Download PDF
Thromb Haemost 2021; 121(08): 1031-1042
DOI: 10.1055/a-1529-2257
Coagulation and Fibrinolysis

Extracorporeal Membrane Oxygenation Induces Early Alterations in Coagulation and Fibrinolysis Profiles in COVID-19 Patients with Acute Respiratory Distress Syndrome

Guillaume Hékimian
1   Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
2   Sorbonne Université, INSERM UMRS_1166, Institute of Cardiometabolism And Nutrition, Paris, France
,
Paul Masi
1   Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
,
Manon Lejeune
2   Sorbonne Université, INSERM UMRS_1166, Institute of Cardiometabolism And Nutrition, Paris, France
3   Department of Hematology, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
,
Guillaume Lebreton
2   Sorbonne Université, INSERM UMRS_1166, Institute of Cardiometabolism And Nutrition, Paris, France
4   Department of Cardiothoracic Surgery, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
,
Juliette Chommeloux
1   Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
,
Cyrielle Desnos
1   Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
,
Marc Pineton De Chambrun
1   Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
,
Isabelle Martin-Toutain
3   Department of Hematology, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
,
Ania Nieszkowska
1   Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
,
Nicolas Bréchot
1   Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
,
Matthieu Schmidt
1   Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
2   Sorbonne Université, INSERM UMRS_1166, Institute of Cardiometabolism And Nutrition, Paris, France
,
Pascal Leprince
2   Sorbonne Université, INSERM UMRS_1166, Institute of Cardiometabolism And Nutrition, Paris, France
4   Department of Cardiothoracic Surgery, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
,
Charles-Edouard Luyt
1   Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
2   Sorbonne Université, INSERM UMRS_1166, Institute of Cardiometabolism And Nutrition, Paris, France
,
Alain Combes
1   Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
2   Sorbonne Université, INSERM UMRS_1166, Institute of Cardiometabolism And Nutrition, Paris, France
,
Corinne Frere 
2   Sorbonne Université, INSERM UMRS_1166, Institute of Cardiometabolism And Nutrition, Paris, France
3   Department of Hematology, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
› Author Affiliations Funding This work was sponsored by Assistance Publique-Hôpitaux de Paris. QPlus® cartridges were provided by Stago BioCare free of charge.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Hemostatic changes induced by extracorporeal membrane oxygenation (ECMO) support have been yet poorly documented in coronavirus-19 (COVID-19) patients who have a baseline complex hypercoagulable state. In this prospective monocentric study of patients with severe acute respiratory distress syndrome (ARDS) rescued by ECMO, we performed longitudinal measurements of coagulation and fibrinolysis markers throughout the course of ECMO support in 20 COVID-19 and 10 non-COVID-19 patients. Blood was sampled before and then 24 hours, 7, and 14 days after ECMO implantation. Clinical outcomes were prospectively assessed until discharge from the intensive care unit or death. The median age of participants was 47 (35–56) years, with a median body mass index of 30 (27–35) kg/m2, and a Sepsis-related Organ Failure Assessment score of 12 (8–16). Baseline levels of von Willebrand factor, fibrinogen, factor VIII, prothrombin F1 + 2, thrombin–antithrombin, D-dimer, and plasminogen activator inhibitor-1 (PAI-1) were elevated in both COVID-19 and non-COVID-19 ARDS patients, indicating that endothelial activation, endogenous thrombin generation, and fibrinolysis shutdown occur in all ARDS patients before ECMO implantation. From baseline to day 7, thrombin generation (prothrombin F1 + 2, p < 0.01) and fibrin formation markers (fibrin monomers, p < 0.001) significantly increased, further resulting in significant decreases in platelet count (p < 0.0001) and fibrinogen level (p < 0.001). PAI-1 levels significantly decreased from baseline to day 7 (p < 0.0001) in all ARDS patients. These changes were more marked in COVID-19 patients, resulting in 14 nonfatal and 3 fatal bleeding. Additional studies are warranted to determine whether monitoring of thrombin generation and fibrinolysis markers might help to early predict bleeding complications in COVID-19 patients supported by ECMO.

