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Coagulation and Inflammation in COVID-19: Reciprocal Relationship between Inflammatory and Coagulation Markers

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Abstract

The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), formerly known as 2019-nCoV. Numerous cellular and biochemical issues arise after COVID-19 infection. The severe inflammation that is caused by a number of cytokines appears to be one of the key hallmarks of COVID-19. Additionally, people with severe COVID-19 have coagulopathy and fulminant thrombotic events. We briefly reviewed the COVID-19 disease at the beginning of this paper. The inflammation and coagulation markers and their alterations in COVID-19 illness are briefly discussed in the parts that follow. Next, we talked about NETosis, which is a crucial relationship between coagulation and inflammation. In the end, we mentioned the two-way relationship between inflammation and coagulation, as well as the factors involved in it. We suggest that inflammation and coagulation are integrated systems in COVID-19 that act on each other in such a way that not only inflammation can activate coagulation but also coagulation can activate inflammation.

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References

  1. Wang L, Wang Y, Ye D, Liu Q (2020) Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence. Int J Antimicrob Agents 55(6):105948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y et al (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395(10223):497–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ludvigsson JF (2020) Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr 109(6):1088–1095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wu Z, McGoogan JM (2020) Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. Jama 323(13):1239–1242

    Article  CAS  PubMed  Google Scholar 

  5. Aktas G (2020) A comprehensive review on rational and effective treatment strategies against an invisible enemy; SARS Cov-2 infection. Exp Biomed Res 3(4):293–311

    Article  CAS  Google Scholar 

  6. Aktas G, Balci B, Yilmaz S, Bardak H, Duman TT, Civil C (2022) Characteristics of Covid-19 infection with the original SARS-Cov-2 virus and other variants: a comparative review. J Bionic Mem 2(3):96–112

    Google Scholar 

  7. Wong RSY (2021) Inflammation in COVID-19: from pathogenesis to treatment. Int J Clin Exp Pathol 14(7):831–844

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Khalid A, Ali Jaffar M, Khan T, Abbas Lail R, Ali S, Aktas G et al (2021) Hematological and biochemical parameters as diagnostic and prognostic markers in SARS-COV-2 infected patients of Pakistan: a retrospective comparative analysis. Hematology 26(1):529–542

    Article  CAS  PubMed  Google Scholar 

  9. Aktas G (2021) Hematological predictors of novel coronavirus infection. Rev Assoc Med Bras 67:1–2

    Article  Google Scholar 

  10. Fei Y, Tang N, Liu H, Cao W (2020) Coagulation dysfunctiona hallmark in COVID-19. Arch Pathol Lab Med 144(10):1223–1229

    Article  PubMed  Google Scholar 

  11. Hadid T, Kafri Z, Al-Katib A (2021) Coagulation and anticoagulation in COVID-19. Blood Rev 47:100761

    Article  CAS  PubMed  Google Scholar 

  12. Ponti G, Maccaferri M, Ruini C, Tomasi A, Ozben T (2020) Biomarkers associated with COVID-19 disease progression. Crit Rev Clin Lab Sci 57(6):389–399

    Article  CAS  PubMed  Google Scholar 

  13. Becker RC (2020) Toward understanding the 2019 coronavirus and its impact on the heart. J Thromb Thrombolysis 50(1):33–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D (2020) Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 183(6):1735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lei J, Kusov Y, Hilgenfeld R (2018) Nsp3 of coronaviruses: structures and functions of a large multi-domain protein. Antivir Res 149:58–74

    Article  CAS  PubMed  Google Scholar 

  16. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W et al (2020) A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579(7798):270–273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liew FY, Girard JP, Turnquist HR (2016) Interleukin-33 in health and disease. Nat Rev Immunol 16(11):676–689

    Article  CAS  PubMed  Google Scholar 

  18. Cayrol C, Girard JP (2018) Interleukin-33 (IL-33): a nuclear cytokine from the IL-1 family. Immunol Rev 281(1):154–168

    Article  CAS  PubMed  Google Scholar 

  19. Liang Y, Ge Y, Sun J (2021) IL-33 in COVID-19: friend or foe? Cell Mol Immunol 18(6):1602–1604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gabryelska A, Kuna P, Antczak A, Białasiewicz P, Panek M (2019) IL-33 Mediated inflammation in chronic respiratory diseases-understanding the role of the member of IL-1 superfamily. Front Immunol 10:692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Spagnolo P, Balestro E, Aliberti S, Cocconcelli E, Biondini D, Casa GD et al (2020) Pulmonary fibrosis secondary to COVID-19: a call to arms? Lancet Respir Med 8(8):750–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hayakawa H, Hayakawa M, Kume A, Tominaga S (2007) Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem 282(36):26369–26380

