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Thromboembolism and COVID-19

COVID IN FOCUS: PERSPECTIVES ON THE LITERATURE

This CHEST series highlights specific studies in the COVID-19 literature that may warrant discourse or reading for members of the chest medicine community. Articles are written by members of CHEST NetWorks. You can read additional articles in this series.

NOTE: The perspectives shared in this article are those of the author(s) and not those of CHEST.

Thromboembolism and COVID-19

By: Ben Kenigsberg, MD; Laveena Chhatwani, MD; and Robert Baeten, DMSc, PA-C
Cardiovascular Medicine and Surgery NetWork

Published: August 9, 2021

SARS-CoV-2 infection and COVID-19 pneumonia have been associated with a range of hematological abnormalities. Macrovascular and microvascular thromboembolism in both the venous and arterial vasculature, as well as disseminated intravascular coagulation, can occur as a manifestation of SARS-CoV-2 infection.1,2 Given these concerns for an elevated risk of thromboembolism, anticoagulation has been a common therapeutic focus during the pandemic.

Epidemiologic studies suggest an overall thromboembolism incidence of up to 30% in ICU patients with COVID-19.3,4,5,6 Similarly, autopsy studies have found a high incidence of thromboembolism in patients with COVID-19, including coronary microthrombi.7,8,9 While nonspecific, D-dimer elevation has also been associated with increased mortality and thrombosis.10 This relatively high thromboembolism incidence has been attributed to inflammation affecting endogenous coagulation pathways.11 Intriguingly, antiphospholipid antibodies have been noted in patients with COVID-19, particularly in patients with a prolonged partial thromboplastin time.12,13,14

Early observational data suggested a potential benefit to the use of prophylactic and full-dose anticoagulation (FDAC) regimens,15,16,17,18 despite an increased bleeding risk.19 However, the INSPIRATION trial of ICU patients with COVID-19 randomized to intermediate-dose or standard-dose prophylactic anticoagulation (SDPAC) found no significant difference between prophylactic anticoagulation dosing (45.7% vs 44.1% for the combined primary outcome [95% CI, 0.76-1.48], P = .70).20

On the other hand, the ATTACC, ACTIV-4a, and REMAP-CAP multiplatform trial of FDAC and SDPAC in hospitalized patients with COVID-19 reported superior efficacy of FDAC with regard to organ support-free days, except in severely ill patients.21,22 In this analysis, patients on ICU-level organ support at baseline had no benefit with FDAC and a concerning trend toward increased harm compared with SDPAC. However, the ACTION trial of hospitalized patients with COVID-19 and an elevated D-dimer randomized to FDAC or SDPAC found no significant difference between anticoagulation regimens (34.8% vs 41.3% for the primary efficacy outcome [95% CI, 0.59-1.22], P = .40) with an increase in bleeding (8% vs 2% [95% CI, 1.61-8.27], P = .0010).23

Thus, while thromboembolism remains a crucial issue in the management of patients with SARS-CoV-2 infection, empiric use of enhanced anticoagulation regimens in ICU patients with COVID-19 is not clearly beneficial and may be harmful, while the efficacy of enhanced anticoagulation use in hospitalized, noncritically ill patients with COVID-19 remains uncertain.


