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

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.

[1]  D. Light,et al.  Amplified anticoagulant activity of tissue factor-targeted thrombomodulin , 2006, Thrombosis and Haemostasis.

[2]  G. Guyatt,et al.  Failure of Anticoagulant Thromboprophylaxis: Risk Factors in Medical-Surgical Critically Ill Patients* , 2015, Critical care medicine.

[3]  C. Basler.  Molecular pathogenesis of viral hemorrhagic fever , 2017, Seminars in Immunopathology.

[4]  Arthur S Slutsky,et al.  Acute Respiratory Distress Syndrome The Berlin Definition , 2012 .

[5]  M. E. Vazquez,et al.  Angiogenic and inflammatory markers in acute respiratory distress syndrome and renal injury associated to A/H1N1 virus infection. , 2013, Experimental and molecular pathology.

[6]  M. Laffan,et al.  Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia , 2020, Journal of Thrombosis and Haemostasis.

[7]  M. Di Nisio,et al.  Revision of the Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) diagnostic criteria using antithrombin activity , 2016, Critical Care.

[8]  W. Kisiel,et al.  Hypoxia/Hypoxemia-Induced activation of the procoagulant pathways and the pathogenesis of ischemia-associated thrombosis. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[9]  H. O. Oudemans-van Straaten.  Hemostasis and Thrombosis in Continuous Renal Replacement Treatment , 2015, Seminars in Thrombosis & Hemostasis.

[10]  E. Seeley.  Updates in the management of acute lung injury: a focus on the overlap between AKI and ARDS. , 2013, Advances in chronic kidney disease.

[11]  P. Asfar,et al.  Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy , 2013, Intensive Care Medicine.

[12]  F B Taylor,et al.  Towards Definition, Clinical and Laboratory Criteria, and a Scoring System for Disseminated Intravascular Coagulation , 2001, Thrombosis and Haemostasis.

[13]  F. Meziani,et al.  Early Detection of Disseminated Intravascular Coagulation During Septic Shock: A Multicenter Prospective Study , 2016, Critical care medicine.

[14]  P. Lollar,et al.  Involvement of the contact phase and intrinsic pathway in herpes simplex virus‐initiated plasma coagulation , 2010, Journal of thrombosis and haemostasis : JTH.

[15]  Bobbie-Jo M. Webb-Robertson,et al.  Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury , 2013, mBio.

[16]  S. Krilis,et al.  The pathogenesis of the antiphospholipid syndrome. , 2013, The New England journal of medicine.

[17]  Y. Shoenfeld,et al.  International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS) , 2006, Journal of thrombosis and haemostasis : JTH.

[18]  Dengju Li,et al.  Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy , 2020, Journal of Thrombosis and Haemostasis.

[19]  F. Lemaire,et al.  Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome. , 1990, The New England journal of medicine.

[20]  Dengju Li,et al.  Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia , 2020, Journal of Thrombosis and Haemostasis.

[21]  C. Sprung,et al.  Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock 2012 , 2013, Critical care medicine.

[22]  F. Azizi,et al.  Nephrogenic acute respiratory distress syndrome: A narrative review on pathophysiology and treatment , 2017, Chinese journal of traumatology = Zhonghua chuang shang za zhi.

[23]  A. Falanga,et al.  ISTH interim guidance on recognition and management of coagulopathy in COVID‐19 , 2020, Journal of Thrombosis and Haemostasis.

[24]  Ezekiel J Emanuel,et al.  Fair Allocation of Scarce Medical Resources in the Time of Covid-19. , 2020, The New England journal of medicine.

[25]  N. Gupta,et al.  The stimulation of thrombosis by hypoxia. , 2019, Thrombosis research.

[26]  Ting Yu,et al.  Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study , 2020, The Lancet.

[27]  P. D. de Groot,et al.  Analysis of thrombotic factors in severe acute respiratory syndrome (SARS) patients , 2006, Thrombosis and Haemostasis.

[28]  A. Undas,et al.  High detection rates of antithrombin deficiency and antiphospholipid syndrome in outpatients aged over 50 years using the standardized protocol for thrombophilia screening. , 2019, Thrombosis research.

[29]  W. Kuebler,et al.  The endothelium in hypoxic pulmonary vasoconstriction. , 2017, Journal of applied physiology.

[30]  Alan E. Jones,et al.  Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016 , 2017, Intensive Care Medicine.

[31]  T. Martin,et al.  Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. , 1989, The Journal of clinical investigation.

[32]  J. Decruyenaere,et al.  Acute Effects of Upright Position on Gas Exchange in Patients With Acute Respiratory Distress Syndrome , 2005, Journal of intensive care medicine.

[33]  Yan Zhao,et al.  Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. , 2020, JAMA.

[34]  M. Yaffe,et al.  ISTH interim guidance on recognition and management of coagulopathy in COVID‐19: A comment , 2020, Journal of Thrombosis and Haemostasis.

[35]  N. Mackman,et al.  Multiple roles of the coagulation protease cascade during virus infection. , 2014, Blood.

[36]  T. Desai,et al.  Participation of urokinase-type plasminogen activator receptor in the clearance of fibrin from the lung. , 1999, American journal of physiology. Lung cellular and molecular physiology.