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CC BY 4.0 · TH Open 2020; 04(04): e288-e299
DOI: 10.1055/s-0040-1718415
Review Article

The Potential Role of Coagulation Factor Xa in the Pathophysiology of COVID-19: A Role for Anticoagulants as Multimodal Therapeutic Agents

Galit H. Frydman
1   Coagulo Medical Technologies, Inc., Auburndale, Massachusetts, United States
2   Center for Biomedical Engineering, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
3   Division of Trauma, Emergency Surgery and Surgical Critical Care, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, United States
,
Michael B. Streiff 
4   Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
,
Jean M. Connors
5   Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States
,
Gregory Piazza
6   Division of Cardiovascular Medicine Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
› Author Affiliations Funding None.
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Abstract

SARS-CoV-2 infection (COVID-19) results in local and systemic activation of inflammation and coagulation. In this review article, we will discuss the potential role of coagulation factor Xa (FXa) in the pathophysiology of COVID-19. FXa, a serine protease, has been shown to play a role in the cleavage of SARS-CoV-1 spike protein (SP), with the inhibition of FXa resulting in the inhibition of viral infectivity. FX is known to be primarily produced in the liver, but it is also expressed by multiple cells types, including alveolar epithelium, cardiac myocytes, and macrophages. Considering that patients with preexisting conditions, including cardiopulmonary disease, are at an increased risk of severe COVID-19, we discuss the potential role of increased levels of FX in these patients, resulting in a potential increased propensity to have a higher infectious rate and viral load, increased activation of coagulation and inflammation, and development of fibrosis. With these observations in mind, we postulate as to the potential therapeutic role of FXa inhibitors as a prophylactic and therapeutic treatment for high-risk patients with COVID-19.

Keywords

SARS-CoV-2 - coronavirus - COVID-19 - coagulation - factor X - factor Xa - anticoagulants


Publication History

Received: 07 September 2020

Accepted: 08 September 2020

Article published online:
07 October 2020

© .

Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Chan JF, To KK, Tse H, Jin DY, Yuen KY. Interspecies transmission and emergence of novel viruses: lessons from bats and birds. Trends Microbiol 2013; 21 (10) 544-555
    CrossrefPubMedGoogle Scholar
  • 2 Arabi YM, Balkhy HH, Hayden FG. et al. Middle East respiratory syndrome. N Engl J Med 2017; 376 (06) 584-594
    CrossrefPubMedGoogle Scholar
  • 3 Lee N, Hui D, Wu A. et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med 2003; 348 (20) 1986-1994
    CrossrefPubMedGoogle Scholar
  • 4 Guan WJ, Ni ZY, Hu Y. China Medical Treatment Expert Group for COVID-19. et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382 (18) 1708-1720
    CrossrefPubMedGoogle Scholar
  • 5 Fauci AS, Lane HC, Redfield RR. Covid-19–navigating the uncharted. N Engl J Med 2020; 382 (13) 1268-1269
    CrossrefPubMedGoogle Scholar
  • 6 Li X, Wang W, Zhao X. et al. Transmission dynamics and evolutionary history of 2019-nCoV. J Med Virol 2020; 92 (05) 501-511
    CrossrefPubMedGoogle Scholar
  • 7 Jin X, Xu K, Jiang P. et al. Virus strain from a mild COVID-19 patient in Hangzhou represents a new trend in SARS-CoV-2 evolution potentially related to Furin cleavage site. Emerg Microbes Infect 2020; 9 (01) 1474-1488
    CrossrefPubMedGoogle Scholar
  • 8 Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020; 17 (05) 259-260
