COVID-19: Not a thrombotic disease but a thromboinflammatory disease
Abstract
While Coronavirus Disease in 2019 (COVID-19) may no longer be classified as a global public health emergency, it still poses a significant risk at least due to its association with thrombotic events. This study aims to reaffirm our previous hypothesis that COVID-19 is fundamentally a thrombotic disease. To accomplish this, we have undertaken an extensive literature review focused on assessing the comprehensive impact of COVID-19 on the entire hemostatic system. Our analysis revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection significantly enhances the initiation of thrombin generation. However, it is noteworthy that the thrombin generation may be modulated by specific anticoagulants present in patients’ plasma. Consequently, higher levels of fibrinogen appear to play a more pivotal role in promoting coagulation in COVID-19, as opposed to thrombin generation. Furthermore, the viral infection can stimulate platelet activation either through widespread dissemination from the lungs to other organs or localized effects on platelets themselves. An imbalance between Von Willebrand Factor (VWF) and ADAMTS-13 also contributes to an exaggerated platelet response in this disease, in addition to elevated D-dimer levels, coupled with a significant increase in fibrin viscoelasticity. This paradoxical phenotype has been identified as ‘fibrinolysis shutdown’. To clarify the pathogenesis underlying these hemostatic disorders in COVID-19, we also examined published data, tracing the reaction process of relevant proteins and cells, from ACE2-dependent viral invasion, through induced tissue inflammation, endothelial injury, and innate immune responses, to occurrence of thrombotic events. We therefrom understand that COVID-19 should no longer be viewed as a thrombotic disease solely based on abnormalities in fibrin clot formation and proteolysis. Instead, it should be regarded as a thromboinflammatory disorder, incorporating both classical elements of cellular inflammation and their intricate interactions with the specific coagulopathy.
Downloads
Download data is not yet available.
References
1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727–33. doi: 10.1056/NEJMoa2001017
2. Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? Eur Heart J 2020;41:1858. doi: 10.1093/eurheartj/ehaa254
3. Bompard F, Monnier H, Saab I, Tordjman M, Abdoul H, Fournier L, et al. Pulmonary embolism in patients with COVID-19 pneumonia. Eur Respir J 2020;56:2001365. doi: 10.1183/13993003.01365-2020
4. Di Minno A, Ambrosino P, Calcaterra I, Di Minno MND. COVID-19 and venous thromboembolism: a meta-analysis of literature studies. Semin Thromb Hemost 2020;46:763–71. doi: 10.1055/s-0040-1715456
5. Wichmann D, Sperhake JP, Lütgehetmann M, Steurer S, Edler C, Heinemann A, et al. Autopsy findings and venous thromboembolism in patients with COVID-19, a prospective cohort study. Ann Intern Med 2020;173:268–77. doi: 10.7326/M20-2003
6. Calabrese F, Pezzuto F, Fortarezza F, Hofman P, Kern I, Panizo A, et al. Pulmonary pathology and COVID-19: lessons from autopsy. The experience of European pulmonary pathologists. Virchows Arch 2020;477:359–72. doi: 10.1007/s00428-020-02886-6
7. Grimes Z, Bryce C, Sordillo EM, Gordon RE, Reidy J, Mondolfi AEP, et al. Fatal pulmonary thromboembolism in SARS-CoV-2-infection. Cardiovasc Pathol 2020;48:107227. doi: 10.1016/j.carpath.2020.107227
8. Shao C, Liu H, Meng L, Sun L, Wang Y, Yue Z, et al. Evolution of severe acute respiratory syndrome coronavirus 2 RNA test results in a patient with fatal coronavirus disease 2019: a case report. Pathology 2020;101:82–8. doi: 10.1016/j.humpath.2020.04.015
9. Bu ja LM, Wolf DA, Zhao B, Akkanti B, McDonald M, Lelenwa L, et al. The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities. Cardiovasc Pathol 2020;48:107233. doi: 10.1016/j.carpath.2020.107233
10. Nicolai L, Leunig A, Brambs S, Kaiser R, Weinberger T, Weigand M, et al. Immunothrombotic dysregulation in COVID-19 pneumonia is associated with respiratory failure and coagulopathy. Circulation 2020;142:1176–89. doi: 10.1161/CIRCULATIONAHA.120.048488
11. Menter T, Haslbauer JD, Nienhold R, Savic S, Hopfer H, Nikolaus D, et al. Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology 2020;77:198–109. doi: 10.1111/his.14134
12. Elsoukkary S, Mostyka M, Dillard A, Berman DR, Ma LX, Chadburn A, et al. Autopsy Findings in 32 patients with COVID-19: a single institution experience. Pathobiology 2021;88:56–68. doi: 10.1159/000511325
13. Fahmy OH, Daas FM, Salunkhe V, Petrey JL, Cosar EF, Ramirez J, et al. Is microthrombosis the main pathology in coronavirus disease 2019 severity? – A systematic review of the postmortem pathologic findings. Crit Care Explor 2021;3:e0427. doi: 10.1097/CCE.0000000000000427
14. Chen W, Pan JY. Anatomical and pathological observation and analysis of SARS and COVID-19: microthrombosis is the main cause of death. Biol Proc Online 2021;23:4. doi: 10.1186/s12575-021-00142-y
15. Buja LM, Zhao B, McDonald M, Ottaviani G, Wolf DA. Commentary on the spectrum of cardiopulmonary pathology in COVID-19. Cardiovasc Pathol 2021;53:107339. doi: 10.1016/j.carpath.2021.107339
16. Wool GD, Miller JL. The impact of COVID-19 disease on platelets and coagulation. Pathobiology 2021;88:15–27. doi: 10.1159/000512007
17. Iba T, Levy JH, Levi M, Thachil JJ. Coagulopathy in COVID-19. J Thromb Haemost 2020;18:2103–9. doi: 10.1111/jth.14975
18. Asakura H, Ogawa H. COVID‑19‑associated coagulopathy and disseminated intravascular coagulation. Int J Hematol 2021;113:45–57. doi: 10.1007/s12185-020-03029-y
19. Toshiaki Iba T, Wada H, Levy JH. Platelet activation and thrombosis in COVID-19. Semin Thromb Hemost 2023;1:55–61. doi: 10.1055/s-0042-1749441
20. Meizoso JP, Moore HB, Moore EE. Fibrinolysis shutdown in COVID-19: clinical manifestations, molecular mechanisms, and therapeutic implications. J Am Coll Surg 2021;232:995–1003. doi: 10.1016/j.jamcollsurg.2021.02.019
21. Scialo F, Daniele A, Amato F, Pastore L, Matera MG, Cazzola M, et al. ACE2: the major cell entry receptor for SARS-CoV-2. Lung 2020;198:867–77. doi: 10.1007/s00408-020-00408-4
