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Published in: Intensive Care Medicine 6/2020

01-06-2020 | Disseminated Intravascular Coagulation | Original

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Authors: Julie Helms, Charles Tacquard, François Severac, Ian Leonard-Lorant, Mickaël Ohana, Xavier Delabranche, Hamid Merdji, Raphaël Clere-Jehl, Malika Schenck, Florence Fagot Gandet, Samira Fafi-Kremer, Vincent Castelain, Francis Schneider, Lélia Grunebaum, Eduardo Anglés-Cano, Laurent Sattler, Paul-Michel Mertes, Ferhat Meziani, CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis)

Published in: Intensive Care Medicine | Issue 6/2020

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Abstract

Purpose

Little evidence of increased thrombotic risk is available in COVID-19 patients. Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.

Methods

All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included. Medical history, symptoms, biological data and imaging were prospectively collected. Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.

Results

150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points). Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting. Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO. Most patients (> 95%) had elevated D-dimer and fibrinogen. No patient developed disseminated intravascular coagulation. Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant. Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs. 2.1%, p < 0.008). Coagulation parameters significantly differed between the two groups.

Conclusion

Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications. Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.
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Literature
1.
go back to reference Glass WG, Subbarao K, Murphy B, Murphy PM (2004) Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol 173:4030–4039CrossRef Glass WG, Subbarao K, Murphy B, Murphy PM (2004) Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol 173:4030–4039CrossRef
4.
go back to reference Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L (2020) Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395:507–513CrossRef Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L (2020) Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395:507–513CrossRef
5.
go back to reference Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z (2020) Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. https://doi.org/10.1001/jama.2020.1585 Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z (2020) Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. https://​doi.​org/​10.​1001/​jama.​2020.​1585
6.
go back to reference Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP (2017) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensiv Care Med 43:304–377CrossRef Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP (2017) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensiv Care Med 43:304–377CrossRef
9.
go back to reference Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS (2012) Acute respiratory distress syndrome: the Berlin Definition. JAMA 307:2526–2533PubMed Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS (2012) Acute respiratory distress syndrome: the Berlin Definition. JAMA 307:2526–2533PubMed
10.
go back to reference Iba T, Di Nisio M, Thachil J, Wada H, Asakura H, Sato K, Kitamura N, Saitoh D (2016) Revision of the Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) diagnostic criteria using antithrombin activity. Crit Care 20:287CrossRef Iba T, Di Nisio M, Thachil J, Wada H, Asakura H, Sato K, Kitamura N, Saitoh D (2016) Revision of the Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) diagnostic criteria using antithrombin activity. Crit Care 20:287CrossRef
