Impact of Viral Infections on the Hemostatic System

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has brought renewed attention to the significant but often overlooked impact of viral infections on the hemostatic system. This review explores the pathophysiological mechanisms underlying the interaction between viruses and hemostasis, directly through viral components or immune-mediated processes. Viruses are recognized as pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) on innate immune cells such as neutrophils, monocytes, and platelets. This recognition triggers immune responses, including the production of type I interferons (IFN-α and IFN-β) and proinflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which recruit immune cells and induce pyroptotic cell death. Inflammatory cytokines contribute to endothelial dysfunction and coagulation activation, interacting with platelets, neutrophils, neutrophil extracellular traps (NETs), and the kallikrein–kinin system. Hyperactivation of the cytokine system, known as the “cytokine storm,” correlates with disease severity. Common features of viral infections include platelet activation and endotheliitis, leading to thrombocytopenia and microvascular thrombosis. Interestingly, similar pathogenic mechanisms in COVID-19 and viral hemorrhagic fevers (VHFs) result in contrasting clinical manifestations. While COVID-19 predominantly induces a thrombotic response characterized by endothelial damage, platelet hyperactivity, and complement activation, VHFs typically lead to hemorrhagic complications due to thrombocytopenia, consumptive coagulopathy, and vascular injury. These differences are influenced by the timing and location of coagulation activation, as well as the dynamics of immune responses. In COVID-19, coagulation initially occurs in the lungs, followed by systemic thrombotic phases, whereas VHFs rapidly progress to consumptive coagulopathy with hemorrhage, compounded by immune suppression.

Keywords

virus - COVID-19 - dengue - viral hemorrhagic fevers - bleeding - thrombosis

Publication History

Received: 26 February 2025

Accepted: 06 May 2025

Accepted Manuscript online:
07 May 2025

Article published online:
27 May 2025

• References

• 1 Iba T, Levy JH, Levi M. Viral-induced inflammatory coagulation disorders: Preparing for another epidemic. Thromb Haemost 2022; 122 (01) 8-19
• 2 Flaumenhaft R, Enjyoji K, Schmaier AA. Vasculopathy in COVID-19. Blood 2022; 140 (03) 222-235
• 3 Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood 2019; 133 (09) 906-918
• 4 Schrottmaier WC, Assinger A. The concept of thromboinflammation. Hamostaseologie 2024; 44 (01) 21-30
• 5 George Pryzdial EL, Perrier JR, Rashid MU, West HE, Sutherland MR. Viral coagulation: pushing the envelope. J Thromb Haemost 2024; 22 (12) 3366-3382
• 6 Sutherland MR, Raynor CM, Leenknegt H, Wright JF, Pryzdial EL. Coagulation initiated on herpesviruses. Proc Natl Acad Sci U S A 1997; 94 (25) 13510-13514
• 7 Wright JF, Kurosky A, Pryzdial EL, Wasi S. Host cellular annexin II is associated with cytomegalovirus particles isolated from cultured human fibroblasts. J Virol 1995; 69 (08) 4784-4791
• 8 Wang LC, Wu SR, Yao HW. et al. Suppression of annexin A1 and its receptor reduces herpes simplex virus 1 lethality in mice. PLoS Pathog 2022; 18 (08) e1010692
• 9 LeBouder F, Morello E, Rimmelzwaan GF. et al. Annexin II incorporated into influenza virus particles supports virus replication by converting plasminogen into plasmin. J Virol 2008; 82 (14) 6820-6828
• 10 Lin BH, Sutherland MR, Rosell FI, Morrissey JH, Pryzdial ELG. Coagulation factor VIIa binds to herpes simplex virus 1-encoded glycoprotein C forming a factor X-enhanced tenase complex oriented on membranes. J Thromb Haemost 2020; 18 (06) 1370-1380