Keywords

extracorporeal membrane oxygenation - COVID-19 - coagulation - fibrinolysis - bleeding

Supplementary Material



Publication History

Received: 13 April 2021

Accepted: 14 June 2021

Accepted Manuscript online:
15 June 2021

Article published online:
11 July 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Alhazzani W, Møller MH, Arabi YM. et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med 2020; 46 (05) 854-887
    CrossrefPubMedSearch in Google Scholar
  • 2 Alhazzani W, Evans L, Alshamsi F. et al. Surviving Sepsis Campaign guidelines on the management of adults with coronavirus disease 2019 (COVID-19) in the ICU: first update. Crit Care Med 2021; 49 (03) e219-e234
    CrossrefPubMedSearch in Google Scholar
  • 3 Annich GM. Extracorporeal life support: the precarious balance of hemostasis. J Thromb Haemost 2015; 13 (Suppl. 01) S336-S342
    CrossrefPubMedSearch in Google Scholar
  • 4 Thomas J, Kostousov V, Teruya J. Bleeding and thrombotic complications in the use of extracorporeal membrane oxygenation. Semin Thromb Hemost 2018; 44 (01) 20-29
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Kowalewski M, Fina D, Słomka A. et al. COVID-19 and ECMO: the interplay between coagulation and inflammation-a narrative review. Crit Care 2020; 24 (01) 205
    CrossrefPubMedSearch in Google Scholar
  • 6 Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020; 135 (23) 2033-2040
    CrossrefPubMedSearch in Google Scholar
  • 7 Joly BS, Siguret V, Veyradier A. Understanding pathophysiology of hemostasis disorders in critically ill patients with COVID-19. Intensive Care Med 2020; 46 (08) 1603-1606
    CrossrefPubMedSearch in Google Scholar
  • 8 Susen S, Tacquard CA, Godon A. et al; GIHP and GFHT. Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring. Crit Care 2020; 24 (01) 364
    CrossrefPubMedSearch in Google Scholar
  • 9 Schmidt M, Hajage D, Lebreton G. et al; Groupe de Recherche Clinique en REanimation et Soins intensifs du Patient en Insuffisance Respiratoire aiguE (GRC-RESPIRE) Sorbonne Université; Paris-Sorbonne ECMO-COVID investigators.. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study. Lancet Respir Med 2020; 8 (11) 1121-1131
    CrossrefPubMedSearch in Google Scholar
  • 10 Shaefi S, Brenner SK, Gupta S. et al; STOP-COVID Investigators.. Extracorporeal membrane oxygenation in patients with severe respiratory failure from COVID-19. Intensive Care Med 2021; 47 (02) 208-221
    CrossrefPubMedSearch in Google Scholar
  • 11 Le Breton C, Besset S, Freita-Ramos S. et al. Extracorporeal membrane oxygenation for refractory COVID-19 acute respiratory distress syndrome. J Crit Care 2020; 60: 10-12
    CrossrefPubMedSearch in Google Scholar
  • 12 Usman AA, Han J, Acker A. et al. A case series of devastating intracranial hemorrhage during venovenous extracorporeal membrane oxygenation for COVID-19. J Cardiothorac Vasc Anesth 2020; 34 (11) 3006-3012
    CrossrefPubMedSearch in Google Scholar
  • 13 Bermea RS, Raz Y, Sertic F. et al. Increased intracranial hemorrhage amid elevated inflammatory markers in those with COVID-19 supported with extracorporeal membrane oxygenation. Shock 2021;
    CrossrefPubMedSearch in Google Scholar
  • 14 Asakura H, Ogawa H. Overcoming bleeding events related to extracorporeal membrane oxygenation in COVID-19. Lancet Respir Med 2020; 8 (12) e87-e88
    CrossrefPubMedSearch in Google Scholar
