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CC BY-NC-ND 4.0 · Semin Thromb Hemost
DOI: 10.1055/s-0044-1790603
DOI: 10.1055/s-0044-1790603
Review Article
Vascular Pathogenesis in Acute and Long COVID: Current Insights and Therapeutic Outlook
Funding E.P.: Funding was provided by National Research Foundation of South Africa (grant number: 142142) and South African Medical Research Council (self-initiated research [SIR] grant), and Balvi Foundation (grant number: B31).
Abstract
Long coronavirus disease 2019 (COVID-19)—a postacute consequence of severe acute respiratory syndrome coronavirus 2 infection—manifests with a broad spectrum of relapsing and remitting or persistent symptoms as well as varied levels of organ damage, which may be asymptomatic or present as acute events such as heart attacks or strokes and recurrent infections, hinting at complex underlying pathogenic mechanisms. Central to these symptoms is vascular dysfunction rooted in thrombotic endothelialitis. We review the scientific evidence that widespread endothelial dysfunction (ED) leads to chronic symptomatology. We briefly examine the molecular pathways contributing to endothelial pathology and provide a detailed analysis of how these cellular processes underpin the clinical picture. Noninvasive diagnostic techniques, such as flow-mediated dilation and peripheral arterial tonometry, are evaluated for their utility in identifying ED. We then explore mechanistic, cellular-targeted therapeutic interventions for their potential in treating ED. Overall, we emphasize the critical role of cellular health in managing Long COVID and highlight the need for early intervention to prevent long-term vascular and cellular dysfunction.
Keywords
postacute COVID-19 syndrome - SARS-CoV-2 - reinfection - endothelium - vascular - thrombosisPublikationsverlauf
Artikel online veröffentlicht:
30. September 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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References
- 1 Wulf Hanson S, Abbafati C, Aerts JG. et al; Global Burden of Disease Long COVID Collaborators. Estimated global proportions of individuals with persistent fatigue, cognitive, and respiratory symptom clusters following symptomatic COVID-19 in 2020 and 2021. JAMA 2022; 328 (16) 1604-1615
- 2 National Academies of Sciences, Engineering, and Medicine.. A Long COVID Definition: A Chronic, Systemic Disease State with Profound Consequences. Washington, DC:: The National Academies Press;; 2024
- 3 Ewing AG, Salamon S, Pretorius E. et al. Review of organ damage from COVID and Long COVID: a disease with a spectrum of pathology. Med Rev 2024;
- 4 Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV. WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis 2022; 22 (04) e102-e107
- 5 Fritsche LG, Jin W, Admon AJ, Mukherjee B. Characterizing and predicting post-acute sequelae of SARS CoV-2 infection (PASC) in a large academic medical center in the US. J Clin Med 2023; 12 (04) 1328
- 6 Proal AD, VanElzakker MB. Long COVID or post-acute sequelae of COVID-19 (PASC): an overview of biological factors that may contribute to persistent symptoms. Front Microbiol 2021; 12: 698169
- 7 Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol 2023; 21 (03) 133-146
- 8 Al-Aly Z, Bowe B, Xie Y. Long COVID after breakthrough SARS-CoV-2 infection. Nat Med 2022; 28 (07) 1461-1467
- 9 Lang M, Som A, Carey D. et al. Pulmonary vascular manifestations of COVID-19 pneumonia. Radiol Cardiothorac Imaging 2020; 2 (03) e200277