    Article  CAS  PubMed  Google Scholar 

  23. Griesenauer B, Paczesny S (2017) The ST2/IL-33 axis in immune cells during inflammatory diseases. Front Immunol 8:475

    Article  PubMed  PubMed Central  Google Scholar 

  24. Zeng Z, Hong X-Y, Zhou H, Liao F-L, Guo S, Li Y et al (2020) Serum soluble ST2 as a novel biomarker reflecting inflammatory status and disease severity in patients with COVID-19. Available at SSRN 3594550

  25. Guo T, Fan Y, Chen M, Wu X, Zhang L, He T et al (2020) Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 5(7):811–818

    Article  PubMed  Google Scholar 

  26. Zeng Z, Hong XY, Li Y, Chen W, Ye G, Li Y, Luo Y (2020) Serum-soluble ST2 as a novel biomarker reflecting inflammatory status and illness severity in patients with COVID-19. Biomark Med 14(17):1619–1629

    Article  CAS  PubMed  Google Scholar 

  27. Baggiolini M, Walz A, Kunkel SL (1989) Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest 84(4):1045–1049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bazzoni F, Cassatella MA, Rossi F, Ceska M, Dewald B, Baggiolini M (1991) Phagocytosing neutrophils produce and release high amounts of the neutrophil-activating peptide 1/interleukin 8. J Exp Med 173(3):771–774

    Article  CAS  PubMed  Google Scholar 

  29. Ma A, Zhang L, Ye X, Chen J, Yu J, Zhuang L et al (2021) High levels of circulating IL-8 and soluble IL-2R are associated with prolonged illness in patients with severe COVID-19. Front Immunol 12:626235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kang S, Tanaka T, Inoue H, Ono C, Hashimoto S, Kioi Y et al (2020) IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. Proc Natl Acad Sci U S A 117(36):22351–22356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, Madison JA et al (2020) Neutrophil extracellular traps in COVID-19. JCI Insight 5(11).

  32. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M et al (2003) Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 107(3):499–511

    Article  PubMed  Google Scholar 

  33. Kushner I (1982) The phenomenon of the acute phase response. Ann N Y Acad Sci 389:39–48

    Article  CAS  PubMed  Google Scholar 

  34. Ridker PM (2003) Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 107(3):363–369

    Article  PubMed  Google Scholar 

  35. Kushner I, Jiang SL, Zhang D, Lozanski G, Samols D (1995) Do post-transcriptional mechanisms participate in induction of C-reactive protein and serum amyloid A by IL-6 and IL-1? Ann N Y Acad Sci 762:102–107

    Article  CAS  PubMed  Google Scholar 

  36. Calabró P, Willerson JT, Yeh ET (2003) Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth muscle cells. Circulation 108(16):1930–1932

    Article  PubMed  Google Scholar 

  37. Black S, Kushner I, Samols D (2004) C-reactive protein. J Biol Chem 279(47):48487–48490

    Article  CAS  PubMed  Google Scholar 

  38. Smilowitz NR, Kunichoff D, Garshick M, Shah B, Pillinger M, Hochman JS, Berger JS (2021) C-reactive protein and clinical outcomes in patients with COVID-19. Eur Heart J 42(23):2270–2279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Huang I, Pranata R, Lim MA, Oehadian A, Alisjahbana B (2020) C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: a meta-analysis. Ther Adv Respir Dis 14:1753466620937175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Quinlan GJ, Martin GS, Evans TW (2005) Albumin: biochemical properties and therapeutic potential. Hepatology 41(6):1211–1219

    Article  CAS  PubMed  Google Scholar 

  41. Rothschild MA, Oratz M, Schreiber SS (1988) Serum albumin. Hepatology 8(2):385–401

    Article  CAS  PubMed  Google Scholar 

  42. Serum Albumin.

  43. Paliogiannis P, Mangoni AA, Cangemi M, Fois AG, Carru C, Zinellu A (2021) Serum albumin concentrations are associated with disease severity and outcomes in coronavirus 19 disease (COVID-19): a systematic review and meta-analysis. Clin Exp Med 21(3):343–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bansal A, Prasad JB (2022) Liver profile in COVID-19: a meta-analysis. Z Gesundh Wiss 30(1):253–258

