Guidance for the Management of Patients with Vascular Disease or Cardiovascular Risk Factors and COVID-19: Position Paper from VAS-European Independent Foundation in Angiology/Vascular Medicine

Abstract

COVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH.

Keywords

COVID-19 - cardiovascular disease - peripheral artery disease - deep vein thrombosis - antithrombotic - antiplatelets - anticoagulants - low-molecular-weight heparin - DOAC

Publikationsverlauf

Eingereicht: 28. Mai 2020

Angenommen: 23. Juli 2020

Artikel online veröffentlicht:
13. September 2020

• References

• 1 Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 2019; 17 (03) 181-192
• 2 Wu F, Zhao S, Yu B. et al. A new coronavirus associated with human respiratory disease in China. Nature 2020; 579 (7798): 265-269
• 3 Lu R, Zhao X, Li J. et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395 (10224): 565-574
• 4 Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS. J Virol 2020; 94 (07) e00127-20
• 5 World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected—interim guidance, March 13, 2020. Accessed July 26, 2020 at: https://www.who.int/publications/i/item/clinical-management-of-covid-19
• 6 Chen N, Zhou M, Dong X. et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395 (10223): 507-513
• 7 Terpos E, Ntanasis-Stathopoulos I, Elalamy I. et al. Hematological findings and complications of COVID-19. Am J Hematol 2020; 95 (07) 834-847
• 8 Maglakelidze N, Manto KM, Craig TJA. A review: does complement or the contact system have a role in protection or pathogenesis of COVID-19?. Pulm Ther 2020; 6 (02) 169-176
• 9 Bikdeli B, Madhavan MV, Jimenez D. et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol 2020; 75 (23) 2950-2973
• 10 Huang C, Wang Y, Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395 (10223): 497-506
• 11 Richardson S, Hirsch JS, Narasimhan M. et al and the Northwell COVID-19 Research Consortium. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA 2020; 323 (20) 2052-2059
• 12 Auld SC, Caridi-Scheible M, Blum JM. et al. ICU and ventilator mortality among critically ill adults with coronavirus disease 2019. Crit Care Med 2020;
• 13 Driggin E, Madhavan MV, Bikdeli B. et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol 2020; 75 (18) 2352-2371
• 14 Bangash MN, Patel J, Parekh D. COVID-19 and the liver: little cause for concern. Lancet Gastroenterol Hepatol 2020; 5 (06) 529-530
• 15 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
• 16 Gimbrone Jr MA, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 2016; 118 (04) 620-636
• 17 Roth GA, Johnson C, Abajobir A. et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol 2017; 70 (01) 1-25
• 18 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
• 19 Hoffmann M, Kleine-Weber H, Schroeder S. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181 (02) 271.e8-280.e8
• 20 Vaarala MH, Porvari KS, Kellokumpu S, Kyllönen AP, Vihko PT. Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues. J Pathol 2001; 193 (01) 134-140
• 21 Song WC, FitzGerald GA. COVID-19, microangiopathy, hemostatic activation, and complement. J Clin Invest 2020; 140183: 140183
• 22 Aimes RT, Zijlstra A, Hooper JD. et al. Endothelial cell serine proteases expressed during vascular morphogenesis and angiogenesis. Thromb Haemost 2003; 89 (03) 561-572
• 23 Du L, Kao RY, Zhou Y. et al. Cleavage of spike protein of SARS coronavirus by protease factor Xa is associated with viral infectivity. Biochem Biophys Res Commun 2007; 359 (01) 174-179
• 24 Yang H, Xie W, Xue X. et al. Design of wide-spectrum inhibitors targeting coronavirus main proteases. PLoS Biol 2005; 3 (10) e324
