),6 fu-                          responsible for destructive endothelial damage and cel-
                          on




eling severe endothelial damage and hyper-inflammation.                             lular death (see later). Complement fractions and MACs
Various cytokines are involved in this reaction, as Inter-                          also stimulate the formation of cellular traps that recruit
leukin (IL)1, IL6, IL18 and tumor necrosis factor, but IL6                          neutrophils and pro-thrombotic factors, thus preparing
                    N




is likely the main actor.7 At the same time, IL6 activates                          convenient scaffolds for thrombogenesis.12 Finally, com-
the parallel pathway of the (pre) kallikrein-kinin system,                          plement participates in the structure of diffuse mi-
and produces an increase of bradykinin,8 a promoter of                              crothrombi occurring in lungs and other organs:
vasodilation and edema (e.g. in lungs).                                             complement components have been identified by im-


Table 1. First steps of thrombogenesis in severe COVID-19.

1   Penetration of the virus (spike protein) into cells (favored by initial proteolytic state)
2   Binding of spike protein to receptor otherwise acting on the renin-angiotensin-aldosterone system (RAAS)
3   Occupancy of the receptor causes distorted production of angiotensin I in favor of the more noxious angiotensin II, a potent vaso-constrictor
4   Angiotensin II also impairs the degradation of bradykinin, which induces vasodilation, capillary leaking, and edema, and stimulates PAI 1, the main
    inhibitor of fibrinolysis
5   Additionally, angiotensin II stimulates interleukins (cytokine storm), recruits Factor XII, and complement fractions (hyper-inflammation and Immuno-
    thrombosis)
6   Kallikrein, bradykinin and interleukin-6 also recruit blood coagulation factors (FXI, XII)
7   The involvement of complement and its cleavage fractions contribute to the activation of coagulation


                                              Bleeding, Thrombosis and Vascular Biology 2022; 1:48
26                                                                 S. Coccheri




munochemistry in the COVID-induced diffuse micro-                             ation of antithrombotic effects versus bleeding risk.17 At
thrombosis of lungs.13 These strict interactions have been                    the same time, a better understanding of the intrinsic path-
defined as “complement-induced coagulopathy”.                                 way focused attention on the multiple links of Factor XII
     A concurrent failure of “first line” innate defense is                   with other systems, such as inflammation and immunity.
due to the fall of Interferon (IFN1), either caused by ge-                    The crosstalk between coagulation, inflammation, and im-
netically reduced synthesis, or the development of IFN1                       munity is driven by Factor XII in the non-activated
auto-antibodies.14                                                            form.18,19 In COVID-19 peculiar changes of Factor XII are
     In conclusion, both innate and adaptive immune sys-                      described, as the increase in the first phases of infection,
tems and particularly the complement, build up an early                       and the sharp decrease in advanced stages, thus suggesting
and sustained defense against viral aggression. Unre-                         a consumption mechanism. This “wave” of Factor XII
strained hyper-activation of complement can however                           seems to indicate that both coagulation pathways (extrin-
contribute to massive endothelial damage, hyper-coagu-                        sic and intrinsic) work simultaneously, and also that the
lation and thrombogenesis, also favoring a marked inhi-                       intrinsic system, besides reinforcing blood coagulation,
bition of fibrinolysis.                                                       brings about inflammatory and immune changes thus ex-
     Disordered immunity may in some cases induce auto-                       plaining co-existence of macro-thrombosis, vasculitis, and
immune complications, interfering with the natural course                     micro-thrombosis.




                                                                                                      ly
of the infection and contributing to poor outcomes. A short




                                                                                               on
list of autoimmune vascular and thrombotic complications                      Fibrinolysis
of COVID-19 is reported in Table 2.15
                                                                                  Fibrinolysis is an essential function of hemostasis that