• 11 Sutherland MR, Ruf W, Pryzdial EL. Tissue factor and glycoprotein C on herpes simplex virus type 1 are protease-activated receptor 2 cofactors that enhance infection. Blood 2012; 119 (15) 3638-3645
• 12 Sutherland MR, Friedman HM, Pryzdial EL. Herpes simplex virus type 1-encoded glycoprotein C enhances coagulation factor VIIa activity on the virus. Thromb Haemost 2004; 92 (05) 947-955
• 13 Sumarheni S, Hong SS, Josserand V. et al. Human full-length coagulation factor X and a GLA domain-derived 40-mer polypeptide bind to different regions of the adenovirus serotype 5 hexon capsomer. Hum Gene Ther 2014; 25 (04) 339-349
• 14 Lenman A, Müller S, Nygren MI, Frängsmyr L, Stehle T, Arnberg N. Coagulation factor IX mediates serotype-specific binding of species A adenoviruses to host cells. J Virol 2011; 85 (24) 13420-13431
• 15 Mackman N, Grover SP, Antoniak S. Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza A virus and coronavirus. J Thromb Haemost 2021; 19 (11) 2652-2658
• 16 Subrahmanian S, Borczuk A, Salvatore S. et al. Tissue factor upregulation is associated with SARS-CoV-2 in the lungs of COVID-19 patients. J Thromb Haemost 2021; 19 (09) 2268-2274
• 17 Girard TJ, Antunes L, Zhang N. et al. Peripheral blood mononuclear cell tissue factor (F3 gene) transcript levels and circulating extracellular vesicles are elevated in severe coronavirus 2019 (COVID-19) disease. J Thromb Haemost 2023; 21 (03) 629-638
• 18 Martins ST, Alves LR. Extracellular vesicles in viral infections: two sides of the same coin?. Front Cell Infect Microbiol 2020; 10: 593170
• 19 Hisada Y, Sachetto ATA, Mackman N. Circulating tissue factor-positive extracellular vesicles and their association with thrombosis in different diseases. Immunol Rev 2022; 312 (01) 61-75
• 20 Carty M, Guy C, Bowie AG. Detection of viral infections by innate immunity. Biochem Pharmacol 2021; 183: 114316
• 21 Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med 2020; 383 (23) 2255-2273
• 22 Qidwai T. Cytokine storm in COVID-19 and malaria: Annals of pro-inflammatory cytokines. Cytokine 2024; 173: 156420
• 23 Zelaya H, Rothmeier AS, Ruf W. Tissue factor at the crossroad of coagulation and cell signaling. J Thromb Haemost 2018; 16 (10) 1941-1952
• 24 Peach CJ, Edgington-Mitchell LE, Bunnett NW, Schmidt BL. Protease-activated receptors in health and disease. Physiol Rev 2023; 103 (01) 717-785
• 25 Hara T, Sata M, Fukuda D. Emerging roles of protease-activated receptors in cardiometabolic disorders. J Cardiol 2023; 81 (04) 337-346
• 26 Subramaniam S, Ruf W, Bosmann M. Advocacy of targeting protease-activated receptors in severe coronavirus disease 2019. Br J Pharmacol 2022; 179 (10) 2086-2099
• 27 Zhuo X, Wu Y, Fu X. et al. The yin-yang roles of protease-activated receptors in inflammatory signalling and diseases. FEBS J 2022; 289 (14) 4000-4020
• 28 Posma JJN, Posthuma JJ, Spronk HMH. Coagulation and non-coagulation effects of thrombin. J Thromb Haemost 2016; 14 (10) 1908-1916
• 29 Azoulay E, Zuber J, Bousfiha AA. et al. Complement system activation: bridging physiology, pathophysiology, and therapy. Intensive Care Med 2024; 50 (11) 1791-1803
• 30 Pryzdial ELG, Leatherdale A, Conway EM. Coagulation and complement: Key innate defense participants in a seamless web. Front Immunol 2022; 13: 918775
• 31 Kumar NA, Kunnakkadan U, Thomas S, Johnson JB. In the crosshairs: RNA viruses OR complement?. Front Immunol 2020; 11: 573583
• 32 Lujan E, Zhang I, Garon AC, Liu F. The interactions of the complement system with human cytomegalovirus. Viruses 2024; 16 (07) 1171
• 33 Afzali B, Noris M, Lambrecht BN, Kemper C. The state of complement in COVID-19. Nat Rev Immunol 2022; 22 (02) 77-84