    Article  PubMed  Google Scholar 

  45. Parohan M, Yaghoubi S, Seraji A (2020) Liver injury is associated with severe coronavirus disease 2019 (COVID-19) infection: a systematic review and meta-analysis of retrospective studies. Hepatol Res 50(8):924–935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang B, Zhou X, Qiu Y, Song Y, Feng F, Feng J et al (2020) Clinical characteristics of 82 cases of death from COVID-19. PLoS One 15(7):e0235458

  47. Torun A, Çakırca TD, Çakırca G (1992) Portakal RD (2021) The value of C-reactive protein/albumin, fibrinogen/albumin, and neutrophil/lymphocyte ratios in predicting the severity of CoVID-19. Rev Assoc Med Bras 67(3):431–436

    Article  Google Scholar 

  48. Park JE, Chung KS, Song JH, Kim SY, Kim EY, Jung JY et al (2018) The C-reactive protein/albumin ratio as a predictor of mortality in critically ill patients. J Clin Med 7(10):333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kalabin A, Mani VR, Valdivieso SC, Donaldson B (2021) Does C reactive protein/albumin ratio have prognostic value in patients with COVID-19. J Infect Dev Ctries 15(08):1086–1093

    Article  CAS  PubMed  Google Scholar 

  50. Karagoz I, Ozer B, Ital I, Turkoglu M, Disikirik A, Ozer S (2023) C-reactive protein-to-serum albumin ratio as a marker of prognosis in adult intensive care population. Bratisl Lek Listy 124(4):277–279

  51. Aktas G (2023) Serum C-reactive protein to albumin ratio as a reliable marker of diabetic neuropathy in type 2 diabetes mellitus. Preprints. https://doi.org/10.20944/preprints202306.0202.v1

  52. Bilgin S, Kurtkulagi O, Tel BMA, Duman TT, Kahveci G, Khalid A, Aktas G (2021) Does C-reactive protein to serum albumin ratio correlate with diabetic nephropathy in patients with type 2 diabetes mellitus? The CARE TIME study. Prim Care Diabetes 15(6):1071–1074

    Article  CAS  PubMed  Google Scholar 

  53. Xie Q, Zhou Y, Xu Z, Yang Y, Kuang D, You H et al (2011) The ratio of CRP to prealbumin levels predict mortality in patients with hospital-acquired acute kidney injury. BMC Nephrol 12:30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kalyon S, Gültop F, Şimşek F, Adaş M (2021) Relationships of the neutrophil-lymphocyte and CRP-albumin ratios with the duration of hospitalization and fatality in geriatric patients with COVID-19. J Int Med Res 49(9):3000605211046112

    Article  CAS  PubMed  Google Scholar 

  55. Karzai W, Oberhoffer M, Meier-Hellmann A, Reinhart K (1997) Procalcitonin--a new indicator of the systemic response to severe infections. Infection 25(6):329–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Organization WH (2014) Antimicrobial resistance: global report on surveillance. World Health Organization, Geneva, Switzerland, p 2017

    Google Scholar 

  57. Delèvaux I, André M, Colombier M, Albuisson E, Meylheuc F, Bègue RJ et al (2003) Can procalcitonin measurement help in differentiating between bacterial infection and other kinds of inflammatory processes? Ann Rheum Dis 62(4):337–340

    Article  PubMed  PubMed Central  Google Scholar 

  58. Russwurm S, Wiederhold M, Oberhoffer M, Stonans I, Zipfel PF, Reinhart K (1999) Molecular aspects and natural source of procalcitonin. Clin Chem Lab Med 37(8):789–797

    Article  CAS  PubMed  Google Scholar 

  59. Sun D, Li H, Lu XX, Xiao H, Ren J, Zhang FR, Liu ZS (2020) Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center’s observational study. World J Pediatr 16(3):251–259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Chen X, Yang Y, Huang M, Liu L, Zhang X, Xu J et al (2020) Differences between COVID-19 and suspected then confirmed SARS-CoV-2-negative pneumonia: a retrospective study from a single center. J Med Virol 92(9):1572–1579