- 10 Patel BV, Arachchillage DJ, Ridge CA. et al. Pulmonary angiopathy in severe COVID-19: physiologic, imaging, and hematologic observations. Am J Respir Crit Care Med 2020; 202 (05) 690-699
- 11 Ridge CA, Desai SR, Jeyin N. et al. Dual-energy CT pulmonary angiography (DECTPA) quantifies vasculopathy in severe COVID-19 pneumonia. Radiol Cardiothorac Imaging 2020; 2 (05) e200428
- 12 Lloyd-Jones G, Alcock R, Oudkerk M. COVID-19 lung disease is a pulmonary vasculopathy. Clin Radiol 2024; 79 (07) e975-e978
- 13 Carsana L, Sonzogni A, Nasr A. et al. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study. Lancet Infect Dis 2020; 20 (10) 1135-1140
- 14 Fox SE, Akmatbekov A, Harbert JL, Li G, Quincy Brown J, Vander Heide RS. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. Lancet Respir Med 2020; 8 (07) 681-686
- 15 van Dam LF, Kroft LJM, van der Wal LI. et al. Clinical and computed tomography characteristics of COVID-19 associated acute pulmonary embolism: a different phenotype of thrombotic disease?. Thromb Res 2020; 193: 86-89
- 16 Eddy RL, Sin DD. Computed tomography vascular tree-in-bud: a novel prognostic imaging biomarker in COVID-19?. Am J Respir Crit Care Med 2020; 202 (05) 642-644
- 17 Nemec SF, Bankier AA, Eisenberg RL. Lower lobe-predominant diseases of the lung. AJR Am J Roentgenol 2013; 200 (04) 712-728
- 18 Deinhardt-Emmer S, Wittschieber D, Sanft J. et al. Early postmortem mapping of SARS-CoV-2 RNA in patients with COVID-19 and the correlation with tissue damage. eLife 2021; 10: e60361
- 19 Bonaventura A, Vecchié A, Dagna L. et al. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol 2021; 21 (05) 319-329
- 20 Ackermann M, Verleden SE, Kuehnel M. et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020; 383 (02) 120-128
- 21 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395 (10234): 1417-1418
- 22 Henkel M, Weikert T, Marston K. et al. Lethal COVID-19: radiologic-pathologic correlation of the lungs. Radiol Cardiothorac Imaging 2020; 2 (06) e200406
- 23 Kianzad A, Meijboom LJ, Nossent EJ. et al. COVID-19: histopathological correlates of imaging patterns on chest computed tomography. Respirology 2021; 26 (09) 869-877
- 24 Calabretta E, Moraleda JM, Iacobelli M. et al. COVID-19-induced endotheliitis: emerging evidence and possible therapeutic strategies. Br J Haematol 2021; 193 (01) 43-51
- 25 Xu SW, Ilyas I, Weng JP. Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies. Acta Pharmacol Sin 2023; 44 (04) 695-709
- 26 Kell DB, Laubscher GJ, Pretorius E. A central role for amyloid fibrin microclots in Long COVID/PASC: origins and therapeutic implications. Biochem J 2022; 479 (04) 537-559
- 27 Pretorius E, Vlok M, Venter C. et al. Persistent clotting protein pathology in Long COVID/post-acute sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovasc Diabetol 2021; 20 (01) 172
- 28 Kruger A, Vlok M, Turner S. 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 (01) 190
- 29 Rosei CA, Gaggero A, Famà F. et al. Skin capillary alterations in patients with acute SarsCoV2 infection. J Hypertens 2022; 40 (12) 2385-2393
- 30 Osiaevi I, Schulze A, Evers G. et al. Persistent capillary rarefication in Long COVID syndrome. Angiogenesis 2023; 26 (01) 53-61
- 31 Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol 2019; 18 (07) 684-696
- 32 Kell DB, Pretorius E. The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications. Biochem J 2022; 479 (16) 1653-1708