• 34 Pires BG, Calado RT. Hyper-inflammation and complement in COVID-19. Am J Hematol 2023; 98 (Suppl. 04) S74-S81
• 35 Xiao MT, Ellsworth CR, Qin X. Emerging role of complement in COVID-19 and other respiratory virus diseases. Cell Mol Life Sci 2024; 81 (01) 94
• 36 Neubauer K, Zieger B. Endothelial cells and coagulation. Cell Tissue Res 2022; 387 (03) 391-398
• 37 Becker BF, Jacob M, Leipert S, Salmon AH, Chappell D. Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases. Br J Clin Pharmacol 2015; 80 (03) 389-402
• 38 Trung DT, Wills B. Systemic vascular leakage associated with dengue infections - the clinical perspective. Curr Top Microbiol Immunol 2010; 338: 57-66
• 39 Zha D, Fu M, Qian Y. Vascular endothelial glycocalyx damage and potential targeted therapy in COVID-19. Cells 2022; 11 (12) 1972
• 40 Malavige GN, Ogg GS. Pathogenesis of vascular leak in dengue virus infection. Immunology 2017; 151 (03) 261-269
• 41 Glasner DR, Ratnasiri K, Puerta-Guardo H, Espinosa DA, Beatty PR, Harris E. Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components. PLoS Pathog 2017; 13 (11) e1006673
• 42 Tang N, Yuan P, Luo M, Li D. Prolonged coagulation times in severe fever with thrombocytopenia syndrome virus infection, the indicators of heparin-like effect and increased haemorrhagic risk. Br J Haematol 2024; 204 (05) 1999-2006
• 43 Johansson PI, Stensballe J, Ostrowski SR. Shock induced endotheliopathy (SHINE) in acute critical illness - a unifying pathophysiologic mechanism. Crit Care 2017; 21 (01) 25
• 44 Iba T, Connors JM, Levy JH. The coagulopathy, endotheliopathy, and vasculitis of COVID-19. Inflamm Res 2020; 69 (12) 1181-1189
• 45 Huerta-Zepeda A, Cabello-Gutiérrez C, Cime-Castillo J. et al. Crosstalk between coagulation and inflammation during Dengue virus infection. Thromb Haemost 2008; 99 (05) 936-943
• 46 Geisbert TW, Young HA, Jahrling PB, Davis KJ, Kagan E, Hensley LE. Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. J Infect Dis 2003; 188 (11) 1618-1629
• 47 Gu SX, Tyagi T, Jain K. et al. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nat Rev Cardiol 2021; 18 (03) 194-209
• 48 Antoniak S, Mackman N. Coagulation, protease-activated receptors, and viral myocarditis. J Cardiovasc Transl Res 2014; 7 (02) 203-211
• 49 Rahbar A, Söderberg-Nauclér C. Human cytomegalovirus infection of endothelial cells triggers platelet adhesion and aggregation. J Virol 2005; 79 (04) 2211-2220
• 50 Lenting PJ, Christophe OD, Denis CV. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood 2015; 125 (13) 2019-2028
• 51 Atiq F, O'Donnell JS. Novel functions for von Willebrand factor. Blood 2024; 144 (12) 1247-1256
• 52 de Larrañaga GF, Petroni A, Deluchi G, Alonso BS, Benetucci JA. Viral load and disease progression as responsible for endothelial activation and/or injury in human immunodeficiency virus-1-infected patients. Blood Coagul Fibrinolysis 2003; 14 (01) 15-18
• 53 Sugiyama MG, Gamage A, Zyla R. et al. Influenza virus infection induces platelet-endothelial adhesion which contributes to lung injury. J Virol 2015; 90 (04) 1812-1823
• 54 O'Sullivan JM, Gonagle DM, Ward SE, Preston RJS, O'Donnell JS. Endothelial cells orchestrate COVID-19 coagulopathy. Lancet Haematol 2020; 7 (08) e553-e555
• 55 Sosothikul D, Seksarn P, Pongsewalak S, Thisyakorn U, Lusher J. Activation of endothelial cells, coagulation and fibrinolysis in children with Dengue virus infection. Thromb Haemost 2007; 97 (04) 627-634
• 56 Jiang Z, Tang X, Xiao R, Jiang L, Chen X. Dengue virus regulates the expression of hemostasis-related molecules in human vein endothelial cells. J Infect 2007; 55 (02) e23-e28
• 57 Chen LC, Shyu HW, Lin HM. et al. Dengue virus induces thrombomodulin expression in human endothelial cells and monocytes in vitro. J Infect 2009; 58 (05) 368-374
