Coagulopathy and adverse outcomes in hospitalized patients with COVID-19: results from the NOR-Solidarity trial

Thor Ueland; Annika E Michelsen; Anders Aune Tveita; Trine Kåsine; Tuva B Dahl; Ane-Kristine Finbråten; Aleksander R Holten; Ole Henning Skjønsberg; Alexander Mathiessen; Katerina N Henriksen; Marius Trøseid; Trond Mogens Aaløkken; Bente Halvorsen; Anne Ma Dyrhol-Riise; Andreas Barratt-Due; Pål Aukrust

doi:10.1016/j.rpth.2023.102289

Coagulopathy and adverse outcomes in hospitalized patients with COVID-19: results from the NOR-Solidarity trial

Res Pract Thromb Haemost. 2023 Dec 7;8(1):102289. doi: 10.1016/j.rpth.2023.102289. eCollection 2024 Jan.

Authors

Thor Ueland^{1

2

3}, Annika E Michelsen^{1

2}, Anders Aune Tveita^{4

5}, Trine Kåsine^{2

6}, Tuva B Dahl¹, Ane-Kristine Finbråten⁷, Aleksander R Holten^{2

8}, Ole Henning Skjønsberg^{2

9}, Alexander Mathiessen¹⁰, Katerina N Henriksen^{11

12}, Marius Trøseid^{1

2

13}, Trond Mogens Aaløkken^{2

14}, Bente Halvorsen^{1

2}, Anne Ma Dyrhol-Riise^{2

15}, Andreas Barratt-Due^{5

6}, Pål Aukrust^{1

2

13}

Affiliations

¹ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
² Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³ Department of Clinical Medicine, Thrombosis Research and Expertise Center, University of Tromsø-the Arctic University of Norway, Tromsø, Norway.
⁴ Department of Internal Medicine, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway.
⁵ Division of Laboratory Medicine, Department of Immunology, Oslo University Hospital, Oslo, Norway.
⁶ Division of Critical Care and Emergencies, Oslo University Hospital, Oslo, Norway.
⁷ Medical Department, Lovisenberg Diaconal Hospital, Oslo, Norway.
⁸ Department of Acute Medicine, Oslo University Hospital, Oslo, Norway.
⁹ Department of Pulmonary Medicine, Oslo University Hospital Ullevål, Oslo, Norway.
¹⁰ Department of Medicine, Diakonhjemmet Hospital, Oslo, Norway.
¹¹ Department of Hematology, Oslo University Hospital, Oslo, Norway.
¹² Hospital Pharmacies, South-Eastern Norway Enterprise, Oslo, Norway.
¹³ Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
¹⁴ Department of Radiology and Nuclear Medicine, Oslo University Hospital Ullevål, Oslo, Norway.
¹⁵ Department of Infectious Diseases, Oslo University Hospital Ullevål, Oslo, Norway.

Abstract

Background: Several studies have examined parameters of increased thrombogenicity in COVID-19, but studies examining their association with long-term outcome and potential effects of antiviral agents in hospitalized patients with COVID-19 are scarce.

Objectives: To evaluate plasma levels of hemostatic proteins during hospitalization in relation to disease severity, treatment modalities, and persistent pulmonary pathology after 3 months.

Methods: In 165 patients with COVID-19 recruited into the NOR-Solidarity trial (NCT04321616) and randomized to treatment with hydroxychloroquine, remdesivir, or standard of care, we analyzed plasma levels of hemostatic proteins during the first 10 days of hospitalization (n = 160) and at 3 months of follow-up (n = 100) by enzyme immunoassay.

Results: Our main findings were as follows: (i) tissue plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI) were increased in patients with severe disease (ie, the combined endpoint of respiratory failure [Po₂-to-FiO₂ ratio, <26.6 kPa] or need for treatment at an intensive care unit) during hospitalization. Compared to patients without severe disease, tPA levels were a median of 42% (P < .001), 29% (P = .002), and 36% (P = .015) higher at baseline, 3 to 5 days, and 7 to 10 days, respectively. For TFPI, median levels were 37% (P = .003), 25% (P < .001), and 10% (P = .13) higher in patients with severe disease at these time points, respectively. No changes in thrombin-antithrombin complex; alpha 2-antiplasmin; a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; or antithrombin were observed in relation to severe disease. (ii) Patients treated with remdesivir had lower levels of TFPI than those in patients treated with standard of care alone. (iii) TFPI levels during hospitalization, but not at 3 months of follow-up, were higher in those with persistent pathology on chest computed tomography imaging 3 months after hospital admission than in those without such pathology. No consistent changes in thrombin-antithrombin complex, alpha 2-antiplasmin, ADAMTS-13, tPA, or antithrombin were observed in relation to pulmonary pathology at 3 months of follow-up.

Conclusion: TFPI and tPA are associated with severe disease in hospitalized patients with COVID-19. For TFPI, high levels measured during the first 10 days of hospitalization were also associated with persistent pulmonary pathology even 3 months after hospital admittance.

Keywords: COVID-19; hospitalization; remdesivir; tissue factor pathway inhibitor; tissue plasminogen activator.