• 25 Biembengut ÍV, de Souza TACB. Coagulation modifiers targeting SARS-CoV-2 main protease Mpro for COVID-19 treatment: an in silico approach. Mem Inst Oswaldo Cruz 2020; 115: e200179
• 26 Eleftheriou P, Amanatidou D, Petrou A, Geronikaki A. In silico evaluation of the effectivity of approved protease inhibitors against the main protease of the novel SARS-CoV-2 virus. Molecules 2020; 25 (11) E2529
• 27 Liu J, Li J, Arnold K, Pawlinski R, Key NS. Using heparin molecules to manage COVID-2019. Res Pract Thromb Haemost 2020; 4 (04) 518-523
• 28 Partridge LJ, Green LR, Monk PN. Unfractionated heparin potently inhibits the binding of SARS-CoV-2 spike protein to a human cell line. bioRxiv 2020;
• 29 Mezger M, Nording H, Sauter R. et al. Platelets and immune responses during thromboinflammation. Front Immunol 2019; 10: 1731
• 30 Colman RW, Schmaier AH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997; 90 (10) 3819-3843
• 31 Maas C, Renné T. Coagulation factor XII in thrombosis and inflammation. Blood 2018; 131 (17) 1903-1909
• 32 Baker CJ, Smith SA, Morrissey JH. Polyphosphate in thrombosis, hemostasis, and inflammation. Res Pract Thromb Haemost 2018; 3 (01) 18-25
• 33 Zuo Y, Yalavarthi S, Shi H. Neutrophil extracellular traps in COVID-19. JCI Insight 2020; 5 (11) e138999
• 34 Zuo Y, Zuo M, Yalavarthi S. et al. Neutrophil extracellular traps and thrombosis in COVID-19. medRxiv 2020; 48 (09) 1358-1364
• 35 Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of coronavirus disease 2019. Crit Care Med 2020; 48 (09) 1358-1364
• 36 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
• 37 Galeano-Valle F, Oblitas CM, Ferreiro-Mazón MM. et al. Antiphospholipid antibodies are not elevated in patients with severe COVID-19 pneumonia and venous thromboembolism. Thromb Res 2020; 192: 113-115
• 38 Pons S, Fodil S, Azoulay E, Zafrani L. The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection. Crit Care 2020; 24 (01) 353
• 39 Khider L, Gendron N, Goudot G. et al. Curative anticoagulation prevents endothelial lesion in COVID-19 patients. J Thromb Haemost 2020;
• 40 Nunes Duarte-Neto A, de Almeida Monteiro RA, da Silva LFF. et al. Pulmonary and systemic involvement of COVID-19 assessed by ultrasound-guided minimally invasive autopsy. Histopathology 2020; 77 (02) 186-197
• 41 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
• 42 Fox SE, Akmatbekov A, Harbert JL. et al. 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
• 43 Wu JH, Li X, Huang B. et al. Pathological changes of fatal coronavirus disease 2019 (COVID-19) in the lungs: report of 10 cases by postmortem needle autopsy [in Chinese]. Zhonghua Bing Li Xue Za Zhi 2020; 49 (06) 568-575
• 44 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;
• 45 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395 (10234): 1417-1418
• 46 Fogarty H, Townsend L, Ni Cheallaigh C. et al. More on COVID-19 coagulopathy in Caucasian patients. Br J Haematol 2020; 189 (06) 1060-1061
• 47 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
• 48 Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association?. Eur Heart J 2020; 41 (19) 1858
• 49 Du Y, Tu L, Zhu P. et al. Clinical features of 85 fatal cases of COVID-19 from Wuhan. A retrospective observational study. Am J Respir Crit Care Med 2020; 201 (11) 1372-1379
• 50 Menter T, Haslbauer JD, Nienhold R. et al. Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology 2020; 77 (02) 198-209
• 51 Lang M, Som A, Mendoza DP. et al. Hypoxaemia related to COVID-19: vascular and perfusion abnormalities on dual-energy CT. Lancet Infect Dis 2020; 20 (12) 1365-1366
• 52 Sharma P, Uppal NN, Wanchoo R. et al. COVID-19–associated kidney injury: a case series of kidney biopsy findings. J Am Soc Nephrol 2020; 31 (09) 1948-1958