22. Jackson CB, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol 2022;23:3–20. doi: 10.1038/s41580-021-00418-x.
23. Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med 2020;383:2255–73. doi: 10.1056/NEJMra2026131
24. Pasrija R, Naime M. The deregulated immune reaction and cytokines release storm (CRS) in COVID-19 disease. Int Immunopharmacol 2021;90:107225. doi: 10.1016/j.intimp.2020.107225
25. Castelli V, Cimini A, Ferri C. Cytokine Storm in COVID-19: when you come out of the storm, You won’t be the same person who walked in. Front Immunol 2020;11:2132. doi: 10.3389/fimmu.2020.02132
26. Hojyo S, Uchida M, Tanaka K, et al. How COVID-19 induces cytokine storm with high mortality. Inflamm Regen 2020;40:37. doi: 10.3389/fimmu.2020.02132
27. Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol 2020;39:2085–94. doi: 10.1007/s10067-020-05190-5
28. Gustine JN, Jones D. Immunopathology of hyperinflammation in COVID-19. Am J Pathol 2021;191:4–17. doi: 10.1016/j.ajpath.2020.08.009
29. Tufa A, Gebremariam TH, Manyazewal T, Getinet T, Webb DL, Hellström PM, et al. Inflammatory mediators profile in patients hospitalized with COVID-19: a comparative study. Front Immunol 2022;13:964179. doi: 10.3389/fimmu.2022.964179
30. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. Engl J Med 2020;383:120–8. doi: 10.1056/NEJMoa2015432
31. Barbosa LC, Gonçalves TL, De Araujo LP, Rosario LVO, Ferrer VP. Endothelial cells and SARS-CoV-2: an intimate relationship. Vascu Pharmacol 2021;137:106829. doi: 10.1016/j.vph.2021.106829
32. Bernard I, Limonta D, Mahal LK, Hobman TC. Endothelium infection and dysregulation by SARS-CoV-2: evidence and avceats in COVID-19. Viruses 2020;13:29. doi: 10.3390/v13010029
33. Amraei R, Rahimi N. COVID-19, renin-angiotensin system and endothelial dysfunction. Cells 2020;9:1652. doi: 10.3390/cells9071652
34. Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J 2020;41:3038–44. doi: 10.1093/eurheartj/ehaa623
35. Nägele MP, Haubner B, Tanner FC, Ruschitzka F, Flammer AJ. Endothelial dysfunction in COVID-19: current findings and therapeutic implications. Atherosclerosis 2020;314:58–62. doi: 10.1016/j.atherosclerosis.2020.10.014
36. Copin MC, Parmentier E, Duburcq T, Poissy J, Mathieu D, Lille COVID-19 ICU and Anatomopathology Group. Time to consider histologic pattern of lung injury to treat critically ill patients with COVID‑19 infection. Intensive Care Med 2020;46:1124–6. doi: 10.1007/s00134-020-06057-8
37. Cañas CA, Cañas F, Bautista-Vargas M, Bonilla-Abadía F. Role of tissue factor in the pathogenesis of COVID-19 and the possible ways to inhibit it. Clin Appl Thromb Hemost 2021;27:10760296211003983. doi: 10.1177/10760296211003983
38. Goshua G, Pine AB, Meizlish ML, Chang CH, Zhang H, Bahel P, et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol 2020;7:e575–82. doi: 10.1016/S2352-3026(20)30216-7
39. Christensen B, Favaloro EJ, Lippi G, Van Cott EM. Hematology laboratory abnormalities in patients with coronavirus disease 2019 (COVID-19). Semin Thromb Hemost 2020;46:845–9. doi: 10.1055/s-0040-1715458
40. Zuo Y, Warnock M, Harbaugh A, Yalavarthi S, Gockman K, Zuo M, et al. Plasma tissue plasminogen activator and plasminogen activator inhibitor‑1 in hospitalized COVID‑19 patients. Sci Rep 2021;11:1580. doi: 10.1038/s41598-020-80010-z
41. Norooznezhad AH, Mansouri K. Endothelial cell dysfunction, coagulation, and angiogenesis in coronavirus disease 2019 (COVID-19). Microvasc Res 2021;137:104188. doi: 10.1016/j.mvr.2021.104188
42. Bouck EG, Denorme F, Holle LA, Middelton EA, Blair AM, De Laat B, et al. COVID-19 and sepsis are associated with different abnormalities in plasma procoagulant and fibrinolytic activity. Arterioscler Thromb Vasc Biol 2021;41:401–14. doi: 10.1161/ATVBAHA.120.315338
43. Rosell A, Havervall S, von Meijenfeldt F, Hisada Y, Aguilera K, Grover SP, et al. 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 2021;41:878–82. doi: 10.1161/ATVBAHA.120.315547
44. Hisada Y, Alexander W, Kasthuri R, Voorhees P, Mobarrez F, Taylor A, McNamara C, et al. Measurement of microparticle tissue factor activity in clinical samples: a summary of two tissue factor-dependent FXa generation assays. Thromb Res 2016;139:90–7. doi: 10.1016/j.thromres.2016.01.011
45. Henderson MW, Lima F, Moraes CRP, Ilich A, Huber SC, Barbosa MS, et al. Contact and intrinsic coagulation pathways are activated and associated with adverse clinical outcomes in COVID-19. Blood Adv 2022;6:3367–77. doi: 10.1182/bloodadvances.2021006620
46. Guervilly C, Bonifay A, Burtey S, Sabatier F, Cauchois R, Abdili E, et al. Dissemination of extreme levels of extracellular vesicles: tissue factor activity in patients with severe COVID-19. Blood Adv 2021;5:628–34. doi: 10.1182/bloodadvances.2020003308
47. Hamali HA, Saboor M, Dobie G, Madkhali AM, Akhter MS, Hakamy A, et al. Procoagulant microvesicles in COVID-19 patients: possible modulators of inflammation and prothrombotic tendency. Infect Drug Resist 2022;15:2359–68. doi: 10.2147/IDR.S355395
48. Subrahmanian S, Borczuk A, Salvatore S, Fung KM, Merrill JT, Laurence J, et al. Tissue factor upregulation is associated with SARS-CoV-2 in the lungs of COVID-19 patients. J Thromb Haemost 2021;19:2268–74. doi: 10.1111/jth.15451
49. Girard TJ, Antunes L, Zhang N, Amrute JM, Subramanian R, Eldem I, 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;21:629–38. doi: 10.1016/j.jtha.2022.11.033
50. Martinelli N, Rigoni AM, De Marchi S, Osti N, Donini M, Montagnana M, et al. High plasma levels of activated Factor VII-antithrombin complex point to increased tissue factor expression in patients with SARS-CoV-2 pneumonia: a potential link with COVID-19 prothrombotic diathesis. Diagnostics (Basel) 2022;12:2792. doi: 10.3390/diagnostics12112792
51. Martinelli N, Girelli D, Baroni M, Guarini P, Sandri M, Lunghi B, et al. Activated factor VII-antithrombin complex predicts mortality in patients with stable coronary artery disease: a cohort study. J Thromb Haemost 2016;14(4):655–66. doi: 10.1111/jth.13274
52. Rao LV, Nordfang O, Hoang AD, Pendurthi UR. Mechanism of antithrombin III inhibition of factor VIIa/tissue factor activity on cell surfaces. Comparison with tissue factor pathway inhibitor/factor Xa-induced inhibition of factor VIIa/tissue factor activity. Blood 1995;85:121–9. doi: 10.1182/blood.V85.1.121.bloodjournal851121
53. Wygrecka M, Birnhuber A, Seeliger B, Michalick L, Pak O, Schultz AS, et al. Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19. Blood Adv 2022;6:1074–87. doi: 10.1182/bloodadvances.2021004816
54. Murray NP, Guzman E, Del Prado M. Transient acquired factor XII deficiency associated with moderately severe COVID-19 pneumonia. Hematol Transfus Cell Ther 2021;43:515–7. doi: 10.1016/j.htct.2021.06.017
55. Bachler M, Niederwanger C, Hell T, Höfer J, Gerstmeyr D, Schenk BT, et al. Influence of factor XII deficiency on activated partial thromboplastin time (aPTT) in critically ill patients. J Thromb Thrombolysis 2019;48:466–74. doi: 10.1007/s11239-019-01879-w
56. He S, MD, Cao HL, Thålin C, Svensson J, Blombäck, M, Wallén H. The clotting trigger is an important determinant for the coagulation pathway in vivo or in vitro – inference from data review. Semin Thromb Hemost 2021;47:63–73. doi: 10.1055/s-0040-1718888
