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CC BY 4.0 · TH Open 2021; 05(03): e253-e263
DOI: 10.1055/s-0041-1731711
Original Article

Endothelium Activation Markers in Severe Hospitalized COVID-19 Patients: Role in Mortality Risk Prediction

Marina Marchetti
1   Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
,
Patricia Gomez-Rosas 
1   Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
2   Hematology Service, Hospital General Regional Tecamac IMSS, Mexico, Mexico
,
Eleonora Sanga
1   Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
,
Sara Gamba
1   Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
,
Cristina Verzeroli
1   Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
,
Laura Russo
1   Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
,
Francesco Restuccia
3   Department of Anesthesiology and Critical Care Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
,
Francesca Schieppati
1   Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
,
Ezio Bonanomi
3   Department of Anesthesiology and Critical Care Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
,
Marco Rizzi
4   Unit of Infectious Diseases, Hospital Papa Giovanni XXIII, Bergamo, Italy
,
Stefano Fagiuoli
5   Department of Internal Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
,
Andrea D'Alessio
6   Department of Medical Oncology and Internal Medicine, Policlinico San Marco, Zingonia, Bergamo, Italy
,
Luca Lorini
3   Department of Anesthesiology and Critical Care Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
,
Anna Falanga
1   Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
7   School of Medicine, University of Milano Bicocca, Milano, Italy
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Abstract

Introduction Endothelial damage and hypercoagulability are major players behind the hemostatic derangement of SARS-CoV-2 infection.

Aim In this prospective study we assessed endothelial and inflammatory biomarkers in a cohort of COVID-19 patients, aiming to identify predictive factors of in-hospital mortality.

Methods COVID-19 patients hospitalized in intensive care (ICU) and non-ICU units at 2 Bergamo (Italy) hospitals from March 23 to May 30, 2020, were enrolled. Markers of endothelium activation including von-Willebrand factor (vWF), soluble thrombomodulin (sTM), and fibrinolytic proteins (t-PA and PAI-1) were measured. Additionally, D-dimer, Fibrinogen, FVIII, nucleosomes, C reactive protein (CRP) and procalcitonin were assessed.

Results Sixty-three (45 ICU, and 18 non-ICU) patients, with a median age of 62 years were analyzed. Increased plasma levels of D-dimer, FVIII, fibrinogen, nucleosomes, CRP, and procalcitonin were observed in the whole cohort. Extremely elevated vWF levels characterized all patients (highest values in ICU-subjects). After a median time of 30 days, death occurred in 13 (21%) patients. By multivariable analysis, vWF-activity, neutrophil-count and PaO2/FiO2 were significantly associated with death. Using these variables, a linear score with 3-risk groups was generated that provided a cumulative incidence of death of 0% in the low-, 32% in the intermediate-, and 78% in the high-risk group.

Conclusions COVID-19-induced hemostatic abnormalities are exacerbated by the severity of the disease and strongly correlate with the inflammatory status, underlying the link between coagulation, endothelial activation, and inflammation. Our study provides evidence for a role of vWF, together with neutrophils and PaO2/FiO2, as a significant predictor of in-hospital mortality by SARSCoV-2 infection.

