https://doi.org/10.4081/btvb.2022.48
A re-appraisal of thrombogenesis in COVID-19, seen as a multiple "Complex system"
Submitted: 27 July 2022
Accepted: 5 September 2022
Published: 24 October 2022
Accepted: 5 September 2022
Abstract Views: 1599
PDF: 234
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
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.
Parisi G. Complex systems: a physicist’s viewpoint. Physica A 1999;263:557-64.
DOI: https://doi.org/10.1016/S0378-4371(98)00524-X
Kroc J, Balihar K, Matejovic M. Complex systems and their use in medicine: Concepts, methods and bio-medical application. 2019. In: Encyclopedia of artificial intelligence; J.R. Rabuñal Dopico, J. Dorado de la Calle, A. Pazos Sierra (eds.). Information Science Reference. 1780 pp.
Perico L, Benigni A, Remuzzi G. Angiotensin-converting enzyme 2: from a vasoactive peptide to the gatekeeper of a global pandemic. Curr Opin Nephrol Hypertens 2021;30:252-63.
DOI: https://doi.org/10.1097/MNH.0000000000000692
Clausen TM, Sandoval DR, Splid CB, et al. SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2. Cell 2020;12:1043-7.
DOI: https://doi.org/10.1016/j.cell.2020.09.033
Skurk T, Lee Yu-Me, Hauner H. Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary care. Hypertension 2001;37:1336-40.
DOI: https://doi.org/10.1161/01.HYP.37.5.1336
Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med 2020;383:2255-73.
DOI: https://doi.org/10.1056/NEJMra2026131
Zhang Y, Zhang Z, Wei R, et al. IL (interleukin)-6 contributes to deep vein thrombosis and is negatively regulated by miR-338-5p. Arteroscler Thromb Vasc Biol 2020;40: 323-34.
DOI: https://doi.org/10.1161/ATVBAHA.119.313137
Kaplan AL, Ghebrehiweert B. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol 2010;47:2161-9.
DOI: https://doi.org/10.1016/j.molimm.2010.05.010
Kearney KJ, Butler J, Posada OM, et al. Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI. Proc Natl Acad Sci USA 2021;19:118.
DOI: https://doi.org/10.1073/pnas.2014810118
Perico L, Benigni A, Casiraghi F, et al. Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat Rev Nephrol 2021;17:46-64.
DOI: https://doi.org/10.1038/s41581-020-00357-4
Lo MW, Kemper C, Woodruff TM. COVID-19: complement, coagulation and collateral damage. J Immunol 2020;205:1488-95.
DOI: https://doi.org/10.4049/jimmunol.2000644
Gillot C, Favresse J, Mullier F et al. NETosis and the immune system in COVID-19: mechanisms and potential treatments. Front Pharmacol 2021;12:708302.
DOI: https://doi.org/10.3389/fphar.2021.708302
Cugno M, Meron PL, Gualtierotti R, et al. Complement activation in patients with COVID-19: a novel therapeutic target. J Allergy Clin Immunol 2020;146:215-7.
DOI: https://doi.org/10.1016/j.jaci.2020.05.006
Jiao P, Fan W, Cao Y, et al. Robust induction of interferon and interferon stimulated gene expression by influenza B/Yamagata lineage virus infection of A549 cells. PLoS One 2020;15:e0231039.
DOI: https://doi.org/10.1371/journal.pone.0231039
Ehrenfeld M, Tincani A, Andreoli A et al. Covid-19 and autoimmunity. Autoimmun Rev 2020;19:1-10.
DOI: https://doi.org/10.1016/j.autrev.2020.102597
Coccheri S. COVID-19: the crucial role of blood coagulation and fibrinolysis. Int Emerg Med 2020;15:1369-73.
DOI: https://doi.org/10.1007/s11739-020-02443-8
Favaloro EJ, Lippi G. Maintaining hemostasis and preventingthrombosis in coronavirus disease 2018 (COVID 19)- part 1. Semin Thromb Hemost 2020;46:757-62.
DOI: https://doi.org/10.1055/s-0040-1717139
Maas C, Rennè T. Coagulation Factor XII in thrombosis and inflammation. Blood 2018;131:1903-9.
DOI: https://doi.org/10.1182/blood-2017-04-569111
Rennè T, Stavrou EX. Roles of Factor XII in innate immunity. Front Immunol 2019;10:2011.