• 58 Cherie TJJ, Choong CSH, Abid MB. et al. Immuno-Haematologic Aspects of Dengue Infection: Biologic Insights and Clinical Implications. Viruses 2024; 16 (07) 1090
• 59 Key NS, Vercellotti GM, Winkelmann JC. et al. Infection of vascular endothelial cells with herpes simplex virus enhances tissue factor activity and reduces thrombomodulin expression. Proc Natl Acad Sci U S A 1990; 87 (18) 7095-7099
• 60 Kumar NG, Clark A, Roztocil E, Caliste X, Gillespie DL, Cullen JP. Fibrinolytic activity of endothelial cells from different venous beds. J Surg Res 2015; 194 (01) 297-303
• 61 Huang YH, Lei HY, Liu HS. et al. Tissue plasminogen activator induced by dengue virus infection of human endothelial cells. J Med Virol 2003; 70 (04) 610-616
• 62 Bok RA, Jacob HS, Balla J. et al. Herpes simplex virus decreases endothelial cell plasminogen activator inhibitor. Thromb Haemost 1993; 69 (03) 253-258
• 63 Goeijenbier M, Meijers JC, Anfasa F. et al. Effect of Puumala hantavirus infection on human umbilical vein endothelial cell hemostatic function: platelet interactions, increased tissue factor expression and fibrinolysis regulator release. Front Microbiol 2015; 6: 220
• 64 Bondu V, Schrader R, Gawinowicz MA. et al. Elevated cytokines, thrombin and PAI-1 in severe HCPS patients due to Sin Nombre virus. Viruses 2015; 7 (02) 559-589
• 65 Woodroffe SB, Kuan S. Human cytomegalovirus infection induces mRNA expression and secretion of plasminogen inhibitor type-1 in endothelial cells. J Med Virol 1998; 55 (04) 268-271
• 66 Qin Z, Liu F, Blair R. et al. Endothelial cell infection and dysfunction, immune activation in severe COVID-19. Theranostics 2021; 11 (16) 8076-8091
• 67 Sriram K, Insel PA. A hypothesis for pathobiology and treatment of COVID-19: The centrality of ACE1/ACE2 imbalance. Br J Pharmacol 2020; 177 (21) 4825-4844
• 68 Villa E, Critelli R, Lasagni S. et al. Dynamic angiopoietin-2 assessment predicts survival and chronic course in hospitalized patients with COVID-19. Blood Adv 2021; 5 (03) 662-673
• 69 van de Weg CAM, Thomazella MV, Marmorato MP. et al. Levels of angiopoietin 2 are predictive for mortality in patients infected with yellow fever virus. J Infect Dis 2024; 230 (01) e60-e64
• 70 Li K, Feng KC, Simon M. et al. Molecular basis for surface-initiated non-thrombin-generated clot formation following viral infection. ACS Appl Mater Interfaces 2024; 16 (24) 30703-30714
• 71 Deppermann C, Kubes P. Platelets and infection. Semin Immunol 2016; 28 (06) 536-545
• 72 Antoniak S, Mackman N. Platelets and viruses. Platelets 2021; 32 (03) 325-330
• 73 Rondina MT. Editorial: special review series on viruses and platelets. Platelets 2022; 33 (02) 174-175
• 74 Fogagnolo A, Campo GC, Mari M. et al. The underestimated role of platelets in severe infection: A narrative review. Cells 2022; 11 (03) 424
• 75 Raadsen M, Du Toit J, Langerak T, van Bussel B, van Gorp E, Goeijenbier M. Thrombocytopenia in virus infections. J Clin Med 2021; 10 (04) 877
• 76 Assinger A, Kral JB, Yaiw KC. et al. Human cytomegalovirus-platelet interaction triggers toll-like receptor 2-dependent proinflammatory and proangiogenic responses. Arterioscler Thromb Vasc Biol 2014; 34 (04) 801-809
• 77 Koupenova M, Vitseva O, MacKay CR. et al. Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis. Blood 2014; 124 (05) 791-802
• 78 Coulson BS, Londrigan SL, Lee DJ. Rotavirus contains integrin ligand sequences and a disintegrin-like domain that are implicated in virus entry into cells. Proc Natl Acad Sci U S A 1997; 94 (10) 5389-5394
• 79 Mackow ER, Gavrilovskaya IN. Cellular receptors and hantavirus pathogenesis. Curr Top Microbiol Immunol 2001; 256: 91-115