Keywords

endothelium - COVID-19 - von willebrand factor - hypercoagulation


Publication History

Received: 07 January 2021

Accepted: 22 May 2021

Article published online:
04 July 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Jung F, Krüger-Genge A, Franke RP, Hufert F, Küpper JH. COVID-19 and the endothelium. Clin Hemorheol Microcirc 2020; 75 (01) 7-11
    CrossrefPubMedSearch in Google Scholar
  • 2 Han H, Yang L, Liu R. et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med 2020; 58 (07) 1116-1120
    CrossrefPubMedSearch in Google Scholar
  • 3 Huang D, Lian X, Song F. et al. Clinical features of severe patients infected with 2019 novel coronavirus: a systematic review and meta-analysis. Ann Transl Med 2020; 8 (09) 576
    CrossrefPubMedSearch in Google Scholar
  • 4 Klok FA, Kruip MJHA, van der Meer NJM. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020; 191: 145-147
    CrossrefPubMedSearch in Google Scholar
  • 5 Mohanty SK, Satapathy A, Naidu MM. et al. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19) - anatomic pathology perspective on current knowledge. Diagn Pathol 2020; 15 (01) 103
    CrossrefPubMedSearch in Google Scholar
  • 6 Ye Q, Wang B, Mao J. The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19. J Infect 2020; 80 (06) 607-613
    CrossrefPubMedSearch in Google Scholar
  • 7 Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med 2020; 8 (06) e46-e47
    CrossrefPubMedSearch in Google Scholar
  • 8 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
    CrossrefPubMedSearch in Google Scholar
  • 9 Maniatis NA, Orfanos SE. The endothelium in acute lung injury/acute respiratory distress syndrome. Curr Opin Crit Care 2008; 14 (01) 22-30
    CrossrefPubMedSearch in Google Scholar
  • 10 Deshmukh V, Motwani R, Kumar A, Kumari C, Raza K. Histopathological observations in COVID-19: a systematic review. J Clin Pathol 2021; 74 (02) 76-83
    CrossrefPubMedSearch in Google Scholar
  • 11 Vasquez-Bonilla WO, Orozco R, Argueta V. et al. A review of the main histopathological findings in coronavirus disease 2019. Hum Pathol 2020; 105: 74-83
    CrossrefPubMedSearch in Google Scholar
  • 12 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395 (10234): 1417-1418
    CrossrefPubMedSearch in Google Scholar
  • 13 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
  • 14 Zhang C. The role of inflammatory cytokines in endothelial dysfunction. Basic Res Cardiol 2008; 103 (05) 398-406
    CrossrefPubMedSearch in Google Scholar
  • 15 Meizlish M. et al. Circulating Markers of Angiogenesis and Endotheliopathy in COVID-19. medRxiv 2020
    PubMedSearch in Google Scholar
  • 16 Bourgonje AR, Abdulle AE, Timens W. et al. Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol 2020; 251 (03) 228-248
    CrossrefPubMedSearch in Google Scholar
  • 17 van Hinsbergh VW. Endothelium--role in regulation of coagulation and inflammation. Semin Immunopathol 2012; 34 (01) 93-106
    CrossrefPubMedSearch in Google Scholar
  • 18 Vassiliou AG, Keskinidou C, Jahaj E. et al. ICU Admission Levels of Endothelial Biomarkers as Predictors of Mortality in Critically Ill COVID-19 Patients. Cells 2021; 10 (01) 186
    CrossrefPubMedSearch in Google Scholar
  • 19 Hardy M, Michaux I, Lessire S. et al. Prothrombotic hemostasis disturbances in patients with severe COVID-19: Individual daily data. Data Brief 2020; 33: 106519
    CrossrefPubMedSearch in Google Scholar
  • 20 Hardy M, Michaux I, Lessire S. et al. Prothrombotic disturbances of hemostasis of patients with severe COVID-19: A prospective longitudinal observational study. Thromb Res 2021; 197: 20-23
    CrossrefPubMedSearch in Google Scholar
  • 21 Du F, Liu B, Zhang S. COVID-19: the role of excessive cytokine release and potential ACE2 down-regulation in promoting hypercoagulable state associated with severe illness. J Thromb Thrombolysis 2021; 51 (02) 313-329
    CrossrefPubMedSearch in Google Scholar