    CrossrefPubMedGoogle Scholar
  • 9 Yang W, Yan F. Patients with RT-PCR-confirmed COVID-19 and normal chest CT. Radiology 2020; 295 (02) E3
    CrossrefPubMedGoogle Scholar
  • 10 Kanne JP, Little BP, Chung JH, Elicker BM, Ketai LH. Essentials for radiologists on COVID-19: an update – radiology scientific expert panel. Radiology 2020; 296 (02) E113-E114
    CrossrefPubMedGoogle Scholar
  • 11 Xia J, Tong J, Liu M, Shen Y, Guo D. Evaluation of coronavirus in tears and conjunctival secretions of patients with SARS-CoV-2 infection. J Med Virol 2020; 92 (06) 589-594
    CrossrefPubMedGoogle Scholar
  • 12 Gu J, Han B, Wang J. COVID-19: gastrointestinal manifestations and potential fecal-oral transmission. Gastroenterology 2020; 158 (06) 1518-1519
    CrossrefPubMedGoogle Scholar
  • 13 Zhou F, Yu T, Du R. et al. Clinical course and risk factors for mortality of adult patients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395 (10229): 1054-1062
    CrossrefPubMedGoogle Scholar
  • 14 Li F. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol 2016; 3 (01) 237-261
    CrossrefPubMedGoogle Scholar
  • 15 Hulswit RJ, de Haan CA, Bosch BJ. Coronavirus spike protein and tropism changes. Adv Virus Res 2016; 96: 29-57
    CrossrefPubMedGoogle Scholar
  • 16 Haga S, Yamamoto N, Nakai-Murakami C. et al. Modulation of TNF-alpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry. Proc Natl Acad Sci U S A 2008; 105 (22) 7809-7814
    CrossrefPubMedGoogle Scholar
  • 17 Imai Y, Kuba K, Penninger JM. The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol 2008; 93 (05) 543-548
    CrossrefPubMedGoogle Scholar
  • 18 Wang D, Chai XQ, Magnussen CG. et al. Renin-angiotensin-system, a potential pharmacological candidate, in acute respiratory distress syndrome during mechanical ventilation. Pulm Pharmacol Ther 2019; 58: 101833
    CrossrefPubMedGoogle Scholar
  • 19 Glowacka I, Bertram S, Herzog P. et al. Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63. J Virol 2010; 84 (02) 1198-1205
    CrossrefPubMedGoogle Scholar
  • 20 Khan A, Benthin C, Zeno B. et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care 2017; 21 (01) 234
    CrossrefPubMedGoogle Scholar
  • 21 Batlle D, Jose Soler M, Ye M. ACE2 and diabetes: ACE of ACEs?. Diabetes 2010; 59 (12) 2994-2996
    CrossrefPubMedGoogle Scholar
  • 22 Esuma M, Ishibashi M, Yamaguchi H. et al. Transmembrane serine protease TMPRSS2 activates hepatitis C virus infection. Hepatology 2015; 16 (02) 437-446
    CrossrefPubMedGoogle Scholar
  • 23 Shen LW, Mao HJ, Wu YL, Tanaka Y, Zhang W. TMPRSS2: a potential target for treatment of influenza virus and coronavirus infections. Biochimie 2017; 142: 1-10
    CrossrefPubMedGoogle Scholar
  • 24 Hofmann H, Geier M, Marzi A. et al. Susceptibility to SARS coronavirus S protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor. Biochem Biophys Res Commun 2004; 319 (04) 1216-1221
    CrossrefPubMedGoogle Scholar
  • 25 Bertram S, Glowacka I, Müller MA. et al. Cleavage and activation of the severe acute respiratory syndrome coronavirus spike protein by human airway trypsin-like protease. J Virol 2011; 85 (24) 13363-13372
    CrossrefPubMedGoogle Scholar
  • 26 Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol 2014; 88 (02) 1293-1307
    CrossrefPubMedGoogle Scholar
  • 27 Bertram S, Heurich A, Lavender H. et al. Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts. PLoS One 2012; 7 (04) e35876
    CrossrefPubMedGoogle Scholar
  • 28 Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res 2020; 81 (05) 537-540
    CrossrefPubMedGoogle Scholar
  • 29 Xu H, Zhong L, Deng J. et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci 2020; 12 (01) 8