• 53 Edler C, Schröder AS, Aepfelbacher M. et al. Dying with SARS-CoV-2 infection-an autopsy study of the first consecutive 80 cases in Hamburg, Germany. Int J Legal Med 2020;
• 54 Calabrese F, Pezzuto F, Fortarezza F. et al. Pulmonary pathology and COVID-19: lessons from autopsy. The experience of European Pulmonary Pathologists. Virchows Arch 2020;
• 55 Fried JA, Ramasubbu K, Bhatt R. et al. The variety of cardiovascular presentations of COVID-19. Circulation 2020; 141 (23) 1930-1936
• 56 Xu Z, Shi L, Wang Y. et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8 (04) 420-422
• 57 Liu Y, Yang Y, Zhang C. et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci 2020; 63 (03) 364-374
• 58 Long B, Brady WJ, Koyfman A, Gottlieb M. Cardiovascular complications in COVID-19. Am J Emerg Med 2020; 38 (07) 1504-1507
• 59 Zheng Z, Peng F, Xu B. et al. Risk factors of critical & mortal COVID-19 cases: a systematic literature review and meta-analysis. J Infect 2020; 81 (02) e16-e25
• 60 Ruan Q, Yang K, Wang W. et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020; 46 (05) 846-848
• 61 Khurshid S, Choi SH, Weng LC. et al. Frequency of cardiac rhythm abnormalities in a half million adults. Circ Arrhythm Electrophysiol 2018; 11 (07) e006273
• 62 Li B, Yang J, Zhao F. et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol 2020; 109 (05) 531-538
• 63 Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020; 323 (13) 1239-1242
• 64 Zheng Z, Peng F, Xu B. et al. Risk factors of critical & mortal COVID-19 cases: a systematic literature review and meta-analysis. J Infect 2020; 81 (02) e16-e25
• 65 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
• 66 Cohen G, Riahi Y, Alpert E, Gruzman A, Sasson S. The roles of hyperglycaemia and oxidative stress in the rise and collapse of the natural protective mechanism against vascular endothelial cell dysfunction in diabetes. Arch Physiol Biochem 2007; 113 (4-5): 259-267
• 67 Zhu L, She ZG, Cheng X. et al. Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing Type 2 diabetes. Cell Metab 2020; 31 (06) 1068-1077
• 68 Olinic DM, Spinu M, Olinic M. et al. Epidemiology of peripheral artery disease in Europe: VAS educational paper. Int Angiol 2018; 37 (04) 327-334
• 69 Zierfuss B, Catalano M, Schernthaner GH. Finally, the big picture of morbidity and mortality in peripheral arterial disease?. Atherosclerosis 2020; 293: 92-93
• 70 Bellosta R, Luzzani L, Natalini G. et al. Acute limb ischemia in patients with COVID-19 pneumonia. J Vasc Surg 2020; 72 (06) 1864-1872
• 71 Perini P, Nabulsi B, Massoni CB, Azzarone M, Freyrie A. Acute limb ischaemia in two young, non-atherosclerotic patients with COVID-19. Lancet 2020; 395 (10236): 1546
• 72 Cantador E, Núñez A, Sobrino P. et al. Incidence and consequences of systemic arterial thrombotic events in COVID-19 patients. J Thromb Thrombolysis 2020; 50 (03) 543-547
• 73 Klok FA, Kruip MJHA, van der Meer NJM. et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res 2020; 191: 148-150
• 74 Lodigiani C, Iapichino G, Carenzo L. et al; Humanitas COVID-19 Task Force. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res 2020; 191: 9-14
• 75 Suchonwanit P, Leerunyakul K, Kositkuljorn C. Cutaneous manifestations in COVID-19: lessons learned from current evidence. J Am Acad Dermatol 2020; 83 (01) e57-e60
• 76 Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol 2020; 34 (05) e212-e213
• 77 Estébanez A, Pérez-Santiago L, Silva E, Guillen-Climent S, García-Vázquez A, Ramón MD. Cutaneous manifestations in COVID-19: a new contribution. J Eur Acad Dermatol Venereol 2020; 34 (06) e250-e251
• 78 Su CJ, Lee CH. Viral exanthem in COVID-19, a clinical enigma with biological significance. J Eur Acad Dermatol Venereol 2020; 34 (06) e251-e252
