Higher Risk of Venous Thromboembolism in Hospitalization for COVID-19 Than Influenza


Evidence suggests that COVID-19 may induce venous thromboembolism, with an estimated 30% of patients hospitalized with COVID-19 developing the condition.

Vincent Lo Re III, MD, MSCE, associate professor of medicine and epidemiology, University of Pennsylvania

Vincent Lo Re III, MD, MSCE

Findings from a recent retrospective study of data from the FDA Sentinel System suggest that hospitalization with COVID-19, regardless of vaccine availability, was associated with a significantly higher risk of 90-day venous thromboembolism compared with hospitalization from influenza.1

The findings from the study help to bring evidence about the incidence of arterial thromboembolism and venous thromboembolism in persons with COVID-19 which have been known to be unclear. Notably, there were no significant differences between the groups with regard to 90-day arterial thromboembolism risk.1

Conducted by principal investigator Vincent Lo Re III, MD, MSCE, associate professor of medicine and epidemiology, University of Pennsylvania, and colleagues, the group assessed a cohort of 93,906 individuals who were hospitalized with COVID-19 (n = 85,637) before (n = 41,443; April to Nov 2020) and after vaccine availability (n = 44,194; Dec 2020 to May 2021) or with influenza (n = 8269; Oct 2018 to April 2019).

“It may be that the microvascular and macrovascular changes present with cardiovascular disease predispose to risk of arterial thromboembolism during hospitalization with COVID-19. Thus, this could be important to monitor among patients hospitalized COVID-19,” Lo Re III told NeurologyLive®.

All told, the 90-day absolute risk of venous thromboembolism was 5.3% (95% CI, 4.9-5.8) among those with influenza compared with 9.5% (95% CI, 9.2-9.7) in the COVID-19 group before vaccine availability (risk difference, 4.1%; 95% CI, 3.6-4.7) and 10.9% (95% CI, 10.6-11.1) in the COVID-19 group during vaccine availability (risk difference, 5.5%; 95% CI, 5.0-6.1). This resulted in a significantly higher risk of venous thromboembolism among patients with COVID-19 both before vaccine availability (adjusted HR, 1.60; 95% CI, 1.43-1.79) and during vaccine availability (adjusted HR, 1.89; 95% CI, 1.68-2.12).

On the other hand, the 90-day absolute risk of arterial thromboembolism was 14.4% (95% CI, 13.6-15.2) among hospitalized patients with influenza versus 15.8% (95% CI, 15.5-16.2) for those hospitalized with COVID-19 before vaccine access and 16.3% (95% CI, 16.0-16.6) during vaccine availability. Those equated to risk differences of 1.4% (95% CI, 1.0-2.3) and 1.9% (95% CI, 1.1%-2.7%).

“We were surprised that an existing cancer diagnosis was associated with a significantly lower risk of arterial thromboembolism during both COVID-19 time periods. We speculated that patients with a cancer diagnosis might have had hematological abnormalities (eg, thrombocytopenia) due to the cancer or possibly from treatment that could have reduced the risk of arterial thromboembolism,” Lo Re III said.

The patients with COVID-19 had baseline variables evaluated as risk factors for arterial thromboembolism and venous thromboembolism. The hypothesis tests were two-sided while the statistical significance produced a P-value less than .05 using Statistical Analysis Software. In comparison to patients with COVID-19, the patients with influenza had significantly higher prevalence of asthma, chronic obstructive pulmonary disease, heart failure, and dispensed corticosteroids.

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The 90-day risk of arterial thromboembolism within each cohort was significantly higher among patients who were male, older, admitted to the intensive care unit or required mechanical ventilation, or had a history of cardiovascular disease. This increased risk may be explained by previously shown differences between these groups. In a 2020 study by Levi et al, data suggested that patients with COVID-19 may have had a higher frequency of thromboses that contributed to organ failure, multisystem injury, and death compared with patients with influenza.2 The risk of arterial thromboembolism was similar across the study periods for those patients who had COVID-19.1

Similarly, Loe Re III et al suggested that this higher risk of venous thromboembolism for patients with COVID-19 may be driven by incited inflammation and abnormalities in coagulation caused by infection, such as an increased abundance of antiphospholipid antibodies and enhanced platelet activity.3 As the abnormalities occur, they may be more marked in patients with COVID-19 than in patients with influenza infections.

There were several limitations in the study, one being the misclassification of thrombotic outcomes as some thrombotic events and deaths might have been missed in the COVID-19 cohorts. Additionally, more testing for venous thromboembolism could have occurred among patients hospitalized with COVID-19 than among patients hospitalized with influenza and might have been affected by factors associated with thrombosis, which may have created or altered associations between the risk factors and the outcomes.

Lo Re III added, “future studies should examine whether risk of COVID-19-related thrombotic events changes over time, evaluate other potential risk factors for thrombotic complications, and develop prognostic models to identify persons at high-risk for thrombosis.”

1. Lo Re V, Dutcher SK, Connolly JG, et al. Association of COVID-19 vs influenza with risk of arterial and venous thrombotic events among hospitalized patients. JAMA. 2022;328(7):637-651. doi:10.1001/jama.2022.13072
2. Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 2020;7(6):e438-e440. doi:10.1016/S2352-3026(20)30145-9
3. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417-1418. doi:10.1016/S0140-6736(20)30937-5
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