  • 15 Kalbhenn J, Glonnegger H, Wilke M, Bansbach J, Zieger B. Hypercoagulopathy, acquired coagulation disorders and anticoagulation before, during and after extracorporeal membrane oxygenation in COVID-19: a case series. Perfusion 2021; 2676591211001791
    PubMedSearch in Google Scholar
  • 16 Chandel A, Patolia S, Looby M, Bade N, Khangoora V, King CS. Association of D-dimer and fibrinogen with hypercoagulability in COVID-19 requiring extracorporeal membrane oxygenation. J Intensive Care Med 2021; 36 (06) 689-695
    CrossrefPubMedSearch in Google Scholar
  • 17 Gaisendrees C, Walter SG, Elderia A. et al. Adequate anticoagulation and ECMO therapy in COVID-19 patients with severe pulmonary embolism. Perfusion 2020; 267659120979887
    PubMedSearch in Google Scholar
  • 18 Streng AS, Delnoij TSR, Mulder MMG. et al. Monitoring of unfractionated heparin in severe COVID-19: an observational study of patients on CRRT and ECMO. TH Open 2020; 4 (04) e365-e375
    Thieme ConnectPubMedSearch in Google Scholar
  • 19 Guo Z, Sun L, Li B. et al. Anticoagulation management in severe coronavirus disease 2019 patients on extracorporeal membrane oxygenation. J Cardiothorac Vasc Anesth 2021; 35 (02) 389-397
    CrossrefPubMedSearch in Google Scholar
  • 20 Ranieri VM, Rubenfeld GD, Thompson BT. et al; ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012; 307 (23) 2526-2533
    PubMedSearch in Google Scholar
  • 21 Combes A, Hajage D, Capellier G. et al; EOLIA Trial Group, REVA, and ECMONet.. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med 2018; 378 (21) 1965-1975
    CrossrefPubMedSearch in Google Scholar
  • 22 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
    CrossrefPubMedSearch in Google Scholar
  • 23 Bartlett RH, Ogino MT, Brodie D. et al. Initial ELSO guidance document: ECMO for COVID-19 patients with severe cardiopulmonary failure. ASAIO J 2020; 66 (05) 472-474
    CrossrefPubMedSearch in Google Scholar
  • 24 von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007; 370 (9596): 1453-1457
    CrossrefPubMedSearch in Google Scholar
  • 25 Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993; 270 (24) 2957-2963
    CrossrefPubMedSearch in Google Scholar
  • 26 Vincent JL, Moreno R, Takala J. et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22 (07) 707-710
    CrossrefPubMedSearch in Google Scholar
  • 27 Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group.. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl (2011) 2012; 2 (01) 6
    PubMedSearch in Google Scholar
  • 28 Geerts WH, Bergqvist D, Pineo GF. et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (06) 381S-453S
    CrossrefPubMedSearch in Google Scholar
  • 29 Barbaro RP, MacLaren G, Boonstra PS. et al; Extracorporeal Life Support Organization. Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry. Lancet 2020; 396 (10257): 1071-1078
    CrossrefPubMedSearch in Google Scholar
  • 30 Görlinger K, Dirkmann D, Gandhi A, Simioni P. COVID-19-associated coagulopathy and inflammatory response: what do we know already and what are the knowledge gaps?. Anesth Analg 2020; 131 (05) 1324-1333
    CrossrefPubMedSearch in Google Scholar
  • 31 Seelhammer TG, Plack D, Lal A, Nabzdyk CGS. COVID-19 and ECMO: an unhappy marriage of endothelial dysfunction and hemostatic derangements. J Cardiothorac Vasc Anesth 2020; 34 (12) 3193-3196
    CrossrefPubMedSearch in Google Scholar
  • 32 Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood 2019; 133 (09) 906-918