• 79 Mahé A, Birckel E, Krieger S, Merklen C, Bottlaender L. A distinctive skin rash associated with coronavirus disease 2019?. J Eur Acad Dermatol Venereol 2020; 34 (06) e246-e247
• 80 Henry D, Ackerman M, Sancelme E, Finon A, Esteve E. Urticarial eruption in COVID-19 infection. J Eur Acad Dermatol Venereol 2020; 34 (06) e244-e245
• 81 Zulfiqar AA, Lorenzo-Villalba N, Hassler P, Andrès E. Immune thrombocytopenic purpura in a patient with Covid-19. N Engl J Med 382 (18) e43
• 82 Alramthan A, Aldaraji W. Two cases of COVID-19 presenting with a clinical picture resembling chilblains: first report from the Middle East. Clin Exp Dermatol 2020; 45 (06) 746-748
• 83 Kolivras A, Dehavay F, Delplace D. et al. Coronavirus (COVID-19) infection-induced chilblains: a case report with histopathologic findings. JAAD Case Rep 2020; 6 (06) 489-492
• 84 Manalo IF, Smith MK, Cheeley J, Jacobs R. A dermatologic manifestation of COVID-19: transient livedo reticularis. J Am Acad Dermatol 2020; 83 (02) 700
• 85 Nyssen A, Benhadou F, Magnée M, André J, Koopmansch C, Wautrecht JC. Chilblains. Vasa 2020; 49 (02) 133-140
• 86 Colmenero I, Santonja C, Alonso-Riaño M. et al. SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultraestructural study of 7 paediatric cases. Br J Dermatol 2020; 183 (04) 729-737
• 87 Bae YS, Kim KH, Choi SW. et al. Information technology-based management of clinically healthy COVID-19 patients: lessons from a living and treatment support center operated by seoul national university hospital. J Med Internet Res 2020; 22 (06) e19938
• 88 Fareed J, Hoppensteadt DA, Bick RL. An update on heparins at the beginning of the new millennium. Semin Thromb Hemost 2000; 26 (Suppl. 01) 5-21
• 89 Darien BJ, Fareed J, Centgraf KS. et al. Low molecular weight heparin prevents the pulmonary hemodynamic and pathomorphologic effects of endotoxin in a porcine acute lung injury model. Shock 1998; 9 (04) 274-281
• 90 Wang L, Brown JR, Varki A, Esko JD. Heparin's anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins. J Clin Invest 2002; 110 (01) 127-136
• 91 Manfredi AA, Rovere-Querini P, D'Angelo A, Maugeri N. Low molecular weight heparins prevent the induction of autophagy of activated neutrophils and the formation of neutrophil extracellular traps. Pharmacol Res 2017; 123: 146-156
• 92 Wan MX, Zhang XW, Törkvist L, Thorlacius H. Low molecular weight heparin inhibits tumor necrosis factor alpha-induced leukocyte rolling. Inflamm Res 2001; 50 (12) 581-584
• 93 Mulloy B, Hogwood J, Gray E, Lever R, Page CP. Pharmacology of heparin and related drugs. Pharmacol Rev 2016; 68 (01) 76-141
• 94 Beun R, Kusadasi N, Sikma M, Westerink J, Huisman A. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. Int J Lab Hematol 2020; 42 (Suppl. 01) 19-20
• 95 Mousa SA. Heparin and low molecular weight heparin in thrombosis and inflammation: emerging link. In: Garg HG, Linhardt RJ, Hales CA. eds. Chemistry and Biology of Heparin and Heparan Sulfate. New York, NY: Elsevier Ltd; 2005: 571-581
• 96 Fareed J, Jeske W, Fareed D. et al. Are all low molecular weight heparins equivalent in the management of venous thromboembolism?. Clin Appl Thromb Hemost 2008; 14 (04) 385-392
• 97 Gerotziafas GT, Petropoulou AD, Verdy E, Samama MM, Elalamy I. Effect of the anti-factor Xa and anti-factor IIa activities of low-molecular-weight heparins upon the phases of thrombin generation. J Thromb Haemost 2007; 5 (05) 955-962
• 98 Salta S, Papageorgiou L, Larsen AK. et al. Comparison of antithrombin-dependent and direct inhibitors of factor Xa or thrombin on the kinetics and qualitative characteristics of blood clots. Res Pract Thromb Haemost 2018; 2 (04) 696-707
• 99 Panigada M, Bottino N, Tagliabue P. 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 (07) 1738-1742