    CrossrefPubMedGoogle Scholar
  • 30 Belouzard S, Chu VC, Whittaker GR. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc Natl Acad Sci U S A 2009; 106 (14) 5871-5876
    CrossrefPubMedGoogle Scholar
  • 31 Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?. Lancet Respir Med 2020; 8 (04) e21
    CrossrefPubMedGoogle Scholar
  • 32. Du L, Kao RY, Chou Y. et al. Cleavage of spike protein of SARS coronavirus by protease factor Xa is associated with viral infectivity. Biochem Biophys Res Common 2007; 359 (01) 174-179
    CrossrefPubMedGoogle Scholar
  • 33 Kanade GD, Pingale KD, Karpe YA. Activities of thrombin and factor Xa are essential for replication of hepatitis E virus and are possibly implicated in ORF1 polyprotein processing. J Virol 2018; 92 (06) e01853-e17
    CrossrefPubMedGoogle Scholar
  • 34 Lê BV, Jandrot-Perrus M, Couture C. et al. Evaluation of anticoagulant agents for the treatment of human metapneumovirus infection in mice. J Gen Virol 2018; 99 (10) 1367-1380
    CrossrefPubMedGoogle Scholar
  • 35 Howell AL, Taylor TH, Miller JD, Groveman DS, Eccles EH, Zacharski LR. Inhibition of HIV-1 infectivity by low molecular weight heparin. Results of in vitro studies and a pilot clinical trial in patients with advanced AIDS. Int J Clin Lab Res 1996; 26 (02) 124-131
    CrossrefPubMedGoogle Scholar
  • 36 Bourgeois C, Bour JB, Lidholt K, Gauthray C, Pothier P. Heparin-like structures on respiratory syncytial virus are involved in its infectivity in vitro. J Virol 1998; 72 (09) 7221-7227
    CrossrefPubMedGoogle Scholar
  • 37 Skidmore MA, Kajaste-Rudnitski A, Wells NM. et al. Inhibition of influenza invasion by modified heparin derivatives. MedChemComm 2015; 6: 640
    CrossrefPubMedGoogle Scholar
  • 38 Simmons G, Bertram S, Glowacka I. et al. Different host cell proteases activate the SARS-coronavirus spike-protein for cell-cell and virus-cell fusion. Virology 2011; 413 (02) 265-274
    CrossrefPubMedGoogle Scholar
  • 39 Venkateswarlu D, Perera L, Darden T, Pedersen LG. Structure and dynamics of zymogen human blood coagulation factor X. Biophys J 2002; 82 (03) 1190-1206
    CrossrefPubMedGoogle Scholar
  • 40 Hung HL, High KA. Liver-enriched transcription factor HNF-4 and ubiquitous factor NF-Y are critical for expression of blood coagulation factor X. J Biol Chem 1996; 271 (04) 2323-2331
    CrossrefPubMedGoogle Scholar
  • 41 Alexander R. The Regulation of Extra-Hepatic Coagulation Factor X Production in Alveolar and Bronchiolar Epithelium. Thesis, University College London; 2016. . Accessed September 29, 2020 at: https://discovery.ucl.ac.uk/id/eprint/1514446/1/RA%20THESIS%20WITH%20CORRECTIONS.pdf
    Google Scholar
  • 42 Scotton CJ, Krupiczojc MA, Königshoff M. et al. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J Clin Invest 2009; 119 (09) 2550-2563
    PubMedGoogle Scholar
  • 43 Guo X, Kolpakov MA, Hooshdaran B. et al. Cardiac expression of factor X mediates cardiac hypertrophy and fibrosis in pressure overload. JACC Basic Transl Sci 2020; 5 (01) 69-83
    CrossrefPubMedGoogle Scholar
  • 44 Shikamoto Y, Morita T. Expression of factor X in both the rat brain and cells of the central nervous system. FEBS Lett 1999; 463 (03) 387-389
    CrossrefPubMedGoogle Scholar
  • 45 Xia H, Sriramula S, Chhabra KH. et al. Brain ACE2 shedding contributes to the development of neurogenic hypertension. Circ Res 2013; 113 (09) 1087-1096
    CrossrefPubMedGoogle Scholar
  • 46 Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004; 203 (02) 631-637
    CrossrefPubMedGoogle Scholar
  • 47 Shi M, Wang L, Zhou J. et al. Direct factor Xa inhibition attenuates acute lung injury progression via modulation of the PAR-2/NF-κB signaling pathway. Am J Transl Res 2018; 10 (08) 2335-2349