57. Busch MH, Timmermans SAMEG, Nagy M, Visser M, Huckriede J, Aendekerk JP, et al. Neutrophils and contact activation of coagulation as potential drivers of COVID-19. Circulation 2020;142:1787–90. doi: 10.1161/CIRCULATIONAHA.120.050656
58. Hvas CL, Larsen JB, Adelborg K, Christensen S, Hvas AM. Dynamic hemostasis and fibrinolysis assays in intensive care COVID-19 patients and association with thrombosis and bleeding – a systematic review and a Cohort study. Semin Thromb Hemost 2022;48:31–54. doi: 10.1055/s-0041-1735454
59. Cacciola R, Cacciola EG, Vecchio V, Cacciola E. Cellular and molecular mechanisms in COVID-19 coagulopathy: role of inflammation and endotheliopathy. J Thromb Thrombolysis 2022;53:282–90. doi: 10.1007/s11239-021-02583-4
60. Hemker HC, Giesen P, Al Dieri R, Regnault V, de Smedt E, Wagenvoord R, et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003;33:4–15. doi: 10.1159/000071636
61. Blasi A, von Meijenfeldt FA, Adelmeijer J, Calvo A, Ibañez C, Perdomo J, et al. In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation. J Thromb Haemost 2020;18:2646–53. doi: 10.1111/jth.15043
62. Benati M, Salvagno GL, Nitto S, Gelati M, Lavorgna B, Fava C, et al. Thrombin generation in patients with coronavirus disease 2019. Semin Thromb Hemost 2021;47:447–50. doi: 10.1055/s-0041-1722844
63. Hardy M, Michaux I, Lessire S, Douxfils J, Dogné JM, Bareille M, et al. Prothrombotic disturbances of hemostasis of patients with severe COVID-19: a prospective longitudinal observational study. Thromb Res 2021;197:20–3. doi: 10.1016/j.thromres.2020.10.025
64. Buffart B, Demulder A, Fangazio M, Rozen L. Global hemostasis potential in COVID-19 positive patients performed on St-genesia show hypercoagulable state. J Clin Med. 2022;11:7255. doi: 10.3390/jcm11247255
65. Nougier C, Benoit R, Simon M, Desmurs-Clavel H, Marcotte G, Argaud L, et al. Hypofibrinolytic state and high thrombin generation may play a major role in SARS-COV2 associated thrombosis. J Thromb Haemost 2020;18:2215–9. doi: 10.1016/j.thromres.2020.10.025
66. Cohen O, Landau N, Avisahai E, Brutman-Barazani T, Budnik I, Livnat T, et al. Association between thrombin generation and clinical characteristics in COVID-19 patients. Acta Haematol 2023;146:151–60. doi: 10.1159/000527581
67. Mennuni MG, Rolla R, Grisafi L, Spinoni EG, Rognoni A, Lio V, et al. Interaction between thrombin potential and age on early clinical outcome in patients hospitalized for COVID-19. J Thromb Thrombolysis 2021;52:746–53. doi: 10.1007/s11239-021-02497-1
68. Gris JC, Guillotin F, Dos Santos TP, Chéa M, Loubet P, Laureillard D, et al. Prognostic value of an automated thrombin generation assay in COVID-19 patients entering hospital: a multicentric, prospective observational study. Thromb Res 2023;222:85–95. doi: 10.1016/j.thromres.2022.12.019
69. Campello E, Bulato C, Spiezia L, Boscolo A, Poletto F, Cola M, et al. Thrombin generation in patients with COVID-19 with and without thromboprophylaxis. Clin Chem Lab Med 2021;59:1323–30. doi: 10.1515/cclm-2021-0108
70. Nordfang O, Kristensen HI, Valentin S, Ostergaard P, Wadt J. The significance of TFPI in clotting assays – comparison and combination with other anticoagulants. Thromb Haemost 1993;70:448–53. doi: 10.1055/s-0038-1649603
71. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and antiphospholipid antibodies in patients with Covid 19. Engl J Med 2020;382:e38. doi: 10.1056/NEJMc2007575
72. Butt A, Erkan D, Lee AI. COVID-19 and antiphospholipid antibodies. Best Pract Res Clin Haematol 2022;35:101402. doi: 10.1016/j.beha.2022.101402
73. Kinev AV, Roubey RAS. Tissue factor in the antiphospholipid syndrome. Lupus 2008; 17:952–8.doi: 10.1177/0961203308096662
74. He S, Wallén H, Thålin C, Svensson J, Blombäck M. Fibrin network porosity and endo-/exogenous thrombin cross-talk. Semin Thromb Hemost 2021;47:775–86. doi: 10.1055/s-0041-1729963
75. Luyendyk JP, Schoenecker JG, Flick MJ. The multifaceted role of fibrinogen in tissue injury and inflammation. Blood 2019;133:511–20. doi: 10.1182/blood-2018-07-818211
76. White D, MacDonald S, Edwards T, Bridgeman C, Hayman M, Sharp M, et al. Evaluation of COVID-19 coagulopathy; laboratory characterization using thrombin generation and nonconventional haemostasis assays. Int J Lab Hematol 2021;43:123–30. doi: 10.1111/ijlh.13329
77. Velavan TP, Meyer CG. Mild versus severe COVID-19: laboratory markers. Int J Infect Dis 2020;95:304–7. doi: 10.1016/j.ijid.2020.04.061
78. Hayıroğlu MI, Cınar T, Tekkeşin AI. Fibrinogen and D-dimer variances and anticoagulation recommendations in Covid-19: current literature review. Rev Assoc Med Bras 2020;66:842–8. doi: 10.1590/1806-9282.66.6.842
79. Wang Z, Du Z, Zhao X, Guo F, Wang T, Zhu F. Determinants of increased fibrinogen in COVID-19 patients with and without diabetes and impaired fasting glucose. Clin Appl Thromb Hemost 2021;27 1076029621996445. doi: 10.1177/1076029621996445
80. Rostami M, Mansouritorghabeh H. D-dimer level in COVID-19 infection: a systematic review. Expert Rev Hematol 2020;13:1265–75. doi: 10.1080/17474086.2020.1831383
81. Zhan H, Chen H, Liu C, Cheng L, Yan S, Li H, et al. Diagnostic value of D-dimer in COVID-19: a meta-analysis and meta-regression. Clin Appl Thromb Hemost 2021;27:10760296211010976. doi: 10.1177/10760296211010976
82. Canzano P, Brambilla M, Porro B, Cosentino N, Tortorici E, Vicini S, et al. Platelet and endothelial activation as potential mechanisms behind the thrombotic complications of COVID-19 patients. JACC Basic Transl Sci 2021;6:202–18. doi: 10.1016/j.jacbts.2020.12.009
83. Iba T, Wada H, Jerrold H. Levy. JH. Platelet activation and thrombosis in COVID-19. Semin Thromb Hemost 2023;49:55–61. doi: 10.1055/s-0042-1749441
84. Mei H, Luo L, Hu Y. Thrombocytopenia and thrombosis in hospitalized patients with COVID-19. Hematol Oncol 2020;13:161. doi: 10.1186/s13045-020-01003-z
85. Jevtic SD, Nazy I. The COVID complex: a review of platelet activation and immune complexes in COVID-19. Front Immunol 2022;13:807934. doi: 10.3389/fimmu.2022.807934
86. Kaur S, Singh A, Kaur J, Verma N, Pandey AK, Das S, et al. Upregulation of cytokine signaling in platelets increases risk of thrombophilia in severe COVID-19 patients. Blood Cells Mol Dis 2022;94:102653. doi: 10.1016/j.bcmd.2022.102653
87. Theofilis P, Sagris M, Antonopoulos AS, Oikonomou E, Tsioufis C, Tousoulis D. Inflammatory mediators of platelet activation: focus on atherosclerosis and COVID-19. Int J Mol Sci 2021;22:11170. doi: 10.3390/ijms222011170
88. Garcia C, Au Duong J, Poëtte M, Ribes A, Payre B, Mémier V, et al. Platelet activation and partial desensitization are associated with viral xenophagy in patients with severe COVID-19. Blood Adv 2022;6:3884–98. doi: 10.1182/bloodadvances.2022007143
89. Zhang S, Liu Y, Wang X, Yang L, Li H, Wang Y, et al. SARS-CoV 2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol 2020;13:120. doi: 10.1186/s13045-020-00954-7
90. Manne BK, Denorme F, Middleton EA, Portier I, Rowley JW, Stubben C, et al. Platelet gene expression and function in patients with COVID-19. Blood 2020;136:1317–32. doi: 10.1182/blood.2020007214
91. Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008;112:11–18. doi: 10.1182/blood.2020007214
92. Peyvandi F, Garagiola I, Baronciani L. Role of von Willebrand factor in the haemostasis. Blood Transfus 2011;9(suppl. 2):s3–s8. doi: 10.2450/2011.002S
93. DeYoung V, Singh K, Kretz CA. Mechanisms of ADAMTS13 regulation. Thromb Haemost 2022;120:2722–32. doi: 10.1111/jth.15873