• 100 Hohlfelder B, Kelly D, Hoang M. et al. Activated clotting times demonstrate weak correlation with heparin dosing in adult extracorporeal membrane oxygenation. Am J Ther 2019;
• 101 McLaughlin K, Rimsans J, Sylvester KW. et al. Evaluation of antifactor-Xa heparin assay and activated partial thromboplastin time values in patients on therapeutic continuous infusion unfractionated heparin therapy. Clin Appl Thromb Hemost 2019;
• 102 Projean D, Lalonde S, Morin J. et al. Study of the bioaccumulation of tinzaparin in renally impaired patients when given at prophylactic doses - the STRIP study. Thromb Res 2019; 174: 48-50
• 103 Olie RH, Meertens NEL, Henskens YMC, Ten Cate H. Empirically reduced dosages of tinzaparin in patients with moderate-to-severe renal insufficiency lead to inadequate anti-Xa levels. Nephron 2017; 137 (02) 113-123
• 104 Atiq F, van den Bemt PM, Leebeek FW, van Gelder T, Versmissen J. A systematic review on the accumulation of prophylactic dosages of low-molecular-weight heparins (LMWHs) in patients with renal insufficiency. Eur J Clin Pharmacol 2015; 71 (08) 921-929
• 105 Spyropoulos AC, Ageno W, Albers GW. et al MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med 2018; 379 (12) 1118-1127
• 106 Cohen AT, Spiro TE, Büller HR. et al MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368 (06) 513-523
• 107 Cohen AT, Harrington RA, Goldhaber SZ. et al APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med 2016; 375 (06) 534-544
• 108 Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost 2010; 103 (03) 572-585
• 109 Glatthaar-Saalmüller B, Mair KH, Saalmüller A. Antiviral activity of aspirin against RNA viruses of the respiratory tract-an in vitro study. Influenza Other Respir Viruses 2017; 11 (01) 85-92
• 110 Wang Y, Zhong M, Wang Z, Song J, Wu W, Zhu D. The preventive effect of antiplatelet therapy in acute respiratory distress syndrome: a meta-analysis. Crit Care 2018; 22 (01) 60
• 111 Jin W, Chuang CC, Jin H, Ye J, Kandaswamy E, Wang L, Zuo L. Effects of pre-hospital antiplatelet therapy on the incidence of ARDS. Respir Care 2020; 65 (07) 1039-1045
• 112 Viecca M, Radovanovic D, Forleo GB, Santus P. Enhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study. Pharmacol Res 2020; 158: 104950
• 113 de Vries AAF. Renin-angiotensin system inhibition in COVID-19 patients. Neth Heart J 2020; 28 (7–8): 396-405
• 114 Zhang X, Li S, Niu S. ACE2 and COVID-19 and the resulting ARDS. Postgrad Med J 2020; 96 (1137): 403-407
• 115 Khera R, Clark C, Lu Y. et al. Association of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers with the risk of hospitalization and death in hypertensive patients with coronavirus disease-19. medRxiv
• 116 Felice C, Nardin C, Di Tanna GL. et al. Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives. Am J Hypertens 2020; 33 (10) 944-948
• 117 Cromwell WC, Otvos JD. Low-density lipoprotein particle number and risk for cardiovascular disease. Curr Atheroscler Rep 2004; 6 (05) 381-387
• 118 Pirillo A, Bonacina F, Norata GD, Catapano AL. The interplay of lipids, lipoproteins, and immunity in atherosclerosis. Curr Atheroscler Rep 2018; 20 (03) 12
• 119 Milos S, Hiansen JQ, Banaschewski B. et al. The effect of diet-induced serum hypercholesterolemia on the surfactant system and the development of lung injury. Biochem Biophys Rep 2016; 7: 180-187
• 120 Wang H, Yuan Z, Pavel MA, Hansen SB. The role of high cholesterol in age-related COVID19 lethality, Version 3. bioRxiv
• 121 Cao X, Yin R, Albrecht H, Fan D, Tan W. Cholesterol: A new game player accelerating vasculopathy caused by SARS-CoV-2?. Am J Physiol Endocrinol Metab 2020; 319 (01) E197-E202
• 122 Reiner Ž, Hatamipour M, Banach M. et al. Statins and the COVID-19 main protease: in silico evidence on direct interaction. Arch Med Sci 2020; 16 (03) 490-496