11.
go back to reference Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M, Scientific Subcommittee on Disseminated Intravascular Coagulation of the International Society on T, Haemostasis (2001) Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 86:1327–1330CrossRef Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M, Scientific Subcommittee on Disseminated Intravascular Coagulation of the International Society on T, Haemostasis (2001) Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 86:1327–1330CrossRef
12.
go back to reference Delabranche X, Boisrame-Helms J, Asfar P, Berger A, Mootien Y, Lavigne T, Grunebaum L, Lanza F, Gachet C, Freyssinet JM, Toti F, Meziani F (2013) Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy. Intensiv Care Med 39:1695–1703CrossRef Delabranche X, Boisrame-Helms J, Asfar P, Berger A, Mootien Y, Lavigne T, Grunebaum L, Lanza F, Gachet C, Freyssinet JM, Toti F, Meziani F (2013) Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy. Intensiv Care Med 39:1695–1703CrossRef
13.
go back to reference Delabranche X, Quenot JP, Lavigne T, Mercier E, Francois B, Severac F, Grunebaum L, Mehdi M, Zobairi F, Toti F, Meziani F, Boisrame-Helms J, Clinical Research in Intensive C, Sepsis N (2016) Early detection of disseminated intravascular coagulation during septic shock: a multicenter prospective study. Crit Care Med 44:e930–e939CrossRef Delabranche X, Quenot JP, Lavigne T, Mercier E, Francois B, Severac F, Grunebaum L, Mehdi M, Zobairi F, Toti F, Meziani F, Boisrame-Helms J, Clinical Research in Intensive C, Sepsis N (2016) Early detection of disseminated intravascular coagulation during septic shock: a multicenter prospective study. Crit Care Med 44:e930–e939CrossRef
14.
go back to reference Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera RH, Derksen RH, de Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost JTH 4:295–306CrossRef Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera RH, Derksen RH, de Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost JTH 4:295–306CrossRef
15.
go back to reference Gershom ES, Sutherland MR, Lollar P, Pryzdial EL (2010) Involvement of the contact phase and intrinsic pathway in herpes simplex virus-initiated plasma coagulation. J Thromb Haemost JTH 8:1037–1043PubMed Gershom ES, Sutherland MR, Lollar P, Pryzdial EL (2010) Involvement of the contact phase and intrinsic pathway in herpes simplex virus-initiated plasma coagulation. J Thromb Haemost JTH 8:1037–1043PubMed
16.
go back to reference Oudemans-van Straaten HM (2015) Hemostasis and thrombosis in continuous renal replacement treatment. Semin Thromb Hemost 41:91–98CrossRef Oudemans-van Straaten HM (2015) Hemostasis and thrombosis in continuous renal replacement treatment. Semin Thromb Hemost 41:91–98CrossRef
17.
go back to reference Lim W, Meade M, Lauzier F, Zarychanski R, Mehta S, Lamontagne F, Dodek P, McIntyre L, Hall R, Heels-Ansdell D, Fowler R, Pai M, Guyatt G, Crowther MA, Warkentin TE, Devereaux PJ, Walter SD, Muscedere J, Herridge M, Turgeon AF, Geerts W, Finfer S, Jacka M, Berwanger O, Ostermann M, Qushmaq I, Friedrich JO, Cook DJ, Investigators PRfTiCCT (2015) Failure of anticoagulant thromboprophylaxis: risk factors in medical-surgical critically ill patients. Crit Care Med 43:401–410CrossRef Lim W, Meade M, Lauzier F, Zarychanski R, Mehta S, Lamontagne F, Dodek P, McIntyre L, Hall R, Heels-Ansdell D, Fowler R, Pai M, Guyatt G, Crowther MA, Warkentin TE, Devereaux PJ, Walter SD, Muscedere J, Herridge M, Turgeon AF, Geerts W, Finfer S, Jacka M, Berwanger O, Ostermann M, Qushmaq I, Friedrich JO, Cook DJ, Investigators PRfTiCCT (2015) Failure of anticoagulant thromboprophylaxis: risk factors in medical-surgical critically ill patients. Crit Care Med 43:401–410CrossRef