    PubMedGoogle Scholar
  • 48 Schuliga M, Jaffar J, Berhan A. et al. Annexin A2 contributes to lung injury and fibrosis by augmenting factor Xa fibrogenic activity. Am J Physiol Lung Cell Mol Physiol 2017; 312 (05) L772-L782
    CrossrefPubMedGoogle Scholar
  • 49 Guo J, Huang Z, Lin L, Lv J. Coronavirus disease 2019 (COVID-19) and cardiovascular disease: a viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on onset and severity of acute respiratory syndrome coronavirus 2 infection. J Am Heart Assoc 2020; 9 (07) e016219
    CrossrefPubMedGoogle Scholar
  • 50 Raizada MK, Ferreira AJ. ACE2: a new target for cardiovascular disease therapeutics. J Cardiovasc Pharmacol 2007; 50 (02) 112-119
    CrossrefPubMedGoogle Scholar
  • 51 Epelman S, Tang WH, Chen SY, Van Lente F, Francis GS, Sen S. Detection of soluble angiotensin-converting enzyme 2 in heart failure: insights into the endogenous counter-regulatory pathway of the renin-angiotensin-aldosterone system. J Am Coll Cardiol 2008; 52 (09) 750-754
    CrossrefPubMedGoogle Scholar
  • 52 Masi P, Hékimian G, Lejeune 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 (06) 611-614
    CrossrefPubMedGoogle Scholar
  • 53 Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci 2020; 11 (07) 995-998
    CrossrefPubMedGoogle Scholar
  • 54 Puelles VG, Lütgehetmann M, Lindenmeyer MT. et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med 2020; 383 (06) 590-592
    CrossrefPubMedGoogle Scholar
  • 55 Ronco C, Reis T, Husain-Syed F. Management of acute kidney injury in patients with COVID-19. Lancet Respir Med 2020; 8 (07) 738-742
    CrossrefPubMedGoogle Scholar
  • 56 Gando S. Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med 2010; 38 (02) S35-S42
    CrossrefPubMedGoogle Scholar
  • 57 Ono T. Roles of coagulation pathway and factor Xa in chronic kidney disease (CKD) [in Japanese]. Yakugaku Zasshi 2012; 132 (04) 449-453
    CrossrefPubMedGoogle Scholar
  • 58 Jourde-Chiche N, Fakhouri F, Dou L. et al. Endothelium structure and function in kidney health and disease. Nat Rev Nephrol 2019; 15 (02) 87-108
    CrossrefPubMedGoogle Scholar
  • 59 Perampalam S, Wang L, Myers-Mason N. et al. Identification of a unique glomerular factor X activator in murine lupus nephritis. J Am Soc Nephrol 1999; 10 (11) 2332-2341
    CrossrefPubMedGoogle Scholar
  • 60 Bowles L, Platton S, Yartey N. et al. Lupus anticoagulant and abnormal coagulation tests in patients with COVID-19. N Engl J Med 2020; 383 (03) 288-290
    CrossrefPubMedGoogle Scholar
  • 61 Zhang Y, Xiao M, Zhang S. et al. Coagulopathy and antiphospholipid antibodies in patients with COVID-19. N Engl J Med 2020; 382 (17) e38
    CrossrefPubMedGoogle Scholar
  • 62 Harzallah I, Debliquis A, Drenou B. Lupus anticoagulant is frequent in patients with COVID-19. J Thromb Haemost 2020; 18 (08) 2064-2065
    CrossrefPubMedGoogle Scholar
  • 63 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395 (10234): 1417-1418
    CrossrefPubMedGoogle Scholar
  • 64 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
    CrossrefPubMedGoogle Scholar
  • 65 Teuwen LA, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vasculature unleashed. Nat Rev Immunol 2020; 20 (07) 389-391
    CrossrefPubMedGoogle Scholar
  • 66 Green SJ. Covid-19 accelerates endothelial dysfunction and nitric oxide deficiency. Microbes Infect 2020; 22 (4-5): 149-150
    CrossrefPubMedGoogle Scholar
  • 67 Wichmann D, Sperhake JP, Lütgehetmann M. et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med 2020; 173 (04) 268-277
    CrossrefPubMedGoogle Scholar