- 33 Mclaughlin M, Sanal-Hayes NEM, Hayes LD, Berry EC, Sculthorpe NF. People with Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome exhibit similarly impaired vascular function. . Am J Med 2023:S0002-9343(23)00609-5
- 34 Chopoorian AH, Wahba A, Celedonio J. et al. Impaired endothelial function in patients with postural tachycardia syndrome. Hypertension 2021; 77 (03) 1001-1009
- 35 Jakubowski M, Turek-Jakubowska A, Szahidewicz-Krupska E, Gawrys K, Gawrys J, Doroszko A. Profiling the endothelial function using both peripheral artery tonometry (EndoPAT) and laser Doppler flowmetry (LD) - complementary studies or waste of time?. Microvasc Res 2020; 130: 104008
- 36 Çakmak F, Demirbuga A, Demirkol D. et al. Nailfold capillaroscopy: a sensitive method for evaluating microvascular involvement in children with SARS-CoV-2 infection. Microvasc Res 2021; 138: 104196
- 37 Natalello G, De Luca G, Gigante L. et al. Nailfold capillaroscopy findings in patients with coronavirus disease 2019: broadening the spectrum of COVID-19 microvascular involvement. Microvasc Res 2021; 133: 104071
- 38 Mondini L, Confalonieri P, Pozzan R. et al. Microvascular alteration in COVID-19 documented by nailfold capillaroscopy. Diagnostics (Basel) 2023; 13 (11) 1905
- 39 Zhang J, Tecson KM, McCullough PA. Endothelial dysfunction contributes to COVID-19-associated vascular inflammation and coagulopathy. Rev Cardiovasc Med 2020; 21 (03) 315-319
- 40 Gimbrone Jr MA, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 2016; 118 (04) 620-636
- 41 Zhang J, Defelice AF, Hanig JP, Colatsky T. Biomarkers of endothelial cell activation serve as potential surrogate markers for drug-induced vascular injury. Toxicol Pathol 2010; 38 (06) 856-871
- 42 Durstenfeld MS, Weiman S, Holtzman M, Blish C, Pretorius R, Deeks SG. Long COVID and post-acute sequelae of SARS-CoV-2 pathogenesis and treatment: a Keystone Symposia report. Ann N Y Acad Sci 2024; 1535 (01) 31-41
- 43 Jing H, Wu X, Xiang M, Liu L, Novakovic VA, Shi J. Pathophysiological mechanisms of thrombosis in acute and Long COVID-19. Front Immunol 2022; 13: 992384
- 44 Huertas A, Montani D, Savale L. et al. Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)?. Eur Respir J 2020; 56 (01) 2001634
- 45 Conway EM, Mackman N, Warren RQ. et al. Understanding COVID-19-associated coagulopathy. Nat Rev Immunol 2022; 22 (10) 639-649
- 46 Fahmy OH, Daas FM, Salunkhe V. 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 (05) e0427
- 47 Haberecker M, Schwarz EI, Steiger P. et al. Autopsy-based pulmonary and vascular pathology: pulmonary endotheliitis and multi-organ involvement in COVID-19 associated deaths. Respiration 2022; 101 (02) 155-165
- 48 Hanley B, Naresh KN, Roufosse C. et al. Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study. Lancet Microbe 2020; 1 (06) e245-e253
- 49 Tsakok MT, Watson RA, Saujani SJ. et al. Reduction in chest CT severity and improved hospital outcomes in SARS-CoV-2 omicron compared with delta variant infection. Radiology 2023; 306 (01) 261-269
- 50 Yoon SH, Lee JH, Kim BN, Chest CT. Chest CT findings in hospitalized patients with SARS-CoV-2: delta versus omicron variants. Radiology 2023; 306 (01) 252-260
- 51 Menni C, Valdes AM, Polidori L. et al. Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study. Lancet 2022; 399 (10335): 1618-1624
- 52 Grobbelaar LM, Kruger A, Venter C. et al. Relative hypercoagulopathy of the SARS-CoV-2 Beta and Delta variants when compared to the less severe Omicron variants is related to TEG parameters, the extent of fibrin amyloid microclots, and the severity of clinical illness. Research Square; 2022.