    Article  CAS  PubMed  Google Scholar 

  61. Yunus I, Fasih A, Wang Y (2018) The use of procalcitonin in the determination of severity of sepsis, patient outcomes and infection characteristics. PLoS One 13(11):e0206527

    Article  PubMed  PubMed Central  Google Scholar 

  62. Wolfisberg S, Gregoriano C, Schuetz P (2022) Procalcitonin for individualizing antibiotic treatment: an update with a focus on COVID-19. Crit Rev Clin Lab Sci 59(1):54–65

    Article  CAS  PubMed  Google Scholar 

  63. Tanaka T, Narazaki M, Kishimoto T (2014) IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 6(10):a016295

    Article  PubMed  PubMed Central  Google Scholar 

  64. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR et al (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368(16):1509–1518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M et al (2020) Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol 146(1):128–36.e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gubernatorova EO, Gorshkova EA, Polinova AI, Drutskaya MS (2020) IL-6: relevance for immunopathology of SARS-CoV-2. Cytokine Growth Factor Rev 53:13–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Abbasifard M, Khorramdelazad H (2020) The bio-mission of interleukin-6 in the pathogenesis of COVID-19: a brief look at potential therapeutic tactics. Life Sci 257:118097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Potere N, Batticciotto A, Vecchié A, Porreca E, Cappelli A, Abbate A et al (2021) The role of IL-6 and IL-6 blockade in COVID-19. Expert Rev Clin Immunol 17(6):601–618

    Article  CAS  PubMed  Google Scholar 

  69. Chen X, Zhao B, Qu Y, Chen Y, Xiong J, Feng Y et al (2020) Detectable serum severe acute respiratory syndrome coronavirus 2 viral load (RNAemia) is closely correlated with drastically elevated interleukin 6 level in critically ill patients with coronavirus disease 2019. Clin Infect Dis 71(8):1937–1942

    Article  CAS  PubMed  Google Scholar 

  70. Liu T, Zhang J, Yang Y, Ma H, Li Z, Zhang J et al (2020) The role of interleukin-6 in monitoring severe case of coronavirus disease 2019. EMBO Mol Med 12(7):e12421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Saraiva M, Vieira P, O'Garra A (2020) Biology and therapeutic potential of interleukin-10. J Exp Med 217(1):e20190418

    Article  PubMed  Google Scholar 

  72. Moore KW, de Waal MR, Coffman RL, O'Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765

    Article  CAS  PubMed  Google Scholar 

  73. Lu L, Zhang H, Dauphars DJ, He YW (2021) A potential role of interleukin 10 in COVID-19 Pathogenesis. Trends Immunol 42(1):3–5

    Article  CAS  PubMed  Google Scholar 

  74. Furlow B (2020) COVACTA trial raises questions about tocilizumab’s benefit in COVID-19. Lancet Rheumatol 2(10):e592

    Article  PubMed  PubMed Central  Google Scholar 

  75. Han H, Ma Q, Li C, Liu R, Zhao L, Wang W et al (2020) Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect 9(1):1123–1130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Dhar SK, Vishnupriyan K, Damodar S, Gujar S, Das M (2021) IL-6 and IL-10 as predictors of disease severity in COVID-19 patients: results from meta-analysis and regression. Heliyon 7(2):e06155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhao Y, Qin L, Zhang P, Li K, Liang L, Sun J et al (2020) Longitudinal COVID-19 profiling associates IL-1RA and IL-10 with disease severity and RANTES with mild disease. JCI Insight 5(13)

  78. Weitz JI, Fredenburgh JC, Eikelboom JW (2017) A test in context: D-dimer. J Am Coll Cardiol 70(19):2411–2420

    Article  CAS  PubMed  Google Scholar 

  79. Adam SS, Key NS, Greenberg CS (2009) D-dimer antigen: current concepts and future prospects. Blood 113(13):2878–2887

    Article  CAS  PubMed  Google Scholar 

  80. Cohen AT, Spiro TE, Spyropoulos AC, Desanctis YH, Homering M, Büller HR et al (2014) D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial. J Thromb Haemost 12(4):479–487

    Article  CAS  PubMed  Google Scholar 

  81. Rao KM, Pieper CS, Currie MS, Cohen HJ (1994) Variability of plasma IL-6 and crosslinked fibrin dimers over time in community dwelling elderly subjects. Am J Clin Pathol 102(6):802–805