18.
go back to reference Grimmer B, Kuebler WM (2017) The endothelium in hypoxic pulmonary vasoconstriction. J Appl Physiol 123:1635–1646CrossRef Grimmer B, Kuebler WM (2017) The endothelium in hypoxic pulmonary vasoconstriction. J Appl Physiol 123:1635–1646CrossRef
19.
go back to reference Yan SF, Mackman N, Kisiel W, Stern DM, Pinsky DJ (1999) Hypoxia/hypoxemia-induced activation of the procoagulant pathways and the pathogenesis of ischemia-associated thrombosis. Arterioscler Thromb Vasc Biol 19:2029–2035CrossRef Yan SF, Mackman N, Kisiel W, Stern DM, Pinsky DJ (1999) Hypoxia/hypoxemia-induced activation of the procoagulant pathways and the pathogenesis of ischemia-associated thrombosis. Arterioscler Thromb Vasc Biol 19:2029–2035CrossRef
20.
go back to reference Gupta N, Zhao YY, Evans CE (2019) The stimulation of thrombosis by hypoxia. Thromb Res 181:77–83CrossRef Gupta N, Zhao YY, Evans CE (2019) The stimulation of thrombosis by hypoxia. Thromb Res 181:77–83CrossRef
21.
go back to reference Hattori N, Sisson TH, Xu Y, Desai TJ, Simon RH (1999) Participation of urokinase-type plasminogen activator receptor in the clearance of fibrin from the lung. Am J Physiol 277:L573–L579PubMed Hattori N, Sisson TH, Xu Y, Desai TJ, Simon RH (1999) Participation of urokinase-type plasminogen activator receptor in the clearance of fibrin from the lung. Am J Physiol 277:L573–L579PubMed
22.
go back to reference Bertozzi P, Astedt B, Zenzius L, Lynch K, LeMaire F, Zapol W, Chapman HA Jr (1990) Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome. N Engl J Med 322:890–897CrossRef Bertozzi P, Astedt B, Zenzius L, Lynch K, LeMaire F, Zapol W, Chapman HA Jr (1990) Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome. N Engl J Med 322:890–897CrossRef
23.
go back to reference Idell S, James KK, Levin EG, Schwartz BS, Manchanda N, Maunder RJ, Martin TR, McLarty J, Fair DS (1989) Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Investig 84:695–705CrossRef Idell S, James KK, Levin EG, Schwartz BS, Manchanda N, Maunder RJ, Martin TR, McLarty J, Fair DS (1989) Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Investig 84:695–705CrossRef
24.
go back to reference Wu YP, Wei R, Liu ZH, Chen B, Lisman T, Ren DL, Han JJ, Xia ZL, Zhang FS, Xu WB, Preissner KT, de Groot PG (2006) Analysis of thrombotic factors in severe acute respiratory syndrome (SARS) patients. Thromb Haemost 96:100–101CrossRef Wu YP, Wei R, Liu ZH, Chen B, Lisman T, Ren DL, Han JJ, Xia ZL, Zhang FS, Xu WB, Preissner KT, de Groot PG (2006) Analysis of thrombotic factors in severe acute respiratory syndrome (SARS) patients. Thromb Haemost 96:100–101CrossRef
25.
go back to reference Hoste EA, Roosens CD, Bracke S, Decruyenaere JM, Benoit DD, Vandewoude KH, Colardyn FA (2005) Acute effects of upright position on gas exchange in patients with acute respiratory distress syndrome. J Intensiv Care Med 20:43–49CrossRef Hoste EA, Roosens CD, Bracke S, Decruyenaere JM, Benoit DD, Vandewoude KH, Colardyn FA (2005) Acute effects of upright position on gas exchange in patients with acute respiratory distress syndrome. J Intensiv Care Med 20:43–49CrossRef
26.
go back to reference Gralinski LE, Bankhead A 3rd, Jeng S, Menachery VD, Proll S, Belisle SE, Matzke M, Webb-Robertson BJ, Luna ML, Shukla AK, Ferris MT, Bolles M, Chang J, Aicher L, Waters KM, Smith RD, Metz TO, Law GL, Katze MG, McWeeney S, Baric RS (2013) Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. mBio 4:e00271CrossRef Gralinski LE, Bankhead A 3rd, Jeng S, Menachery VD, Proll S, Belisle SE, Matzke M, Webb-Robertson BJ, Luna ML, Shukla AK, Ferris MT, Bolles M, Chang J, Aicher L, Waters KM, Smith RD, Metz TO, Law GL, Katze MG, McWeeney S, Baric RS (2013) Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. mBio 4:e00271CrossRef