- 53 Lloyd-Jones G, Molayem S, Pontes C, Chapple I. The COVID-19 pathway: a proposed oral-vascular-pulmonary route of SARS-CoV-2 infection and the importance of oral healthcare measures. J Oral Med Dent Res 2021; 2 (01) 1-25
- 54 Lloyd-Jones G, Oudkerk M. COVID-19: angiotensin II in development of lung immunothrombosis and vasculitis mimics. Lancet Rheumatol 2021; 3 (05) e325-e326
- 55 Patel SK, Juno JA, Lee WS. et al. Plasma ACE2 activity is persistently elevated following SARS-CoV-2 infection: implications for COVID-19 pathogenesis and consequences. Eur Respir J 2021; 57 (05) 2003730
- 56 Loo J, Spittle DA, Newnham M. COVID-19, immunothrombosis and venous thromboembolism: biological mechanisms. Thorax 2021; 76 (04) 412-420
- 57 Beyerstedt S, Casaro EB, Rangel EB. COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection. Eur J Clin Microbiol Infect Dis 2021; 40 (05) 905-919
- 58 Altmann DM, Whettlock EM, Liu S, Arachchillage DJ, Boyton RJ. The immunology of Long COVID. Nat Rev Immunol 2023; 23 (10) 618-634
- 59 Montezano AC, Camargo LL, Mary S. et al. SARS-CoV-2 spike protein induces endothelial inflammation via ACE2 independently of viral replication. Sci Rep 2023; 13 (01) 14086
- 60 Ashall L, Horton CA, Nelson DE. et al. Pulsatile stimulation determines timing and specificity of NF-kappaB-dependent transcription. Science 2009; 324 (5924) 242-246
- 61 Hasanvand A. COVID-19 and the role of cytokines in this disease. Inflammopharmacology 2022; 30 (03) 789-798
- 62 Colunga Biancatelli RML, Solopov PA, Sharlow ER, Lazo JS, Marik PE, Catravas JD. The SARS-CoV-2 spike protein subunit S1 induces COVID-19-like acute lung injury in Κ18-hACE2 transgenic mice and barrier dysfunction in human endothelial cells. Am J Physiol Lung Cell Mol Physiol 2021; 321 (02) L477-L484
- 63 Teuwen LA, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vasculature unleashed. Nat Rev Immunol 2020; 20 (07) 389-391
- 64 Baycan OF, Barman HA, Bolen F. et al. Plasminogen activator inhibitor-1 levels as an indicator of severity and mortality for COVID-19. North Clin Istanb 2023; 10 (01) 1-9
- 65 Zhang Z, Dai W, Zhu W. et al. Plasma tissue-type plasminogen activator is associated with lipoprotein(a) and clinical outcomes in hospitalized patients with COVID-19. Res Pract Thromb Haemost 2023; 7 (06) 102164
- 66 Zuo Y, Warnock M, Harbaugh A. et al. Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients. Sci Rep 2021; 11 (01) 1580
- 67 Whyte CS, Simpson M, Morrow GB. et al. The suboptimal fibrinolytic response in COVID-19 is dictated by high PAI-1. J Thromb Haemost 2022; 20 (10) 2394-2406
- 68 Pretorius E, Venter C, Laubscher GJ, Lourens PJ, Steenkamp J, Kell DB. Prevalence of readily detected amyloid blood clots in 'unclotted' type 2 diabetes mellitus and COVID-19 plasma: a preliminary report. Cardiovasc Diabetol 2020; 19 (01) 193
- 69 Venter C, Bezuidenhout JA, Laubscher GJ. et al. Erythrocyte, platelet, serum ferritin, and P-selectin pathophysiology implicated in severe hypercoagulation and vascular complications in COVID-19. Int J Mol Sci 2020; 21 (21) 8234
- 70 Turner S, Khan MA, Putrino D, Woodcock A, Kell DB, Pretorius E. Long COVID: pathophysiological factors and abnormalities of coagulation. Trends Endocrinol Metab 2023; 34 (06) 321-344
- 71 Wang C, Yu C, Jing H. et al. Long COVID: the nature of thrombotic sequelae determines the necessity of early anticoagulation. Front Cell Infect Microbiol 2022; 12: 861703
- 72 Zhang S, Liu Y, Wang X. et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol 2020; 13 (01) 120
