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Open Access 01-12-2024 | COVID-19 | Review

Mechanisms of endothelial activation, hypercoagulation and thrombosis in COVID-19: a link with diabetes mellitus

Authors: Inés Valencia, Jairo Lumpuy-Castillo, Giselle Magalhaes, Carlos F. Sánchez-Ferrer, Óscar Lorenzo, Concepción Peiró

Published in: Cardiovascular Diabetology | Issue 1/2024

Abstract

Early since the onset of the COVID-19 pandemic, the medical and scientific community were aware of extra respiratory actions of SARS-CoV-2 infection. Endothelitis, hypercoagulation, and hypofibrinolysis were identified in COVID-19 patients as subsequent responses of endothelial dysfunction. Activation of the endothelial barrier may increase the severity of the disease and contribute to long-COVID syndrome and post-COVID sequelae. Besides, it may cause alterations in primary, secondary, and tertiary hemostasis. Importantly, these responses have been highly decisive in the evolution of infected patients also diagnosed with diabetes mellitus (DM), who showed previous endothelial dysfunction. In this review, we provide an overview of the potential triggers of endothelial activation related to COVID-19 and COVID-19 under diabetic milieu. Several mechanisms are induced by both the viral particle itself and by the subsequent immune-defensive response (i.e., NF-κB/NLRP3 inflammasome pathway, vasoactive peptides, cytokine storm, NETosis, activation of the complement system). Alterations in coagulation mediators such as factor VIII, fibrin, tissue factor, the von Willebrand factor: ADAMST-13 ratio, and the kallikrein-kinin or plasminogen-plasmin systems have been reported. Moreover, an imbalance of thrombotic and thrombolytic (tPA, PAI-I, fibrinogen) factors favors hypercoagulation and hypofibrinolysis. In the context of DM, these mechanisms can be exacerbated leading to higher loss of hemostasis. However, a series of therapeutic strategies targeting the activated endothelium such as specific antibodies or inhibitors against thrombin, key cytokines, factor X, complement system, the kallikrein-kinin system or NETosis, might represent new opportunities to address this hypercoagulable state present in COVID-19 and DM. Antidiabetics may also ameliorate endothelial dysfunction, inflammation, and platelet aggregation. By improving the microvascular pathology in COVID-19 and post-COVID subjects, the associated comorbidities and the risk of mortality could be reduced.

Borissoff JI, Spronk HMH, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med. 2011;364(18):1746–60. https://doi.org/10.1056/NEJMra1011670.CrossRefPubMed

van der Meijden PEJ, Heemskerk JWM. Platelet biology and functions: new concepts and clinical perspectives. Nat Rev Cardiol. 2019;16(3):166–79. https://doi.org/10.1038/s41569-018-0110-0.CrossRefPubMed

Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V, et al. Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. 2020;18(7):1738–42. https://doi.org/10.1111/jth.14850.CrossRefPubMedPubMedCentral

von Meijenfeldt FA, Havervall S, Adelmeijer J, Lundström A, Rudberg A, Magnusson M, et al. Prothrombotic changes in patients with COVID-19 are associated with disease severity and mortality. Res Pract Thromb Haemost. 2021;5(1):132–41. https://doi.org/10.1002/rth2.12462.CrossRef

Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120–8. https://doi.org/10.1056/NEJMoa2015432.CrossRefPubMedPubMedCentral

Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020;18(6):1421–4. https://doi.org/10.1111/jth.14830.CrossRefPubMedPubMedCentral

Ren B, Yan F, Deng Z, Zhang S, Xiao L, Wu M, et al. Extremely high incidence of lower extremity deep venous thrombosis in 48 Patients with severe COVID-19 in Wuhan. Circulation. 2020;142(2):181–3. https://doi.org/10.1161/CIRCULATIONAHA.120.047407.CrossRefPubMed

Vassiliou AG, Vrettou CS, Keskinidou C, Dimopoulou I, Kotanidou A, Orfanos SE. Endotheliopathy in Acute COVID-19 and Long COVID. Int J Mol Sci. 2023;24(9):8237. https://doi.org/10.3390/ijms24098237.CrossRefPubMedPubMedCentral

Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med. 2020;8(6):e46–7. https://doi.org/10.1016/S2213-2600(20)30216-2.CrossRefPubMed

10.

Kole C, Stefanou Ε, Karvelas N, Schizas D, Toutouzas KP. Acute and post-acute COVID-19 cardiovascular complications: a comprehensive review. Cardiovasc Drugs Ther. 2023. https://doi.org/10.1007/s10557-023-07465-w.CrossRefPubMedPubMedCentral

11.

Saluja P, Gautam N, Yadala S, Venkata AN. Thrombotic thrombocytopenic purpura (TTP) after COVID-19 vaccination: a systematic review of reported cases. Thromb Res. 2022;214:115–21. https://doi.org/10.1016/j.thromres.2022.04.020.CrossRefPubMedPubMedCentral

12.

Yasmin F, Najeeb H, Naeem U, Moeed A, Atif AR, Asghar MS, et al. Adverse events following COVID-19 mRNA vaccines: a systematic review of cardiovascular complication, thrombosis, and thrombocytopenia. Immun Inflamm Dis. 2023;11(3):e807. https://doi.org/10.1002/iid3.807.CrossRefPubMedPubMedCentral

13.

Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. 2007;7(10):803–15. https://doi.org/10.1038/nri2171.CrossRefPubMed

14.

Nassar M, Daoud A, Nso N, Medina L, Ghernautan V, Bhangoo H, et al. Diabetes mellitus and COVID-19: review article. Diabetes Metab Syndr. 2021;15(6):102268. https://doi.org/10.1016/j.dsx.2021.102268.CrossRefPubMedPubMedCentral

15.

Goshua G, Pine AB, Meizlish ML, Chang C, Zhang H, Bahel P, et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol. 2020;7(8):e575–82. https://doi.org/10.1016/S2352-3026(20)30216-7.CrossRefPubMedPubMedCentral

16.

Zhang N, Wang C, Zhu F, Mao H, Bai P, Chen L, et al. Risk factors for poor outcomes of diabetes patients with COVID-19: a single-center, retrospective study in early outbreak in China. Front Endocrinol. 2020;11:571037. https://doi.org/10.3389/fendo.2020.571037.CrossRef

17.

Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417–8. https://doi.org/10.1016/S0140-6736(20)30937-5.CrossRefPubMedPubMedCentral

18.

Eberhardt N, Noval MG, Kaur R, Amadori L, Gildea M, Sajja S, et al. SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels. Nat Cardiovasc Res. 2023;2(10):899–916. https://doi.org/10.1038/s44161-023-00336-5.

19.

Martínez-Salazar B, Holwerda M, Stüdle C, Piragyte I, Mercader N, Engelhardt B, et al. COVID-19 and the vasculature: current aspects and long-term consequences. Front Cell Dev Biol. 2022;10:824851. https://doi.org/10.3389/fcell.2022.824851.CrossRefPubMedPubMedCentral

20.

Xu S, Ilyas I, Little PJ, Li H, Kamato D, Zheng X, et al. Endothelial dysfunction in atherosclerotic cardiovascular diseases and beyond: from mechanism to pharmacotherapies. Pharmacol Rev. 2021;73(3):924–67. https://doi.org/10.1124/pharmrev.120.000096.CrossRefPubMed

21.

Birnhuber A, Fließer E, Gorkiewicz G, Zacharias M, Seeliger B, David S, et al. Between inflammation and thrombosis: endothelial cells in COVID-19. Eur Respir J. 2021;58(3):2100377. https://doi.org/10.1183/13993003.00377-2021.CrossRefPubMedPubMedCentral

22.

D’Ardes D, Boccatonda A, Cocco G, Fabiani S, Rossi I, Bucci M, et al. Impaired coagulation, liver dysfunction and COVID-19: discovering an intriguing relationship. World J Gastroenterol. 2022;28(11):1102–12. https://doi.org/10.3748/wjg.v28.i11.1102.CrossRefPubMedPubMedCentral

23.

D’Agnillo F, Walters K, Xiao Y, Sheng Z, Scherler K, Park J, et al. Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19. Sci Transl Med. 2021;13(620):7790. https://doi.org/10.1126/scitranslmed.abj7790.CrossRef

24.

Hunt BJ, Jurd KM. Endothelial cell activation. BMJ. 1998;316(7141):1328–9.CrossRefPubMedPubMedCentral

25.

Watany MM, Abdou S, Elkolaly R, Elgharbawy N, Hodeib H. Evaluation of admission levels of P, E and L selectins as predictors for thrombosis in hospitalized COVID-19 patients. Clin Exp Med. 2022;22(4):567–75. https://doi.org/10.1007/s10238-021-00787-9.CrossRefPubMedPubMedCentral

26.

Montazersaheb S, Hosseiniyan Khatibi SM, Hejazi MS, Tarhriz V, Farjami A, Ghasemian Sorbeni F, et al. COVID-19 infection: an overview on cytokine storm and related interventions. Virol J. 2022;19(1):92. https://doi.org/10.1186/s12985-022-01814-1.CrossRefPubMedPubMedCentral

27.

Hu B, Huang S, Yin L. The cytokine storm and COVID-19. J Med Virol. 2021;93(1):250–6. https://doi.org/10.1002/jmv.26232.CrossRefPubMed

28.

Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 2020;383(23):2255–73. https://doi.org/10.1056/NEJMra2026131.CrossRefPubMedPubMedCentral

29.

Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science. 2020;368(6490):473–4. https://doi.org/10.1126/science.abb8925.ADSCrossRefPubMed

30.

Low RN, Low RJ, Akrami A. A review of cytokine-based pathophysiology of Long COVID symptoms. Front Med. 2023;10:1011936. https://doi.org/10.3389/fmed.2023.1011936.CrossRef

31.

Kruger A, Vlok M, Turner S, Venter C, Laubscher GJ, Kell DB, et al. Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system. Cardiovasc Diabetol. 2022;21(1):190. https://doi.org/10.1186/s12933-022-01623-4.CrossRefPubMedPubMedCentral

32.

Henry BM, Vikse J, Benoit S, Favaloro EJ, Lippi G. Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis. Clin Chim Acta. 2020;507:167–73. https://doi.org/10.1016/j.cca.2020.04.027.CrossRefPubMedPubMedCentral

33.

Conti P, Caraffa A, Gallenga CE, Ross R, Kritas SK, Frydas I, et al. IL-1 induces throboxane-A2 (TxA2) in COVID-19 causing inflammation and micro-thrombi: inhibitory effect of the IL-1 receptor antagonist (IL-1Ra). J Biol Regul Homeost Agents. 2020;34(5):1623–7. https://doi.org/10.23812/20-34-4EDIT-65.CrossRefPubMed

34.

Carpenter RM, Young MK, Petri WAO, Lyons GR, Gilchrist C, Carey RM, et al. Repressed Ang 1–7 in COVID-19 Is inversely associated with inflammation and coagulation. mSphere. 2022;7(4):e0022022. https://doi.org/10.1128/msphere.00220-22.CrossRefPubMed

35.

Peiró C, Moncada S. Substituting angiotensin-(1–7) to prevent lung damage in SARS-CoV-2 infection? Circulation. 2020;141(21):1665–6. https://doi.org/10.1161/CIRCULATIONAHA.120.047297.CrossRefPubMedPubMedCentral

36.

Qin G, Liu S, Yang L, Yu W, Zhang Y. Myeloid cells in COVID-19 microenvironment. Signal Transduct Target Ther. 2021;6(1):372. https://doi.org/10.1038/s41392-021-00792-0.CrossRefPubMedPubMedCentral

37.

Vorobjeva NV, Chernyak BV. NETosis: molecular mechanisms, role in physiology and pathology. Biochemistry. 2020;85(10):1178–90. https://doi.org/10.1134/S0006297920100065.CrossRefPubMed

38.

Thiam HR, Wong SL, Wagner DD, Waterman CM. Cellular mechanisms of NETosis. Annu Rev Cell Dev Biol. 2020;36:191–218. https://doi.org/10.1146/annurev-cellbio-020520-111016.CrossRefPubMedPubMedCentral

39.

Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5. https://doi.org/10.1126/science.1092385.ADSCrossRefPubMed

40.

Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107(36):15880–5. https://doi.org/10.1073/pnas.1005743107.ADSCrossRefPubMedPubMedCentral

41.

Folco EJ, Mawson TL, Vromman A, Bernardes-Souza B, Franck G, Persson O, et al. Neutrophil extracellular traps induce endothelial cell activation and tissue factor production through interleukin-1α and cathepsin G. Arterioscler Thromb Vasc Biol. 2018;38(8):1901–12. https://doi.org/10.1161/ATVBAHA.118.311150.CrossRefPubMedPubMedCentral

42.

Barnes BJ, Adrover JM, Baxter-Stoltzfus A, Borczuk A, Cools-Lartigue J, Crawford JM, et al. Targeting potential drivers of COVID-19: neutrophil extracellular traps. J Exp Med. 2020;217(6):e20200652. https://doi.org/10.1084/jem.20200652.CrossRefPubMedPubMedCentral

43.

Yu S, Liu J, Yan N. Endothelial dysfunction induced by extracellular neutrophil traps plays important role in the occurrence and treatment of extracellular neutrophil traps-related disease. Int J Mol Sci. 2022;23(10):5626. https://doi.org/10.3390/ijms23105626.CrossRefPubMedPubMedCentral

44.

Moschonas IC, Tselepis AD. The pathway of neutrophil extracellular traps towards atherosclerosis and thrombosis. Atherosclerosis. 2019;288:9–16. https://doi.org/10.1016/j.atherosclerosis.2019.06.919.CrossRefPubMed

45.

Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, Madison JA, et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020;5(11):e138999. https://doi.org/10.1172/jci.insight.138999.CrossRefPubMedPubMedCentral

46.

Walport MJ. Complement first of two parts. N Engl J Med. 2001;344(14):1058–66. https://doi.org/10.1056/NEJM200104053441406.CrossRefPubMed

47.

Cugno M, Meroni PL, Gualtierotti R, Griffini S, Grovetti E, Torri A, et al. Complement activation in patients with COVID-19: a novel therapeutic target. J Allergy Clin Immunol. 2020;146(1):215–7. https://doi.org/10.1016/j.jaci.2020.05.006.CrossRefPubMedPubMedCentral

48.

Skendros P, Mitsios A, Chrysanthopoulou A, Mastellos DC, Metallidis S, Rafailidis P, et al. Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis. J Clin Invest. 2020;130(11):6151–7. https://doi.org/10.1172/JCI141374.CrossRefPubMedPubMedCentral

49.

Ma L, Sahu SK, Cano M, Kuppuswamy V, Bajwa J, McPhatter J, et al. Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection. Sci Immunol. 2021;6(59):abh2259. https://doi.org/10.1126/sciimmunol.abh2259.CrossRef

50.

Sinkovits G, Mező B, Réti M, Müller V, Iványi Z, Gál J, et al. Complement overactivation and consumption predicts in-hospital mortality in SARS-CoV-2 infection. Front Immunol. 2021;12:663187. https://doi.org/10.3389/fimmu.2021.663187.CrossRefPubMedPubMedCentral

51.

Propson NE, Roy ER, Litvinchuk A, Köhl J, Zheng H. Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging. J Clin Invest. 2021;131(1):e140966. https://doi.org/10.1172/JCI140966.CrossRefPubMedPubMedCentral

52.

Albrecht EA, Chinnaiyan AM, Varambally S, Kumar-Sinha C, Barrette TR, Sarma JV, et al. C5a-induced gene expression in human umbilical vein endothelial cells. Am J Pathol. 2004;164(3):849–59. https://doi.org/10.1016/S0002-9440(10)63173-2.CrossRefPubMedPubMedCentral

53.

Fischetti F, Tedesco F. Cross-talk between the complement system and endothelial cells in physiologic conditions and in vascular diseases. Autoimmunity. 2006;39(5):417–28. https://doi.org/10.1080/08916930600739712.CrossRefPubMed

54.

Otifi HM, Adiga BK. Endothelial dysfunction in Covid-19 infection. Am J Med Sci. 2022;363(4):281–7. https://doi.org/10.1016/j.amjms.2021.12.010.CrossRefPubMedPubMedCentral

55.

Bhargavan B, Kanmogne GD. SARS-CoV-2 spike proteins and cell-cell communication inhibits TFPI and induces thrombogenic factors in human lung microvascular endothelial cells and neutrophils: implications for COVID-19 coagulopathy pathogenesis. Int J Mol Sci. 2022;23(18):10436. https://doi.org/10.3390/ijms231810436.CrossRefPubMedPubMedCentral

56.

Perico L, Benigni A, Remuzzi G. SARS-CoV-2 and the spike protein in endotheliopathy. Trends Microbiol. 2023. https://doi.org/10.1016/j.tim.2023.06.004.CrossRefPubMedPubMedCentral

57.

Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020;181(4):905-913.e7. https://doi.org/10.1016/j.cell.2020.04.004.CrossRefPubMedPubMedCentral

58.

Rotoli BM, Barilli A, Visigalli R, Ferrari F, Dall’Asta V. Endothelial cell activation by SARS-CoV-2 spike S1 protein: a crosstalk between endothelium and innate immune cells. Biomedicines. 2021;9(9):1220. https://doi.org/10.3390/biomedicines9091220.CrossRefPubMedPubMedCentral

59.

Villacampa A, Alfaro E, Morales C, Díaz-García E, López-Fernández C, Bartha JL, et al. SARS-CoV-2 protein activates NLRP3 inflammasome and deregulates coagulation factor in endothelial and immune cells. Cell Commun Signal. 2023. https://doi.org/10.1186/s12964-023-01397-6.CrossRef

60.

Ahamed J, Laurence J. Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches. J Clin Invest. 2022;132(15):e161167. https://doi.org/10.1172/JCI161167.CrossRefPubMedPubMedCentral

61.

Jin Y, Ji W, Yang H, Chen S, Zhang W, Duan G. Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches. Signal Transduct Target Ther. 2020;5(1):293. https://doi.org/10.1038/s41392-020-00454-7.CrossRefPubMedPubMedCentral

62.

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(11):3367–77. https://doi.org/10.1182/bloodadvances.2021006620.CrossRefPubMedPubMedCentral

63.

Grover SP, Mackman N. Tissue factor: an essential mediator of hemostasis and trigger of thrombosis. Arterioscler Thromb Vasc Biol. 2018;38(4):709–25. https://doi.org/10.1161/ATVBAHA.117.309846.CrossRefPubMed

64.