• 80 Nardi M, Feinmark SJ, Hu L, Li Z, Karpatkin S. Complement-independent Ab-induced peroxide lysis of platelets requires 12-lipoxygenase and a platelet NADPH oxidase pathway. J Clin Invest 2004; 113 (07) 973-980
• 81 Zhang W, Nardi MA, Borkowsky W, Li Z, Karpatkin S. Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C-related immunologic thrombocytopenia. Blood 2009; 113 (17) 4086-4093
• 82 Quirino-Teixeira AC, Andrade FB, Pinheiro MBM, Rozini SV, Hottz ED. Platelets in dengue infection: more than a numbers game. Platelets 2022; 33 (02) 176-183
• 83 Maugeri N, Cattaneo M, Rovere-Querini P, Manfredi AA. Platelet clearance by circulating leukocytes: a rare event or a determinant of the “immune continuum”?. Platelets 2014; 25 (03) 224-225
• 84 Othman M, Labelle A, Mazzetti I, Elbatarny HS, Lillicrap D. Adenovirus-induced thrombocytopenia: the role of von Willebrand factor and P-selectin in mediating accelerated platelet clearance. Blood 2007; 109 (07) 2832-2839
• 85 Bade NA, Giffi VS, Baer MR, Zimrin AB, Law JY. Thrombotic microangiopathy in the setting of human immunodeficiency virus infection: High incidence of severe thrombocytopenia. J Clin Apher 2018; 33 (03) 342-348
• 86 Ramasubbu K, Mullick T, Koo A. et al. Thrombotic microangiopathy and cytomegalovirus in liver transplant recipients: a case-based review. Transpl Infect Dis 2003; 5 (02) 98-103
• 87 Belford A, Myles O, Magill A, Wang J, Myhand RC, Waselenko JK. Thrombotic microangiopathy (TMA) and stroke due to human herpesvirus-6 (HHV-6) reactivation in an adult receiving high-dose melphalan with autologous peripheral stem cell transplantation. Am J Hematol 2004; 76 (02) 156-162
• 88 Koupenova M, Corkrey HA, Vitseva O. et al. SARS-CoV-2 initiates programmed cell death in platelets. Circ Res 2021; 129 (06) 631-646
• 89 Luppi M, Barozzi P, Schulz TF. et al. Bone marrow failure associated with human herpesvirus 8 infection after transplantation. N Engl J Med 2000; 343 (19) 1378-1385
• 90 Baranski B, Armstrong G, Truman JT, Quinnan Jr GV, Straus SE, Young NS. Epstein-Barr virus in the bone marrow of patients with aplastic anemia. Ann Intern Med 1988; 109 (09) 695-704
• 91 Jiang H, Li Y, Sheng Q, Dou X. Relationship between Hepatitis B virus infection and platelet production and dysfunction. Platelets 2022; 33 (02) 212-218
• 92 Afdhal N, McHutchison J, Brown R. et al. Thrombocytopenia associated with chronic liver disease. J Hepatol 2008; 48 (06) 1000-1007
• 93 Gonelli A, Mirandola P, Grill V, Secchiero P, Zauli G. Human herpesvirus 7 infection impairs the survival/differentiation of megakaryocytic cells. Haematologica 2002; 87 (11) 1223-1225
• 94 Isomura H, Yoshida M, Namba H. et al. Suppressive effects of human herpesvirus-6 on thrombopoietin-inducible megakaryocytic colony formation in vitro. J Gen Virol 2000; 81 (Pt 3): 663-673
• 95 Gibellini D, Clò A, Morini S, Miserocchi A, Ponti C, Re MC. Effects of human immunodeficiency virus on the erythrocyte and megakaryocyte lineages. World J Virol 2013; 2 (02) 91-101
• 96 Schrottmaier WC, Schmuckenschlager A, Pirabe A, Assinger A. Platelets in viral infections - brave soldiers or Trojan horses. Front Immunol 2022; 13: 856713
• 97 Awamura T, Nakasone ES, Gangcuangco LM. et al. Platelet and HIV interactions and their contribution to non-AIDS comorbidities. Biomolecules 2023; 13 (11) 1608
• 98 Morodomi Y, Kanaji S, Sullivan BM. et al. Inflammatory platelet production stimulated by tyrosyl-tRNA synthetase mimicking viral infection. Proc Natl Acad Sci U S A 2022; 119 (48) e2212659119
• 99 Garcia C, Compagnon B, Poëtte M. et al. Platelet versus megakaryocyte: Who is the real bandleader of thromboinflammation in sepsis?. Cells 2022; 11 (09) 1507
• 100 Stakos D, Skendros P, Konstantinides S, Ritis K, Traps N. Traps n′ clots: NET-mediated thrombosis and related diseases. Thromb Haemost 2020; 120 (03) 373-383