- 73 Haffke M, Freitag H, Rudolf G. et al. Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS). J Transl Med 2022; 20 (01) 138
- 74 Charfeddine S, Ibn Hadj Amor H, Jdidi J. et al. Long COVID 19 syndrome: is it related to microcirculation and endothelial dysfunction? Insights from TUN-EndCOV study. Front Cardiovasc Med 2021; 8: 745758
- 75 Jarrott B, Head R, Pringle KG, Lumbers ER, Martin JH. “Long COVID”-a hypothesis for understanding the biological basis and pharmacological treatment strategy. Pharmacol Res Perspect 2022; 10 (01) e00911
- 76 Vijayakumar B, Boustani K, Ogger PP. et al. Immuno-proteomic profiling reveals aberrant immune cell regulation in the airways of individuals with ongoing post-COVID-19 respiratory disease. Immunity 2022; 55 (03) 542-556.e5
- 77 Vollenberg R, Tepasse PR, Ochs K. et al. Indications of persistent glycocalyx damage in convalescent COVID-19 patients: a prospective multicenter study and hypothesis. Viruses 2021; 13 (11) 2324
- 78 Fogarty H, Ward SE, Townsend L. et al; Irish COVID-19 Vasculopathy Study (iCVS) Investigators. Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in Long COVID syndrome is related to immune dysfunction. J Thromb Haemost 2022; 20 (10) 2429-2438
- 79 Patel MA, Knauer MJ, Nicholson M. et al. Elevated vascular transformation blood biomarkers in long-COVID indicate angiogenesis as a key pathophysiological mechanism. Mol Med 2022; 28 (01) 122
- 80 Banecki KMRM, Dora KA. Endothelin-1 in health and disease. Int J Mol Sci 2023; 24 (14) 11295
- 81 Talotta R. Impaired VEGF-A-mediated neurovascular crosstalk induced by SARS-CoV-2 spike protein: a potential hypothesis explaining Long COVID-19 symptoms and COVID-19 vaccine side effects?. Microorganisms 2022; 10 (12) 2452
- 82 Kell DB, Pretorius E. Are fibrinaloid microclots a cause of autoimmunity in Long COVID and other post-infection diseases?. Biochem J 2023; 480 (15) 1217-1240
- 83 Philogene MC, Johnson T, Vaught AJ, Zakaria S, Fedarko N. Antibodies against angiotensin II type 1 and endothelin A receptors: relevance and pathogenicity. Hum Immunol 2019; 80 (08) 561-567
- 84 Miedema J, Schreurs M, van der Sar-van der Brugge S. et al. Antibodies against angiotensin II receptor type 1 and endothelin A receptor are associated with an unfavorable COVID19 disease course. Front Immunol 2021; 12: 684142
- 85 Wallukat G, Hohberger B, Wenzel K. et al. Functional autoantibodies against G-protein coupled receptors in patients with persistent long-COVID-19 symptoms. J Transl Autoimmun 2021; 4: 100100
- 86 Civieri G, Iop L, Tona F. Antibodies against angiotensin II type 1 and endothelin 1 type A receptors in cardiovascular pathologies. Int J Mol Sci 2022; 23 (02) 927
- 87 Yao Q, Doyle ME, Qing-Rong L. et al. Long-term dysfunction of taste papillae in SARS-CoV-2. NEJM Evid 2023; 2 (09)
- 88 Lima TM, Martins RB, Miura CS. et al. Tonsils are major sites of prolonged SARS-COV-2 infection in children. Microbiol Spectr 2023; 11 (05) e0134723
- 89 Omidvari N, Jones T, Price PM. et al. First-in-human immunoPET imaging of COVID-19 convalescent patients using dynamic total-body PET and a CD8-targeted minibody. Sci Adv 2023; 9 (41) eadh7968
- 90 Peluso MJ, Swank ZN, Goldberg SA. et al. Plasma-based antigen persistence in the post-acute phase of COVID-19. Lancet Infect Dis 2024; 24 (06) e345-e347
- 91 Vuuren MJV, Nell TA, Carr JA, Kell DB, Pretorius E. Iron dysregulation and inflammagens related to oral and gut health are central to the development of Parkinson's disease. Biomolecules 2020; 11 (01) 30