94. Zheng XL. Structure-function and regulation of ADAMTS13 protease. J Thromb Haemost 2013;11:11–23. doi: 10.1111/jth.12221
95. George JN. TTP: the evolution of clinical practice. Blood 2021;137:719–720. doi: 10.1182/blood.2020009654
96. Azhdari Tehrani H, Darnahal M, Vaezi M, Haghighi S. COVID-19 associated thrombotic thrombocytopenic purpura (TTP): a case series and mini-review. Int Immunopharmacol 2021;93:107397. doi: 10.1016/j.intimp.2021.107397
97. Altowyan E, Alnujeidi O, Alhujilan A, Alkathlan M. COVID-19 presenting as thrombotic thrombocytopenic purpura (TTP). BMJ Case Rep 2020;13:e238026. doi: 10.1136/bcr-2020-238026
98. Chaudhary H, Nasir U, Syed K, Labra M, Reggio C, Aziz A, et al. COVID-19-associated thrombotic thrombocytopenic purpura: a case report and systematic review. Hematol Rep 2022;14:253–60. doi: 10.3390/hematolrep14030035
99. Zheng XL, Vesely SK, Cataland SR, Coppo P, Geldziler B, Iorio A, et al. ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost 2020;18:2486–95. doi: 10.1111/jth.15006
100. Mancini I, Baronciani L, Artoni A, Colpani P, Biganzoli M, Cozzi G, et al. The ADAMTS13-von Willebrand factor axis in COVID-19 patients. J Thromb Haemost 2021;19:513–21. doi: 10.1111/jth.15191
101. Maharaj S, Xue R, Rojan A. Thrombotic thrombocytopenic purpura (TTP) response following COVID-19 infection: implications for the ADAMTS-13-von Willebrand factor axis. J Thromb Haemost 2021;19:1130–2. doi: 10.1111/jth.15230
102. Favaloro EJ, Henry BM, Lippi G. Increased VWF and decreased ADAMTS-13 in COVID-19: creating a Milieu for (Micro)thrombosis. Semin Thromb Hemost 2021;47:400–18. doi: 10.1111/jth.15230
103. Henry BM, Benoit SW, Hoehn J, Lippi G, Favaloro EJ, Benoit JL. Circulating plasminogen concentration at admission in patients with coronavirus disease 2019 (COVID-19). Semin Thromb Hemost 2020;46:859–62. doi: 10.1055/s-0040-1715454
104. Whyte CS, Simpson M, Morrow GB, Wallace CA, Mentzer AJ, Knight JC, et al. The suboptimal fibrinolytic response in COVID-19 is dictated by high PAI-1. J Thromb Haemost 2022;20:2394–406. doi: 10.1111/jth.15806
105. D’Alonzo D, De Fenza M, Pavone V. COVID-19 and pneumonia: a role for the uPA/uPAR system. Drug Discov Today 2020;25:1528–34. doi: 10.1016/j.drudis.2020.06.013
106. Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol 2014;89:228–32. doi: 10.1002/ajh.23599
107. Pavoni V, Gianesello L, Pazzi M, Stera C, Meconi T, Frigieri CF. Evaluation of coagulation function by rotation thromboelastometry in critically ill patients with severe COVID-19 pneumonia. J Thromb Thrombolysis 2020;50:281–6. doi: 10.1007/s11239-020-02130-7
108. Salem N, Atallah B, El Nekidy WS, Sadik ZG, Park WM, Mallat J. Thromboelastography findings in critically ill COVID-19 patients. J Thromb Thrombolysis 2021;51:961–5. doi: 10.1007/s11239-020-02300-7
109. Collett LW, Gluck S, Strickland RM. Evaluation of coagulation status using viscoelastic testing in intensive care patients with coronavirus disease 2019 (COVID-19): an observational point prevalence cohort study. Aust Crit Care 2021;34:155–9. doi: 10.1016/j.aucc.2020.07.003
110. Bachler M, Bösch J, Stürzel DP, Hell T, Giebl A, Ströhle M, et al. Impaired fibrinolysis in critically ill COVID-19 patients. Br J Anaesth 2021;126:590–8. doi: 10.1016/j.bja.2020.12.010
111. Creel-Bulos C, Auld SC, Caridi-Scheible M, Barker NA, Friend S, Gaddh M, et al. Fibrinolytic shutdown in COVID-19 is likely a misnomer. Shock 2021;55:316–20. doi: 10.1097/SHK.0000000000001635
112. Seheult JN, Seshadri A, Neal MD. Fibrinolysis shutdown and thrombosis in severe COVID-19. J Am Coll Surg 2020;231:203–4. doi: 10.1016/j.jamcollsurg.2020.05.021
113. Wright FL, Vogler TO, Moore EE, Moore HB, Wohlauer MV, Urban S, et al. Fibrinolysis shutdown correlation with thromboembolic events in severe COVID-19 infection. J Am Coll Surg 2020;231:193–203.e1. doi: 10.1016/j.jamcollsurg.2020.05.007
114. Creel-Bulos C, Sniecinski R. Fibrinolysis shutdown and thrombosis in a COVID-19 ICU. Shock 2021;55:845–6. doi: 10.1097/SHK.0000000000001666
115. Manzoor D, Bui C, Makhoul E, Luthringer D, Marchevsky A, Volod O. Improvement in plasma D-dimer level in severe SARS-CoV-2 infection can be an indicator of fibrinolysis suppression: case reports. Medicine (Baltimore) 2021;100:e25255. doi: 10.1097/MD.0000000000025255
116. Moore HB, Moore EE, Neal MD, Sheppard FR, Kornblith LZ, Draxler DF, et al. Fibrinolysis shutdown in trauma: historical review and clinical implications. Anesth Analg 2019;129:762–73. doi: 10.1213/ANE.0000000000004234
117. Moore EE. Temporal changes in fibrinolysis shutdown following injury. J Am Coll Surg 2016;222:347–55.
118. Nakae R, Murai Y, Wada T, Fujiki Y, Kanaya T, Takayama Y, et al. Hyperfibrinolysis and fibrinolysis shutdown in patients with traumatic brain injury. Sci Rep 2022;12:19107. doi: 10.1038/s41598-022-23912-4
119. Moore HD. Fibrinolysis shutdown and hypofibrinolysis are not synonymous terms: the clinical significance of differentiating low fibrinolytic states. Semin Thromb Hemost 2023;49:433–43. doi: 10.1055/s-0042-1758057
120. Chandler WL, Alessi MC, Aillaud MF, Henderson P, Vague P, Juhan-Vague I. Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels. Circulation 1997;96:761–8. doi: 10.1161/01.cir.96.3.761
121. Idell S. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med 2003;31(4 suppl.):S213–20. doi: 10.1097/01.CCM.0000057846.21303.AB
122. Ibañez C, Perdomo J, Calvo A, Ferrando C, Reverter JC, Tassies D, et al. High D dimers and low global fibrinolysis coexist in COVID19 patients: what is going on in there? J Thromb Thrombolysis 2021;51:308–12. doi: 10.1007/s11239-020-02226-0
123. Kwaan HC, Lindholm PF. The central role of fibrinolytic response in COVID-19-a hematologist’s perspective. Int J Mol Sci. 2021;22:1283. doi: 10.3390/ijms22031283
124. Savitt AG, Manimala S, White T, Fandaros M, Yin W, Duan H, et al. ARS-CoV-2 exacerbates COVID-19 pathology through activation of the complement and Kinin systems. Front Immunol 2021;12:767347. doi: 10.3389/fimmu.2021.767347
125. McCarthy CG, Wilczynski S, Wenceslau CF, Webb RC. A new storm on the horizon in COVID-19: Bradykinin-induced vascular complications. Vascul Pharmacol 2021;137:106826. doi: 10.1016/j.vph.2020.106826
126. Tabassum A, Iqbal MS, Sultan S, Alhuthali RA, Alshubaili DI, Sayyam RS, et al. Dysregulated BradykinIn: mystery in the pathogenesis of COVID-19. Mediators Inflamm 2022;2022:7423537. doi: 10.1155/2022/7423537
127. Malaquias MAS, Gadotti AC, Motta-Junior JDS, Martins APC, Azevedo MLV, Benevides APK, et al. The role of the lectin pathway of the complement system in SARS-CoV-2 lung injury. Transl Res 2021;231:55–63. doi: 10.1016/j.trsl.2020.11.008
128. Niederreiter J, Eck C, Ries T, Hartmann A, Märkl B, Büttner-Herold M, et al. Complement activation via the Lectin and alternative pathway in patients with severe COVID-19. Front Immunol 2022;13:835156. doi: 10.3389/fimmu.2022.835156
129. Szturmowicz M, Demkow U. Neutrophil extracellular traps (NETs) in severe SARS-CoV-2 lung disease. Int J Mol Sci 2021;22:8854. doi: 10.3390/ijms22168854
130. Li S, Wang H, Shao Q. The central role of neutrophil extracellular traps (NETs) and by-products in COVID-19 related pulmonary thrombosis. Immun Inflamm Dis 2023;11:e94. doi: 10.1002/iid3.949
