##common.pageHeaderLogo.altText##

Original article

Vol. 150 No. 2122 (2020)

D-dimer and mortality in COVID-19: a self-fulfilling prophecy or a pathophysiological clue?

  • Neal Breakey
  • Robert Escher
Cite this as:
Swiss Med Wkly. 2020;150:w20293
Published
26.05.2020

Summary

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a global phenomenon has presented clinicians around the world with multiple challenges. Thromboembolic events are recognised complications of viral infection, but the diagnosis of an acute pulmonary thrombotic complication in the context of coronavirus disease 2019 (COVID-19) can be challenging because of the similarities of presentation, logistical considerations of diagnosis in a patient isolated for infection control reasons and the effects of cognitive errors in diagnostic reasoning. We present the case of a patient who was diagnosed with a pulmonary thrombotic complication during inpatient care for COVID-19. The haemostasis parameters we observed, including increased levels of von Willebrand factor and factor VIII, point towards a relevant involvement of endothelial cells in patients with severe COVID-19. We suggest that it is possible to hypothesise a spectrum of secondarily acquired, prothrombotic coagulopathy mediated by the endothelial interaction with SARS-CoV-2 as a cause of mortality in a subset of patients with a complicated clinical course of COVID-19. We support the recommendation of thromboembolic chemoprophylaxis for inpatients with COVID-19 as a very minimum in the absence of strict contraindications, while recognising that pulmonary thrombotic complications can occur under standard thromboprophylaxis. We suggest that higher, possibly therapeutic levels of anticoagulation might be mandatory for a further subset of patients with COVID-19 where a discrepant evolution of C-reactive protein and D-dimer is observed. Therapeutic levels of anticoagulation are obligatory where new evidence of a macrovascular thrombotic complication has been documented. More research to delineate the macro- and microvascular thrombotic complications of COVID-19, and the therapeutic implications for this patient group is required.