Parry GC, Mackman N. Transcriptional regulation of tissue factor expression in human endothelial cells. Arterioscler Thromb Vasc Biol. 1995;15(5):612–21. https://doi.org/10.1161/01.atv.15.5.612.CrossRefPubMed

65.

De Palma R, Cirillo P, Ciccarelli G, Barra G, Conte S, Pellegrino G, et al. Expression of functional tissue factor in activated T-lymphocytes in vitro and in vivo: a possible contribution of immunity to thrombosis? Int J Cardiol. 2016;218:188–95. https://doi.org/10.1016/j.ijcard.2016.04.177.CrossRefPubMed

66.

Mandal SK, Iakhiaev A, Pendurthi UR, Mohan Rao LV. Acute cholesterol depletion impairs functional expression of tissue factor in fibroblasts: modulation of tissue factor activity by membrane cholesterol. Blood. 2005;105(1):153–60. https://doi.org/10.1182/blood-2004-03-0990.CrossRefPubMed

67.

Musgrave KM, Scott J, Sendama W, Gardner AI, Dewar F, Lake CJ, et al. Tissue factor expression in monocyte subsets during human immunothrombosis, endotoxemia and sepsis. Thromb Res. 2023;228:10–20. https://doi.org/10.1016/j.thromres.2023.05.018.CrossRefPubMed

68.

Kothari H, Pendurthi UR, Rao LVM. Analysis of tissue factor expression in various cell model systems: cryptic vs. active. J Thromb Haemost. 2013;11(7):1353–63. https://doi.org/10.1111/jth.12272.CrossRefPubMedPubMedCentral

69.

Owens AP, Mackman N. Role of tissue factor in atherothrombosis. Curr Atheroscler Rep. 2012;14(5):394–401. https://doi.org/10.1007/s11883-012-0269-5.CrossRefPubMedPubMedCentral

70.

Mackman N. The role of tissue factor and factor VIIa in hemostasis. Anesth Analg. 2009;108(5):1447–52. https://doi.org/10.1213/ane.0b013e31819bceb1.CrossRefPubMedPubMedCentral

71.

Girard TJ, Broze GJ. Tissue factor pathway inhibitor. Methods Enzymol. 1993;222:195–209. https://doi.org/10.1016/0076-6879(93)22014-7.CrossRefPubMed

72.

Subrahmanian S, Borczuk A, Salvatore SP, Laurence J, Ahamed J. Higher tissue factor (TF) expression in the lungs of COVID-19 pneumonia patients than patients with acute respiratory distress syndrome: association with thrombi formation. Blood. 2020;136:4. https://doi.org/10.1182/blood-2020-142827.CrossRef

73.

Subrahmanian S, Borczuk A, Salvatore S, Fung K, 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(9):2268–74. https://doi.org/10.1111/jth.15451.CrossRefPubMed

74.

Nascimento Conde J, Schutt WR, Gorbunova EE, Mackow ER. Recombinant ACE2 expression is required for SARS-CoV-2 To infect primary human endothelial cells and induce inflammatory and procoagulative responses. MBio. 2020;11(6):3185. https://doi.org/10.1128/mBio.03185-20.CrossRef

75.

FitzGerald ES, Chen Y, Fitzgerald KA, Jamieson AM. Lung epithelial cell transcriptional regulation as a factor in COVID-19-associated coagulopathies. Am J Respir Cell Mol Biol. 2021;64(6):687–97. https://doi.org/10.1165/rcmb.2020-0453OC.CrossRefPubMedPubMedCentral

76.

Sachetto ATA, Mackman N. Tissue factor and COVID-19: an update. Curr Drug Targets. 2022;23(17):1573–7. https://doi.org/10.2174/1389450123666220926144432.CrossRefPubMed

77.

Rosenberg JB, Foster PA, Kaufman RJ, Vokac EA, Moussalli M, Kroner PA, et al. Intracellular trafficking of factor VIII to von Willebrand factor storage granules. J Clin Invest. 1998;101(3):613–24. https://doi.org/10.1172/JCI1250.CrossRefPubMedPubMedCentral

78.

Grover SP, Mackman N. Intrinsic pathway of coagulation and thrombosis. Arterioscler Thromb Vasc Biol. 2019;39(3):331–8. https://doi.org/10.1161/ATVBAHA.118.312130.CrossRefPubMed

79.

Mazurkiewicz-Pisarek A, Płucienniczak G, Ciach T, Płucienniczak A. The factor VIII protein and its function. Acta Biochim Pol. 2016;63(1):11–6. https://doi.org/10.18388/abp.2015_1056.CrossRefPubMed

80.

Nogami K, Shima M, Hosokawa K, Suzuki T, Koide T, Saenko EL, et al. Role of factor VIII C2 domain in factor VIII binding to factor Xa. J Biol Chem. 1999;274(43):31000–7. https://doi.org/10.1074/jbc.274.43.31000.CrossRefPubMed

81.

Martín-Rojas RM, Pérez-Rus G, Delgado-Pinos VE, Domingo-González A, Regalado-Artamendi I, Alba-Urdiales N, et al. COVID-19 coagulopathy: an in-depth analysis of the coagulation system. Eur J Haematol. 2020;105(6):741–50. https://doi.org/10.1111/ejh.13501.CrossRefPubMedPubMedCentral

82.

Voicu S, Delrue M, Chousterman BG, Stépanian A, Bonnin P, Malissin I, et al. Imbalance between procoagulant factors and natural coagulation inhibitors contributes to hypercoagulability in the critically ill COVID-19 patient: clinical implications. Eur Rev Med Pharmacol Sci. 2020;24(17):9161–8. https://doi.org/10.26355/eurrev_202009_22866.CrossRefPubMed

83.

Abd El-Lateef AE, Alghamdi S, Ebid G, Khalil K, Kabrah S, Abdel Ghafar MT. Coagulation profile in COVID-19 patients and its relation to disease severity and overall survival: a single-center study. Br J Biomed Sci. 2022;79:10098. https://doi.org/10.3389/bjbs.2022.10098.CrossRefPubMedPubMedCentral

84.

Prasannan N, Heightman M, Hillman T, Wall E, Bell R, Kessler A, et al. Impaired exercise capacity in post-COVID-19 syndrome: the role of VWF-ADAMTS13 axis. Blood Adv. 2022;6(13):4041–8. https://doi.org/10.1182/bloodadvances.2021006944.CrossRefPubMedPubMedCentral

85.

Nicolai L, Kaiser R, Stark K. Thromboinflammation in long COVID—the elusive key to postinfection sequelae? J Thromb Haemost. 2023. https://doi.org/10.1016/j.jtha.2023.04.039.CrossRefPubMedPubMedCentral

86.

Duminuco A, Calagna M, Markovic U, Esposito B, Grasso S, Riccobene C, et al. Acquired hemophilia A following COVID-19 vaccination—the importance of prompt diagnosis: a case report. Transfus Apher Sci. 2022. https://doi.org/10.1016/j.transci.2022.103577.CrossRefPubMedPubMedCentral

87.

Hollerbach A, Müller-Calleja N, Pedrosa D, Canisius A, Sprinzl MF, Falter T, et al. Pathogenic lipid-binding antiphospholipid antibodies are associated with severity of COVID-19. J Thromb Haemost. 2021;19(9):2335–47. https://doi.org/10.1111/jth.15455.CrossRefPubMed

88.

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(18):1787–90. https://doi.org/10.1161/CIRCULATIONAHA.120.050656.CrossRefPubMedPubMedCentral

89.

Bryant JW, Shariat-Madar Z. Human plasma kallikrein-kinin system: physiological and biochemical parameters. Cardiovasc Hematol Agents Med Chem. 2009;7(3):234–50.CrossRefPubMedPubMedCentral

90.

Didiasova M, Wujak L, Schaefer L, Wygrecka M. Factor XII in coagulation, inflammation and beyond. Cell Signal. 2018;51:257–65. https://doi.org/10.1016/j.cellsig.2018.08.006.CrossRefPubMed

91.

Marcondes S, Antunes E. The plasma and tissue kininogen-kallikrein-kinin system: role in the cardiovascular system. Curr Med Chem Cardiovasc Hematol Agents. 2005;3(1):33–44. https://doi.org/10.2174/1568016052773351.CrossRefPubMed

92.

Alfaro E, Díaz-García E, García-Tovar S, Zamarrón E, Mangas A, Galera R, et al. Impaired kallikrein-kinin system in COVID-19 patients’ severity. Front Immunol. 2022;13:909342. https://doi.org/10.3389/fimmu.2022.909342.CrossRefPubMedPubMedCentral

93.

Lipcsey M, Persson B, Eriksson O, Blom AM, Fromell K, Hultström M, et al. The outcome of critically Ill COVID-19 patients is linked to thromboinflammation dominated by the Kallikrein/Kinin system. Front Immunol. 2021;12:627579. https://doi.org/10.3389/fimmu.2021.627579.CrossRefPubMedPubMedCentral

94.

Kanaji S, Fahs SA, Shi Q, Haberichter SL, Montgomery RR. Contribution of platelet versus endothelial VWF to platelet adhesion and hemostasis. J Thromb Haemost. 2012;10(8):1646–52. https://doi.org/10.1111/j.1538-7836.2012.04797.x.CrossRefPubMedPubMedCentral

95.

Verhenne S, Denorme F, Libbrecht S, Vandenbulcke A, Pareyn I, Deckmyn H, et al. Platelet-derived VWF is not essential for normal thrombosis and hemostasis but fosters ischemic stroke injury in mice. Blood. 2015;126(14):1715–22. https://doi.org/10.1182/blood-2015-03-632901.CrossRefPubMed

96.