  • 68 Cohen CT, Turner NA, Moake JL. Production and control of coagulation proteins for factor X activation in human endothelial cells and fibroblasts. Sci Rep 2020; 10 (01) 2005
    CrossrefPubMedGoogle Scholar
  • 69 Rodgers GM, Shuman MA. Prothrombin is activated on vascular endothelial cells by factor Xa and calcium. Proc Natl Acad Sci U S A 1983; 80 (22) 7001-7005
    CrossrefPubMedGoogle Scholar
  • 70 Stern D, Nawroth P, Handley D, Kisiel W. An endothelial cell-dependent pathway of coagulation. Proc Natl Acad Sci U S A 1985; 82 (08) 2523-2527
    CrossrefPubMedGoogle Scholar
  • 71 van Hinsbergh VWM. Endothelium--role in regulation of coagulation and inflammation. Semin Immunopathol 2012; 34 (01) 93-106
    CrossrefPubMedGoogle Scholar
  • 72 Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395 (10229): 1033-1034
    CrossrefPubMedGoogle Scholar
  • 73 Tian S, Hu W, Niu L, Liu H, Xu H, Xiao SY. Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J Thorac Oncol 2020; 15 (05) 700-704
    CrossrefPubMedGoogle Scholar
  • 74 Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (04) 844-847
    CrossrefPubMedGoogle Scholar
  • 75 Cheung CY, Poon LLM, Ng IHY. et al. Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J Virol 2005; 79 (12) 7819-7826
    CrossrefPubMedGoogle Scholar
  • 76 Yilla M, Harcourt BH, Hickman CJ. et al. SARS-coronavirus replication in human peripheral monocytes/macrophages. Virus Res 2005; 107 (01) 93-101
    CrossrefPubMedGoogle Scholar
  • 77 Funk CJ, Wang J, Ito Y. et al. Infection of human alveolar macrophages by human coronavirus strain 229E. J Gen Virol 2012; 93 (Pt 3): 494-503
    CrossrefPubMedGoogle Scholar
  • 78 Osterud B, Lindahl U, Seljelid R. Macrophages produce blood coagulation factors. FEBS Lett 1980; 120 (01) 41-43
    CrossrefPubMedGoogle Scholar
  • 79 McGee MP, Wallin R, Wheeler FB, Rothberger H. Initiation of the extrinsic pathway of coagulation by human and rabbit alveolar macrophages: a kinetic study. Blood 1989; 74 (05) 1583-1590
    CrossrefPubMedGoogle Scholar
  • 80 Zuo P, Zuo Z, Wang X. et al. Factor Xa induces pro-inflammatory cytokine expression in RAW 264.7 macrophages via protease-activated receptor-2 activation. Am J Transl Res 2015; 7 (11) 2326-2334
    PubMedGoogle Scholar
  • 81 Chapman Jr HA, Allen CL, Stone OL, Fair DS. Human alveolar macrophages synthesize factor VII in vitro. Possible role in interstitial lung disease. J Clin Invest 1985; 75 (06) 2030-2037
    CrossrefPubMedGoogle Scholar
  • 82 Graf C, Wilgenbus P, Pagel S. et al. Myeloid cell-synthesized coagulation factor X dampens antitumor immunity. Sci Immunol 2019; 4 (39) eaaw8405
    Google Scholar
  • 83 Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res 2016; 118 (09) 1392-1408
    CrossrefPubMedGoogle Scholar
  • 84 Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020; 18 (05) 1094-1099
    CrossrefPubMedGoogle Scholar
  • 85 Paranjpe I, Fuster V, Lala A. et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol 2020; 76 (01) 122-124
    CrossrefPubMedGoogle Scholar
  • 86 Laurent M, Joimel U, Varin R. et al. Comparative study of the effect of rivaroxaban and fondaparinux on monocyte's coagulant activity and cytokine release. Exp Hematol Oncol 2014; 3 (01) 30
    CrossrefPubMedGoogle Scholar
  • 87 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
    CrossrefPubMedGoogle Scholar
  • 88 Schoenmakers SH, Reitsma PH, Spek CA. Blood coagulation factors as inflammatory mediators. Blood Cells Mol Dis 2005; 34 (01) 30-37
    CrossrefPubMedGoogle Scholar
  • 89 Chang JC. Acute respiratory distress syndrome as an organ phenotype of vascular microthrombotic disease: based on hemostatic theory and endothelial molecular pathogenesis. Clin Appl Thromb Hemost 2019; 25: 1076029619887437
