Hospitalized adult COVID-19 patients before and after SARS-CoV-2 vaccine availability had significantly higher odds of venous—but not arterial—thromboembolism than those hospitalized for influenza before the pandemic, finds a study published today in JAMA.

A team led by University of Pennsylvania researchers retrospectively studied rates of venous thromboembolism (blood clot in a vein) and arterial thromboembolism (blood clot in an artery) in 41,443 COVID-19 patients hospitalized before the vaccine rollout (April to November 2020), 44,194 COVID-19 patients admitted after vaccines became available (December 2020 to May 2021), and 8,269 patients hospitalized with the flu from October 2018 to April 2019.

Thromboembolism can cause blockage of a blood vessel and thus can be severe.

Death rates were collected through Aug 28, 2019, for flu patients and through Sep 28, 2021, for COVID-19 patients. Data were derived from the US Food and Drug Administration (FDA) Sentinel System. Average age of all patients was 72 years.

Risk of venous thromboembolism

The absolute risk of venous thromboembolism by 90 days was 5.3% in flu patients, versus 9.5% in COVID-19 patients before vaccines (risk difference, 4.1 percentage points) and 10.9% after (risk difference, 5.5 percentage points).

Relative to flu patients, the risk of venous thromboembolism was significantly greater among COVID-19 patients both before (adjusted hazard ratio [aHR], 1.60) and after (aHR, 1.89) vaccine availability—a 60% and 89% higher risk, respectively.

In both flu and COVID-19 patients, the risk of venous thromboembolism by 90 days was greater for patients admitted to an intensive care unit (ICU) or who needed mechanical ventilation or had a previous venous thromboembolism.

After adjustment, the risk of venous thromboembolism was significantly elevated in COVID-19 patients both before (aHR, 1.60) and after (aHR, 1.89) vaccine availability. The risks were similar for venous thromboembolism with an emergency department (ED) or hospital release diagnosis of deep vein thrombosis, pulmonary embolism (blood clot in the lungs), or venous thrombosis of medical devices, implants, or grafts in COVID-19 patients before (aHR, 1.57) and after (aHR, 1.84) the vaccine rollout.

Relative to flu patients with no previous venous clots, COVID-19 patients with no history of venous thromboembolism were at significantly higher risk for the clots both before (aHR, 1.77) and after (aHR, 2.09) vaccine availability.

Compared with flu patients with a history of venous clots, COVID-19 patients with previous venous clots were not at significantly higher risk for subsequent venous thromboembolism before vaccine availability (aHR, 1.22) but were after the rollout (aHR, 1.42). Relative to flu patients, 30-day all-cause death rates after an inpatient venous thromboembolism in COVID-19 patients were elevated both before (aHR, 2.96) and after (aHR, 3.80) the vaccine rollout.

In addition to male sex and older age, risk factors for venous thromboembolism in both vaccine periods included antiphospholipid antibody syndrome (clot-promoting disorder), cancer, chronic kidney disease, chronic obstructive pulmonary disease, heart failure, previous venous thromboembolism, inherited thrombophilia, obesity, pregnancy, thrombocytosis, and recent outpatient use of a blood thinner.

Risk of arterial thromboembolism

The absolute risk of arterial thromboembolism by 90 days, in contrast, was 14.4% in flu patients, compared with 15.8% in COVID-19 patients before vaccine availability (risk difference, 1.4%) and 16.3% in COVID-19 patients after the vaccine rollout (risk difference, 1.9%). Relative to flu patients, the risk of arterial thromboembolism wasn’t significantly greater among COVID-19 patients before vaccine availability (aHR, 1.04) and after (aHR, 1.07).

The risk of arterial thromboembolism with an ED or hospital release diagnosis of heart attack, ischemic stroke, chest pain, transient ischemic attack (mini stroke), or peripheral artery disease in COVID-19 patients was comparable before (aHR, 1.02) and after (aHR, 1.03) the vaccine rollout.

Among patients with cardiovascular disease and relative to flu patients, the risk of arterial thromboembolism was significantly greater among COVID-19 patients before (aHR, 1.10) and after (aHR, 1.13). Relative to flu patients, COVID-19 patients who had arterial thrombosis were more likely to die before (aHR, 3.45) and after (aHR, 3.45) vaccine availability.

In all groups, the 90-day risk of arterial thromboembolism was significantly greater in older patients, men, and those who were admitted to an ICU, needed mechanical ventilation, or were previously diagnosed as having cardiovascular disease.

Potential causes of elevated risk

The researchers said that the elevated risk of venous thromboembolism in COVID-19 patients could be due to virus-induced inflammation and blood-clotting abnormalities. 

“Alternatively, heightened awareness of thrombosis with COVID-19 might have led to a greater ascertainment of events in patients with COVID-19 after case series published early in the pandemic reported high rates of these complications,” they wrote. “However, no association between COVID-19 and arterial thromboembolism was observed, which might be subject to similarly increased event ascertainment.”

The increased risk of death among COVID-19 patients may have been due to higher rates of thromboses that contributed to organ failure or multisystem injury, the authors said. “However, data regarding the severity of the thrombotic events were not available in this study,” they wrote. “Further research is needed to understand the mechanisms for this observation.”