Valentijn KM, Sadler JE, Valentijn JA, Voorberg J, Eikenboom J. Functional architecture of weibel-palade bodies. Blood. 2011;117(19):5033–43. https://doi.org/10.1182/blood-2010-09-267492.CrossRefPubMedPubMedCentral

97.

Ward SE, Curley GF, Lavin M, Fogarty H, Karampini E, McEvoy NL, et al. Von Willebrand factor propeptide in severe coronavirus disease 2019 (COVID-19): evidence of acute and sustained endothelial cell activation. Br J Haematol. 2021;192(4):714–9. https://doi.org/10.1111/bjh.17273.CrossRefPubMed

98.

Wibowo A, Pranata R, Lim MA, Akbara MR, Martha JW. Endotheliopathy marked by high von Willebrand factor (vWF) antigen in COVID-19 is associated with poor outcome: a systematic review and meta-analysis. Int J Infect Dis. 2022;117:267–73. https://doi.org/10.1016/j.ijid.2021.06.051.CrossRefPubMed

99.

Karampini E, Fogarty H, Elliott S, Morrin H, Bergin C, O’Sullivan JM, et al. Endothelial cell activation, Weibel-Palade body secretion, and enhanced angiogenesis in severe COVID-19. Res Pract Thromb Haemost. 2023;7(2):100085. https://doi.org/10.1016/j.rpth.2023.100085.CrossRefPubMedPubMedCentral

100.

Zheng XL. ADAMTS13 and von willebrand factor in thrombotic thrombocytopenic purpura. Annu Rev Med. 2015;66:211–25. https://doi.org/10.1146/annurev-med-061813-013241.CrossRefPubMedPubMedCentral

101.

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(2):513–21. https://doi.org/10.1111/jth.15191.CrossRefPubMed

102.

Xu X, Feng Y, Jia Y, Zhang X, Li L, Bai X, et al. Prognostic value of von willebrand factor and ADAMTS13 in patients with COVID-19: a systematic review and meta-analysis. Thromb Res. 2022;218:83–98. https://doi.org/10.1016/j.thromres.2022.08.017.CrossRefPubMedPubMedCentral

103.

Mei ZW, van Wijk Xander MR, Pham HP, Marin MJ. Role of von willebrand factor in COVID-19 associated coagulopathy. J Appl Lab Med. 2021;6(5):1305–15. https://doi.org/10.1093/jalm/jfab042.CrossRefPubMed

104.

Shah H, Kim A, Sukumar S, Mazepa M, Kohli R, Braunstein EM, et al. SARS-CoV-2 vaccination and immune thrombotic thrombocytopenic purpura. Blood. 2022;139(16):2570–3. https://doi.org/10.1182/blood.2022015545.CrossRefPubMedPubMedCentral

105.

Fogarty H, Ward SE, Townsend L, Karampini E, Elliott S, Conlon N, et al. Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction. J Thromb Haemost. 2022;20(10):2429–38. https://doi.org/10.1111/jth.15830.CrossRefPubMedPubMedCentral

106.

Medcalf RL, Keragala CB. The fibrinolytic system: mysteries and opportunities. Hemasphere. 2021;5(6):e570. https://doi.org/10.1097/HS9.0000000000000570.CrossRefPubMedPubMedCentral

107.

Neubauer K, Zieger B. Endothelial cells and coagulation. Cell Tissue Res. 2022;387(3):391–8. https://doi.org/10.1007/s00441-021-03471-2.CrossRefPubMed

108.

Keragala CB, Medcalf RL, Myles PS. Fibrinolysis and COVID-19: a tale of two sites? J Thromb Haemost. 2020;18(9):2430–2. https://doi.org/10.1111/jth.15017.CrossRefPubMedPubMedCentral

109.

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(1):1580. https://doi.org/10.1038/s41598-020-80010-z.ADSCrossRefPubMedPubMedCentral

110.

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(9):2215–9. https://doi.org/10.1111/jth.15016.CrossRefPubMedPubMedCentral

111.

Cabrera-Garcia D, Miltiades A, Yim P, Parsons S, Elisman K, Mansouri MT, et al. Plasma biomarkers associated with survival and thrombosis in hospitalized COVID-19 patients. Int J Hematol. 2022;116(6):937–46. https://doi.org/10.1007/s12185-022-03437-2.CrossRefPubMedPubMedCentral

112.

Shenoy RD, Nithin Kuriakose N, Vijaykrishnaraj MN, Patil P, Jayaswamy PK, Alagundagi DB, et al. Tissue plasminogen activator receptor ANXA2 and its complementary regulator anti-inflammatory ANXA1 as prognostic indicators of inflammatory response in COVID-19 pathogenesis. Immunobiology. 2023;228(5):152728. https://doi.org/10.1016/j.imbio.2023.152728.CrossRefPubMed

113.

Santos Silva BR, Poblete Jara C, Sidarta-Oliveira D, Velloso LA, Velander WH, Araújo EP. Downregulation of the protein C signaling system is associated with COVID-19 hypercoagulability-A single-cell transcriptomics analysis. Viruses. 2022;14(12):2753. https://doi.org/10.3390/v14122753.CrossRef

114.

Isermann B, Vinnikov IA, Madhusudhan T, Herzog S, Kashif M, Blautzik J, et al. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med. 2007;13(11):1349–58. https://doi.org/10.1038/nm1667.CrossRefPubMed

115.

Prasannan N, Heightman M, Hillman T, Wall E, Bell R, Kessler A, et al. Impaired exercise capacity in post–COVID-19 syndrome: the role of VWF-ADAMTS13 axis. Blood Adv. 2022;6(13):4041–8. https://doi.org/10.1182/bloodadvances.2021006944.CrossRefPubMedPubMedCentral

116.

Pretorius E, Venter C, Laubscher GJ, Kotze MJ, Oladejo SO, Watson LR, et al. Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Cardiovasc Diabetol. 2022;21(1):148. https://doi.org/10.1186/s12933-022-01579-5.CrossRefPubMedPubMedCentral

117.

Calvet L, Thouy F, Mascle O, Sapin A, Grapin K, Liteaudon JM, et al. Hypercoagulability in critically ill patients with COVID 19, an observational prospective study. PLoS ONE. 2022;17(11):e0277544. https://doi.org/10.1371/journal.pone.0277544.CrossRefPubMedPubMedCentral

118.

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(2):308–12. https://doi.org/10.1007/s11239-020-02226-0.CrossRefPubMed

119.

Baycan OF, Barman HA, Bolen F, Atici A, Erman H, Korkmaz R, et al. Plasminogen activator inhibitor-1 levels as an indicator of severity and mortality for COVID-19. North Clin Istanb. 2023;10(1):1–9. https://doi.org/10.14744/nci.2022.09076.CrossRefPubMedPubMedCentral

120.

Nielsen ND, Rollins-Raval MA, Raval JS, Thachil J. Is it hyperfibrinolysis or fibrinolytic shutdown in severe COVID-19? Thromb Res. 2022;210:1–3. https://doi.org/10.1016/j.thromres.2021.12.012.CrossRefPubMed

121.

diabetes Lw, Policy P. IDF Diabetes Atlas | Tenth Edition. https://diabetesatlas.org/. Accessed 8 Oct 2023.

122.

WHO Coronavirus (COVID-19) Dashboard. https://covid19.who.int. Accessed 8 Oct 2023.

123.

Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708–20. https://doi.org/10.1056/NEJMoa2002032.CrossRefPubMed

124.

Bhatraju PK, Ghassemieh BJ, Nichols M, Kim R, Jerome KR, Nalla AK, et al. Covid-19 in critically Ill patients in the seattle region—case series. N Engl J Med. 2020;382(21):2012–22. https://doi.org/10.1056/NEJMoa2004500.CrossRefPubMed

125.

Roncon L, Zuin M, Rigatelli G, Zuliani G. Diabetic patients with COVID-19 infection are at higher risk of ICU admission and poor short-term outcome. J Clin Virol. 2020;127:104354. https://doi.org/10.1016/j.jcv.2020.104354.CrossRefPubMedPubMedCentral

126.

Kumar A, Arora A, Sharma P, Anikhindi SA, Bansal N, Singla V, et al. Is diabetes mellitus associated with mortality and severity of COVID-19? A meta-analysis. Diabetes Metab Syndr. 2020;14(4):535–45. https://doi.org/10.1016/j.dsx.2020.04.044.CrossRefPubMedPubMedCentral

127.

Li R, Shen M, Yang Q, Fairley CK, Chai Z, McIntyre R, et al. Global diabetes prevalence in COVID-19 patients and contribution to COVID-19- related severity and mortality: a systematic review and meta-analysis. Diabetes Care. 2023;46(4):890–7. https://doi.org/10.2337/dc22-1943.CrossRefPubMedPubMedCentral

128.

Mahamat-Saleh Y, Fiolet T, Rebeaud ME, Mulot M, Guihur A, El Fatouhi D, et al. Diabetes, hypertension, body mass index, smoking and COVID-19-related mortality: a systematic review and meta-analysis of observational studies. BMJ Open. 2021;11(10):e052777. https://doi.org/10.1136/bmjopen-2021-052777.CrossRefPubMed

129.