    Article  CAS  PubMed  Google Scholar 

  82. Shorr AF, Thomas SJ, Alkins SA, Fitzpatrick TM, Ling GS (2002) D-dimer correlates with proinflammatory cytokine levels and outcomes in critically ill patients. Chest 121(4):1262–1268

    Article  PubMed  Google Scholar 

  83. Lowe GD, Yarnell JW, Rumley A, Bainton D, Sweetnam PM (2001) C-reactive protein, fibrin D-dimer, and incident ischemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis? Arterioscler Thromb Vasc Biol 21(4):603–610

  84. Xu Y, Qian Y, Gu Q, Tang J (2020) Relationship between D-dimer concentration and inflammatory factors or organ function in patients with coronavirus disease 2019. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 32(5):559–563

    PubMed  Google Scholar 

  85. Moreno G, Carbonell R, Bodí M, Rodríguez A (2021) Systematic review of the prognostic utility of D-dimer, disseminated intravascular coagulation, and anticoagulant therapy in COVID-19 critically ill patients. Med Intensiva (Engl Ed) 45(1):42–55

    Article  CAS  PubMed  Google Scholar 

  86. Weisel JW (2005) Fibrinogen and fibrin. Adv Protein Chem 70:247–299

    Article  CAS  PubMed  Google Scholar 

  87. Weisel JW, Litvinov RI (2017) Fibrin formation, structure and properties. Subcell Biochem 82:405–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Levi M, Toh CH, Thachil J, Watson HG (2009) Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 145(1):24–33

    Article  CAS  PubMed  Google Scholar 

  89. Han H, Yang L, Liu R, Liu F, Wu KL, Li J et al (2020) Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med 58(7):1116–1120

    Article  CAS  PubMed  Google Scholar 

  90. Giannis D, Ziogas IA, Gianni P (2020) Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol 127:104362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ranucci M, Ballotta A, Di Dedda U, Baryshnikova E, Dei Poli M, Resta M et al (2020) The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost 18(7):1747–1751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Morrissey JH, Fakhrai H, Edgington TS (1987) Molecular cloning of the cDNA for tissue factor, the cellular receptor for the initiation of the coagulation protease cascade. Cell 50(1):129–135

    Article  CAS  PubMed  Google Scholar 

  93. Morrissey JH (2001) Tissue factor: an enzyme cofactor and a true receptor. Thromb Haemost 86(1):66–74

    CAS  PubMed  Google Scholar 

  94. Bauer W, Galtung N, Neuwinger N, Kaufner L, Langer E, Somasundaram R et al (2021) A Matter of caution: coagulation parameters in COVID-19 do not differ from patients with ruled-out SARS-CoV-2 infection in the emergency department. TH Open 5(1):e43–e55

    Article  PubMed  PubMed Central  Google Scholar 

  95. Camerer E, Huang W, Coughlin SR (2000) Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci U S A 97(10):5255–5260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Mackman N (2009) The many faces of tissue factor. J Thromb Haemost 7 Suppl 1(Suppl 1):136–139

    Article  CAS  PubMed  Google Scholar 

  97. Foley JH, Conway EM (2016) Cross talk pathways between coagulation and inflammation. Circ Res 118(9):1392–1408

    Article  CAS  PubMed  Google Scholar 

  98. Eslamifar Z, Behzadifard M, Soleimani M, Behzadifard S (2020) Coagulation abnormalities in SARS-CoV-2 infection: overexpression tissue factor. Thromb J 18(1):38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Geisbert TW, Hensley LE, Jahrling PB, Larsen T, Geisbert JB, Paragas J et al (2003) Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet 362(9400):1953–1958

    Article  CAS  PubMed  Google Scholar 

  100. Hottz ED, Azevedo-Quintanilha IG, Palhinha L, Teixeira L, Barreto EA, Pão CRR et al (2020) Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood 136(11):1330–1341

    Article  CAS  PubMed  Google Scholar 

  101. Rosell A, Havervall S, von Meijenfeldt F, Hisada Y, Aguilera K, Grover SP et al (2021) Patients with COVID-19 have elevated levels of circulating extracellular vesicle tissue factor activity that is associated with severity and mortality-brief report. Arterioscler Thromb Vasc Biol 41(2):878–882

