CC BY 4.0 · TH Open 2022; 06(01): e50-e59
DOI: 10.1055/a-1725-9221
Original Article

Hypercoagulation Detected by Rotational Thromboelastometry Predicts Mortality in COVID-19: A Risk Model Based on a Prospective Observational Study

1   Department of Anaesthesiology and Intensive Care, Capio St. Göran's Hospital, Stockholm, Sweden
2   Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
,
Agneta Wikman
3   Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
4   Department of CLINTEC, Karolinska Institutet, Stockholm, Sweden
,
Jonas Svensson
5   Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Karolinska University Hospital, Stockholm, Sweden
,
Matteo Bottai
6   Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
,
Mariann Kotormán
1   Department of Anaesthesiology and Intensive Care, Capio St. Göran's Hospital, Stockholm, Sweden
,
Carl-Magnus Wahlgren
2   Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
7   Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden
,
Michael Wanecek
1   Department of Anaesthesiology and Intensive Care, Capio St. Göran's Hospital, Stockholm, Sweden
8   Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
,
Jan van der Linden
2   Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
9   Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden
,
Anna Ågren
2   Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
10   Coagulation Unit, Hematology Centre, Karolinska University Hospital, Stockholm, Sweden
11   Department of Clinical Sciences, Danderyd Hospital and Karolinska Institutet, Stockholm, Sweden
› Author Affiliations
Funding This work was supported by a grant from the Swedish Society of Thrombosis and Haemostasis (L.M.A.), an unrestricted grant from CSL Behring (A.W.), grants from Karolinska Institutet (J.v.d.L.), a grant from the Swedish Society of Medicine (A.Å.), and a grant from the Tetra Laval Group through the Development Office of Karolinska Institutet (A.Å.).

Abstract

Background Severe disease due to the novel coronavirus disease 2019 (COVID-19) has been shown to be associated with hypercoagulation. The aim of this study was to assess the Rotational Thromboelastometry (ROTEM) as a marker of coagulopathy in hospitalized COVID-19 patients.

Methods This was a prospective, observational study where patients hospitalized due to a COVID-19 infection were eligible for inclusion. Conventional coagulation tests and ROTEM were taken after hospital admission, and patients were followed for 30 days. A prediction model, including variables ROTEM EXTEM-MCF (Maximum Clot Firmness) which in previous data has been suggested a suitable marker of hypercoagulation, age, and respiratory frequency, was developed using logistic regression to evaluate the probability of death.

Results Out of the 141 patients included, 18 (13%) died within 30 days. In the final prediction model, the risk of death within 30 days for a patient hospitalized due to COVID-19 was increased with increased EXTEM-MCF, age, and respiratory frequency. Longitudinal ROTEM data in the severely ill subpopulation showed enhanced hypercoagulation. In an in vitro analysis, no heparin effect on EXTEM–coagulation time (CT) was observed, supporting a severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) effect on prolonged initiation of coagulation.

Conclusion Here, we show that hypercoagulation measured with ROTEM predicts 30-day mortality in COVID-19. Longitudinal ROTEM data strengthen the hypothesis of hypercoagulation as a driver of severe disease in COVID-19. Thus, ROTEM may be a useful tool to assess disease severity in COVID-19 and could potentially guide anticoagulation therapy.

Ethics Approval and Consent to Participate

The study was approved by the Swedish Ethical Review Authority (identifier no.: D-nr 2020–01875).


Availability of Data and Materials

The study was published on the preprint server and open-access platform medRxiv.org prior to submission.


Authors' Contributions

L.M.A., A.W., J.S., M.B., C.-M.W., M.W., J.v.d.L. and A.Å. conceived and designed the study. L.M.A. performed the data collection and M.K. contributed to the data collection. J.S. and M.B. performed the data analyses and visualizations. L.M.A. drafted the manuscript. A.W., C.-M.W., M.W., J.v.d.L., and A.Å. provided input for interpretation of results and clinical expertise. All authors have read, critically revised, and approved the final manuscript.