DOI: https://doi.org/10.3389/fimmu.2019.02011
Albrechtsen OK The fibrinolytic activity of human tissues Br J Hematol 1957;39:284-90.
DOI: https://doi.org/10.1111/j.1748-1716.1957.tb01429.x
Kwaan H. Coronavirus disease 2019: the role of fibrinolytic system from transmission to organ injury and sequelae. Semin Thromb Hemost 2020:46:841-4.
DOI: https://doi.org/10.1055/s-0040-1709996
Kwaan H, Lindholm PF. The central role of fibrinolytic response in COVID-19. A hematologist’s perspective. Int J Mol Sci 2021;22:1283.
DOI: https://doi.org/10.3390/ijms22031283
Godier A, Clausse D, Meslin S, et al. Major bleeding complications in critically ill patients with COVID-19 pneumonia. J Thromb Thrombolys 2021;52:18-21.
DOI: https://doi.org/10.1007/s11239-021-02403-9
Meizoso JP, Moore HB, Moore EE. Fibrinolysis shutdown in COVID-19: clinical manifestations, molecular mechanisms, and therapeutic implications. J Am Coll Surg 2021;232:995-1006.
DOI: https://doi.org/10.1016/j.jamcollsurg.2021.02.019
Wright FL, Vogler TO, Moore EE, et al. Fibrinolysis shutdown correlates to thrombotic events in severe COVID19 infection. J Am Coll Surgeons 2020;231:193-203.
DOI: https://doi.org/10.1016/j.jamcollsurg.2020.05.007
Fard MB, Fard BS, Ramazi S, et al. Thrombosis in COVID- 19 infection: role of platelet activation-mediated immunity. Thromb J 2021;19:59-63.
DOI: https://doi.org/10.1186/s12959-021-00311-9
Mancini I, Baronciani L, Artoni A, et al. The ADAMTS13 – vonWillebrand factor axis in COVID 19 patients. J Thromb Haemost 2020;18:101-11.
DOI: https://doi.org/10.1111/jth.15191
Joly BS, Darmon M, Dekimpe C, et al. Imbalance of von- Willebrand factor and ADAMTS13 axis is rather a biomarker of strong inflammation and endothelial damage than cause of thrombotic process in critically ill COVID-19 patients. J Thromb Haemost 2021;19:2193-8.
DOI: https://doi.org/10.1111/jth.15445
Chang JC. COVID-19 sepsis: pathogenesis and endothelial molecular mechanisms based on “Two-path unifying theory” of hemostasis and endotheliopathy associated vascular microthrombotic disease, and proposed therapeutic approach with antimicrothrombotic therapy. Vasc Health Risk Manag 2021;17:273-98.
DOI: https://doi.org/10.2147/VHRM.S299357
Rostami M, Mensouritorghabeh H, Parsa-Kondelaji M. High levels of von Willebrand factor markers in COVID 19: a systematic review and meta-analysis. Clin Exp Med 2021;6:1-11.
DOI: https://doi.org/10.1007/s10238-021-00769-x
Bazzan M, Montaruli B, Sciascia S et al. Low ADAMST 13 plasma levels are predictors of mortality in COVID 19 patients. Intern Emerg Med 2020;18:1-3.
DOI: https://doi.org/10.1007/s11739-020-02394-0
Pairo-Castineira E, Clohisey S, Klaric L, et al. Genetic mechanism of critical illness in COVID-19. Nature 2021;591:92-8.
DOI: https://doi.org/10.1038/s41586-020-03065-y
Zhang Q, Bastard P, Liu Z, et al. Inborn errors of type I IFN immunity in patients with life-treatment COVID 19. Science 2020;23:370-5.
Yang C, Chapman KR, Wong A, et al. Alfa1-antitrypsin deficiency and the risk of COVID 19: an urgent call to action. Lancet Respir Med 2021;9:337-9.
DOI: https://doi.org/10.1016/S2213-2600(21)00018-7
Shapira G, Shomron N, Curwitz D. Ethnic differences in alpha-1 antitrypsin deficiency allele frequencies may partially explain national differences in COVID-19 fatality rates. FASEB J 2020;34:14160-5.