    CrossrefPubMedGoogle Scholar
  • 90 Savchenko AS, Martinod K, Seidman MA. et al. Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development. J Thromb Haemost 2014; 12 (06) 860-870
    CrossrefPubMedGoogle Scholar
  • 91 Frydman GH, Tessier SN, Wong KHK. et al. Megakaryocytes contain extranuclear histones and may be a source of platelet-associated histones during sepsis. Sci Rep 2020; 10 (01) 4621
    CrossrefPubMedGoogle Scholar
  • 92 Levi M, Schultz M, van der Poll T. Sepsis and thrombosis. Semin Thromb Hemost 2013; 39 (05) 559-566
    Article in Thieme ConnectPubMedGoogle Scholar
  • 93 Goeijenbier M, van Wissen M, van de Weg C. et al. Review: viral infections and mechanisms of thrombosis and bleeding. J Med Virol 2012; 84 (10) 1680-1696
    CrossrefPubMedGoogle Scholar
  • 94 Branchford BR, Carpenter SL. The role of inflammation in venous thromboembolism. Front Pediatr 2018; 6: 142
    Google Scholar
  • 95 Kaplan D, Casper TC, Elliott CG. et al. VTE incidence and risk factors in patients with severe sepsis and septic shock. Chest 2015; 148 (05) 1224-1230
    CrossrefPubMedGoogle Scholar
  • 96 Artigas A, Camprubí-Rimblas M, Tantinyà N, Bringué J, Guillamat-Prats R, Matthay MA. Inhalation therapies in acute respiratory distress syndrome. Ann Transl Med 2017; 5 (14) 293
    CrossrefPubMedGoogle Scholar
  • 97 Glas GJ, Serpa Neto A, Horn J. et al. Nebulized heparin for patients under mechanical ventilation: an individual patient data meta-analysis. Ann Intensive Care 2016; 6 (01) 33
    CrossrefPubMedGoogle Scholar
  • 98 Juschten J, Tuinman PR, Juffermans NP, Dixon B, Levi M, Schultz MJ. Nebulized anticoagulants in lung injury in critically ill patients-an updated systematic review of preclinical and clinical studies. Ann Transl Med 2017; 5 (22) 444
    CrossrefPubMedGoogle Scholar
  • 99 Gram J, Munster AM, Filling-Hansen B. et al. Inhalation/intravenous recombinant tissue plasminogen activator and inhaled heparin in a patient with acute respiratory distress syndrome. Fibrinolysis Proteolysis 1999; 13 (4–5): 209-212
    CrossrefPubMedGoogle Scholar
  • 100 Bielecki S, Lee D, Hamad B. The market for oral anticoagulants. Nat Rev Drug Discov 2018; 17 (09) 617-618
    CrossrefPubMedGoogle Scholar
  • 101 White D, MacDonald S, Bull T. et al. Heparin resistance in COVID-19 patients in the intensive care unit. J Thromb Thrombolysis 2020; 50 (02) 287-291
    CrossrefPubMedGoogle Scholar
  • 102 Moore HB, Barrett CD, Moore EE. et al. Is there a role for tissue plasminogen activator as a novel treatment for refractory COVID-19 associated acute respiratory distress syndrome?. J Trauma Acute Care Surg 2020; 88 (06) 713-714
    CrossrefPubMedGoogle Scholar
  • 103 Acuthan S, Ahluwalia J, Shafiq N. et al. Hydroxychloroquine's efficacy as an antiplatelet agent study in healthy volunteers: a proof of concept study. J Cardiovasc Pharmacol Ther 2015; 20 (02) 174-180
    CrossrefPubMedGoogle Scholar
  • 104 Gautret P, Lagier JC, Parola P. et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020; 56 (01) 105949
    Google Scholar
  • 105 Stork CM, Marraffa JM, Ragosta K, Wojcik SM, Angelino KL. Elevated International Normalized Ratio associated with long-term azithromycin therapy in a child with cerebral palsy. Am J Health Syst Pharm 2011; 68 (11) 1012-1014
    CrossrefPubMedGoogle Scholar
  • 106 Foster DR, Milan NL. Potential interaction between azithromycin and warfarin. Pharmacotherapy 2012; 19 (07) 902-908
    CrossrefPubMedGoogle Scholar
  • 107 Geleris J, Sun Y, Platt J. et al. Observational study of hydroxychloriquine in hospitalized patients with COVID-19. N Engl J Med 2020; 382 (25) 2411-2418
    CrossrefPubMedGoogle Scholar