Publication History

Received: 22 June 2021

Accepted: 15 December 2021

Accepted Manuscript online:
21 December 2021

Article published online:
07 March 2022

© 2022. 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/)

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  • References

  • 1 Hottz ED, Azevedo-Quintanilha IG, Palhinha L. et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood 2020; 136 (11) 1330-1341
  • 2 Wynants L, Van Calster B, Collins GS. et al. Prediction models for diagnosis and prognosis of covid-19: systematic review and critical appraisal. BMJ 2020; 369: m1328
  • 3 Klok FA, Mjha K, 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 [Internet] 2020 Apr 30 [cited 2020 May 3]; Available from: http://www.sciencedirect.com/science/article/pii/S0049384820301572
  • 4 Kruse JM, Magomedov A, Kurreck A. et al. Thromboembolic complications in critically ill COVID-19 patients are associated with impaired fibrinolysis. Crit Care 2020; 24 (01) 676
  • 5 Tremblay D, van Gerwen M, Alsen M. et al. Impact of anticoagulation prior to COVID-19 infection: a propensity score-matched cohort study. Blood 2020; 136 (01) 144-147
  • 6 Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA. et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost 2020; 18 (06) 1517-1519
  • 7 Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (06) 1421-1424
  • 8 Hunt BJ, De Paula EV, McLintock C, Dumantepe M. Prophylactic anticoagulation for patients in hospital with covid-19. BMJ 2021; 372 (487) n487
  • 9 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
  • 10 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
  • 11 Brown W, Lunati M, Maceroli M. et al. Ability of Thromboelastography to Detect Hypercoagulability: A Systematic Review and Meta-Analysis. J Orthop Trauma 2020; 34 (06) 278-286
  • 12 Davies NA, Harrison NK, Sabra A. et al. Application of ROTEM to assess hypercoagulability in patients with lung cancer. Thromb Res 2015; 135 (06) 1075-1080
  • 13 Görlinger K, Almutawah H, Almutawaa F. et al. The Role of Rotational Thromboelastometry during the COVID-19 Pandemic: A Narrative Review. Korean J Anesthesiol [Internet] 2021 Jan 13 [cited 2021 Feb 12]; Available from: http://ekja.org/journal/view.php?doi=10.4097/kja.21006
  • 14 Rodrigues A, Seara Sevivas T, Leal Pereira C, Caiado A, Robalo Nunes A. Viscoelastic Tests in the Evaluation of Haemostasis Disturbances in SARS-CoV2 Infection. Acta Med Port 2021; 34 (01) 44-55
  • 15 Smart L, Mumtaz K, Scharpf D. et al. Rotational Thromboelastometry or Conventional Coagulation Tests in Liver Transplantation: Comparing Blood Loss, Transfusions, and Cost. Ann Hepatol 2017; 16 (06) 916-923
  • 16 Akay OM. The Double Hazard of Bleeding and Thrombosis in Hemostasis From a Clinical Point of View: A Global Assessment by Rotational Thromboelastometry (ROTEM). Clin Appl Thromb Hemost 2018; 24 (06) 850-858
  • 17 Davies GR, Lawrence M, Pillai S. et al. The effect of sepsis and septic shock on the viscoelastic properties of clot quality and mass using rotational thromboelastometry: A prospective observational study. J Crit Care 2018; 44: 7-11
  • 18 Spiezia L, Boscolo A, Poletto F, Cerruti L, Tiberio I, Campello E. et al. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Thromb Haemost 21.04.2020. 2020;(EFirst)