131. Al-Kuraishy HM, Al-Gareeb AI, Al-Hussaniy HA, Al-Harcan NAH, Alexiou A, Batiha GE. Neutrophil extracellular traps (NETs) and Covid-19: a new frontiers for therapeutic modality. Int Immunopharmacol 2022;104:108516. doi: 10.1016/j.intimp.2021.108516
132. Middleton EA, He XY, Denorme F, Campbell RA, Ng D, Salvatore SP, et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 2020;136:1169–79. doi: 10.1182/blood.2020007008
133. Schultze JL, Aschenbrenner AC. COVID-19 and the human innate immune system. Cell 2021;184:1671–92. doi: 10.1016/j.cell.2021.02.029
134. De Andrade SA, De Souza DA, Torres AL, De Lima CFG, Ebram MC, Celano RMG, et al. Pathophysiology of COVID-19: critical role of hemostasis. Front Cell Infect Microbiol 2022;12:896972. doi: 10.3389/fcimb.2022.896972
135. Gando S, Wada T. Thromboplasminflammation in COVID-19 coagulopathy: three viewpoints for diagnostic and therapeutic strategies. Front Immunol 2021;12:649122. doi: 10.3389/fimmu.2021.649122
136. Wagner DD, Heger LA. Thromboinflammation: from atherosclerosis to COVID-19. Arterioscler Thromb Vasc Biol 2022;42:1103–12. doi: 10.1161/ATVBAHA.122.317162
137. Ali MAM, Spinler SA.Trends. COVID-19 and thrombosis: from bench to bedside. Cardiovasc Med 2021;31:143–60. doi: 10.1016/j.tcm.2020.12.004
138. Zhu Z, Lian X, Su X, Wu W, Marraro GA, Zeng Y. From SARS and MERS to COVID-19: a brief summary and comparison of severe acute respiratory infections caused by three highly pathogenic human coronaviruses. Respir Res 2020;21(1):224. doi: 10.1186/s12931-020-01479-w
2. Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? Eur Heart J 2020;41:1858. doi: 10.1093/eurheartj/ehaa254
3. Bompard F, Monnier H, Saab I, Tordjman M, Abdoul H, Fournier L, et al. Pulmonary embolism in patients with COVID-19 pneumonia. Eur Respir J 2020;56:2001365. doi: 10.1183/13993003.01365-2020
4. Di Minno A, Ambrosino P, Calcaterra I, Di Minno MND. COVID-19 and venous thromboembolism: a meta-analysis of literature studies. Semin Thromb Hemost 2020;46:763–71. doi: 10.1055/s-0040-1715456
5. Wichmann D, Sperhake JP, Lütgehetmann M, Steurer S, Edler C, Heinemann A, et al. Autopsy findings and venous thromboembolism in patients with COVID-19, a prospective cohort study. Ann Intern Med 2020;173:268–77. doi: 10.7326/M20-2003
6. Calabrese F, Pezzuto F, Fortarezza F, Hofman P, Kern I, Panizo A, et al. Pulmonary pathology and COVID-19: lessons from autopsy. The experience of European pulmonary pathologists. Virchows Arch 2020;477:359–72. doi: 10.1007/s00428-020-02886-6
7. Grimes Z, Bryce C, Sordillo EM, Gordon RE, Reidy J, Mondolfi AEP, et al. Fatal pulmonary thromboembolism in SARS-CoV-2-infection. Cardiovasc Pathol 2020;48:107227. doi: 10.1016/j.carpath.2020.107227
8. Shao C, Liu H, Meng L, Sun L, Wang Y, Yue Z, et al. Evolution of severe acute respiratory syndrome coronavirus 2 RNA test results in a patient with fatal coronavirus disease 2019: a case report. Pathology 2020;101:82–8. doi: 10.1016/j.humpath.2020.04.015
9. Bu ja LM, Wolf DA, Zhao B, Akkanti B, McDonald M, Lelenwa L, et al. The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities. Cardiovasc Pathol 2020;48:107233. doi: 10.1016/j.carpath.2020.107233
10. Nicolai L, Leunig A, Brambs S, Kaiser R, Weinberger T, Weigand M, et al. Immunothrombotic dysregulation in COVID-19 pneumonia is associated with respiratory failure and coagulopathy. Circulation 2020;142:1176–89. doi: 10.1161/CIRCULATIONAHA.120.048488
11. Menter T, Haslbauer JD, Nienhold R, Savic S, Hopfer H, Nikolaus D, et al. Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology 2020;77:198–109. doi: 10.1111/his.14134
12. Elsoukkary S, Mostyka M, Dillard A, Berman DR, Ma LX, Chadburn A, et al. Autopsy Findings in 32 patients with COVID-19: a single institution experience. Pathobiology 2021;88:56–68. doi: 10.1159/000511325
13. Fahmy OH, Daas FM, Salunkhe V, Petrey JL, Cosar EF, Ramirez J, et al. Is microthrombosis the main pathology in coronavirus disease 2019 severity? – A systematic review of the postmortem pathologic findings. Crit Care Explor 2021;3:e0427. doi: 10.1097/CCE.0000000000000427
14. Chen W, Pan JY. Anatomical and pathological observation and analysis of SARS and COVID-19: microthrombosis is the main cause of death. Biol Proc Online 2021;23:4. doi: 10.1186/s12575-021-00142-y
15. Buja LM, Zhao B, McDonald M, Ottaviani G, Wolf DA. Commentary on the spectrum of cardiopulmonary pathology in COVID-19. Cardiovasc Pathol 2021;53:107339. doi: 10.1016/j.carpath.2021.107339
16. Wool GD, Miller JL. The impact of COVID-19 disease on platelets and coagulation. Pathobiology 2021;88:15–27. doi: 10.1159/000512007
17. Iba T, Levy JH, Levi M, Thachil JJ. Coagulopathy in COVID-19. J Thromb Haemost 2020;18:2103–9. doi: 10.1111/jth.14975
18. Asakura H, Ogawa H. COVID‑19‑associated coagulopathy and disseminated intravascular coagulation. Int J Hematol 2021;113:45–57. doi: 10.1007/s12185-020-03029-y
19. Toshiaki Iba T, Wada H, Levy JH. Platelet activation and thrombosis in COVID-19. Semin Thromb Hemost 2023;1:55–61. doi: 10.1055/s-0042-1749441
20. Meizoso JP, Moore HB, Moore EE. Fibrinolysis shutdown in COVID-19: clinical manifestations, molecular mechanisms, and therapeutic implications. J Am Coll Surg 2021;232:995–1003. doi: 10.1016/j.jamcollsurg.2021.02.019
21. Scialo F, Daniele A, Amato F, Pastore L, Matera MG, Cazzola M, et al. ACE2: the major cell entry receptor for SARS-CoV-2. Lung 2020;198:867–77. doi: 10.1007/s00408-020-00408-4
22. Jackson CB, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol 2022;23:3–20. doi: 10.1038/s41580-021-00418-x.
23. Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med 2020;383:2255–73. doi: 10.1056/NEJMra2026131
24. Pasrija R, Naime M. The deregulated immune reaction and cytokines release storm (CRS) in COVID-19 disease. Int Immunopharmacol 2021;90:107225. doi: 10.1016/j.intimp.2020.107225
25. Castelli V, Cimini A, Ferri C. Cytokine Storm in COVID-19: when you come out of the storm, You won’t be the same person who walked in. Front Immunol 2020;11:2132. doi: 10.3389/fimmu.2020.02132
26. Hojyo S, Uchida M, Tanaka K, et al. How COVID-19 induces cytokine storm with high mortality. Inflamm Regen 2020;40:37. doi: 10.3389/fimmu.2020.02132
27. Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol 2020;39:2085–94. doi: 10.1007/s10067-020-05190-5
28. Gustine JN, Jones D. Immunopathology of hyperinflammation in COVID-19. Am J Pathol 2021;191:4–17. doi: 10.1016/j.ajpath.2020.08.009
29. Tufa A, Gebremariam TH, Manyazewal T, Getinet T, Webb DL, Hellström PM, et al. Inflammatory mediators profile in patients hospitalized with COVID-19: a comparative study. Front Immunol 2022;13:964179. doi: 10.3389/fimmu.2022.964179
30. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. Engl J Med 2020;383:120–8. doi: 10.1056/NEJMoa2015432
31. Barbosa LC, Gonçalves TL, De Araujo LP, Rosario LVO, Ferrer VP. Endothelial cells and SARS-CoV-2: an intimate relationship. Vascu Pharmacol 2021;137:106829. doi: 10.1016/j.vph.2021.106829
32. Bernard I, Limonta D, Mahal LK, Hobman TC. Endothelium infection and dysregulation by SARS-CoV-2: evidence and avceats in COVID-19. Viruses 2020;13:29. doi: 10.3390/v13010029
33. Amraei R, Rahimi N. COVID-19, renin-angiotensin system and endothelial dysfunction. Cells 2020;9:1652. doi: 10.3390/cells9071652
34. Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J 2020;41:3038–44. doi: 10.1093/eurheartj/ehaa623