References

  1. Iba T, Levy JH, Levi M, et al. Coagulopathy of coronavirus disease 2019. Crit Care Med. 2020;48(9):1358-1364.
  2. Bikdeli B, Madhavan MV, Jimenez D, et al; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(23):2950-2973.
  3. 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.
  4. Bilaloglu S, Aphinyanaphongs Y, Jones S, et al. Thrombosis in hospitalized patients with COVID-19 in a New York City health system. JAMA. 2020;324(8):799-801.
  5. Maatman TK, Jalali F, Feizpour C, et al. Routine venous thromboembolism prophylaxis may be inadequate in the hypercoagulable state of severe coronavirus disease 2019. Crit Care Med. 2020;48(9):e783-e790.
  6. Piazza G, Campia U, Hurwitz S, et al. Registry of arterial and venous thromboembolic complications in patients with COVID-19. J Am Coll Cardiol. 2020;76(18):2060-2072.
  7. Wichmann D, Sperhake JP, Lütgehetmann M, et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med. 2020;173(4):268-277.
  8. Guagliumi G, Sonzogni A, Pescetelli I, et al. Microthrombi and ST-segment-elevation myocardial infarction in COVID-19. Circulation. 2020;142(8):804-809.
  9. Pellegrini D, Kawakami R, Guagliumi G, et al. Microthrombi as a major cause of cardiac injury in COVID-19: a pathologic study. Circulation. 2021;143(10):1031-1042.
  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(6):1324-1329.
  11. Fauvel C, Weizman O, Trimaille A, et al; Critical Covid-19 France Investigators. Pulmonary embolism in COVID-19 patients: a French multicentre cohort study. Eur Heart J. 2020;41(32):3058-3068.
  12. Zhang Y, Xiao M, Zhang S, et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med. 2020;382(17):e38.
  13. Zuo Y, Estes SK, Ali RA, et al. Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Sci Transl Med. 2020;12(570):eabd3876.
  14. Bowles L, Platton S, Yartey N, et al. Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19. N Engl J Med. 2020;383(3):288-290.
  15. Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099.
  16. Paranjpe I, Fuster V, Lala A, et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol. 2020;76(1):122-124.
  17. Nadkarni GN, Lala A, Bagiella E, et al. Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19. J Am Coll Cardiol. 2020;76(16):1815-1826.
  18. Taccone FS, Gevenois PA, Peluso L, et al. Higher intensity thromboprophylaxis regimens and pulmonary embolism in critically ill coronavirus disease 2019 patients. Crit Care Med. 2020;48(11):e1087-e1090.
  19. Pesavento R, Ceccato D, Pasquetto G, et al. The hazard of (sub)therapeutic doses of anticoagulants in non-critically ill patients with Covid-19: the Padua province experience. J Thromb Haemost. 2020;18(10):2629-2635.
  20. Sadeghipour P, Talasaz AH, Rashidi F, et al; INSPIRATION Investigators. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial. JAMA. 2021;325(16):1620-1630.
  21. ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators, Lawler PR, Goligher EC, Berger JS, et al. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N Engl J Med. 2021 Aug 4. Epub ahead of print. https://www.nejm.org/doi/10.1056/NEJMoa2105911
  22. REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators, Goligher EC, Bradbury CA, McVerry BJ, et al. Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N Engl J Med. 2021 Aug 4. Epub ahead of print. https://www.nejm.org/doi/full/10.1056/NEJMoa2103417
  23. Lopes RD, de Barros E Silva PGM, Furtado RHM, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021;397:2253-63.

Ben Kenigsberg, MD

Ben Kenigsberg, MD

Dr. Kenigsberg is a Cardiac Intensivist at MedStar Washington Hospital Center and an Assistant Professor of Clinical Medicine at Georgetown University in Washington, DC.

Robert Baeten, DMSc, PA-C, FCCP

Robert Baeten, DMSc, PA-C, FCCP

Dr. Baeten works in cardiac critical care at Piedmont Heart Institute and is a Clinical Assistant Professor in Physician Assistant Studies at Mercer University in Atlanta, GA.

Laveena Chhatwani, MD

Dr. Chhatwani is a Clinical Assistant Professor in Pulmonary, Allergy, and Critical Care Medicine at Stanford University in Stanford, CA.


Read more COVID in Focus: Perspectives on the Literature:

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Immunomodulation Therapy in Severe COVID-19 Infection: Where Do We Stand?

Clinical Outcomes of COVID-19 in Patients With COPD

Diagnosis and Containment of Patients With Suspected Lung Cancer in the COVID-19 Pandemic—What Does the Literature Say?