Harding JL, Oviedo SA, Ali MK, Ofotokun I, Gander JC, Patel SA, et al. The bidirectional association between diabetes and long-COVID-19—a systematic review. Diabetes Res Clin Pract. 2023;195:110202. https://doi.org/10.1016/j.diabres.2022.110202.CrossRefPubMed

130.

Sardu C, D’Onofrio N, Balestrieri ML, Barbieri M, Rizzo MR, Messina V, et al. Outcomes in patients with hyperglycemia affected by COVID-19: can we do more on glycemic control? Diabetes Care. 2020;43(7):1408–15. https://doi.org/10.2337/dc20-0723.CrossRefPubMedPubMedCentral

131.

Guo W, Li M, Dong Y, Zhou H, Zhang Z, Tian C, et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev. 2020;36(7):e3319. https://doi.org/10.1002/dmrr.3319.CrossRefPubMedPubMedCentral

132.

Zhu L, She Z, Cheng X, Qin J, Zhang X, Cai J, et al. Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes. Cell Metab. 2020;31(6):1068-1077.e3. https://doi.org/10.1016/j.cmet.2020.04.021.CrossRefPubMedPubMedCentral

133.

Bramante CT, Buse JB, Liebovitz DM, Nicklas JM, Puskarich MA, Cohen K, et al. Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial. Lancet Infect Dis. 2023;23(10):1119–29. https://doi.org/10.1016/S1473-3099(23)00299-2.CrossRefPubMed

134.

Tong L, Xiao X, Li M, Fang S, Ma E, Yu X, et al. A glucose-like metabolite deficient in diabetes inhibits cellular entry of SARS-CoV-2. Nat Metab. 2022;4(5):547–58. https://doi.org/10.1038/s42255-022-00567-z.CrossRefPubMed

135.

Xie Y, Al-Aly Z. Risks and burdens of incident diabetes in long COVID: a cohort study. Lancet Diabetes Endocrinol. 2022;10(5):311–21. https://doi.org/10.1016/S2213-8587(22)00044-4.CrossRefPubMedPubMedCentral

136.

Liu F, Long X, Zhang B, Zhang W, Chen X, Zhang Z. ACE2 expression in pancreas may cause pancreatic damage after SARS-CoV-2 infection. Clin Gastroenterol Hepatol. 2020;18(9):2128-2130.e2. https://doi.org/10.1016/j.cgh.2020.04.040.CrossRefPubMedPubMedCentral

137.

Burnett FN, Coucha M, Bolduc DR, Hermanns VC, Heath SP, Abdelghani M, et al. SARS-CoV-2 spike protein intensifies cerebrovascular complications in diabetic hACE2 mice through RAAS and TLR signaling activation. Int J Mol Sci. 2023;24(22):16394. https://doi.org/10.3390/ijms242216394.CrossRefPubMedPubMedCentral

138.

Fadini GP, Morieri ML, Longato E, Avogaro A. Prevalence and impact of diabetes among people infected with SARS-CoV-2. J Endocrinol Invest. 2020;43(6):867–9. https://doi.org/10.1007/s40618-020-01236-2.CrossRefPubMedPubMedCentral

139.

Polat G, Güçsav MO, Özdemir Ö, Türk MA, Unat DS, Tatar D. The association between glycemia and clinical outcomes in patients with diabetes mellitus and pulmonary thromboembolism. Arch Endocrinol Metab. 2023;67(3):341–7. https://doi.org/10.20945/2359-3997000000544.CrossRefPubMedPubMedCentral

140.

Gęca T, Wojtowicz K, Guzik P, Góra T. Increased risk of COVID-19 in patients with diabetes mellitus-current challenges in pathophysiology, treatment and prevention. Int J Environ Res Public Health. 2022;19(11):6555. https://doi.org/10.3390/ijerph19116555.CrossRefPubMedPubMedCentral

141.

Varikasuvu SR, Varshney S, Dutt N. Markers of coagulation dysfunction and inflammation in diabetic and non-diabetic COVID-19. J Thromb Thrombolysis. 2021;51(4):941–6. https://doi.org/10.1007/s11239-020-02270-w.CrossRefPubMed

142.

Alosaimi B, Mubarak A, Hamed ME, Almutairi AZ, Alrashed AA, AlJuryyan A, et al. Complement anaphylatoxins and inflammatory cytokines as prognostic markers for COVID-19 severity and in-hospital mortality. Front Immunol. 2021;12:668725. https://doi.org/10.3389/fimmu.2021.668725.CrossRefPubMedPubMedCentral

143.

George TP, Joy SS, Rafiullah M, Siddiqui K. Cytokines involved in COVID-19 patients with diabetes: a systematic review. Curr Diabetes Rev. 2023;19(3):e180122200321. https://doi.org/10.2174/1573399818666220118100743.CrossRefPubMed

144.

Menegazzo L, Scattolini V, Cappellari R, Bonora BM, Albiero M, Bortolozzi M, et al. The antidiabetic drug metformin blunts NETosis in vitro and reduces circulating NETosis biomarkers in vivo. Acta Diabetol. 2018;55(6):593–601. https://doi.org/10.1007/s00592-018-1129-8.CrossRefPubMed

145.

Njeim R, Azar WS, Fares AH, Azar ST, Kfoury Kassouf H, Eid AA. NETosis contributes to the pathogenesis of diabetes and its complications. J Mol Endocrinol. 2020;65(4):R65–76. https://doi.org/10.1530/JME-20-0128.CrossRefPubMed

146.

Ghosh A, Gao L, Thakur A, Siu PM, Lai CWK. Role of free fatty acids in endothelial dysfunction. J Biomed Sci. 2017;24:50. https://doi.org/10.1186/s12929-017-0357-5.CrossRefPubMedPubMedCentral

147.

Matuschik L, Riabov V, Schmuttermaier C, Sevastyanova T, Weiss C, Klüter H, et al. Hyperglycemia induces inflammatory response of human macrophages to CD163-mediated scavenging of hemoglobin-haptoglobin complexes. Int J Mol Sci. 2022;23(3):1385. https://doi.org/10.3390/ijms23031385.CrossRefPubMedPubMedCentral

148.

Li X, Weber NC, Cohn DM, Hollmann MW, DeVries JH, Hermanides J, et al. Effects of hyperglycemia and diabetes mellitus on coagulation and hemostasis. J Clin Med. 2021;10(11):2419. https://doi.org/10.3390/jcm10112419.CrossRefPubMedPubMedCentral

149.

Chourasia P, Goyal L, Kansal D, Roy S, Singh R, Mahata I, et al. Risk of new-onset diabetes mellitus as a post-COVID-19 condition and possible mechanisms: a scoping review. J Clin Med. 2023;12(3):1159. https://doi.org/10.3390/jcm12031159.CrossRefPubMedPubMedCentral

150.

Calvisi SL, Ramirez GA, Scavini M, Da Prat V, Di Lucca G, Laurenzi A, et al. Thromboembolism risk among patients with diabetes/stress hyperglycemia and COVID-19. Metabolism. 2021;123:154845. https://doi.org/10.1016/j.metabol.2021.154845.CrossRefPubMedPubMedCentral

151.

Schiattarella GG, Carrizzo A, Ilardi F, Damato A, Ambrosio M, Madonna M, et al. Rac1 modulates endothelial function and platelet aggregation in diabetes mellitus. J Am Heart Assoc. 2018;7(8):e007322. https://doi.org/10.1161/JAHA.117.007322.CrossRefPubMedPubMedCentral

152.

Siddiqui K, George TP, Mujammami M, Isnani A, Alfadda AA. The association of cell adhesion molecules and selectins (VCAM-1, ICAM-1, E-selectin, L-selectin, and P-selectin) with microvascular complications in patients with type 2 diabetes: a follow-up study. Front Endocrinol (Lausanne). 2023;14:1072288. https://doi.org/10.3389/fendo.2023.1072288.CrossRefPubMed

153.

Palella E, Cimino R, Pullano SA, Fiorillo AS, Gulletta E, Brunetti A, et al. Laboratory parameters of hemostasis, adhesion molecules, and inflammation in type 2 diabetes mellitus: correlation with glycemic control. Int J Environ Res Public Health. 2020;17(1):300. https://doi.org/10.3390/ijerph17010300.CrossRefPubMedPubMedCentral

154.

Kim HK, Kim JE, Park SH, Kim YI, Nam-Goong IS, Kim ES. High coagulation factor levels and low protein C levels contribute to enhanced thrombin generation in patients with diabetes who do not have macrovascular complications. J Diabetes Complications. 2014;28(3):365–9. https://doi.org/10.1016/j.jdiacomp.2014.01.006.CrossRefPubMed

155.

van der Toorn FA, de Mutsert R, Lijfering WM, Rosendaal FR, van Hylckama VA. Glucose metabolism affects coagulation factors: the NEO study. J Thromb Haemost. 2019;17(11):1886–97. https://doi.org/10.1111/jth.14573.CrossRefPubMed

156.

Barillari G, Fabbro E, Pasca S, Bigotto E. Coagulation and oxidative stress plasmatic levels in a type 2 diabetes population. Blood Coagul Fibrinolysis. 2009;20(4):290–6. https://doi.org/10.1097/MBC.0b013e328329e49b.CrossRefPubMed

157.

Rothschild AM, Reis ML, Melo VL, Foss MC, Gallo L. Increased kininogen levels observed in plasma of diabetic patients are corrected by the administration of insulin. Horm Metab Res. 1999;31(5):326–8. https://doi.org/10.1055/s-2007-978746.CrossRefPubMed

158.