• 101 Abrams ST, Su D, Sahraoui Y. et al. Assembly of alternative prothrombinase by extracellular histones initiates and disseminates intravascular coagulation. Blood 2021; 137 (01) 103-114
• 102 Yong J, Abrams ST, Wang G, Toh CH. Cell-free histones and the cell-based model of coagulation. J Thromb Haemost 2023; 21 (07) 1724-1736
• 103 Sung PS, Huang TF, Hsieh SL. Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2. Nat Commun 2019; 10 (01) 2402
• 104 Vedpathak S, Palkar S, Mishra A, Arankalle VA, Shrivastava S. Dengue infection changes the expressions of CD154 and CD148 in human platelets. Virus Res 2025; 351: 199519
• 105 Hewson R. Understanding Viral Haemorrhagic Fevers: Virus Diversity, Vector Ecology, and Public Health Strategies. Pathogens 2024; 13 (10) 909
• 106 Basler CF. Molecular pathogenesis of viral hemorrhagic fever. Semin Immunopathol 2017; 39 (05) 551-561
• 107 Iannetta M, Di Caro A, Nicastri E. et al. Viral hemorrhagic fevers other than Ebola and Lassa. Infect Dis Clin North Am 2019; 33 (04) 977-1002
• 108 Lafoux B, Baillet N, Picard C. et al. Hemostasis defects underlying the hemorrhagic syndrome caused by mammarenaviruses in a cynomolgus macaque model. Blood 2023; 142 (24) 2092-2104
• 109 Frank MG, Weaver G, Raabe V. State of the Clinical Science Working Group of the National Emerging Pathogens Training and Education Center's Special Pathogens Research Network. Crimean Congo hemorrhagic fever virus for clinicians-virology, pathogenesis, and pathology. Emerg Infect Dis 2024; 30 (05) 847-853
• 110 Jacob ST, Crozier I, Fischer II WA. et al. Ebola virus disease. Nat Rev Dis Primers 2020; 6 (01) 13
• 111 Sen ES, Ramanan A. Cytokine storm syndrome associated with hemorrhagic fever and other viruses. In: Cron RQ, Behrens EM. eds. Cytokine Storm Syndrome. Springer, Cham: Advances in Experimental Medicine and Biology. 2024;Vol 1448
• 112 Tariq M, Kim DM. Hemorrhagic fever with renal syndrome: Literature review, epidemiology, clinical picture and pathogenesis. Infect Chemother 2022; 54 (01) 1-19
• 113 Marietta M, Coluccio V, Luppi M. COVID-19, coagulopathy and venous thromboembolism: more questions than answers. Intern Emerg Med 2020; 15 (08) 1375-1387
• 114 McGonagle D, O'Donnell JS, Sharif K, Emery P, Bridgewood C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatol 2020; 2 (07) e437-e445
• 115 Conway EM, Mackman N, Warren RQ. et al. Understanding COVID-19-associated coagulopathy. Nat Rev Immunol 2022; 22 (10) 639-649
• 116 Perico L, Benigni A, Remuzzi G. SARS-CoV-2 and the spike protein in endotheliopathy. Trends Microbiol 2024; 32 (01) 53-67
• 117 Middleton EA, He X-Y, Denorme F. et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 2020; 136 (10) 1169-1179
• 118 Barrett TJ, Cornwell M, Myndzar K. et al. Platelets amplify endotheliopathy in COVID-19. Sci Adv 2021; 7 (37) eabh2434
• 119 Brambilla M, Canzano P, Becchetti A, Tremoli E, Camera M. Alterations in platelets during SARS-CoV-2 infection. Platelets 2022; 33 (02) 192-199
• 120 Conway EM, Pryzdial ELG. Complement contributions to COVID-19. Curr Opin Hematol 2022; 29 (05) 259-265
• 121 WHO. COVID-19 dashboard. Accessed on February 5, 2025 at: https://data.who.int/dashboards/covid19/cases
• 122 European Centre for Disease Prevention and Control. Dengue worldwide overview. Accessed on February 5, 2025 at: https://www.ecdc.europa.eu/en/dengue-monthly
• 123 European Centre for Disease Prevention and Control. Viral haemorrhagic fevers. Accessed on February 5, 2025 at: https://www.ecdc.europa.eu/en/viral-haemorrhagic-fevers
• 124 WHO. One Health. Accessed on February 5, 2025 at: https://www.who.int/news-room/questions-and-answers/item/one-health