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
,
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
› Institutsangaben
Funding None.

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.



Publikationsverlauf

Eingereicht: 07. September 2020

Angenommen: 08. September 2020

Artikel online veröffentlicht:
07. Oktober 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
  • 2 Arabi YM, Balkhy HH, Hayden FG. et al. Middle East respiratory syndrome. N Engl J Med 2017; 376 (06) 584-594
  • 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
  • 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
  • 5 Fauci AS, Lane HC, Redfield RR. Covid-19–navigating the uncharted. N Engl J Med 2020; 382 (13) 1268-1269
  • 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
  • 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
  • 8 Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020; 17 (05) 259-260
  • 9 Yang W, Yan F. Patients with RT-PCR-confirmed COVID-19 and normal chest CT. Radiology 2020; 295 (02) E3
  • 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
  • 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
  • 12 Gu J, Han B, Wang J. COVID-19: gastrointestinal manifestations and potential fecal-oral transmission. Gastroenterology 2020; 158 (06) 1518-1519
  • 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
  • 14 Li F. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol 2016; 3 (01) 237-261
  • 15 Hulswit RJ, de Haan CA, Bosch BJ. Coronavirus spike protein and tropism changes. Adv Virus Res 2016; 96: 29-57
  • 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
  • 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
  • 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
  • 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
  • 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
  • 21 Batlle D, Jose Soler M, Ye M. ACE2 and diabetes: ACE of ACEs?. Diabetes 2010; 59 (12) 2994-2996
  • 22 Esuma M, Ishibashi M, Yamaguchi H. et al. Transmembrane serine protease TMPRSS2 activates hepatitis C virus infection. Hepatology 2015; 16 (02) 437-446
  • 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
  • 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
  • 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
  • 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
  • 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
  • 28 Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res 2020; 81 (05) 537-540
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 37 Skidmore MA, Kajaste-Rudnitski A, Wells NM. et al. Inhibition of influenza invasion by modified heparin derivatives. MedChemComm 2015; 6: 640
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 50 Raizada MK, Ferreira AJ. ACE2: a new target for cardiovascular disease therapeutics. J Cardiovasc Pharmacol 2007; 50 (02) 112-119
  • 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
  • 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
  • 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
  • 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
  • 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
  • 56 Gando S. Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med 2010; 38 (02) S35-S42
  • 57 Ono T. Roles of coagulation pathway and factor Xa in chronic kidney disease (CKD) [in Japanese]. Yakugaku Zasshi 2012; 132 (04) 449-453
  • 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
  • 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
  • 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
  • 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
  • 62 Harzallah I, Debliquis A, Drenou B. Lupus anticoagulant is frequent in patients with COVID-19. J Thromb Haemost 2020; 18 (08) 2064-2065
  • 63 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395 (10234): 1417-1418
  • 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
  • 65 Teuwen LA, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vasculature unleashed. Nat Rev Immunol 2020; 20 (07) 389-391
  • 66 Green SJ. Covid-19 accelerates endothelial dysfunction and nitric oxide deficiency. Microbes Infect 2020; 22 (4-5): 149-150
  • 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
  • 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
  • 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
  • 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
  • 71 van Hinsbergh VWM. Endothelium--role in regulation of coagulation and inflammation. Semin Immunopathol 2012; 34 (01) 93-106
  • 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
  • 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
  • 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
  • 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
  • 76 Yilla M, Harcourt BH, Hickman CJ. et al. SARS-coronavirus replication in human peripheral monocytes/macrophages. Virus Res 2005; 107 (01) 93-101
  • 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
  • 78 Osterud B, Lindahl U, Seljelid R. Macrophages produce blood coagulation factors. FEBS Lett 1980; 120 (01) 41-43
  • 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
  • 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
  • 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
  • 82 Graf C, Wilgenbus P, Pagel S. et al. Myeloid cell-synthesized coagulation factor X dampens antitumor immunity. Sci Immunol 2019; 4 (39) eaaw8405
  • 83 Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res 2016; 118 (09) 1392-1408
  • 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
  • 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
  • 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
  • 87 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
  • 88 Schoenmakers SH, Reitsma PH, Spek CA. Blood coagulation factors as inflammatory mediators. Blood Cells Mol Dis 2005; 34 (01) 30-37
  • 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
  • 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
  • 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
  • 92 Levi M, Schultz M, van der Poll T. Sepsis and thrombosis. Semin Thromb Hemost 2013; 39 (05) 559-566
  • 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
  • 94 Branchford BR, Carpenter SL. The role of inflammation in venous thromboembolism. Front Pediatr 2018; 6: 142
  • 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
  • 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
  • 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
  • 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
  • 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
  • 100 Bielecki S, Lee D, Hamad B. The market for oral anticoagulants. Nat Rev Drug Discov 2018; 17 (09) 617-618
  • 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
  • 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
  • 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
  • 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
  • 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
  • 106 Foster DR, Milan NL. Potential interaction between azithromycin and warfarin. Pharmacotherapy 2012; 19 (07) 902-908
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 120 Thachil J. What do monitoring platelet counts in COVID-19 teach us?. J Thromb Haemost 2020; 18 (08) 2071-2072
  • 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.
  • 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.
  • 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
  • 124 Heming N, Sivanandamoorthy S, Meng P, Bounab R, Annane D. Immune effects of corticosteroids in sepsis. Front Immunol 2018; 9: 1736