    Article  CAS  PubMed  Google Scholar 

  102. Subrahmanian S, Borczuk A, Salvatore S, Fung KM, Merrill JT, Laurence J, Ahamed J (2021) Tissue factor upregulation is associated with SARS-CoV-2 in the lungs of COVID-19 patients. J Thromb Haemost 19(9):2268–2274

    Article  CAS  PubMed  Google Scholar 

  103. Hassan MI, Saxena A, Ahmad F (2012) Structure and function of von Willebrand factor. Blood Coagul Fibrinolysis 23(1):11–22

    Article  CAS  PubMed  Google Scholar 

  104. Li S, Wang Z, Liao Y, Zhang W, Shi Q, Yan R et al (2010) The glycoprotein Ibalpha-von Willebrand factor interaction induces platelet apoptosis. J Thromb Haemost 8(2):341–350

    Article  CAS  PubMed  Google Scholar 

  105. Zhang X, Halvorsen K, Zhang CZ, Wong WP, Springer TA (2009) Mechanoenzymatic cleavage of the ultralarge vascular protein von Willebrand factor. Science 324(5932):1330–1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bockmeyer CL, Claus RA, Budde U, Kentouche K, Schneppenheim R, Lösche W et al (2008) Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor. Haematologica 93(1):137–140

    Article  CAS  PubMed  Google Scholar 

  107. Sporn LA, Chavin SI, Marder VJ, Wagner DD (1985) Biosynthesis of von Willebrand protein by human megakaryocytes. J Clin Invest 76(3):1102–1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. van Breevoort D, van Agtmaal EL, Dragt BS, Gebbinck JK, Dienava-Verdoold I, Kragt A et al (2012) Proteomic screen identifies IGFBP7 as a novel component of endothelial cell-specific Weibel-Palade bodies. J Proteome Res 11(5):2925–2936

    Article  PubMed  Google Scholar 

  109. Kawecki C, Lenting PJ, Denis CV (2017) von Willebrand factor and inflammation. J Thromb Haemost 15(7):1285–1294

    Article  CAS  PubMed  Google Scholar 

  110. Rostami M, Mansouritorghabeh H, Parsa-Kondelaji M (2022) High levels of Von Willebrand factor markers in COVID-19: a systematic review and meta-analysis. Clin Exp Med 22(3):347–357

    Article  CAS  PubMed  Google Scholar 

  111. Aird WC (2003) The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101(10):3765–3777

    Article  CAS  PubMed  Google Scholar 

  112. Bazzan M, Montaruli B, Sciascia S, Cosseddu D, Norbiato C, Roccatello D (2020) Low ADAMTS 13 plasma levels are predictors of mortality in COVID-19 patients. Intern Emerg Med 15(5):861–863

    Article  PubMed  PubMed Central  Google Scholar 

  113. Xu J, Esmon NL, Esmon CT (1999) Reconstitution of the human endothelial cell protein C receptor with thrombomodulin in phosphatidylcholine vesicles enhances protein C activation. J Biol Chem 274(10):6704–6710

    Article  CAS  PubMed  Google Scholar 

  114. Walker FJ (1980) Regulation of activated protein C by a new protein. A possible function for bovine protein S. J Biol Chem 255(12):5521–5524

    Article  CAS  PubMed  Google Scholar 

  115. Mosnier LO, Zlokovic BV, Griffin JH (2007) The cytoprotective protein C pathway. Blood 109(8):3161–3172

    Article  CAS  PubMed  Google Scholar 

  116. Oto J, Fernandez-Pardo A, Miralles M, Plana E, Espana F, Navarro S, Medina P (2020) Activated protein C assays: a review. Clin Chim Acta 502:227–232

    Article  CAS  PubMed  Google Scholar 

  117. Mosnier LO, Griffin JH (2006) Protein C anticoagulant activity in relation to anti-inflammatory and anti-apoptotic activities. Front Biosci 11:2381–2399

  118. Esmon CT (2003) The protein C pathway. Chest 124(3 Suppl):26s–32s

    Article  CAS  PubMed  Google Scholar 

  119. Healy LD, Puy C, Fernández JA, Mitrugno A, Keshari RS, Taku NA et al (2017) Activated protein C inhibits neutrophil extracellular trap formation in vitro and activation in vivo. J Biol Chem 292(21):8616–8629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Griffin JH, Zlokovic BV, Mosnier LO (2012) Protein C anticoagulant and cytoprotective pathways. Int J Hematol 95(4):333–345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Mazzeffi MA, Chow JH, Tanaka K (2021) COVID-19 associated hypercoagulability: manifestations, mechanisms, and management. Shock 55(4):465–471