DOI: https://doi.org/10.1096/fj.202002097
Georgakopoulou A, Papadimitriou-Olivageris M, Karakantza M, et al. Role of inherited thrombophilic profile on survival
of patients with sepsis. J Invest Med 2019;67:1131-5.
DOI: https://doi.org/10.1136/jim-2019-001034
Burlacu A, Genovesi S, Popa IV, et al. Unpuzzling COVID-19 prothrombotic state: are preexisting thrombophilic risk profiles responsible for heterogeneous thrombotic events. Clin Appl Thromb Hemost 2020;26:107602920952884.
DOI: https://doi.org/10.1177/1076029620952884
Durak K. Thromboembolism and bleeding in COVID-19. J Multidisciplinary Scientific Journal 2021;4:476-85.
DOI: https://doi.org/10.3390/j4030036
Edeling W, Arabnejad H, Sinclair R, et al. The impact of uncertainty on predictions of the COVIDSim epidemiological code. Nature Computational Science 2021;1:128-35.
DOI: https://doi.org/10.1038/s43588-021-00028-9
Coccheri S. Error, contradiction and reversal in science and medicine. Eur J Intern Med 2017;41:28-9.
DOI: https://doi.org/10.1016/j.ejim.2017.03.026
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.
DOI: https://doi.org/10.1016/S1473-3099(22)00433-9
How to Cite
Coccheri, S. (2022). A re-appraisal of thrombogenesis in COVID-19, seen as a multiple "Complex system". Bleeding, Thrombosis and Vascular Biology, 1(3). https://doi.org/10.4081/btvb.2022.48
Copyright (c) 2022 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- Giovanni L. Tiscia, Donatella Colaizzo, Antonio De Laurenzo, Filomena Cappucci, Lucia Fischetti, Elena Chinni, Mario Mastroianno, Giovanni Favuzzi, Massimo Carella, Elvira Grandone, Thrombin generation assay in COVID-19 patients shows a hypocoagulable pattern , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. 3 (2024)
- Bianca Clerici, Mariangela Scavone, Gian Marco Podda, Recent advances in classic heparin-induced thrombocytopenia (HIT), autoimmune HIT, spontaneous HIT, and vaccine-induced immune thrombotic thrombocytopenia , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. 2 (2024)
- Daniela Poli, Walter Ageno, Emilia Antonucci, Salvatore Bradamante, Eugenio Bucherini, Paolo Chiarugi, Antonio Chistolini, Benilde Cosmi, Anna Falanga, Antonio Insana, Domenico Lione, Rosa Maria Lombardi, Giuseppe Malcangi, Rossella Marcucci, Giuliana Martini, Lucilla Masciocco, Carmelo Paparo, Daniele Pastori, Simona Pedrini, Vittorio Pengo, Pasquale Pignatelli, Andrea Toma, Sophie Testa, Gualtiero Palareti, Management of anticoagulation in atrial fibrillation patients in Italy: insight from the Atrial Fibrillation-Survey on Anticoagulated Patients Register (AF-START) , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 2 (2023)
- Nadim Tawil, Lata Adnani, Janusz Rak, Coagulome and tumor microenvironment: impact of oncogenes, cellular heterogeneity and extracellular vesicles , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. s1 (2024): 12th ICTHIC
- Anne Eichmann, The Lefoulon Delalande Foundation honors the lymphatic vascular system , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 4 (2023)
- Francesco Cicconi, Ankle brachial index for the diagnosis of asymptomatic lower extremity peripheral arterial disease , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. 2 (2024)
- Federica Mancazzo, Antonia Vitulli, Lavinia Dirienzo, Concetta T. Ammollo, Fabrizio Semeraro, Mario Colucci, Influence of emicizumab on protein C-mediated clotting regulation , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 4 (2023)
- Federica Azzolini, Antonio Bruno, Ettore Dolcetti, Diego Centonze, Fabio Buttari, Tumor necrosis factor superfamily in multiple sclerosis: from pathology to therapeutic implications , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 2 (2023)
- Stefania Momi, Paolo Gresele, Blood platelets and Charles Darwin’s natural selection , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 1 (2023)
- Boris Shenkman, Ivan Budnik, Yulia Einav, Interaction between adenosine diphosphate receptors and protein-kinase C isoforms in platelet adhesion under flow condition , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 1 (2023)
You may also start an advanced similarity search for this article.