- 92 Soffritti I, D'Accolti M, Fabbri C. et al. Oral microbiome dysbiosis is associated with symptoms severity and local immune/inflammatory response in COVID-19 patients: a cross-sectional study. Front Microbiol 2021; 12: 687513
- 93 Lloyd-Jones G, Pontes CC, Molayem S, Chapple ILC. The oral-vascular-pulmonary infection route: a pathogenic mechanism linking oral health status to acute and post-acute COVID-19. Curr Oral Health Rep 2023; 10: 163-174
- 94 Gualtero DF, Lafaurie GI, Buitrago DM, Castillo Y, Vargas-Sanchez PK, Castillo DM. Oral microbiome mediated inflammation, a potential inductor of vascular diseases: a comprehensive review. Front Cardiovasc Med 2023; 10: 1250263
- 95 Eberhardt N, Noval MG, Kaur R. et al. SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels. Nat Cardiovasc Res 2023; 2 (10) 899-916
- 96 Nyström S, Hammarström P. Amyloidogenesis of SARS-CoV-2 spike protein. J Am Chem Soc 2022; 144 (20) 8945-8950
- 97 Parry PI, Lefringhausen A, Turni C. et al. 'Spikeopathy': COVID-19 spike protein is pathogenic, from both virus and vaccine mRNA. Biomedicines 2023; 11 (08) 2287
- 98 Cano-Mendez A, García-Larragoiti N, Damian-Vazquez M. et al. Platelet reactivity and inflammatory phenotype induced by full-length spike SARS-CoV-2 protein and its RBD domain. Int J Mol Sci 2022; 23 (23) 15191
- 99 Perico L, Morigi M, Galbusera M. et al. SARS-CoV-2 spike protein 1 activates microvascular endothelial cells and complement system leading to platelet aggregation. Front Immunol 2022; 13: 827146
- 100 Grobbelaar LM, Venter C, Vlok M. et al. SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19. Biosci Rep 2021; 41 (08) BSR20210611
- 101 Saud Z, Tyrrell VJ, Zaragkoulias A. et al. The SARS-CoV2 envelope differs from host cells, exposes procoagulant lipids, and is disrupted in vivo by oral rinses. J Lipid Res 2022; 63 (06) 100208
- 102 Laubscher GJ, Lourens PJ, Venter C, Kell DB, Pretorius E. TEG®, microclot and platelet mapping for guiding early management of severe COVID-19 coagulopathy. J Clin Med 2021; 10 (22) 5381
- 103 Pretorius E, Venter C, Laubscher GJ. 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 (01) 148
- 104 Turner S, Naidoo CA, Usher TJ. et al. Increased levels of inflammatory and endothelial biomarkers in blood of Long COVID patients point to thrombotic endothelialitis. Semin Thromb Hemost 2023; 50 (02) 288-294
- 105 Kell DB, Pretorius E. Proteins behaving badly. Substoichiometric molecular control and amplification of the initiation and nature of amyloid fibril formation: lessons from and for blood clotting. Prog Biophys Mol Biol 2017; 123: 16-41
- 106 Xie Y, Choi T, Al-Aly Z. Postacute sequelae of SARS-CoV-2 infection in the pre-delta, delta, and omicron Eras. N Engl J Med 2024; 391 (06) 515-525
- 107 Fan BE, Ng J, Chan SSW. et al. COVID-19 associated coagulopathy in critically ill patients: a hypercoagulable state demonstrated by parameters of haemostasis and clot waveform analysis. J Thromb Thrombolysis 2021; 51 (03) 663-674
- 108 Fogarty H, Townsend L, Morrin H. et al; Irish COVID-19 Vasculopathy Study (iCVS) investigators. Persistent endotheliopathy in the pathogenesis of Long COVID syndrome. J Thromb Haemost 2021; 19 (10) 2546-2553
- 109 Zuin M, Barco S, Giannakoulas G. et al. Risk of venous thromboembolic events after COVID-19 infection: a systematic review and meta-analysis. J Thromb Thrombolysis 2023; 55 (03) 490-498
- 110 Patell R, Bogue T, Koshy A. et al. Postdischarge thrombosis and hemorrhage in patients with COVID-19. Blood 2020; 136 (11) 1342-1346