35. Nägele MP, Haubner B, Tanner FC, Ruschitzka F, Flammer AJ. Endothelial dysfunction in COVID-19: current findings and therapeutic implications. Atherosclerosis 2020;314:58–62. doi: 10.1016/j.atherosclerosis.2020.10.014
36. Copin MC, Parmentier E, Duburcq T, Poissy J, Mathieu D, Lille COVID-19 ICU and Anatomopathology Group. Time to consider histologic pattern of lung injury to treat critically ill patients with COVID‑19 infection. Intensive Care Med 2020;46:1124–6. doi: 10.1007/s00134-020-06057-8
37. Cañas CA, Cañas F, Bautista-Vargas M, Bonilla-Abadía F. Role of tissue factor in the pathogenesis of COVID-19 and the possible ways to inhibit it. Clin Appl Thromb Hemost 2021;27:10760296211003983. doi: 10.1177/10760296211003983
38. Goshua G, Pine AB, Meizlish ML, Chang CH, Zhang H, Bahel P, et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol 2020;7:e575–82. doi: 10.1016/S2352-3026(20)30216-7
39. Christensen B, Favaloro EJ, Lippi G, Van Cott EM. Hematology laboratory abnormalities in patients with coronavirus disease 2019 (COVID-19). Semin Thromb Hemost 2020;46:845–9. doi: 10.1055/s-0040-1715458
40. Zuo Y, Warnock M, Harbaugh A, Yalavarthi S, Gockman K, Zuo M, et al. Plasma tissue plasminogen activator and plasminogen activator inhibitor‑1 in hospitalized COVID‑19 patients. Sci Rep 2021;11:1580. doi: 10.1038/s41598-020-80010-z
41. Norooznezhad AH, Mansouri K. Endothelial cell dysfunction, coagulation, and angiogenesis in coronavirus disease 2019 (COVID-19). Microvasc Res 2021;137:104188. doi: 10.1016/j.mvr.2021.104188
42. Bouck EG, Denorme F, Holle LA, Middelton EA, Blair AM, De Laat B, et al. COVID-19 and sepsis are associated with different abnormalities in plasma procoagulant and fibrinolytic activity. Arterioscler Thromb Vasc Biol 2021;41:401–14. doi: 10.1161/ATVBAHA.120.315338
43. Rosell A, Havervall S, von Meijenfeldt F, Hisada Y, Aguilera K, Grover SP, et al. 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 2021;41:878–82. doi: 10.1161/ATVBAHA.120.315547
44. Hisada Y, Alexander W, Kasthuri R, Voorhees P, Mobarrez F, Taylor A, McNamara C, et al. Measurement of microparticle tissue factor activity in clinical samples: a summary of two tissue factor-dependent FXa generation assays. Thromb Res 2016;139:90–7. doi: 10.1016/j.thromres.2016.01.011
45. Henderson MW, Lima F, Moraes CRP, Ilich A, Huber SC, Barbosa MS, et al. Contact and intrinsic coagulation pathways are activated and associated with adverse clinical outcomes in COVID-19. Blood Adv 2022;6:3367–77. doi: 10.1182/bloodadvances.2021006620
46. Guervilly C, Bonifay A, Burtey S, Sabatier F, Cauchois R, Abdili E, et al. Dissemination of extreme levels of extracellular vesicles: tissue factor activity in patients with severe COVID-19. Blood Adv 2021;5:628–34. doi: 10.1182/bloodadvances.2020003308
47. Hamali HA, Saboor M, Dobie G, Madkhali AM, Akhter MS, Hakamy A, et al. Procoagulant microvesicles in COVID-19 patients: possible modulators of inflammation and prothrombotic tendency. Infect Drug Resist 2022;15:2359–68. doi: 10.2147/IDR.S355395
48. Subrahmanian S, Borczuk A, Salvatore S, Fung KM, Merrill JT, Laurence J, et al. Tissue factor upregulation is associated with SARS-CoV-2 in the lungs of COVID-19 patients. J Thromb Haemost 2021;19:2268–74. doi: 10.1111/jth.15451
49. Girard TJ, Antunes L, Zhang N, Amrute JM, Subramanian R, Eldem I, 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;21:629–38. doi: 10.1016/j.jtha.2022.11.033
50. Martinelli N, Rigoni AM, De Marchi S, Osti N, Donini M, Montagnana M, et al. High plasma levels of activated Factor VII-antithrombin complex point to increased tissue factor expression in patients with SARS-CoV-2 pneumonia: a potential link with COVID-19 prothrombotic diathesis. Diagnostics (Basel) 2022;12:2792. doi: 10.3390/diagnostics12112792
51. Martinelli N, Girelli D, Baroni M, Guarini P, Sandri M, Lunghi B, et al. Activated factor VII-antithrombin complex predicts mortality in patients with stable coronary artery disease: a cohort study. J Thromb Haemost 2016;14(4):655–66. doi: 10.1111/jth.13274
52. Rao LV, Nordfang O, Hoang AD, Pendurthi UR. Mechanism of antithrombin III inhibition of factor VIIa/tissue factor activity on cell surfaces. Comparison with tissue factor pathway inhibitor/factor Xa-induced inhibition of factor VIIa/tissue factor activity. Blood 1995;85:121–9. doi: 10.1182/blood.V85.1.121.bloodjournal851121
53. Wygrecka M, Birnhuber A, Seeliger B, Michalick L, Pak O, Schultz AS, et al. Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19. Blood Adv 2022;6:1074–87. doi: 10.1182/bloodadvances.2021004816
54. Murray NP, Guzman E, Del Prado M. Transient acquired factor XII deficiency associated with moderately severe COVID-19 pneumonia. Hematol Transfus Cell Ther 2021;43:515–7. doi: 10.1016/j.htct.2021.06.017
55. Bachler M, Niederwanger C, Hell T, Höfer J, Gerstmeyr D, Schenk BT, et al. Influence of factor XII deficiency on activated partial thromboplastin time (aPTT) in critically ill patients. J Thromb Thrombolysis 2019;48:466–74. doi: 10.1007/s11239-019-01879-w
56. He S, MD, Cao HL, Thålin C, Svensson J, Blombäck, M, Wallén H. The clotting trigger is an important determinant for the coagulation pathway in vivo or in vitro – inference from data review. Semin Thromb Hemost 2021;47:63–73. doi: 10.1055/s-0040-1718888
57. Busch MH, Timmermans SAMEG, Nagy M, Visser M, Huckriede J, Aendekerk JP, et al. Neutrophils and contact activation of coagulation as potential drivers of COVID-19. Circulation 2020;142:1787–90. doi: 10.1161/CIRCULATIONAHA.120.050656
58. Hvas CL, Larsen JB, Adelborg K, Christensen S, Hvas AM. Dynamic hemostasis and fibrinolysis assays in intensive care COVID-19 patients and association with thrombosis and bleeding – a systematic review and a Cohort study. Semin Thromb Hemost 2022;48:31–54. doi: 10.1055/s-0041-1735454
59. Cacciola R, Cacciola EG, Vecchio V, Cacciola E. Cellular and molecular mechanisms in COVID-19 coagulopathy: role of inflammation and endotheliopathy. J Thromb Thrombolysis 2022;53:282–90. doi: 10.1007/s11239-021-02583-4
60. Hemker HC, Giesen P, Al Dieri R, Regnault V, de Smedt E, Wagenvoord R, et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003;33:4–15. doi: 10.1159/000071636
61. Blasi A, von Meijenfeldt FA, Adelmeijer J, Calvo A, Ibañez C, Perdomo J, et al. In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation. J Thromb Haemost 2020;18:2646–53. doi: 10.1111/jth.15043
62. Benati M, Salvagno GL, Nitto S, Gelati M, Lavorgna B, Fava C, et al. Thrombin generation in patients with coronavirus disease 2019. Semin Thromb Hemost 2021;47:447–50. doi: 10.1055/s-0041-1722844
63. Hardy M, Michaux I, Lessire S, Douxfils J, Dogné JM, Bareille M, et al. Prothrombotic disturbances of hemostasis of patients with severe COVID-19: a prospective longitudinal observational study. Thromb Res 2021;197:20–3. doi: 10.1016/j.thromres.2020.10.025
64. Buffart B, Demulder A, Fangazio M, Rozen L. Global hemostasis potential in COVID-19 positive patients performed on St-genesia show hypercoagulable state. J Clin Med. 2022;11:7255. doi: 10.3390/jcm11247255
65. Nougier C, Benoit R, Simon M, Desmurs-Clavel H, Marcotte G, Argaud L, et al. Hypofibrinolytic state and high thrombin generation may play a major role in SARS-COV2 associated thrombosis. J Thromb Haemost 2020;18:2215–9. doi: 10.1016/j.thromres.2020.10.025