    Article  CAS  PubMed  Google Scholar 

  122. Stanne TM, Pedersen A, Gisslén M, Jern C (2021) Low admission protein C levels are a risk factor for disease worsening and mortality in hospitalized patients with COVID-19. Thromb Res 204:13–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Stoichitoiu LE, Pinte L, Balea MI, Nedelcu V, Badea C, Baicus C (2020) Anticoagulant protein S in COVID-19: low activity, and associated with outcome. Rom J Intern Med 58(4):251–258

    PubMed  Google Scholar 

  124. Hanchard J, Capó-Vélez CM, Deusch K, Lidington D, Bolz SS (2020) Stabilizing cellular barriers: raising the shields against COVID-19. Front Endocrinol (Lausanne) 11:583006

    Article  PubMed  Google Scholar 

  125. Pepper MS (2001) Extracellular proteolysis and angiogenesis. Thromb Haemost 86(1):346–355

    CAS  PubMed  Google Scholar 

  126. Levin EG, Marzec U, Anderson J, Harker LA (1984) Thrombin stimulates tissue plasminogen activator release from cultured human endothelial cells. J Clin Invest 74(6):1988–1995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Myles T, Nishimura T, Yun TH, Nagashima M, Morser J, Patterson AJ et al (2003) Thrombin activatable fibrinolysis inhibitor, a potential regulator of vascular inflammation. J Biol Chem 278(51):51059–51067

    Article  CAS  PubMed  Google Scholar 

  128. Kolev K, Machovich R (2003) Molecular and cellular modulation of fibrinolysis. Thromb Haemost 89(4):610–621

    Article  CAS  PubMed  Google Scholar 

  129. Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B et al (2010) Molecular intercommunication between the complement and coagulation systems. J Immunol 185(9):5628–5636

    Article  CAS  PubMed  Google Scholar 

  130. Tang N, Li D, Wang X, Sun Z (2020) Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 18(4):844–847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ji HL, Zhao R, Matalon S, Matthay MA (2020) Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility. Physiol Rev 100(3):1065–1075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kam YW, Okumura Y, Kido H, Ng LF, Bruzzone R, Altmeyer R (2009) Cleavage of the SARS coronavirus spike glycoprotein by airway proteases enhances virus entry into human bronchial epithelial cells in vitro. PLoS One 4(11):e7870

    Article  PubMed  PubMed Central  Google Scholar 

  133. Antoniak S, Mackman N (2014) Multiple roles of the coagulation protease cascade during virus infection. Blood 123(17):2605–2613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Gacche RN, Gacche RA, Chen J, Li H, Li G (2021) Predictors of morbidity and mortality in COVID-19. Eur Rev Med Pharmacol Sci 25(3):1684–1707

    CAS  PubMed  Google Scholar 

  135. Wu YP, Wei R, Liu ZH, Chen B, Lisman T, Ren DL et al (2006) Analysis of thrombotic factors in severe acute respiratory syndrome (SARS) patients. Thromb Haemost 96(1):100–101

    CAS  PubMed  Google Scholar 

  136. Matsuyama T, Kubli SP, Yoshinaga SK, Pfeffer K, Mak TW (2020) An aberrant STAT pathway is central to COVID-19. Cell Death Differ 27(12):3209–3225

    Article  CAS  PubMed  Google Scholar 

  137. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS et al (2004) Neutrophil extracellular traps kill bacteria. Science 303(5663):1532–1535

    Article  CAS  PubMed  Google Scholar 

  138. Li B, Liu Y, Hu T, Zhang Y, Zhang C, Li T et al (2019) Neutrophil extracellular traps enhance procoagulant activity in patients with oral squamous cell carcinoma. J Cancer Res Clin Oncol 145(7):1695–1707

    Article  CAS  PubMed  Google Scholar 

  139. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V et al (2007) Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 176(2):231–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A (2010) Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 191(3):677–691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Björnsdottir H, Welin A, Michaëlsson E, Osla V, Berg S, Christenson K et al (2015) Neutrophil NET formation is regulated from the inside by myeloperoxidase-processed reactive oxygen species. Free Radic Biol Med 89:1024–1035