                                                                                          e
                                                                              drives and controls the rate of formation and dissolution
The “coagulation cascade” in COVID-19
    The “coagulation cascade” includes two distinct and
highly interconnected pathways. The extrinsic system un-
                                                                                       us
                                                                              of fibrin. Similarly, to coagulation, fibrinolysis belongs to
                                                                              a complex system that includes many correlated factors,
                                                                              as activators and inhibitors of clot formation, strictly, in-
                                                                            al
dergoes activation directly at the viral attack on the en-                    terconnected with activators and inhibitors of clot disso-
dothelium,16 causing cellular damage of relevant degree,                      lution, through mechanisms of signaling, retroaction and
                                                             ci

with externalization and release of tissue factor (TF). On                    feedback.
                                                           er


the other hand, the “intrinsic” system is activated by the                        The effect of fibrinolysis should not be seen as lim-
contact of blood with several surfaces, inorganic or organic,                 ited to the dissolution of pre-existing clots or thrombi.
                                                          m




such as blood cells, bacteria, viruses, cellular traps, and                   It can be surmised that agents responsible for coagula-
                                                 om




other negatively charged (anionic) materials. This pathway                    tion, anticoagulation and fibrinolysis are constantly
starts with the involvement of Factor XII following contact                   working at a restrained pace, in order to maintain blood
with some of the above sets of surfaces. Activated Factor                     fluidity while being ready for fast clot activation, inhi-
                                            -c




XII (Factor XIIa) in turn activates Factor XI, assembling a                   bition, or dissolution, thus giving rise to a fairly unstable
complex that activates Factor X (prothrombinase) respon-                      equilibrium.
                                   on




sible of the conversion of fibrinogen to fibrin.                                  The main physiological agents of the fibrinolytic sys-
    In recent years, the mechanisms of the two pathways                       tem are the tissue plasminogen activator (tPA) and the
                             N




of blood coagulation have been partly revised and subtle                      urokinase-type plasminogen activation (uPA). The first,
differences between the formation of thrombotic versus                        tPA, is widely but unequally distributed among most or-
hemostatic clots have emerged. In fact, Factor XI and Fac-                    gans and tissues, including the vascular walls,20 while
tor XII have been found as “indispensable” for thrombo-                       uPA is mainly present in urinary organs and in airways
genesis, but “dispensable” for hemostasis and prevention                      and lungs, where it contributes with tPA to keeping bron-
of bleeding, thus opening the way to therapeutic dissoci-                     cho-alveolar surfaces viable and free from fibrin de-


Table 2. Autoimmune complications of hemostatic or vascular nature related to COVID-19 (from 15, modified).

1    Immunologic thrombocytopenic purpura (ITP)
2    Thrombotic thrombocytopenic purpura (TTP): due to disease or vaccine (VITT)
3    Anti-heparin antibodies induced heparin resistance
4    Antiphospholipid antibodies and lupus-like anticoagulant (LLA)
5    Anti-interferon (FN1) autoantibodies
6    Anti α1 antitrypsin autoantibodies
7    Kawasaki-like disease with systemic vasculitis and shock syndrome (in children)


                                            Bleeding, Thrombosis and Vascular Biology 2022; 1:48
                            A re-appraisal of thrombogenesis in COVID-19 as a multiple complex system                                 27



posits. Both tPA and uPA are counteracted by one and                    may lead to a condition called fibrinolysis shutdown.24
the same inhibitor, PAI I. An additional factor for inhi-               This expression indicates a profound, acute condition of
bition of fibrinolysis is available, the thrombin-activat-              hypofibrinolysis, detectable by global tests such as
able fibrinolysis inhibitor (TAFI), a peptidase that acts               thromboelastography (TEG) or rotational viscoelastom-
by removing specific binding sites for fibrinolysis acti-               etry (ROTEM). Fibrinolytic shutdown (FS) defines a sit-
vation, thus impairing the affinity of newly formed fibrin              uation clinically correlated with a high incidence of
for fibrinolytic enzymes.21 This pathway works in fact                  macro or micro-thrombosis. FS has been reported in
as a feedback system to strengthen the stability of the                 about 40% of severe COVID-19 patients,25 and also in
clot (Figure 1).                                                        other conditions such as liver transplantation, severe
    The first action of the fibrinolytic system in COVID-               trauma, multiple organ failure, and severe cardiac dam-
19 is the activated proteolysis that favors the penetration             age involving extensive tissue injury. At first approach,
of the virus and its binding to the receptor. Thereafter,               FS seems to be a situation of total and persistent fibrinol-
distortion of RAAS system with suppression of an-                       ysis inhibition due to a prevailing effect of PAI 1. How-
giotensin in favor of angiotensin II stimulates the pro-                ever, it is known that even in this apparent condition of
duction of PAI I, thus preparing the ground for vascular                fibrinolytic blockade, a previous increase in D-dimer
and alveolar thrombotic obstruction. But the inflamma-                  may persist. This “D-dimer paradox” discloses a con-