• 123 Lee KCH, Sewa DW, Phua GC. Potential role of statins in COVID-19. Int J Infect Dis 2020; 96: 615-617
• 124 Horby P, Lim WS, Emberson JR. et al RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N Engl J Med 2020;
• 125 Itkonen MK, Tornio A, Lapatto-Reiniluoto O. et al. Clopidogrel increases dasabuvir exposure with or without ritonavir, and ritonavir inhibits the bioactivation of clopidogrel. Clin Pharmacol Ther 2019; 105 (01) 219-228
• 126 Marsousi N, Daali Y, Fontana P. et al. Impact of boosted antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites. Clin Pharmacokinet 2018; 57 (10) 1347-1354
• 127 Testa S, Prandoni P, Paoletti O. et al. Direct oral anticoagulant plasma levels' striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents: the Cremona experience. J Thromb Haemost 2020; 18 (06) 1320-1323
• 128 Langer F, Kluge S, Klamroth R, Oldenburg J. Coagulopathy in COVID-19 and its implication for safe and efficacious thromboprophylaxis. Hamostaseologie 2020; 40 (03) 264-269
• 129 Al-Ani F, Chehade S, Lazo-Langner A. Thrombosis risk associated with COVID-19 infection. A scoping review. Thromb Res 2020; 192: 152-160
• 130 Liu X, Zhang R, He G. Hematological findings in coronavirus disease 2019: indications of progression of disease. Ann Hematol 2020; 99 (07) 1421-1428
• 131 Zhang L, Yan X, Fan Q. et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost 2020; 18 (06) 1324-1329
• 132 Gris JC, Quéré I, Pérez-Martin A, Lefrant JY, Sotto A. Uncertainties on the prognostic value of D-dimers in COVID-19 patients. J Thromb Haemost 2020; 18 (08) 2066-2067
• 133 Zhang L. Response to “uncertainties on the prognostic value of D-dimers in COVID-19 patients”. J Thromb Haemost 2020; 18 (08) 2067-2068
• 134 Zhou F, Yu T, Du R. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395 (10229): 1054-1062
• 135 Wang D, Hu B, Hu C. et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020; 323 (11) 1061-1069
• 136 Krupinski J, Catena E, Miguel M. et al. D-dimer local expression is increased in symptomatic patients undergoing carotid endarterectomy. Int J Cardiol 2007; 116 (02) 174-179
• 137 Di Castelnuovo A, Agnoli C, de Curtis A. et al. Elevated levels of D-dimers increase the risk of ischaemic and haemorrhagic stroke. Findings from the EPICOR Study. Thromb Haemost 2014; 112 (05) 941-946
• 138 Wada H, Trachil J, Di Nisio M. et al The Scientific Standardization Committee on DIC of the International Society on Thrombosis Haemostasis. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost 2013; 11: 761-767
• 139 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
• 140 Papageorgiou C, Jourdi G, Adjambri E. et al. Disseminated intravascular coagulation: an update on pathogenesis, diagnosis, and therapeutic strategies. Clin Appl Thromb Hemost 2018; 24 (9_suppl): 8S-28S
• 141 Levy JH, Sniecinski RM, Welsby IJ, Levi M. Antithrombin: anti-inflammatory properties and clinical applications. Thromb Haemost 2016; 115 (04) 712-728
• 142 Taylor Jr FB, Toh CH, Hoots WK, Wada H, Levi M. Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86 (05) 1327-1330
• 143 Wu C, Chen X, Cai Y. et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020; 180 (07) 1-11
• 144 Fogarty H, Townsend L, Ni Cheallaigh C. et al. COVID19 coagulopathy in Caucasian patients. Br J Haematol 2020; 189 (06) 1044-1049
• 145 Deng Y, Liu W, Liu K. et al. Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 in Wuhan, China: a retrospective study. Chin Med J (Engl) 2020; 133 (11) 1261-1267
• 146 Gerotziafas GT, Sergentanis TN, Voiriot G. et al. Derivation and validation of a predictive score for disease worsening in patients with COVID-19. Thromb Haemost 2020; 120 (12) 1680-1690