- 111 Rijken DC, Abdul S, Malfliet JJ, Leebeek FW, Uitte de Willige S. Compaction of fibrin clots reveals the antifibrinolytic effect of factor XIII. J Thromb Haemost 2016; 14 (07) 1453-1461
- 112 Mosesson MW, Siebenlist KR, Hernandez I, Lee KN, Christiansen VJ, McKee PA. Evidence that alpha2-antiplasmin becomes covalently ligated to plasma fibrinogen in the circulation: a new role for plasma factor XIII in fibrinolysis regulation. J Thromb Haemost 2008; 6 (09) 1565-1570
- 113 Nalbandian A, Sehgal K, Gupta A. et al. Post-acute COVID-19 syndrome. Nat Med 2021; 27 (04) 601-615
- 114 Jiang JH, Wang N, Li A. et al. Hypoxia can contribute to the induction of the Epstein-Barr virus (EBV) lytic cycle. J Clin Virol 2006; 37 (02) 98-103
- 115 Huang R, Huestis M, Gan ES, Ooi EE, Ohh M. Hypoxia and viral infectious diseases. JCI Insight 2021; 6 (07) e147190
- 116 Ufuk F, Savaş R. Chest CT features of the novel coronavirus disease (COVID-19). Turk J Med Sci 2020; 50 (04) 664-678
- 117 Kerchberger VE, Bastarache JA. Pulmonary vasculopathy in COVID-19 acute respiratory distress syndrome: a step closer to the full picture. Am J Respir Crit Care Med 2022; 206 (07) 809-810
- 118 Mohamed I, de Broucker V, Duhamel A. et al. Pulmonary circulation abnormalities in post-acute COVID-19 syndrome: dual-energy CT angiographic findings in 79 patients. Eur Radiol 2023; 33 (07) 4700-4712
- 119 Heiss R, Tan L, Schmidt S. et al. Pulmonary dysfunction after pediatric COVID-19. Radiology 2023; 306 (03) e221250
- 120 Dhawan RT, Gopalan D, Howard L. et al. Beyond the clot: perfusion imaging of the pulmonary vasculature after COVID-19. Lancet Respir Med 2021; 9 (01) 107-116
- 121 Raitakari OT, Celermajer DS. Flow-mediated dilatation. Br J Clin Pharmacol 2000; 50 (05) 397-404
- 122 Celermajer DS, Sorensen KE, Gooch VM. et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992; 340 (8828) 1111-1115
- 123 Corretti MC, Anderson TJ, Benjamin EJ. et al; International Brachial Artery Reactivity Task Force. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002; 39 (02) 257-265
- 124 Thijssen DH, Black MA, Pyke KE. et al. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol 2011; 300 (01) H2-H12
- 125 Holder SM, Bruno RM, Shkredova DA. et al. Reference intervals for brachial artery flow-mediated dilation and the relation with cardiovascular risk factors. Hypertension 2021; 77 (05) 1469-1480
- 126 Maruhashi T, Kajikawa M, Kishimoto S. et al. Diagnostic criteria of flow-mediated vasodilation for normal endothelial function and nitroglycerin-induced vasodilation for normal vascular smooth muscle function of the brachial artery. J Am Heart Assoc 2020; 9 (02) e013915
- 127 Heiss C, Rodriguez-Mateos A, Bapir M, Skene SS, Sies H, Kelm M. Flow-mediated dilation reference values for evaluation of endothelial function and cardiovascular health. Cardiovasc Res 2023; 119 (01) 283-293
- 128 Ambrosino P, Sanduzzi Zamparelli S, Mosella M. et al. Clinical assessment of endothelial function in convalescent COVID-19 patients: a meta-analysis with meta-regressions. Ann Med 2022; 54 (01) 3234-3249
- 129 Gao YP, Zhou W, Huang PN. et al. Persistent endothelial dysfunction in coronavirus disease-2019 survivors late after recovery. Front Med (Lausanne) 2022; 9: 809033
- 130 Cimino G, Vizzardi E, Calvi E. et al. Endothelial dysfunction in COVID-19 patients assessed with Endo-PAT2000. Monaldi Arch Chest Dis 2022; 92 (04)
- 131 Smith V, Ickinger C, Hysa E. et al. Nailfold capillaroscopy. Best Pract Res Clin Rheumatol 2023; 37 (01) 101849
- 132 Laubscher GJ, Khan M, Venter C. et al. Treatment of Long COVID symptoms with triple anticoagulant therapy. Res Square 2023; [Preprint].