Sambola A, Osende J, Hathcock J, Degen M, Nemerson Y, Fuster V, et al. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation. 2003;107(7):973–7. https://doi.org/10.1161/01.cir.0000050621.67499.7d.CrossRefPubMed

159.

Kietsiriroje N, Pearson SM, O’Mahoney LL, West DJ, Ariëns RA, Ajjan RA, et al. Glucose variability is associated with an adverse vascular profile but only in the presence of insulin resistance in individuals with type 1 diabetes: an observational study. Diab Vasc Dis Res. 2022;19(3):14791641221103216. https://doi.org/10.1177/14791641221103217.CrossRefPubMedPubMedCentral

160.

De Mattia G, Bravi MC, Laurenti O, Moretti A, Cipriani R, Gatti A, et al. Endothelial dysfunction and oxidative stress in type 1 and type 2 diabetic patients without clinical macrovascular complications. Diabetes Res Clin Pract. 2008;79(2):337–42. https://doi.org/10.1016/j.diabres.2007.09.005.CrossRefPubMed

161.

Dhanesha N, Doddapattar P, Chorawala MR, Nayak MK, Kokame K, Staber JM, et al. ADAMTS13 retards progression of diabetic nephropathy by inhibiting intrarenal thrombosis in mice. Arterioscler Thromb Vasc Biol. 2017;37(7):1332–8. https://doi.org/10.1161/ATVBAHA.117.309539.CrossRefPubMedPubMedCentral

162.

Dunn EJ, Philippou H, Ariëns RAS, Grant PJ. Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus. Diabetologia. 2006;49(5):1071–80. https://doi.org/10.1007/s00125-006-0197-4.CrossRefPubMed

163.

Cheng L, Fu Q, Zhou L, Fan Y, Liu F, Fan Y, et al. D-dimer as a predictor of cardiovascular outcomes in patients with diabetes mellitus. BMC Cardiovasc Disord. 2022;22(1):82. https://doi.org/10.1186/s12872-022-02531-x.CrossRefPubMedPubMedCentral

164.

Ajjan RA, Gamlen T, Standeven KF, Mughal S, Hess K, Smith KA, et al. Diabetes is associated with posttranslational modifications in plasminogen resulting in reduced plasmin generation and enzyme-specific activity. Blood. 2013;122(1):134–42. https://doi.org/10.1182/blood-2013-04-494641.CrossRefPubMed

165.

Uitte de Willige S, Malfliet Joyce JCM, Abdul S, Leebeek FWG, Rijken DC. The level of circulating fibroblast activation protein correlates with incorporation of alpha-2-antiplasmin into the fibrin clot. Thromb Res. 2018;166:19–21. https://doi.org/10.1016/j.thromres.2018.03.018.CrossRefPubMed

166.

Agren A, Jörneskog G, Elgue G, Henriksson P, Wallen H, Wiman B. Increased incorporation of antiplasmin into the fibrin network in patients with type 1 diabetes. Diabetes Care. 2014;37(7):2007–14. https://doi.org/10.2337/dc13-1776.CrossRefPubMed

167.

Akwiwu E, Edem M, Akpotuzor J, Asemota E, Isong I. Glycated haemogloin, fasting plasma glucose, plasminogen activator inhibitor type-1, and soluble thrombomodulin levels in patients with type 2 diabetes mellitus. Niger J Physiol Sci. 2021;36(2):159–64. https://doi.org/10.54548/njps.v36i2.3.CrossRefPubMed

168.

Kitagawa N, Yano Y, Gabazza EC, Bruno NE, Araki R, Matsumoto K, et al. Different metabolic correlations of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 in non-obese type 2 diabetic patients. Diabetes Res Clin Pract. 2006;73(2):150–7. https://doi.org/10.1016/j.diabres.2005.12.008.CrossRefPubMed

169.

Miri C, Charii H, Bouazzaoui M, Laouan Brem F, Boulouiz S, Abda N, et al. D-dimer level and diabetes in the COVID-19 infection. Clin Appl Thromb Hemost. 2021;27:10760296211045902. https://doi.org/10.1177/10760296211045902.CrossRefPubMedPubMedCentral

170.

Iskandar A, Mayashinta DK, Robert R, Samsu N, Endharti AT, Widjajanto E. Correlation between IL-8, C-reactive proteins (CRP) and neutrophil to lymphocyte ratio (NLR) as predictor of mortality in COVID-19 patients with diabetes mellitus comorbidity. Int J Gen Med. 2023;16:2349–54. https://doi.org/10.2147/IJGM.S412070.CrossRefPubMedPubMedCentral

171.

Francischetti IMB, Toomer K, Zhang Y, Jani J, Siddiqui Z, Brotman DJ, et al. Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection. EClinicalMedicine. 2021;39:101069. https://doi.org/10.1016/j.eclinm.2021.101069.CrossRefPubMedPubMedCentral

172.

Soma P, Swanepoel AC, Bester J, Pretorius E. Tissue factor levels in type 2 diabetes mellitus. Inflamm Res. 2017;66(5):365–8. https://doi.org/10.1007/s00011-017-1030-x.CrossRefPubMed

173.

Masi P, Hékimian G, Lejeune M, Chommeloux J, Desnos C, Pineton De Chambrun M, et al. Systemic inflammatory response syndrome is a major contributor to COVID-19-associated coagulopathy: insights from a prospective, single-center cohort study. Circulation. 2020;142(6):611–4. https://doi.org/10.1161/CIRCULATIONAHA.120.048925.CrossRefPubMedPubMedCentral

174.

Zhang Y, Cao W, Jiang W, Xiao M, Li Y, Tang N, et al. Profile of natural anticoagulant, coagulant factor and anti-phospholipid antibody in critically ill COVID-19 patients. J Thromb Thrombolysis. 2020;50(3):580–6. https://doi.org/10.1007/s11239-020-02182-9.CrossRefPubMedPubMedCentral

175.

Kedzierska K, Ciechanowski K, Gołembiewska E, Safranow K, Ciechanowicz A, Domański L, et al. Plasma prekallikrein as a risk factor for diabetic retinopathy. Arch Med Res. 2005;36(5):539–43. https://doi.org/10.1016/j.arcmed.2005.03.050.CrossRefPubMed

176.

Colhoun HM, Zito F, Norman Chan N, Rubens MB, Fuller JH, Humphries SE. Activated factor XII levels and factor XII 46C>T genotype in relation to coronary artery calcification in patients with type 1 diabetes and healthy subjects. Atherosclerosis. 2002;163(2):363–9. https://doi.org/10.1016/s0021-9150(02)00022-9.CrossRefPubMed

177.

Ceballos FC, Ryan P, Blancas R, Martin-Vicente M, Vidal-Alcántara EJ, Peréz-García F, et al. Are reduced levels of coagulation proteins upon admission linked to COVID-19 severity and mortality? Front Med. 2021;8:718053. https://doi.org/10.3389/fmed.2021.718053.CrossRef

178.

Paszek E, Polak M, Bryk-Wiązania AH, Konieczyńska M, Undas A. Elevated plasma factor XI predicts cardiovascular events in patients with type 2 diabetes: a long-term observational study. Cardiovasc Diabetol. 2023;22(1):182. https://doi.org/10.1186/s12933-023-01905-5.CrossRefPubMedPubMedCentral

179.

Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089–98. https://doi.org/10.1007/s00134-020-06062-x.CrossRefPubMedPubMedCentral

180.

Ephraim RK, Awuku YA, Adu P, Ampomah LT, Adoba P, Panford S, et al. High risk of coagulopathy among Type-2 diabetes mellitus clients at a municipal hospital in Ghana. Ghana Med J. 2017;51(3):101–7. https://doi.org/10.4314/gmj.v51i3.2.CrossRefPubMedPubMedCentral

181.

Althaus K, Marini I, Zlamal J, Pelzl L, Singh A, Häberle H, et al. Antibody-induced procoagulant platelets in severe COVID-19 infection. Blood. 2021;137(8):1061–71. https://doi.org/10.1182/blood.2020008762.CrossRefPubMedPubMedCentral

182.

Marchetti M, Gomez-Rosas P, Russo L, Gamba S, Sanga E, Verzeroli C, et al. Fibrinolytic proteins and factor XIII as predictors of thrombotic and hemorrhagic complications in hospitalized COVID-19 patients. Front Cardiovasc Med. 2022;9:896362. https://doi.org/10.3389/fcvm.2022.896362.CrossRefPubMedPubMedCentral

183.

Sauls DL, Banini AE, Boyd LC, Hoffman M. Elevated prothrombin level and shortened clotting times in subjects with type 2 diabetes. J Thromb Haemost. 2007;5(3):638–9. https://doi.org/10.1111/j.1538-7836.2007.02366.x.CrossRefPubMed

184.

Zhao Y, Zhang J, Zhang J, Wu J. Diabetes mellitus is associated with shortened activated partial thromboplastin time and increased fibrinogen values. PLoS ONE. 2011;6(1):e16470. https://doi.org/10.1371/journal.pone.0016470.ADSCrossRefPubMedPubMedCentral

185.

Sui J, Noubouossie DF, Gandotra S, Cao L. Elevated plasma fibrinogen is associated with excessive inflammation and disease severity in COVID-19 patients. Front Cell Infect Microbiol. 2021;11:734005. https://doi.org/10.3389/fcimb.2021.734005.CrossRefPubMedPubMedCentral

186.