  • 19 Pavoni V, Gianesello L, Pazzi M, Stera C, Meconi T, Frigieri FC. Evaluation of coagulation function by rotation thromboelastometry in critically ill patients with severe COVID-19 pneumonia. J Thromb Thrombolysis 2020; 50 (02) 281-286 DOI: 10.1007/s11239-020-02130-7. [Internet]
  • 20 Almskog LM, Wikman A, Svensson J. et al. Rotational thromboelastometry results are associated with care level in COVID-19. J Thromb Thrombolysis 2020 Oct 17 [cited 2021 Feb 12]; Available from: http://link.springer.com/10.1007/s11239-020-02312-3
  • 21 Prokop M, van Everdingen W, van Rees Vellinga T. et al; COVID-19 Standardized Reporting Working Group of the Dutch Radiological Society. CO-RADS: A Categorical CT Assessment Scheme for Patients Suspected of Having COVID-19-Definition and Evaluation. Radiology 2020; 296 (02) E97-E104
  • 22 Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol 2014; 89 (02) 228-232
  • 23 Feuring M, Wehling M, Schultz A. Dalteparin dose-dependently increases ROTEM(®) thrombelastography parameters only at supratherapeutic anti-factor Xa levels: an in vitro study. Clin Exp Pharmacol Physiol 2011; 38 (11) 783-786
  • 24 Alvarez-Perez FJ, Castelo-Branco M, Alvarez-Sabin J. Usefulness of measurement of fibrinogen, D-dimer, D-dimer/fibrinogen ratio, C reactive protein and erythrocyte sedimentation rate to assess the pathophysiology and mechanism of ischaemic stroke. J Neurol Neurosurg Psychiatry 2011; 82 (09) 986-992
  • 25 Jonmarker S, Hollenberg J, Dahlberg M. et al. Dosing of thromboprophylaxis and mortality in critically ill COVID-19 patients. Crit Care 2020; 24 (01) 653
  • 26 van der Linden J, Almskog L, Liliequist A. et al. Thromboembolism, Hypercoagulopathy, and Antiphospholipid Antibodies in Critically Ill Coronavirus Disease 2019 Patients: A Before and After Study of Enhanced Anticoagulation. Crit Care Explor 2020; 2 (12) e0308
  • 27 Veigas PV, Callum J, Rizoli S, Nascimento B, da Luz LT. A systematic review on the rotational thrombelastometry (ROTEM®) values for the diagnosis of coagulopathy, prediction and guidance of blood transfusion and prediction of mortality in trauma patients. Scand J Trauma Resusc Emerg Med 2016; 24 (01) 114
  • 28 Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol 2020; 7 (06) e438-e440
  • 29 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
  • 30 Roberts I. Fibrinolytic shutdown: fascinating theory but randomized controlled trial data are needed. Transfusion 2016; 56 (Suppl 02 S115-S118
  • 31 Cabrera-Garcia D, Miltiades A, Parsons S. et al. High levels of plasminogen activator inhibitor-1, tissue plasminogen activator and fibrinogen in patients with severe COVID-19. medRxiv 2021 Jan 1;2020.12.29.20248869
  • 32 Iba T, Levy JH, Connors JM, Warkentin TE, Thachil J, Levi M. The unique characteristics of COVID-19 coagulopathy. Crit Care 2020; 24 (01) 360
  • 33 Hulshof A-M, Brüggemann RAG, Mulder MMG. et al. Serial EXTEM, FIBTEM, and tPA Rotational Thromboelastometry Observations in the Maastricht Intensive Care COVID Cohort-Persistence of Hypercoagulability and Hypofibrinolysis Despite Anticoagulation. Front Cardiovasc Med 2021; 8: 654174
  • 34 Hunt BJ, Levi M. Re The source of elevated plasma D-dimer levels in COVID-19 infection. Br J Haematol 2020; 190 (03) e133-e134 https://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.16907 cited 2021Feb13 [Internet]
  • 35 Kucher N, Kohler H-P, Dornhöfer T, Wallmann D, Lämmle B. Accuracy of D-dimer/fibrinogen ratio to predict pulmonary embolism: a prospective diagnostic study. J Thromb Haemost 2003; 1 (04) 708-713