  • 108 Lagier JC, Million M, Gautret P. IHU COVID-19 Task Force. et al. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: a retrospective analysis. Travel Med Infect Dis 2020; 36: 101791
    CrossrefPubMedGoogle Scholar
  • 109 Rand JH, Wu XX, Quinn AS. et al. Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug. Blood 2010; 115 (11) 2292-2299
    CrossrefPubMedGoogle Scholar
  • 110 Tremblay D, van Gerwen M, Alsen M. et al. Impact of anticoagulation prior to COVID-19 infection: a propensity score-matched cohort study. Blood 2020; 136 (01) 144-147
    CrossrefPubMedGoogle Scholar
  • 111 Rossi R, Coppi F, Talarico M, Boriani G. Protective role of chronic treatment with direct oral anticoagulants in elderly patients affected by interstitial pneumonia in COVID-19 era. Eur J Intern Med 2020; 77: 158-160
    CrossrefPubMedGoogle Scholar
  • 112 Porfidia A, Pola R. Venous thromboembolism and heparin use in COVID-19 patients: juggling between pragmatic choices, suggestions of medical societies. J Thromb Thrombolysis 2020; 4: 1-4
    PubMedGoogle Scholar
  • 113 Massachusetts General Hospital, Hematology Recommendations and Dosing Guidelines during COVID-19. Available at: https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/guidance-from-mass-general-hematology.pdf. Accessed September 16, 2020
  • 114 Boston Medical Center, Boston Medical Center MICU and Pulmonary COVID-19 Best Practices. Accessed September 29, 2020 at: https://www.bumc.bu.edu/pulmonarycenter/boston-medical-center-micu-and-pulmonary-covid-19-best-practices/
  • 115 Thachil J, Tang N, Gando S. et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020; 18 (05) 1023-1026
    CrossrefPubMedGoogle Scholar
  • 116 Barrett CD, Moore HB, Yaffe MB. et al. ISTH interim guidance on recognition and management of coagulopathy: a comment. J Thromb Haemost 2020; 18 (08) 2060-2063
    CrossrefPubMedGoogle Scholar
  • 117 Cattaneo M, Bertinato EM, Birocchi S. et al. Pulmonary embolism or pulmonary thrombosis in COVID-19? Is the recommendation to use high-dose heparin for thromboprophylaxis justified?. Thromb Haemost 2020; 120 (08) 1230-1232
    Article in Thieme ConnectPubMedGoogle Scholar
  • 118 Nahum J, Morichau-Beauchant T, Daviaud F. et al. Venous thrombosis among critically ill patients with coronavirus disease 2019 (COVID-19). JAMA Netw Open 2020; 3 (05) e2010478
    Google Scholar
  • 119 Guha A, Bonsu J, Dey A. et al. Community and socioeconomic factors associated with COVID-19 in the United States: zip code level cross sectional analysis. medRxiv 2020; (epub ahead of print) DOI: 10.1101/2020.04.19.20071944.
    CrossrefPubMedGoogle Scholar
  • 120 Thachil J. What do monitoring platelet counts in COVID-19 teach us?. J Thromb Haemost 2020; 18 (08) 2071-2072
    CrossrefPubMedGoogle Scholar
  • 121 Horby P, Lim WS, Emberson J. et al. Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report. medRxiv 2020; (epub ahead of print) DOI: 10.1101/2020.06.22.20137273.
    CrossrefPubMedGoogle Scholar
  • 122 Shatzel JJ, DeLoughery EP, Lorentz CU. et al. The contact activation system as a potential therapeutic target in patients with COVID-19. Res Pract Thromb Haemostasis 2020; (epub ahead of print) DOI: 10.1002/rth2.12349.
    CrossrefPubMedGoogle Scholar
  • 123 Bae JS, Yang L, Rezaie AR. Factor X/Xa elicits protective signaling responses in endothelial cells directly via PAR-2 and indirectly via endothelial protein C receptor-dependent recruitment of PAR-1. J Biol Chem 2010; 285 (45) 34803-34812
    CrossrefPubMedGoogle Scholar
  • 124 Heming N, Sivanandamoorthy S, Meng P, Bounab R, Annane D. Immune effects of corticosteroids in sepsis. Front Immunol 2018; 9: 1736
    CrossrefPubMedGoogle Scholar