Mansfield MW, Kohler HP, Ariëns RA, McCormack LJ, Grant PJ. Circulating levels of coagulation factor XIII in subjects with type 2 diabetes and in their first-degree relatives. Diabetes Care. 2000;23(5):703–5. https://doi.org/10.2337/diacare.23.5.703.CrossRefPubMed

187.

Lichter Y, Badelbayov T, Shalev I, Schvartz R, Szekely Y, Benisty D, et al. Low FXIII activity levels in intensive care unit hospitalized COVID-19 patients. Thromb J. 2021;19(1):79. https://doi.org/10.1186/s12959-021-00333-3.CrossRefPubMedPubMedCentral

188.

Medina MG, Ledesma MD, Domínguez JE, Medina M, Zafra D, Alameda F, et al. Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation. EMBO J. 2005;24(9):1706–16. https://doi.org/10.1038/sj.emboj.7600650.CrossRefPubMedPubMedCentral

189.

Andrianto N, Al-Farabi MJ, Nugraha RA, Marsudi BA, Azmi Y. Biomarkers of endothelial dysfunction and outcomes in coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis. Microvasc Res. 2021;138:104224. https://doi.org/10.1016/j.mvr.2021.104224.CrossRefPubMedPubMedCentral

190.

Carmassi F, Morale M, Puccetti R, De Negri F, Monzani F, Navalesi R, et al. Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus. Thromb Res. 1992;67(6):643–54. https://doi.org/10.1016/0049-3848(92)90068-l.CrossRefPubMed

191.

Della-Morte D, Pacifici F, Ricordi C, Massoud R, Rovella V, Proietti S, et al. Low level of plasminogen increases risk for mortality in COVID-19 patients. Cell Death Dis. 2021;12(8):773. https://doi.org/10.1038/s41419-021-04070-3.CrossRefPubMedPubMedCentral

192.

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(1):401–14. https://doi.org/10.1161/ATVBAHA.120.315338.CrossRefPubMed

193.

Boknäs N, Laine C, Hillarp A, Macwan AS, Gustafsson KM, Lindahl TL, et al. Associations between hemostatic markers and mortality in COVID-19—compounding effects of D-dimer, antithrombin and PAP complex. Thromb Res. 2022;213:97–104. https://doi.org/10.1016/j.thromres.2022.03.013.CrossRefPubMedPubMedCentral

194.

De Jongh R, Ninivaggi M, Mesotten D, Bai C, Marcus B, Huskens D, et al. Vascular activation is a strong predictor of mortality in coronavirus disease 2019 patients on the ICU. Blood Coagul Fibrinolysis. 2021;32(4):290–3. https://doi.org/10.1097/MBC.0000000000001007.CrossRefPubMed

195.

Zhuang L, Yu C, Xu F, Zhao L, Wang X, Wang C, et al. Increased plasma D-dimer levels may be a promising indicator for diabetic peripheral neuropathy in type 2 diabetes. Front Endocrinol. 2022;13:930271. https://doi.org/10.3389/fendo.2022.930271.CrossRef

196.

Pérez-García N, García-González J, Requena-Mullor M, Rodríguez-Maresca MÁ, Alarcón-Rodríguez R. Comparison of analytical values D-Dimer, glucose, ferritin and C-reactive protein of symptomatic and asymptomatic COVID-19 patients. Int J Environ Res Public Health. 2022;19(9):5354. https://doi.org/10.3390/ijerph19095354.CrossRefPubMedPubMedCentral

197.

Fukahori S, Han JY, Vera I, Lockey R, Kim K, Cho S. Elevated PAI-1 levels are associated with severe COVID-19. J Allergy Clin Immunol. 2023;151(2):190. https://doi.org/10.1016/j.jaci.2022.12.595.CrossRef

198.

Pandolfi A, Cetrullo D, Polishuck R, Alberta MM, Calafiore A, Pellegrini G, et al. Plasminogen activator inhibitor type 1 is increased in the arterial wall of type II diabetic subjects. Arterioscler Thromb Vasc Biol. 2001;21(8):1378–82. https://doi.org/10.1161/hq0801.093667.CrossRefPubMed

199.

Agosti F, Toffolutti V, Cavalli N, Nivakoski S, Mascherini M, Aassve A. Information and vaccine hesitancy: Evidence from the early stage of the vaccine roll-out in 28 European countries. PLoS One. 2022;17(9):e0273555. https://doi.org/10.1371/journal.pone.0273555.

200.

de Gregorio C, Calcaterra G, Kounis NG, Bassareo PP, Mehta JL. Cerebral venous thrombosis after COVID-19 vaccines: Do we know the mechanism? Lancet Reg Health Eur. 2022;16:100387. https://doi.org/10.1016/j.lanepe.2022.100387.

201.

Brambilla M, Canzano P, Valle PD, Becchetti A, Conti M, Alberti M, et al. Head-to-head comparison of four COVID-19 vaccines on platelet activation, coagulation and inflammation. The TREASURE study. Thromb Res. 2023;223:24–33. https://doi.org/10.1016/j.thromres.2023.01.015.

202.

Kompaniyets L, Pennington AF, Goodman AB, Rosenblum HG, Belay B, Ko JY, et al. Underlying Medical Conditions and Severe Illness Among 540,667 Adults Hospitalized With COVID-19, March 2020-March 2021. Prev Chronic Dis. 2021;18:E66. https://doi.org/10.5888/pcd18.210123.

203.

Zhang R, Ouyang H, Fu L, Wang S, Han J, Huang K, et al. CT features of SARS-CoV-2 pneumonia according to clinical presentation: a retrospective analysis of 120 consecutive patients from Wuhan city. Eur Radiol. 2020;30(8):4417–26. https://doi.org/10.1007/s00330-020-06854-1.CrossRefPubMedPubMedCentral

204.

Cohen JI, Burbelo PD. Reinfection with SARS-CoV-2: implications for vaccines. Clin Infect Dis. 2021;73(11):e4223–8. https://doi.org/10.1093/cid/ciaa1866.CrossRefPubMed

205.

Sun J, Zheng Q, Madhira V, Olex AL, Anzalone AJ, Vinson A, et al. Association between immune dysfunction and COVID-19 breakthrough infection after SARS-CoV-2 vaccination in the US. JAMA Intern Med. 2022;182(2):153–62. https://doi.org/10.1001/jamainternmed.2021.7024.CrossRefPubMed

206.

Yang Y, Cai Z, Zhang J. Insulin treatment may increase adverse outcomes in patients with COVID-19 and diabetes: a systematic review and meta-analysis. Front Endocrinol. 2021;12:696087. https://doi.org/10.3389/fendo.2021.696087.CrossRef

207.

Liu J, Aylor KW, Chai W, Barrett EJ, Liu Z. Metformin prevents endothelial oxidative stress and microvascular insulin resistance during obesity development in male rats. Am J Physiol Endocrinol Metab. 2022;322(3):E293–306. https://doi.org/10.1152/ajpendo.00240.2021.CrossRefPubMedPubMedCentral

208.

Abad-Jiménez Z, López-Domènech S, Díaz-Rúa R, Iannantuoni F, Gómez-Abril SÁ, Periañez-Gómez D, et al. Systemic oxidative stress and visceral adipose tissue mediators of NLRP3 inflammasome and autophagy are reduced in obese type 2 diabetic patients treated with metformin. Antioxidants. 2020;9(9):892. https://doi.org/10.3390/antiox9090892.CrossRefPubMedPubMedCentral

209.

Victor VM, Rovira-Llopis S, Bañuls C, Diaz-Morales N, Lopez-Domenech S, Escribano-López I, et al. Metformin modulates human leukocyte/endothelial cell interactions and proinflammatory cytokines in polycystic ovary syndrome patients. Atherosclerosis. 2015;242(1):167–73. https://doi.org/10.1016/j.atherosclerosis.2015.07.017.CrossRefPubMed

210.

Gongol B, Marin T, Peng I, Woo B, Martin M, King S, et al. AMPKα2 exerts its anti-inflammatory effects through PARP-1 and Bcl-6. Proc Natl Acad Sci U S A. 2013;110(8):3161–6. https://doi.org/10.1073/pnas.1222051110.ADSCrossRefPubMedPubMedCentral

211.

Witkowski M, Friebel J, Tabaraie T, Grabitz S, Dörner A, Taghipour L, et al. Metformin is associated with reduced tissue factor procoagulant activity in patients with poorly controlled diabetes. Cardiovasc Drugs Ther. 2021;35(4):809–13. https://doi.org/10.1007/s10557-020-07040-7.CrossRefPubMed

212.

Xin G, Wei Z, Ji C, Zheng H, Gu J, Ma L, et al. Metformin uniquely prevents thrombosis by inhibiting platelet activation and mtDNA release. Sci Rep. 2016;6:36222. https://doi.org/10.1038/srep36222.ADSCrossRefPubMedPubMedCentral

213.

Apicella M, Campopiano MC, Mantuano M, Mazoni L, Coppelli A, Del Prato S. COVID-19 in people with diabetes: understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol. 2020;8(9):782–92. https://doi.org/10.1016/S2213-8587(20)30238-2.CrossRefPubMedPubMedCentral

214.