- 133 Kell DB. Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Med Genomics 2009; 2: 2
- 134 Wolfrum S, Jensen KS, Liao JK. Endothelium-dependent effects of statins. Arterioscler Thromb Vasc Biol 2003; 23 (05) 729-736
- 135 Amraei R, Rahimi N. COVID-19, renin-angiotensin system and endothelial dysfunction. Cells 2020; 9 (07) 1652
- 136 Lei Y, Zhang J, Schiavon CR. et al. SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE 2. Circ Res 2021; 128 (09) 1323-1326
- 137 Fraga-Silva RA, Costa-Fraga FP, Murça TM. et al. Angiotensinconverting enzyme 2 activation improves endothelial function. Hypertension 2013; 61 (06) 1233-1238
- 138 NICE guideline 2021. COVID-19 rapid guideline: managing COVID-19. https://www.nice.org.uk/guidance/ng191
- 139 Taub PR, Zadourian A, Lo HC, Ormiston CK, Golshan S, Hsu JC. Randomized trial of ivabradine in patients with hyperadrenergic postural orthostatic tachycardia syndrome. J Am Coll Cardiol 2021; 77 (07) 861-871
- 140 Ross AJ, Ocon AJ, Medow MS, Stewart JM. A double-blind placebo-controlled cross-over study of the vascular effects of midodrine in neuropathic compared with hyperadrenergic postural tachycardia syndrome. Clin Sci (Lond) 2014; 126 (04) 289-296
- 141 Bramante CT, Buse JB, Liebovitz DM. et al; COVID-OUT Study Team. 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) 1119-1129
- 142 Ma Z, Patel N, Vemparala P, Krishnamurthy M. Metformin is associated with favorable outcomes in patients with COVID-19 and type 2 diabetes mellitus. Sci Rep 2022; 12 (01) 5553
- 143 Jung SM, Kim W-U. Targeted immunotherapy for autoimmune disease. Immune Netw 2022; 22 (01) e9
- 144 Pathangey G, Fadadu PP, Hospodar AR, Abbas AE. Angiotensin-converting enzyme 2 and COVID-19: patients, comorbidities, and therapies. Am J Physiol Lung Cell Mol Physiol 2021; 320 (03) L301-L330
- 145 Pliszka AG. Modafinil: a review and its potential use in the treatment of Long COVID fatigue and neurocognitive deficits. Am J Psychiatry Resid J 2022; 17: 5-7
- 146 Li P, Xie C, Zhong J, Guo Z, Guo K, Tu Q. Melatonin attenuates ox-LDL-induced endothelial dysfunction by reducing ER stress and inhibiting JNK/Mff signaling. Oxid Med Cell Longev 2021; 2021: 5589612
- 147 Wang L, Wang W, Han R, Liu Y, Wu B, Luo J. Protective effects of melatonin on myocardial microvascular endothelial cell injury under hypertensive state by regulating Mst1. BMC Cardiovasc Disord 2023; 23 (01) 179
- 148 McGrane IR, Leung JG, St Louis EK, Boeve BF. Melatonin therapy for REM sleep behavior disorder: a critical review of evidence. Sleep Med 2015; 16 (01) 19-26
- 149 Wong AYS, Tomlinson LA, Brown JP. et al; OpenSAFELY Collaborative. Association between warfarin and COVID-19-related outcomes compared with direct oral anticoagulants: population-based cohort study. J Hematol Oncol 2021; 14 (01) 172
- 150 Abdelmaksoud A, Goldust M, Vestita M. Omalizumab and COVID-19 treatment: could it help?. Dermatol Ther 2020; 33 (04) e13792
- 151 Wood RA, Togias A, Sicherer SH. et al. Omalizumab for the treatment of multiple food allergies. N Engl J Med 2024; 390 (10) 889-899
- 152 Pala D, Pistis M. Anti-IL5 drugs in COVID-19 patients: role of eosinophils in SARS-CoV-2-induced immunopathology. Front Pharmacol 2021; 12: 622554
- 153 Charfeddine S, Ibnhadjamor H, Jdidi J. et al. Sulodexide significantly improves endothelial dysfunction and alleviates chest pain and palpitations in patients with long-COVID-19: insights from TUN-EndCOV study. Front Cardiovasc Med 2022; 9: 866113