    CrossrefPubMedSearch in Google Scholar
  • 33 Levy JH, Iba T, Connors JM. Editorial commentary: vascular injury in acute infections and COVID-19: everything old is new again. Trends Cardiovasc Med 2021; 31 (01) 6-7
    CrossrefPubMedSearch in Google Scholar
  • 34 Malfertheiner MV, Philipp A, Lubnow M. et al. Hemostatic changes during extracorporeal membrane oxygenation: a prospective randomized clinical trial comparing three different extracorporeal membrane oxygenation systems. Crit Care Med 2016; 44 (04) 747-754
    CrossrefPubMedSearch in Google Scholar
  • 35 Nougier C, Benoit R, Simon M. et al. Hypofibrinolytic state and high thrombin generation may play a major role in SARS-COV2 associated thrombosis. J Thromb Haemost 2020; 18 (09) 2215-2219
    CrossrefPubMedSearch in Google Scholar
  • 36 Bouck EG, Denorme F, Holle LA. et al. COVID-19 and sepsis are associated with different abnormalities in plasma procoagulant and fibrinolytic activity. Arterioscler Thromb Vasc Biol 2021; 41 (01) 401-414
    PubMedSearch in Google Scholar
  • 37 Panigada M, Artoni A, Passamonti SM. et al. Hemostasis changes during veno-venous extracorporeal membrane oxygenation for respiratory support in adults. Minerva Anestesiol 2016; 82 (02) 170-179
    PubMedSearch in Google Scholar
  • 38 Jiritano F, Serraino GF, Ten Cate H. et al. Platelets and extra-corporeal membrane oxygenation in adult patients: a systematic review and meta-analysis. Intensive Care Med 2020; 46 (06) 1154-1169
    CrossrefPubMedSearch in Google Scholar
  • 39 Heilmann C, Geisen U, Beyersdorf F. et al. Acquired von Willebrand syndrome in patients with extracorporeal life support (ECLS). Intensive Care Med 2012; 38 (01) 62-68
    CrossrefPubMedSearch in Google Scholar
  • 40 Kalbhenn J, Schlagenhauf A, Rosenfelder S, Schmutz A, Zieger B. Acquired von Willebrand syndrome and impaired platelet function during venovenous extracorporeal membrane oxygenation: rapid onset and fast recovery. J Heart Lung Transplant 2018; 37 (08) 985-991
    CrossrefPubMedSearch in Google Scholar
  • 41 Lukito P, Wong A, Jing J. et al. Mechanical circulatory support is associated with loss of platelet receptors glycoprotein Ibα and glycoprotein VI. J Thromb Haemost 2016; 14 (11) 2253-2260
    CrossrefPubMedSearch in Google Scholar
  • 42 Granja T, Hohenstein K, Schüssel P. et al. Multi-modal characterization of the coagulopathy associated with extracorporeal membrane oxygenation. Crit Care Med 2020; 48 (05) e400-e408
    CrossrefPubMedSearch in Google Scholar
  • 43 Tauber H, Ott H, Streif W. et al. Extracorporeal membrane oxygenation induces short-term loss of high-molecular-weight von Willebrand factor multimers. Anesth Analg 2015; 120 (04) 730-736
    CrossrefPubMedSearch in Google Scholar
  • 44 Tauber H, Streif W, Fritz J. et al. Predicting transfusion requirements during extracorporeal membrane oxygenation. J Cardiothorac Vasc Anesth 2016; 30 (03) 692-701
    CrossrefPubMedSearch in Google Scholar
  • 45 Wright FL, Vogler TO, Moore EE. et al. Fibrinolysis shutdown correlation with thromboembolic events in severe COVID-19 infection. J Am Coll Surg 2020; 231 (02) 193-203
    CrossrefPubMedSearch in Google Scholar
  • 46 Panigada M, E Iapichino G, Brioni M. et al. Thromboelastography-based anticoagulation management during extracorporeal membrane oxygenation: a safety and feasibility pilot study. Ann Intensive Care 2018; 8 (01) 7
    CrossrefPubMedSearch in Google Scholar