66. Cohen O, Landau N, Avisahai E, Brutman-Barazani T, Budnik I, Livnat T, et al. Association between thrombin generation and clinical characteristics in COVID-19 patients. Acta Haematol 2023;146:151–60. doi: 10.1159/000527581
67. Mennuni MG, Rolla R, Grisafi L, Spinoni EG, Rognoni A, Lio V, et al. Interaction between thrombin potential and age on early clinical outcome in patients hospitalized for COVID-19. J Thromb Thrombolysis 2021;52:746–53. doi: 10.1007/s11239-021-02497-1
68. Gris JC, Guillotin F, Dos Santos TP, Chéa M, Loubet P, Laureillard D, et al. Prognostic value of an automated thrombin generation assay in COVID-19 patients entering hospital: a multicentric, prospective observational study. Thromb Res 2023;222:85–95. doi: 10.1016/j.thromres.2022.12.019
69. Campello E, Bulato C, Spiezia L, Boscolo A, Poletto F, Cola M, et al. Thrombin generation in patients with COVID-19 with and without thromboprophylaxis. Clin Chem Lab Med 2021;59:1323–30. doi: 10.1515/cclm-2021-0108
70. Nordfang O, Kristensen HI, Valentin S, Ostergaard P, Wadt J. The significance of TFPI in clotting assays – comparison and combination with other anticoagulants. Thromb Haemost 1993;70:448–53. doi: 10.1055/s-0038-1649603
71. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and antiphospholipid antibodies in patients with Covid 19. Engl J Med 2020;382:e38. doi: 10.1056/NEJMc2007575
72. Butt A, Erkan D, Lee AI. COVID-19 and antiphospholipid antibodies. Best Pract Res Clin Haematol 2022;35:101402. doi: 10.1016/j.beha.2022.101402
73. Kinev AV, Roubey RAS. Tissue factor in the antiphospholipid syndrome. Lupus 2008; 17:952–8.doi: 10.1177/0961203308096662
74. He S, Wallén H, Thålin C, Svensson J, Blombäck M. Fibrin network porosity and endo-/exogenous thrombin cross-talk. Semin Thromb Hemost 2021;47:775–86. doi: 10.1055/s-0041-1729963
75. Luyendyk JP, Schoenecker JG, Flick MJ. The multifaceted role of fibrinogen in tissue injury and inflammation. Blood 2019;133:511–20. doi: 10.1182/blood-2018-07-818211
76. White D, MacDonald S, Edwards T, Bridgeman C, Hayman M, Sharp M, et al. Evaluation of COVID-19 coagulopathy; laboratory characterization using thrombin generation and nonconventional haemostasis assays. Int J Lab Hematol 2021;43:123–30. doi: 10.1111/ijlh.13329
77. Velavan TP, Meyer CG. Mild versus severe COVID-19: laboratory markers. Int J Infect Dis 2020;95:304–7. doi: 10.1016/j.ijid.2020.04.061
78. Hayıroğlu MI, Cınar T, Tekkeşin AI. Fibrinogen and D-dimer variances and anticoagulation recommendations in Covid-19: current literature review. Rev Assoc Med Bras 2020;66:842–8. doi: 10.1590/1806-9282.66.6.842
79. Wang Z, Du Z, Zhao X, Guo F, Wang T, Zhu F. Determinants of increased fibrinogen in COVID-19 patients with and without diabetes and impaired fasting glucose. Clin Appl Thromb Hemost 2021;27 1076029621996445. doi: 10.1177/1076029621996445
80. Rostami M, Mansouritorghabeh H. D-dimer level in COVID-19 infection: a systematic review. Expert Rev Hematol 2020;13:1265–75. doi: 10.1080/17474086.2020.1831383
81. Zhan H, Chen H, Liu C, Cheng L, Yan S, Li H, et al. Diagnostic value of D-dimer in COVID-19: a meta-analysis and meta-regression. Clin Appl Thromb Hemost 2021;27:10760296211010976. doi: 10.1177/10760296211010976
82. Canzano P, Brambilla M, Porro B, Cosentino N, Tortorici E, Vicini S, et al. Platelet and endothelial activation as potential mechanisms behind the thrombotic complications of COVID-19 patients. JACC Basic Transl Sci 2021;6:202–18. doi: 10.1016/j.jacbts.2020.12.009
83. Iba T, Wada H, Jerrold H. Levy. JH. Platelet activation and thrombosis in COVID-19. Semin Thromb Hemost 2023;49:55–61. doi: 10.1055/s-0042-1749441
84. Mei H, Luo L, Hu Y. Thrombocytopenia and thrombosis in hospitalized patients with COVID-19. Hematol Oncol 2020;13:161. doi: 10.1186/s13045-020-01003-z
85. Jevtic SD, Nazy I. The COVID complex: a review of platelet activation and immune complexes in COVID-19. Front Immunol 2022;13:807934. doi: 10.3389/fimmu.2022.807934
86. Kaur S, Singh A, Kaur J, Verma N, Pandey AK, Das S, et al. Upregulation of cytokine signaling in platelets increases risk of thrombophilia in severe COVID-19 patients. Blood Cells Mol Dis 2022;94:102653. doi: 10.1016/j.bcmd.2022.102653
87. Theofilis P, Sagris M, Antonopoulos AS, Oikonomou E, Tsioufis C, Tousoulis D. Inflammatory mediators of platelet activation: focus on atherosclerosis and COVID-19. Int J Mol Sci 2021;22:11170. doi: 10.3390/ijms222011170
88. Garcia C, Au Duong J, Poëtte M, Ribes A, Payre B, Mémier V, et al. Platelet activation and partial desensitization are associated with viral xenophagy in patients with severe COVID-19. Blood Adv 2022;6:3884–98. doi: 10.1182/bloodadvances.2022007143
89. Zhang S, Liu Y, Wang X, Yang L, Li H, Wang Y, et al. SARS-CoV 2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol 2020;13:120. doi: 10.1186/s13045-020-00954-7
90. Manne BK, Denorme F, Middleton EA, Portier I, Rowley JW, Stubben C, et al. Platelet gene expression and function in patients with COVID-19. Blood 2020;136:1317–32. doi: 10.1182/blood.2020007214
91. Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008;112:11–18. doi: 10.1182/blood.2020007214
92. Peyvandi F, Garagiola I, Baronciani L. Role of von Willebrand factor in the haemostasis. Blood Transfus 2011;9(suppl. 2):s3–s8. doi: 10.2450/2011.002S
93. DeYoung V, Singh K, Kretz CA. Mechanisms of ADAMTS13 regulation. Thromb Haemost 2022;120:2722–32. doi: 10.1111/jth.15873
94. Zheng XL. Structure-function and regulation of ADAMTS13 protease. J Thromb Haemost 2013;11:11–23. doi: 10.1111/jth.12221
95. George JN. TTP: the evolution of clinical practice. Blood 2021;137:719–720. doi: 10.1182/blood.2020009654
96. Azhdari Tehrani H, Darnahal M, Vaezi M, Haghighi S. COVID-19 associated thrombotic thrombocytopenic purpura (TTP): a case series and mini-review. Int Immunopharmacol 2021;93:107397. doi: 10.1016/j.intimp.2021.107397
97. Altowyan E, Alnujeidi O, Alhujilan A, Alkathlan M. COVID-19 presenting as thrombotic thrombocytopenic purpura (TTP). BMJ Case Rep 2020;13:e238026. doi: 10.1136/bcr-2020-238026
98. Chaudhary H, Nasir U, Syed K, Labra M, Reggio C, Aziz A, et al. COVID-19-associated thrombotic thrombocytopenic purpura: a case report and systematic review. Hematol Rep 2022;14:253–60. doi: 10.3390/hematolrep14030035
99. Zheng XL, Vesely SK, Cataland SR, Coppo P, Geldziler B, Iorio A, et al. ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost 2020;18:2486–95. doi: 10.1111/jth.15006
100. Mancini I, Baronciani L, Artoni A, Colpani P, Biganzoli M, Cozzi G, et al. The ADAMTS13-von Willebrand factor axis in COVID-19 patients. J Thromb Haemost 2021;19:513–21. doi: 10.1111/jth.15191
101. Maharaj S, Xue R, Rojan A. Thrombotic thrombocytopenic purpura (TTP) response following COVID-19 infection: implications for the ADAMTS-13-von Willebrand factor axis. J Thromb Haemost 2021;19:1130–2. doi: 10.1111/jth.15230
102. Favaloro EJ, Henry BM, Lippi G. Increased VWF and decreased ADAMTS-13 in COVID-19: creating a Milieu for (Micro)thrombosis. Semin Thromb Hemost 2021;47:400–18. doi: 10.1111/jth.15230
103. Henry BM, Benoit SW, Hoehn J, Lippi G, Favaloro EJ, Benoit JL. Circulating plasminogen concentration at admission in patients with coronavirus disease 2019 (COVID-19). Semin Thromb Hemost 2020;46:859–62. doi: 10.1055/s-0040-1715454