                                                                                          ly
tory reaction (cytokine storm), and the concurrent in-                  comitant, discreet fibrinolytic activity, probably mainly




                                                                                   on
volvement of kallikrein with coagulation Factor XII in                  localized in microthrombi and/or in tissues and organs
reciprocal activation, also stimulate the production of                 rich in tissue plasminogen activator (t-PA).
the plasminogen activator tPA. The concurrent effects of                    To summarize, in COVID-19 fibrinolysis undergoes




                                                                             e
tPA and PAI I give rise to an unstable equilibrium be-                  initial activation, inducing proteolysis that favors viral
tween fibrinolysis and anti-fibrinolysis.22 This over-reg-
ulated fibrinolytic balance (more activation and more
inhibition) is subject to high instability with concomitant
                                                                      uspenetration. Afterwards, the situation can be overturned
                                                                        by PAI I and tPA concurrent hyperproduction. In severe
                                                                        cases, a fibrinolytic shutdown may occur, giving rise to
                                                              al
thrombotic, but also bleeding risk although less frequent               intra-alveolar micro-thrombosis and hemorrhage, with
                                                 ci

(Figure 1).23                                                           heavy respiratory insufficiency, that can be lethal or may
    The course of such an unstable fibrinolytic balance                 favor chronic alveolar fibrosis.
                                               er
                                              m
                                    om
                               -c
                       on
                  N




Figure 1. The fibrinolysis balance. The balance between activators and inhibitors of fibrinolysis includes a positive feedback mechanism:
fibrinolytic activators and plasmin are very active on fresh fibrin, but thrombin moderates this effect by activating TAFI, thus
strengthening stability of the clot.


                                        Bleeding, Thrombosis and Vascular Biology 2022; 1:48
28                                                         S. Coccheri




Platelets                                                           19 patients. All different forms of the Factor VIII – von
                                                                    Willebrand factor were found to be markedly increased,30
    During viral infections, circulating platelets may un-
                                                                    while levels of ADAMTS13 were correspondently de-
dergo alterations in number and functional activities. In
                                                                    creased. It was also confirmed that the activity of
COVID-19 platelets count may be increased, normal, or
                                                                    ADAMTS13 enzyme, responsible for cleavage of the
even severely decreased, indicating either an abnormal
                                                                    extra-large multimers, is generally reduced in severe pa-
rate of production and/or an excessive rate of consump-
                                                                    tients, and associated with poor prognosis.31
tion and cellular death. It is well known that sera from
severe COVID-19, added to normal platelet-rich plasma,
                                                                    Genetic influences
induce apoptosis and destruction of platelets.
    Like other cells, platelets contain the receptor for                As only a fraction of COVID-19 infected subjects de-
spike protein of the COV-SARS2 virus, thus concurring               velops severe disease and thrombosis, it seems likely to
to early endothelial damage and inflammatory plus im-               surmise that genetic factors may predispose to an exces-
mune reactions. Thrombocytopenia or thrombocytosis                  sive or defective response.
may coexist with inflammation, immuno- thrombosis,                      In a large study, genome-wide significant associations
and intra-alveolar microthrombi and hemorrhages.26                  with severe COVID disease were identified in various




                                                                                             ly
    Infected platelets also show increased adhesion to              chromosomes, and especially in a cluster of genes encod-
substrates like fibrinogen, fibrin, and collagen, and form          ing control of proteolytic enzymes that play an important




                                                                                     on
structures as platelet-neutrophil aggregates12 producing            role in early viral penetration and binding to the receptor.32
extracellular traps (NETs). These multiple roles of                 Also, low expression of the gene for the synthesis of in-
                                                                    terferon, and high expression of the gene for receptors of




                                                                                e
platelets comply with the properties of variability
and unpredictable response appropriate for Complex                  macrophages have been described as associated with se-
Systems.                                                                 us
                                                                    vere disease.33
                                                                        Genetic control of alpha-1 antitrypsin (AAT), a serin-
                                                                  al
An alternative (or additional?) mechanism                           protease with antithrombin and antiplasmin activities, is
for micro-thrombosis                                                thought to be an important factor in the control of initial
                                                      ci