27.
go back to reference Giannakopoulos B, Krilis SA (2013) The pathogenesis of the antiphospholipid syndrome. N Engl J Med 368:1033–1044CrossRef Giannakopoulos B, Krilis SA (2013) The pathogenesis of the antiphospholipid syndrome. N Engl J Med 368:1033–1044CrossRef
28.
go back to reference Goldman-Mazur S, Wypasek E, Karpinski M, Stanisz A, Undas A (2019) High detection rates of antithrombin deficiency and antiphospholipid syndrome in outpatients aged over 50 years using the standardized protocol for thrombophilia screening. Thromb Res 176:67–73CrossRef Goldman-Mazur S, Wypasek E, Karpinski M, Stanisz A, Undas A (2019) High detection rates of antithrombin deficiency and antiphospholipid syndrome in outpatients aged over 50 years using the standardized protocol for thrombophilia screening. Thromb Res 176:67–73CrossRef
29.
go back to reference Bautista E, Arcos M, Jimenez-Alvarez L, Garcia-Sancho MC, Vazquez ME, Pena E, Higuera A, Ramirez G, Fernandez-Plata R, Cruz-Lagunas A, Garcia-Moreno SA, Urrea F, Ramirez R, Correa-Rotter R, Perez-Padilla JR, Zuniga J (2013) Angiogenic and inflammatory markers in acute respiratory distress syndrome and renal injury associated to A/H1N1 virus infection. Exp Mol Pathol 94:486–492CrossRef Bautista E, Arcos M, Jimenez-Alvarez L, Garcia-Sancho MC, Vazquez ME, Pena E, Higuera A, Ramirez G, Fernandez-Plata R, Cruz-Lagunas A, Garcia-Moreno SA, Urrea F, Ramirez R, Correa-Rotter R, Perez-Padilla JR, Zuniga J (2013) Angiogenic and inflammatory markers in acute respiratory distress syndrome and renal injury associated to A/H1N1 virus infection. Exp Mol Pathol 94:486–492CrossRef
30.
go back to reference Seeley EJ (2013) Updates in the management of acute lung injury: a focus on the overlap between AKI and ARDS. Adv Chronic Kidney Dis 20:14–20CrossRef Seeley EJ (2013) Updates in the management of acute lung injury: a focus on the overlap between AKI and ARDS. Adv Chronic Kidney Dis 20:14–20CrossRef
31.
go back to reference Malek M, Hassanshahi J, Fartootzadeh R, Azizi F, Shahidani S (2018) Nephrogenic acute respiratory distress syndrome: a narrative review on pathophysiology and treatment. Chin J Traumatol 21:4–10CrossRef Malek M, Hassanshahi J, Fartootzadeh R, Azizi F, Shahidani S (2018) Nephrogenic acute respiratory distress syndrome: a narrative review on pathophysiology and treatment. Chin J Traumatol 21:4–10CrossRef
32.
go back to reference Antoniak S, Mackman N (2014) Multiple roles of the coagulation protease cascade during virus infection. Blood 123:2605–2613CrossRef Antoniak S, Mackman N (2014) Multiple roles of the coagulation protease cascade during virus infection. Blood 123:2605–2613CrossRef
33.
go back to reference Basler CF (2017) Molecular pathogenesis of viral hemorrhagic fever. Semin Immunopathol 39:551–561CrossRef Basler CF (2017) Molecular pathogenesis of viral hemorrhagic fever. Semin Immunopathol 39:551–561CrossRef
Metadata
Title
High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study
Authors
Julie Helms
Charles Tacquard
François Severac
Ian Leonard-Lorant
Mickaël Ohana
Xavier Delabranche
Hamid Merdji
Raphaël Clere-Jehl
Malika Schenck
Florence Fagot Gandet
Samira Fafi-Kremer
Vincent Castelain
Francis Schneider
Lélia Grunebaum
Eduardo Anglés-Cano
Laurent Sattler
Paul-Michel Mertes
Ferhat Meziani
CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis)
Publication date
01-06-2020
Publisher
Springer Berlin Heidelberg
Published in
Intensive Care Medicine / Issue 6/2020
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-020-06062-x

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