• 147 Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol 2020; 7 (06) e438-e440
• 148 Thachil J, Tang N, Gando S. et al. Laboratory haemostasis monitoring in COVID-19. J Thromb Haemost 2020; 18 (08) 2058-2060
• 149 Tang N, Bai H, Chen X. et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18: 844-847
• 150 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
• 151 Ayerbe L, Risco C, Ayis S. The association between treatment with heparin and survival in patients with Covid-19. J Thromb Thrombolysis 2020; 50 (02) 298-301
• 152 Harenberg J, Favaloro E. COVID-19: progression of disease and intravascular coagulation - present status and future perspectives. Clin Chem Lab Med 2020; 58 (07) 1029-1036
• 153 Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020; 135 (23) 2033-2040
• 154 Warren BL, Eid A, Singer P. et al; KyberSept Trial Study Group. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286 (15) 1869-1878
• 155 Ranucci M, Ballotta A, Di Dedda U. et al. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost 2020; 18 (07) 1747-1751
• 156 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
• 157 Wang J, Hajizadeh N, Moore EE. et al. Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): a case series. J Thromb Haemost 2020; 18 (07) 1752-1755
• 158 Barrett CD, Oren-Grinberg A, Chao E. et al. Rescue therapy for severe COVID-19 associated acute respiratory distress syndrome (ARDS) with tissue plasminogen activator (tPA): a case series. J Trauma Acute Care Surg 2020; 89 (03) 453-457
• 159 Christie III DB, Nemec HM, Scott AM. et al. Early outcomes with utilization of tissue plasminogen activator in COVID-19 associated respiratory distress: a series of five cases. J Trauma Acute Care Surg 2020; 89 (03) 448-452
• 160 WHO. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: interim guidance, 13 March 2020. Accessed July 26, 2020 at: https://apps.who.int/iris/handle/10665/331446?locale-attribute=fr&
• 161 Zhai Z, Li C, Chen Y. et al; Prevention Treatment of VTE Associated with COVID-19 Infection Consensus Statement Group. Prevention and treatment of venous thromboembolism associated with coronavirus disease 2019 infection: a consensus statement before guidelines. Thromb Haemost 2020; 120 (06) 937-948
• 162 Spyropoulos AC, Levy JH, Ageno W. et al; Subcommittee on Perioperative, Critical Care Thrombosis, Haemostasis of the Scientific, Standardization Committee of the International Society on Thrombosis, Haemostasis+. Scientific and Standardization Committee Communication: clinical guidance on the diagnosis, prevention and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1859-1865
• 163 Moores LK, Tritschler T, Brosnahan S. et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST guideline and expert panel report. Chest 2020; 158 (03) 1143-1163
• 164 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
• 165 Barnes GD, Burnett A, Allen A. et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis 2020; 50 (01) 72-81
• 166 Watson RA, Johnson DM, Dharia RN, Merli GJ, Doherty JU. Anti-coagulant and anti-platelet therapy in the COVID-19 patient: a best practices quality initiative across a large health system. Hosp Pract (1995) 2020; 48 (04) 169-179
• 167 Kollias A, Kyriakoulis KG, Dimakakos E, Poulakou G, Stergiou GS, Syrigos K. Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action. Br J Haematol 2020; 189 (05) 846-847
• 168 Kahn SR, Lim W, Dunn AS. et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 14 (2 Suppl): e195S-e226S
• 169 Nicolaides AN, Fareed J, Kakkar AK. et al. Prevention and treatment of venous thromboembolism--international consensus statement. Int Angiol 2013; 32 (02) 111-260
• 170 Llitjos JF, Leclerc M, Chochois C. et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost 2020; 18 (07) 1743-1746