                                                                    proteolysis. AAT also exerts a protective activity against
    A different look at endothelial injury leading to diffuse
                                                    er


                                                                    intra-alveolar deposition of fibrin, and loss of functional
micro-thrombosis entails activation of a pathway of cel-            polymorphisms of the genes for AAT have been for-
                                                   m



lular damage and disruption caused by extra-large multi-            warded as possible causes of severe respiratory insuffi-
mers of von Willebrand Factor, found in the blood during            ciency and pulmonary fibrosis.34 These views were
                                          om




severe COVID-19.                                                    supported by studies describing concordance between
    Usually, such multimers are cleaved and suppressed              the geographic distribution of the AAT polymorphisms
by a coenzyme known as ADAMTS-13, but in case of                    and the frequency of severe cases of COVID-19. How-
                                    -c




over-activation of VWF and/or absolute or relatively low            ever, a recent study suggests that polymorphisms bound
                             on




levels of ADAMTS-13, they produce high-degree damage                to mild AAT deficiency do not influence the clinical
to platelets and endothelial cells.27                               course of respiratory failure, but no data for severe “loss
    This condition was suggested to mimic a spontaneous             of function” polymorphisms are available.35
                         N




disease, “Thrombotic Thrombocytopenic Purpura (TTP)”,                   A further clinical question is whether genetic throm-
and was therefore labeled as “TTP-like syndrome” of se-             bophilias affect thrombogenesis in COVID-19. Genetic
vere COVID-19.                                                      thrombophilias are not rare diseases and constitute a
    It seems however reasonable to surmise that the TTP-            highly heterogeneous cohort of subjects with a variable
like syndrome may coexist in various proportions with               predisposition to thrombosis, according to the type of
classic activation of the coagulation cascade. The TTP-             defect, its homozygote or heterozygote nature, and its
like pathway could represent an additional thrombosis               role as main or accessory cause or concause of throm-
mechanism, or a biomarker, rather than an alternative               bosis. This wide variability of the prothrombotic effects
phenotype of thrombogenesis.28 However, the role of the             curtails the possibility of a simple answer to the
above mechanism and the related clinical presentation               question.
are still discussed. Some authors29 argue in fact that the              Some authors consider pre-existing “thrombophilic
described TTP-like syndrome is the specific mechanism               risk profiles” to be co-responsible for thrombotic events
responsible for micro-thrombosis, while macro-throm-                occurring during COVID-19. But, in a study of patients
bosis would depend on the classic activation of blood               with generic sepsis,36 only fibrinogen and PAI 1 genotypes
clotting.                                                           were found associated with septic shock and mortality.
    In this perspective, the so-called “von Willebrand”             Conversely, another study ruled out any statistical asso-
axis has been thoroughly investigated in severe COVID-              ciation between the common thrombophilic polymor-

                                     Bleeding, Thrombosis and Vascular Biology 2022; 1:48
                               A re-appraisal of thrombogenesis in COVID-19 as a multiple complex system                                    29



phisms (of Factor II, Factor V and PAI), and micro-throm-                      recruitment, beyond the coagulation system, of other com-
botic pneumonia of COVID-19.37                                                 plex mechanisms such as inflammation and immune re-
    It seems likely that the limited pro-thrombotic power                      sponses, may allow to define this condition as a multiple
of these defects could have been dwarfed by the massive                        complex system, MCS (Table 3).
burst of inflammatory and immune thrombosis peculiar                                It can be noted that biological and medical CS share
to severe COVID-19.                                                            many properties with CS of physics, in terms of variabil-
                                                                               ity, instability, and unpredictable final outcomes. For in-
                                                                               stance, in the MCS discussed here, the outcome of
DISCUSSION                                                                     thrombosis generally prevails, but bleeding may also ap-
                                                                               pear either associated or consecutive.38
    Complex Systems are sets of entities of various types                           Already at the early binding of the virus to the ACE2
(e.g. elementary particles, molecules, cells, bacteria,                        receptor, these contradictory effects may occur, inducing
viruses, antibodies, enzymes… etc.) that drive and control                     vasodilation or vasoconstriction; inflammation is en-
relevant functions in different domains of science. CS                         hanced but also disordered, and auto-immune responses
have been described in physics, chemistry, mathematics,                        can be observed. To increase variability, changes directly
statistics, but also in biology, medicine, anthropology, so-                   caused by the viral burden coexist with deranged effects