  • 22 Bernard I, Limonta D, Mahal LK, Hobman TC. Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19. Viruses 2020; 13 (01) E29
    CrossrefPubMedSearch in Google Scholar
  • 23 Teijaro JR, Walsh KB, Cahalan S. et al. Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell 2011; 146 (06) 980-991
    CrossrefPubMedSearch in Google Scholar
  • 24 Escher R, Breakey N, Lämmle B. Severe COVID-19 infection associated with endothelial activation. Thromb Res 2020; 190: 62
    CrossrefPubMedSearch in Google Scholar
  • 25 Goshua G, Pine AB, Meizlish ML. et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol 2020; 7 (08) e575-e582
    CrossrefPubMedSearch in Google Scholar
  • 26 Iba T, Levy JH. Inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis. J Thromb Haemost 2018; 16 (02) 231-241
    CrossrefPubMedSearch in Google Scholar
  • 27 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
  • 28 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
    CrossrefPubMedSearch in Google Scholar
  • 29 Austin PC, Steyerberg EW. Events per variable (EPV) and the relative performance of different strategies for estimating the out-of-sample validity of logistic regression models. Stat Methods Med Res 2017; 26 (02) 796-808
    CrossrefPubMedSearch in Google Scholar
  • 30 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 31 Abassi Z, Higazi AAR, Kinaneh S, Armaly Z, Skorecki K, Heyman SN. ACE2, COVID-19 Infection, Inflammation, and Coagulopathy: Missing Pieces in the Puzzle. Front Physiol 2020; 11: 574753
    CrossrefPubMedSearch in Google Scholar
  • 32 Li G, He X, Zhang L. et al. Assessing ACE2 expression patterns in lung tissues in the pathogenesis of COVID-19. J Autoimmun 2020; 112: 102463
    CrossrefPubMedSearch in Google Scholar
  • 33 Zhang S, Liu Y, Wang X. et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol 2020; 13 (01) 120
    CrossrefPubMedSearch in Google Scholar
  • 34 Reinhart K, Bayer O, Brunkhorst F, Meisner M. Markers of endothelial damage in organ dysfunction and sepsis. Crit Care Med 2002; 30 (05) S302-S312
    CrossrefPubMedSearch in Google Scholar
  • 35 Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol 2020; 39 (07) 2085-2094
    CrossrefPubMedSearch in Google Scholar
  • 36 Johnson K, Choi Y, DeGroot E, Samuels I, Creasey A, Aarden L. Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation. J Immunol 1998; 160 (10) 5130-5135
    CrossrefPubMedSearch in Google Scholar
  • 37 Cugno M, Meroni PL, Gualtierotti R. et al. Complement activation and endothelial perturbation parallel COVID-19 severity and activity. J Autoimmun 2021; 116: 102560
    CrossrefPubMedSearch in Google Scholar
  • 38 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; 20 (10) 1135-1140
    CrossrefPubMedSearch in Google Scholar
  • 39 Fox SE, Akmatbekov A, Harbert JL, Li G, Quincy Brown J, Vander Heide RS. 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
    CrossrefPubMedSearch in Google Scholar
  • 40 Zuo Y, Yalavarthi S, Shi H. et al. Neutrophil extracellular traps in COVID-19. JCI Insight 2020; 5 (11) 138999
    PubMedSearch in Google Scholar
  • 41 Barnes BJ, Adrover JM, Baxter-Stoltzfus A. et al. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J Exp Med 2020; 217 (06) e20200652
    CrossrefPubMedSearch in Google Scholar
  • 42 Blasi A, von Meijenfeldt FA, Adelmeijer J. et al. In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation. J Thromb Haemost 2020; 18 (10) 2646-2653
    CrossrefPubMedSearch in Google Scholar
  • 43 Ackermann M, Mentzer SJ, Kolb M, Jonigk D. Inflammation and intussusceptive angiogenesis in COVID-19: everything in and out of flow. Eur Respir J 2020; 56 (05) 2003147
    CrossrefPubMedSearch in Google Scholar
  • 44 Mastellos DC, Pires da Silva BGP, Fonseca BAL. et al. Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy. Clin Immunol 2020; 220: 108598
    CrossrefPubMedSearch in Google Scholar