Ganesh A, Randall MD. Does metformin affect outcomes in COVID-19 patients with new or pre-existing diabetes mellitus? A systematic review and meta-analysis. Br J Clin Pharmacol. 2022;88(6):2642–56. https://doi.org/10.1111/bcp.15258.CrossRefPubMed

215.

Parthasarathy H, Tandel D, Siddiqui AH, Harshan KH. Metformin suppresses SARS-CoV-2 in cell culture. Virus Res. 2023;323:199010. https://doi.org/10.1016/j.virusres.2022.199010.CrossRefPubMed

216.

Cory TJ, Emmons RS, Yarbro JR, Davis KL, Pence BD. Metformin suppresses monocyte immunometabolic activation by SARS-CoV-2 spike protein subunit 1. Front Immunol. 2021;12:733921. https://doi.org/10.3389/fimmu.2021.733921.CrossRefPubMedPubMedCentral

217.

Shaseb E, Ghaffary S, Garjani A, Zoghi E, Maleki Dizaji N, Soltani S, et al. Long and short-term metformin consumption as a potential therapy to prevent complications of COVID-19. Adv Pharm Bull. 2023;13(3):621–6. https://doi.org/10.34172/apb.2023.066.CrossRefPubMed

218.

Wiernsperger N, Al-Salameh A, Cariou B, Lalau J. Protection by metformin against severe Covid-19: an in-depth mechanistic analysis. Diabetes Metab. 2022;48(4):101359. https://doi.org/10.1016/j.diabet.2022.101359.CrossRefPubMedPubMedCentral

219.

Shestakova MV, Vikulova OK, Elfimova AR, Deviatkin AA, Dedov II, Mokrysheva NG. Risk factors for COVID-19 case fatality rate in people with type 1 and type 2 diabetes mellitus: a nationwide retrospective cohort study of 235,248 patients in the Russian Federation. Front Endocrinol. 2022;13:909874. https://doi.org/10.3389/fendo.2022.909874.CrossRef

220.

Khunti K, Knighton P, Zaccardi F, Bakhai C, Barron E, Holman N, et al. Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England. Lancet Diabetes Endocrinol. 2021;9(5):293–303. https://doi.org/10.1016/S2213-8587(21)00050-4.CrossRefPubMedPubMedCentral

221.

Luk AOY, Yip TCF, Zhang X, Kong APS, Wong VW, Ma RCW, et al. Glucose-lowering drugs and outcome from COVID-19 among patients with type 2 diabetes mellitus: a population-wide analysis in Hong Kong. BMJ Open. 2021;11(10):e052310. https://doi.org/10.1136/bmjopen-2021-052310.CrossRefPubMed

222.

ASH Guidelines on Use of Anticoagulation in Patients with COVID-19—Hematology.org. https://www.hematology.org/education/clinicians/guidelines-and-quality-care/clinical-practice-guidelines/venous-thromboembolism-guidelines/ash-guidelines-on-use-of-anticoagulation-in-patients-with-covid-19. Accessed 28 Sep 2023.

223.

Cuker A, Tseng EK, Nieuwlaat R, Angchaisuksiri P, Blair C, Dane K, et al. American society of hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv. 2021;5(3):872–88. https://doi.org/10.1182/bloodadvances.2020003763.CrossRefPubMedPubMedCentral

224.

Chaves OA, Sacramento CQ, Fintelman-Rodrigues N, Temerozo JR, Pereira-Dutra F, Mizurini DM, et al. Apixaban, an orally available anticoagulant, inhibits SARS-CoV-2 replication and its major protease in a non-competitive way. J Mol Cell Biol. 2022;14(6):mjac039. https://doi.org/10.1093/jmcb/mjac039.CrossRefPubMedPubMedCentral

225.

Gianni P, Goldin M, Ngu S, Zafeiropoulos S, Geropoulos G, Giannis D. Complement-mediated microvascular injury and thrombosis in the pathogenesis of severe COVID-19: a review. World J Exp Med. 2022;12(4):53–67. https://doi.org/10.5493/wjem.v12.i4.53.CrossRefPubMedPubMedCentral

226.

van de Veerdonk FL, Kouijzer IJE, de Nooijer AH, van der Hoeven HG, Maas C, Netea MG, et al. Outcomes associated with use of a kinin B2 receptor antagonist among patients with COVID-19. JAMA Netw Open. 2020;3(8):e2017708. https://doi.org/10.1001/jamanetworkopen.2020.17708.CrossRefPubMedPubMedCentral

227.

Aboudounya MM, Heads RJ. COVID-19 and toll-like receptor 4 (TLR4): SARS-CoV-2 may bind and activate TLR4 to increase ACE2 expression, facilitating entry and causing hyperinflammation. Med Inflamm. 2021;2021:8874339. https://doi.org/10.1155/2021/8874339.CrossRef

228.

Fontes-Dantas FL, Fernandes GG, Gutman EG, De Lima EV, Antonio LS, Hammerle MB, et al. SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice. Cell Rep. 2023;42(3):112189. https://doi.org/10.1016/j.celrep.2023.112189.CrossRefPubMedPubMedCentral

229.

Zhao D, Qin Y, Liu J, Tang K, Lu S, Liu Z, et al. Orally administered BZL-sRNA-20 oligonucleotide targeting TLR4 effectively ameliorates acute lung injury in mice. Sci China Life Sci. 2023;66(7):1589–99. https://doi.org/10.1007/s11427-022-2219-0.CrossRefPubMed

230.

Wei W, Liaw C, Tsai K, Chiou C, Tseng Y, Chiou W, et al. Targeting spike protein-induced TLR/NET axis by COVID-19 therapeutic NRICM102 ameliorates pulmonary embolism and fibrosis. Pharmacol Res. 2022;184:106424. https://doi.org/10.1016/j.phrs.2022.106424.CrossRefPubMedPubMedCentral

231.

Gadanec L, Qaradakhi T, Renee McSweeney K, Ashiana Ali B, Zulli A, Apostolopoulos V. Dual targeting of Toll-like receptor 4 and angiotensin-converting enzyme 2: a proposed approach to SARS-CoV-2 treatment. Future Microbiol. 2021;16:205–9. https://doi.org/10.2217/fmb-2021-0018.CrossRef

232.

Griffin JH, Lyden P. COVID-19 hypothesis: activated protein C for therapy of virus-induced pathologic thromboinflammation. Res Pract Thromb Haemost. 2020;4(4):506–9. https://doi.org/10.1002/rth2.12362.CrossRefPubMedPubMedCentral

233.

Ali RA, Gandhi AA, Meng H, Yalavarthi S, Vreede AP, Estes SK, et al. Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome. Nat Commun. 2019;10:1916. https://doi.org/10.1038/s41467-019-09801-x.ADSCrossRefPubMedPubMedCentral

234.

Okeke EB, Louttit C, Fry C, Najafabadi AH, Han K, Nemzek J, et al. Inhibition of neutrophil elastase prevents neutrophil extracellular trap formation and rescues mice from endotoxic shock. Biomaterials. 2020;238:119836. https://doi.org/10.1016/j.biomaterials.2020.119836.CrossRefPubMedPubMedCentral

235.

Wienkamp A, Erpenbeck L, Rossaint J. Platelets in the NETworks interweaving inflammation and thrombosis. Front Immunol. 2022;13:953129. https://doi.org/10.3389/fimmu.2022.953129.CrossRefPubMedPubMedCentral

236.

Yang L, Xie X, Tu Z, Fu J, Xu D, Zhou Y. The signal pathways and treatment of cytokine storm in COVID-19. Sig Transduct Target Ther. 2021;6(1):1–20. https://doi.org/10.1038/s41392-021-00679-0.CrossRef

237.

Kim JS, Lee JY, Yang JW, Lee KH, Effenberger M, Szpirt W, et al. Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics. 2021;11(1):316–29. https://doi.org/10.7150/thno.49713.CrossRefPubMedPubMedCentral

238.

Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, Arabi YM, et al. Interleukin-6 receptor antagonists in critically Ill patients with Covid-19. N Engl J Med. 2021;384(16):1491–502. https://doi.org/10.1056/NEJMoa2100433.CrossRefPubMed

239.

Hepprich M, Mudry JM, Gregoriano C, Jornayvaz FR, Carballo S, Wojtusciszyn A, et al. Canakinumab in patients with COVID-19 and type 2 diabetes—A multicentre, randomised, double-blind, placebo-controlled trial. EClinicalMedicine. 2022;53:101649. https://doi.org/10.1016/j.eclinm.2022.101649.CrossRefPubMedPubMedCentral

240.

Yonekawa A, Shimono N. Clinical significance of COVID-19 and diabetes: in the pandemic situation of SARS-CoV-2 variants including omicron B.1.1.529. Biology. 2022;11(3):400. https://doi.org/10.3390/biology11030400.CrossRefPubMedPubMedCentral

Title: Mechanisms of endothelial activation, hypercoagulation and thrombosis in COVID-19: a link with diabetes mellitus
Authors: Inés Valencia
Jairo Lumpuy-Castillo
Giselle Magalhaes
Carlos F. Sánchez-Ferrer
Óscar Lorenzo
Concepción Peiró
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: COVID-19
Diabetes
SARS-CoV-2
Thrombosis
Long-COVID Syndrome
Tissue Plasminogen Activator
Published in: Cardiovascular Diabetology / Issue 1/2024
Electronic ISSN: 1475-2840
DOI: https://doi.org/10.1186/s12933-023-02097-8

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