                                                                                                    ly
ciology, economics, informatics and other domains. In bi-                      by the host response, as influenced by genetic factors, im-
ological and medical sciences CS acquire a capital role in




                                                                                          on
                                                                               munologic status and individual biological memory.
clarifying the highly interconnected mechanisms related                             The instability of fibrinolysis due to concurrent high
to the control of human variability in health and disease.                     levels of activators and inhibitors is likely responsible of




                                                                                    e
    CS are characterized by several properties. First of                       the co-existence of intra-alveolar micro-thrombosis with
all, their final outcomes are of collective nature and
often do not correspond to the effects of single compo-
nents. Outcomes are variable or even contradictory ac-
                                                                            us hemorrhages. Fibrinolytic shutdown in advanced cases
                                                                               also favors thrombosis but does not prevent bleeding, or
                                                                               late alveolar fibrosis.25
                                                                     al
cording to time, phase, activation and inhibition, thus                             In the presence of so many available pathways of ac-
inducing a disproportion of responses versus inputs
                                                     ci

                                                                               tivation and inhibition of coagulation, fibrinolysis, and in-
(non-linearity of response). CS also present a co-exis-                        flammatory and immune mechanisms, a preliminary
                                                   er


tence of deterministic (causal) and non-deterministic be-                      question arises: are we sure that all mechanisms described
haviors      (randomness),        and   in     consequence                     mainly in experimental conditions, do really participate
                                                  m




unpredictability of final outcomes as a result of even                         in the pathophysiological course of the disease? The only
                                        om




small, but multiple modifications.                                             possible answer at this state of knowledge seems to be
    In this paper, it is assumed that a system like that of                    that all these links, feedbacks, and retroactions “are avail-
blood coagulation, due to its multiple complex interac-                        able”: perhaps inactive in mild cases, they could be ex-
                                  -c




tions, internal and external information mechanisms,                           ploited in severe cases especially depending on viral load
retro-actions, feedbacks and shortcuts, may produce dif-                       and intensity of response.
                         on




ferent or even contradictory outcomes (e.g. hemostasis,                             The “choice” among the numerous practicable path-
thrombosis, hemorrhage, activation or inhibition of fibri-                     ways and shortcuts may occur by the selection of the
                    N




nolysis, fibrosis, etc.), and could be seen as a CS. More-                     “fittest mechanism” (“Darwinian” hypothesis) or by
over, in the case of thrombogenesis of COVID-19, the                           chance (random hypothesis).


Table 3. Retroactions, feedbacks and short-cuts in thrombogenesis of severe COVID-19 (in ten points).

1   Angiotensin II stimulates synthesis and release of PAI I
2   Angiotensin II recruits Factor XII and complement
3   Cytokines, mainly Interleukin 6, release tPA from tissues and cells
4   Kallikrein and bradykinin activate clotting Factors XI and XII (essential for thrombogenesis)
5   Complement in turn retro-activates blood coagulation and fibrinolysis
6   Products of complement cleavage, as MAC stimulate tissue factor, platelets, fibrinogen, and PAI I
7   Concurrent activation of both extrinsic and intrinsic clotting pathways overstimulates coagulation and the immune system
8   Large multimers of von Willebrand factor destroy platelets and severely damage endothelial cells
9   Fibrinolysis can be blocked (fibrinolytic shutdown); however, previously increased D-dimer can persist (D-dimer paradox)
10 The two main proteolytic enzymes, thrombin and plasmin, are self-regulating through feedback mechanisms: thrombin also produces the clotting
   inhibitor Prot. C, and plasmin can mitigate fibrinolytic effects, by TAFI


                                           Bleeding, Thrombosis and Vascular Biology 2022; 1:48
30                                                         S. Coccheri




    Anyway, the viral aggression will resemble a tsunami            -    Considering the very early involvement of inflamma-
that, while bursting into dryland, overruns any preformed                tion, blood coagulation and fibrinolysis, appropriate
or non-preformed stream (Table 3).                                       therapy should be initiated as soon as possible, in
                                                                         order to block the repetitive pathways, feedback and
Communication of complexity                                              shortcuts available.41
    The multilateral complexity of thrombogenesis in
COVID-19 would be obviously tough for general audi-
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