• 171 Helms J, Tacquard C, Severac F. et al; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; 46 (06) 1089-1098
• 172 Leonard-Lorant I, Delabranche X, Severac F. et al. Acute pulmonary embolism in COVID-19 patients on CT angiography and relationship to D-dimer levels. Radiology 2020; 296 (03) E189-E191
• 173 Grillet F, Behr J, Calame P, Aubry S, Delabrousse E. Acute pulmonary embolism associated with COVID-19 pneumonia detected by pulmonary CT angiography. Radiology 2020; 296 (03) E186-E188
• 174 Middeldorp S, Coppens M, van Haaps TF. et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1995-2002
• 175 Artifoni M, Danic G, Gautier G. et al. Systematic assessment of venous thromboembolism in COVID-19 patients receiving thromboprophylaxis: incidence and role of D-dimer as predictive factors. J Thromb Thrombolysis 2020; 50 (01) 211-216
• 176 Al-Samkari H, Karp Leaf RS, Dzik WH. et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood 2020; 136 (04) 489-500
• 177 Samama MM, Cohen AT, Darmon JY. et al; Prophylaxis in Medical Patients with Enoxaparin Study Group. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999; 341 (11) 793-800
• 178 Leizorovicz A, Cohen AT, Turpie AGG, Olsson CG, Vaitkus PT, Goldhaber SZ. PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110 (07) 874-879
• 179 Cohen AT, Davidson BL, Gallus AS. et al; ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006; 332 (7537): 325-329
• 180 Violi F, Pastori D, Cangemi R, Pignatelli P, Loffredo L. Hypercoagulation and antithrombotic treatment in coronavirus 2019: a new challenge. Thromb Haemost 2020; 120 (06) 949-956
• 181 ClinicalTrials.org. . Accessed July 26, 2020 at: https://clinicaltrials.gov/ct2/results?cond=Covid19&term=LMWH&cntry=&state=&city=&dist=
• 182 Gerotziafas GT, Papageorgiou L, Salta S, Nikolopoulou K, Elalamy I. Updated clinical models for VTE prediction in hospitalized medical patients. Thromb Res 2018; 164 (Suppl. 01) S62-S69
• 183 Hull RD, Schellong SM, Tapson VF. et al; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 2010; 153 (01) 8-18
• 184 Laskier V, Guy H, Fisher M. et al. Effectiveness and safety of betrixaban extended prophylaxis for venous thromboembolism compared with standard-duration prophylaxis intervention in acute medically ill patients: a systematic literature review and network meta-analysis. J Med Econ 2019; 22 (10) 1063-1072
• 185 Spyropoulos AC, Anderson Jr FA, FitzGerald G. et al IMPROVE Investigators. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011; 140 (03) 706-714
• 186 Spyropoulos AC, Lipardi C, Xu J. et al. Modified IMPROVE VTE risk score and elevated D-dimer identify a high venous thromboembolism risk in acutely ill medical population for extended thromboprophylaxis. TH Open 2020; 4 (01) e59-e65
• 187 Rosenberg D, Eichorn A, Alarcon M, McCullagh L, McGinn T, Spyropoulos AC. External validation of the risk assessment model of the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) for medical patients in a tertiary health system. J Am Heart Assoc 2014; 3 (06) e001152
• 188 Cohoon KP, De Sanctis Y, Haskell L, McBane RD, Spiro TE. Rivaroxaban for thromboprophylaxis among patients recently hospitalized for acute infectious diseases: a subgroup analysis of the MAGELLAN study. J Thromb Haemost 2018; 16 (07) 1278-1287
• 189 Schünemann HJ, Cushman M, Burnett AE. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv 2018; 2 (22) 3198-3225
• 190 Bikdeli B, Madhavan MV, Gupta A. et al; Global COVID-19 Thrombosis Collaborative Group. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost 2020; 120 (07) 1004-1024
• 191 Guan WJ, Ni ZY, Hu Y. et al; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382 (18) 1708-1720