References

  1. Escher R, Breakey N, Lämmle B. Severe COVID-19 infection associated with endothelial activation. Thromb Res. 2020;190:62. doi:.https://doi.org/10.1016/j.thromres.2020.04.014
  2. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417–8. doi:.https://doi.org/10.1016/S0140-6736(20)30937-5
  3. Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, et al.; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020 May 4. [Online ahead of print] doi:.https://doi.org/10.1007/s00134-020-06062-x
  4. Wichmann D, Sperhake J-P, Lütgehetmann M, Steurer S, Edler C, Heinemann A, et al. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study. Ann Intern Med. 2020 May 6;M20-2003. [Online ahead of print] doi:.https://doi.org/10.7326/M20-2003
  5. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, 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):1054–62. doi:.https://doi.org/10.1016/S0140-6736(20)30566-3
  6. Guan W-J, Ni Z-Y, Hu Y, Liang W-H, Ou C-Q, He J-X, et al.; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):1708–20. doi:.https://doi.org/10.1056/NEJMoa2002032
  7. Casini A, Alberio L, Angelillo-Scherrer A, Fontana P, Gerber B, Graf L, et al. Thromboprophylaxis and laboratory monitoring for in-hospital patients with COVID-19 - a Swiss consensus statement by the Working Party Hemostasis. Swiss Med Wkly. 2020;150:w20247. doi:.https://doi.org/10.4414/smw.2020.20247
  8. 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 April 9;jth.14830. [Online ahead of print] doi:.https://doi.org/10.1111/jth.14830
  9. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 April 10;S0049-3848(20)30120-1. [Online ahead of print] doi:.https://doi.org/10.1016/j.thromres.2020.04.013
  10. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers D, Kant KM, et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020 Apr 30;S0049-3848(20)30157-2. [Online ahead of print] doi:.https://doi.org/10.1016/j.thromres.2020.04.041
  11. Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, Müller MCA, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020 May 5;jth.14888. [Online ahead of print] doi:.https://doi.org/10.1111/jth.14888
  12. Rühl H, Berens C, Winterhagen A, Müller J, Oldenburg J, Pötzsch B. Label-Free Kinetic Studies of Hemostasis-Related Biomarkers Including D-Dimer Using Autologous Serum Transfusion. PLoS One. 2015;10(12):e0145012. doi:.https://doi.org/10.1371/journal.pone.0145012
  13. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–4. doi:.https://doi.org/10.1016/S0140-6736(20)30628-0
  14. Cascio A, Pernice LM, Barberi G, Delfino D, Biondo C, Beninati C, et al. Secondary hemophagocytic lymphohistiocytosis in zoonoses. A systematic review. Eur Rev Med Pharmacol Sci. 2012;16(10):1324–37. doi:https://www.ncbi.nlm.nih.gov/pubmed/23104648
  15. McGonagle D, O’Donnell JS, Sharif K, Emery P, Bridgewood C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. The Lancet Rheumatology. 2020 May 7. doi:.https://doi.org/10.1016/S2665-9913(20)30121-1
  16. Debaugnies F, Mahadeb B, Ferster A, Meuleman N, Rozen L, Demulder A, et al. Performances of the H-Score for Diagnosis of Hemophagocytic Lymphohistiocytosis in Adult and Pediatric Patients. Am J Clin Pathol. 2016;145(6):862–70. doi:.https://doi.org/10.1093/ajcp/aqw076
  17. Taylor FB, Jr, 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(5):1327–30. doi:.https://doi.org/10.1055/s-0037-1616068
  18. 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(4):844–7. doi:.https://doi.org/10.1111/jth.14768
  19. Yin S, Huang M, Li D, Tang N. Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2. J Thromb Thrombolysis. 2020 Apr 3. [Online ahead of print] doi:.https://doi.org/10.1007/s11239-020-02105-8
  20. Gando S, Saitoh D, Ogura H, Fujishima S, Mayumi T, Araki T, et al.; Japanese Association for Acute Medicine Sepsis Registry Study Group. A multicenter, prospective validation study of the Japanese Association for Acute Medicine disseminated intravascular coagulation scoring system in patients with severe sepsis. Crit Care. 2013;17(3):R111. doi:.https://doi.org/10.1186/cc12783
  21. Kawecki C, Lenting PJ, Denis CV. von Willebrand factor and inflammation. J Thromb Haemost. 2017;15(7):1285–94. doi:.https://doi.org/10.1111/jth.13696
  22. Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631–7. doi:.https://doi.org/10.1002/path.1570
  23. Lang M, Som A, Mendoza DP, Flores EJ, Reid N, Carey D, et al. Hypoxaemia related to COVID-19: vascular and perfusion abnormalities on dual-energy CT. Lancet Infect Dis. 2020 Apr 30;S1473-3099(20)30367-4. [Online ahead of print] doi:.https://doi.org/10.1016/S1473-3099(20)30367-4
  24. Han H, Yang L, Liu R, Liu F, Wu K-L, Li J, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med. 2020;0(0):3. Available at: http://www.degruyter.com/view/j/cclm.ahead-of-print/cclm-2020-0188/cclm-2020-0188.xml. doi:.https://doi.org/10.1515/cclm-2020-0188
  25. Croskerry P. The importance of cognitive errors in diagnosis and strategies to minimize them. Acad Med. 2003;78(8):775–80. doi:.https://doi.org/10.1097/00001888-200308000-00003
  26. Croskerry P. Achieving Quality in Clinical Decision Making: Cognitive Strategies and Detection of Bias. Acad Emerg Med. 2002;9(11):1184–204. doi:http://doi.wiley.com/10.1197/aemj.9.11.1184
  27. Stelfox HT, Bates DW, Redelmeier DA. Safety of patients isolated for infection control. JAMA. 2003;290(14):1899–905. doi:.https://doi.org/10.1001/jama.290.14.1899
  28. Ong SWX, Tan YK, Chia PY, Lee TH, Ng OT, Wong MSY, et al. Air, Surface Environmental, and Personal Protective Equipment Contamination by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) From a Symptomatic Patient. JAMA. 2020;323(16):1610. doi:.https://doi.org/10.1001/jama.2020.3227
  29. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020;323(11):1061. doi:.https://doi.org/10.1001/jama.2020.1585
  30. Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing G-J, Harjola V-P, et al.; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543–603. doi:.https://doi.org/10.1093/eurheartj/ehz405
  31. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al.; and the Northwell COVID-19 Research Consortium. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020 Apr 22. [Online ahead of print] doi:.https://doi.org/10.1001/jama.2020.6775
  32. Fanelli V, Fiorentino M, Cantaluppi V, Gesualdo L, Stallone G, Ronco C, et al. Acute kidney injury in SARS-CoV-2 infected patients. Crit Care. 2020;24(1):155. doi:.https://doi.org/10.1186/s13054-020-02872-z
  33. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475–81. doi:.https://doi.org/10.1016/S2213-2600(20)30079-5
  34. Hinson JS, Ehmann MR, Fine DM, Fishman EK, Toerper MF, Rothman RE, et al. Risk of Acute Kidney Injury After Intravenous Contrast Media Administration. Ann Emerg Med. 2017;69(5):577–586.e4. doi:.https://doi.org/10.1016/j.annemergmed.2016.11.021
  35. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020;200642:200642. doi:.https://doi.org/10.1148/radiol.2020200642
  36. Simpson S, Kay FU, Abbara S, Bhalla S, Chung JH, Chung M, et al. Radiological Society of North America Expert Consensus Statement on Reporting Chest CT Findings Related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA. J Thorac Imaging. 2020;2(2):e200152. doi:.https://doi.org/10.1148/ryct.2020200152
  37. Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up. J Am Coll Cardiol. 2020 Apr 15;S0735-1097(20)35008-7. doi:.https://doi.org/10.1016/j.jacc.2020.04.031
  38. Propositions de la Société Française de Médecine Vasculaire pour la prévention, le diagnostic et le traitement de la maladie thromboembolique veineuse des patients avec COVID 19 non hospitalisés [Internet]. [cited 2020 May 13]. Available from: https://www.portailvasculaire.fr/sites/default/files/docs/propositions_sfmv_covid_mtev.pdf
  39. COVID-19 and Coagulopathy - American Society of Hematology [Internet]. [cited 2020 May 13]. Available from: https://www.hematology.org/covid-19/covid-19-and-coagulopathy
  40. Marietta M, Ageno W, Artoni A, De Candia E, Gresele P, Marchetti M, et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus. 2020 Apr 8. [Online ahead of print] doi:.https://doi.org/10.2450/2020.0083-20
  41. BTS Guidance on Venous Thromboembolic Disease in patients with COVID-19 – British Thoracic Society [Internet]. [cited 2020 May 17]. Available from: https://www.brit-thoracic.org.uk/document-library/quality-improvement/covid-19/bts-guidance-on-venous-thromboembolic-disease-in-patients-with-covid-19/
  42. Atallah B, Mallah SI, AlMahmeed W. Anticoagulation in COVID-19. Eur Heart J Cardiovasc Pharmacother. 2020 Apr 30;pvaa036. [Online ahead of print] doi:.https://doi.org/10.1093/ehjcvp/pvaa036