104. Whyte CS, Simpson M, Morrow GB, Wallace CA, Mentzer AJ, Knight JC, et al. The suboptimal fibrinolytic response in COVID-19 is dictated by high PAI-1. J Thromb Haemost 2022;20:2394–406. doi: 10.1111/jth.15806
105. D’Alonzo D, De Fenza M, Pavone V. COVID-19 and pneumonia: a role for the uPA/uPAR system. Drug Discov Today 2020;25:1528–34. doi: 10.1016/j.drudis.2020.06.013
106. Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol 2014;89:228–32. doi: 10.1002/ajh.23599
107. Pavoni V, Gianesello L, Pazzi M, Stera C, Meconi T, Frigieri CF. Evaluation of coagulation function by rotation thromboelastometry in critically ill patients with severe COVID-19 pneumonia. J Thromb Thrombolysis 2020;50:281–6. doi: 10.1007/s11239-020-02130-7
108. Salem N, Atallah B, El Nekidy WS, Sadik ZG, Park WM, Mallat J. Thromboelastography findings in critically ill COVID-19 patients. J Thromb Thrombolysis 2021;51:961–5. doi: 10.1007/s11239-020-02300-7
109. Collett LW, Gluck S, Strickland RM. Evaluation of coagulation status using viscoelastic testing in intensive care patients with coronavirus disease 2019 (COVID-19): an observational point prevalence cohort study. Aust Crit Care 2021;34:155–9. doi: 10.1016/j.aucc.2020.07.003
110. Bachler M, Bösch J, Stürzel DP, Hell T, Giebl A, Ströhle M, et al. Impaired fibrinolysis in critically ill COVID-19 patients. Br J Anaesth 2021;126:590–8. doi: 10.1016/j.bja.2020.12.010
111. Creel-Bulos C, Auld SC, Caridi-Scheible M, Barker NA, Friend S, Gaddh M, et al. Fibrinolytic shutdown in COVID-19 is likely a misnomer. Shock 2021;55:316–20. doi: 10.1097/SHK.0000000000001635
112. Seheult JN, Seshadri A, Neal MD. Fibrinolysis shutdown and thrombosis in severe COVID-19. J Am Coll Surg 2020;231:203–4. doi: 10.1016/j.jamcollsurg.2020.05.021
113. Wright FL, Vogler TO, Moore EE, Moore HB, Wohlauer MV, Urban S, et al. Fibrinolysis shutdown correlation with thromboembolic events in severe COVID-19 infection. J Am Coll Surg 2020;231:193–203.e1. doi: 10.1016/j.jamcollsurg.2020.05.007
114. Creel-Bulos C, Sniecinski R. Fibrinolysis shutdown and thrombosis in a COVID-19 ICU. Shock 2021;55:845–6. doi: 10.1097/SHK.0000000000001666
115. Manzoor D, Bui C, Makhoul E, Luthringer D, Marchevsky A, Volod O. Improvement in plasma D-dimer level in severe SARS-CoV-2 infection can be an indicator of fibrinolysis suppression: case reports. Medicine (Baltimore) 2021;100:e25255. doi: 10.1097/MD.0000000000025255
116. Moore HB, Moore EE, Neal MD, Sheppard FR, Kornblith LZ, Draxler DF, et al. Fibrinolysis shutdown in trauma: historical review and clinical implications. Anesth Analg 2019;129:762–73. doi: 10.1213/ANE.0000000000004234
117. Moore EE. Temporal changes in fibrinolysis shutdown following injury. J Am Coll Surg 2016;222:347–55.
118. Nakae R, Murai Y, Wada T, Fujiki Y, Kanaya T, Takayama Y, et al. Hyperfibrinolysis and fibrinolysis shutdown in patients with traumatic brain injury. Sci Rep 2022;12:19107. doi: 10.1038/s41598-022-23912-4
119. Moore HD. Fibrinolysis shutdown and hypofibrinolysis are not synonymous terms: the clinical significance of differentiating low fibrinolytic states. Semin Thromb Hemost 2023;49:433–43. doi: 10.1055/s-0042-1758057
120. Chandler WL, Alessi MC, Aillaud MF, Henderson P, Vague P, Juhan-Vague I. Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels. Circulation 1997;96:761–8. doi: 10.1161/01.cir.96.3.761
121. Idell S. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med 2003;31(4 suppl.):S213–20. doi: 10.1097/01.CCM.0000057846.21303.AB
122. Ibañez C, Perdomo J, Calvo A, Ferrando C, Reverter JC, Tassies D, et al. High D dimers and low global fibrinolysis coexist in COVID19 patients: what is going on in there? J Thromb Thrombolysis 2021;51:308–12. doi: 10.1007/s11239-020-02226-0
123. Kwaan HC, Lindholm PF. The central role of fibrinolytic response in COVID-19-a hematologist’s perspective. Int J Mol Sci. 2021;22:1283. doi: 10.3390/ijms22031283
124. Savitt AG, Manimala S, White T, Fandaros M, Yin W, Duan H, et al. ARS-CoV-2 exacerbates COVID-19 pathology through activation of the complement and Kinin systems. Front Immunol 2021;12:767347. doi: 10.3389/fimmu.2021.767347
125. McCarthy CG, Wilczynski S, Wenceslau CF, Webb RC. A new storm on the horizon in COVID-19: Bradykinin-induced vascular complications. Vascul Pharmacol 2021;137:106826. doi: 10.1016/j.vph.2020.106826
126. Tabassum A, Iqbal MS, Sultan S, Alhuthali RA, Alshubaili DI, Sayyam RS, et al. Dysregulated BradykinIn: mystery in the pathogenesis of COVID-19. Mediators Inflamm 2022;2022:7423537. doi: 10.1155/2022/7423537
127. Malaquias MAS, Gadotti AC, Motta-Junior JDS, Martins APC, Azevedo MLV, Benevides APK, et al. The role of the lectin pathway of the complement system in SARS-CoV-2 lung injury. Transl Res 2021;231:55–63. doi: 10.1016/j.trsl.2020.11.008
128. Niederreiter J, Eck C, Ries T, Hartmann A, Märkl B, Büttner-Herold M, et al. Complement activation via the Lectin and alternative pathway in patients with severe COVID-19. Front Immunol 2022;13:835156. doi: 10.3389/fimmu.2022.835156
129. Szturmowicz M, Demkow U. Neutrophil extracellular traps (NETs) in severe SARS-CoV-2 lung disease. Int J Mol Sci 2021;22:8854. doi: 10.3390/ijms22168854
130. Li S, Wang H, Shao Q. The central role of neutrophil extracellular traps (NETs) and by-products in COVID-19 related pulmonary thrombosis. Immun Inflamm Dis 2023;11:e94. doi: 10.1002/iid3.949
131. Al-Kuraishy HM, Al-Gareeb AI, Al-Hussaniy HA, Al-Harcan NAH, Alexiou A, Batiha GE. Neutrophil extracellular traps (NETs) and Covid-19: a new frontiers for therapeutic modality. Int Immunopharmacol 2022;104:108516. doi: 10.1016/j.intimp.2021.108516
132. Middleton EA, He XY, Denorme F, Campbell RA, Ng D, Salvatore SP, et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 2020;136:1169–79. doi: 10.1182/blood.2020007008
133. Schultze JL, Aschenbrenner AC. COVID-19 and the human innate immune system. Cell 2021;184:1671–92. doi: 10.1016/j.cell.2021.02.029
134. De Andrade SA, De Souza DA, Torres AL, De Lima CFG, Ebram MC, Celano RMG, et al. Pathophysiology of COVID-19: critical role of hemostasis. Front Cell Infect Microbiol 2022;12:896972. doi: 10.3389/fcimb.2022.896972
135. Gando S, Wada T. Thromboplasminflammation in COVID-19 coagulopathy: three viewpoints for diagnostic and therapeutic strategies. Front Immunol 2021;12:649122. doi: 10.3389/fimmu.2021.649122
136. Wagner DD, Heger LA. Thromboinflammation: from atherosclerosis to COVID-19. Arterioscler Thromb Vasc Biol 2022;42:1103–12. doi: 10.1161/ATVBAHA.122.317162
137. Ali MAM, Spinler SA.Trends. COVID-19 and thrombosis: from bench to bedside. Cardiovasc Med 2021;31:143–60. doi: 10.1016/j.tcm.2020.12.004
138. Zhu Z, Lian X, Su X, Wu W, Marraro GA, Zeng Y. From SARS and MERS to COVID-19: a brief summary and comparison of severe acute respiratory infections caused by three highly pathogenic human coronaviruses. Respir Res 2020;21(1):224. doi: 10.1186/s12931-020-01479-w
Published
2024-01-22
How to Cite
He S., Blombäck M., & Wallén H. (2024). COVID-19: Not a thrombotic disease but a thromboinflammatory disease. Upsala Journal of Medical Sciences, 129, e9863. https://doi.org/10.48101/ujms.v129.9863
Section
Review Articles
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors retain copyright of their work, with first publication rights granted to Upsala Medical Society. Read the full Copyright- and Licensing Statement.