    Article  PubMed  Google Scholar 

  142. Gould TJ, Vu TT, Swystun LL, Dwivedi DJ, Mai SH, Weitz JI, Liaw PC (2014) Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler Thromb Vasc Biol 34(9):1977–1984

    Article  CAS  PubMed  Google Scholar 

  143. Ammollo CT, Semeraro F, Xu J, Esmon NL, Esmon CT (2011) Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J Thromb Haemost 9(9):1795–1803

    Article  CAS  PubMed  Google Scholar 

  144. Barranco-Medina S, Pozzi N, Vogt AD, Di Cera E (2013) Histone H4 promotes prothrombin autoactivation. J Biol Chem 288(50):35749–35757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Glaser CB, Morser J, Clarke JH, Blasko E, McLean K, Kuhn I et al (1992) Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation. J Clin Invest 90(6):2565–2573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, Knippers R (2001) DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 61(4):1659–1665

    CAS  PubMed  Google Scholar 

  147. Nakazawa F, Kannemeier C, Shibamiya A, Song Y, Tzima E, Schubert U et al (2005) Extracellular RNA is a natural cofactor for the (auto-)activation of factor VII-activating protease (FSAP). Biochem J 385(Pt 3):831–838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Kannemeier C, Shibamiya A, Nakazawa F, Trusheim H, Ruppert C, Markart P et al (2007) Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci U S A 104(15):6388–6393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Steinhoff M, Buddenkotte J, Shpacovitch V, Rattenholl A, Moormann C, Vergnolle N et al (2005) Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev 26(1):1–43

    Article  CAS  PubMed  Google Scholar 

  150. Strukova S (2006) Blood coagulation-dependent inflammation. Coagulation-dependent inflammation and inflammation-dependent thrombosis. Front Biosci 11:59–80

    Article  CAS  PubMed  Google Scholar 

  151. Tunjungputri RN, Li Y, de Groot PG, Dinarello CA, Smeekens SP, Jaeger M et al (2018) The inter-relationship of platelets with interleukin-1β-mediated inflammation in humans. Thromb Haemost 118(12):2112–2125

    Article  PubMed  Google Scholar 

  152. Cavalli G, Colafrancesco S, Emmi G, Imazio M, Lopalco G, Maggio MC et al (2021) Interleukin 1α: a comprehensive review on the role of IL-1α in the pathogenesis and treatment of autoimmune and inflammatory diseases. Autoimmun Rev 20(3):102763

    Article  CAS  PubMed  Google Scholar 

  153. José RJ, Williams AE, Chambers RC (2014) Proteinase-activated receptors in fibroproliferative lung disease. Thorax 69(2):190–192

    Article  PubMed  Google Scholar 

  154. Levi M, Keller TT, van Gorp E, ten Cate H (2003) Infection and inflammation and the coagulation system. Cardiovasc Res 60(1):26–39

    Article  CAS  PubMed  Google Scholar 

  155. Li X, Geng M, Peng Y, Meng L, Lu S (2020) Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal 10(2):102–108

    Article  PubMed  PubMed Central  Google Scholar 

  156. Li G, Chen X, Xu A (2003) Profile of specific antibodies to the SARS-associated coronavirus. N Engl J Med 349(5):508–509

    Article  PubMed  Google Scholar 

  157. Levi M, van der Poll T (2017) Coagulation and sepsis. Thromb Res 149:38–44

    Article  CAS  PubMed  Google Scholar 

  158. Llitjos JF, Leclerc M, Chochois C, Monsallier JM, Ramakers M, Auvray M, Merouani K (2020) High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost 18(7):1743–1746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Laboratory Hematology and Blood Banking, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran

    Rasoul Ebrahimi, Fatemeh Nasri & Tahereh Kalantari

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  1. Rasoul Ebrahimi
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All authors contributed to the study’s conception and design. Tahereh Kalantari and Rasoul Ebrahimi had the idea for this article, Rasoul Ebrahimi performed the literature search, Rasoul Ebrahimi has written the article, and Fatemeh Nasri has critically revised the article. All authors read and approved the final manuscript.

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Ebrahimi, R., Nasri, F. & Kalantari, T. Coagulation and Inflammation in COVID-19: Reciprocal Relationship between Inflammatory and Coagulation Markers. Ann Hematol 103, 1819–1831 (2024). https://doi.org/10.1007/s00277-024-05630-1

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