The coronavirus disease (COVID-19) pandemic has elicited a global scientific effort to understand the novel disease’s transmission, symptom onset, and treatment protocols. Among its associated morbidities is the notable onset of thromboembolic complications, including ischemic stroke, among affected patients. To add to growing anecdotal evidence of ischemic stroke as a complication among COVID-19 cases, NYU Langone Health launched a first-of-its-kind study to examine the association—and uncover potential preventive strategies.

Symptoms Indicate a Dangerous Association

With more than 300,000 confirmed cases of COVID-19 by April 2020, New York state had quickly become a hot spot for the illness. With the novel virus came wide-ranging symptoms, with mounting evidence of affected patients having clinically significant coagulopathy with thromboembolic complications, including ischemic stroke. Moreover, autopsies performed at NYU Langone Health indicated the presence of clots throughout organ systems, including kidneys, lungs, and hearts.

Acute phase reactants—inflammation markers that increase in the context of infection or injury—have been documented in the setting of other respiratory infections, typically returning to normal range once the illness resolves and the patient recovers. Though it is suspected that such infections accelerate clotting factors through inflammation and direct action on small arteries, there are limited data on the clinical characteristics of thrombotic complications in the context of COVID-19.

With early reports indicating an association between COVID-19 and cerebrovascular disease, a team led by Shadi Yaghi, MD, associate professor in the Department of Neurology and research director of the Center for Stroke and Neurovascular Diseases, identified the critical, unmet need to document the mechanisms and outcomes of patients who have both a stroke and COVID-19.

Stratifying Stroke to Compare Cause

Dr. Yaghi and team designed a retrospective, observational study examining ischemic stroke in patients with COVID-19 in order to elucidate the characteristics and causes of stroke with this specific etiology. “We set out to answer whether the strokes we are seeing in patients with confirmed cases of COVID-19 are qualitatively different—in cause and course—than pre–COVID-19 cases we saw at the same time last year,” notes Dr. Yaghi.

The study, published in May 2020 in Stroke, examined all patients admitted for stroke across NYU Langone hospital locations in Manhattan, Brooklyn, and Long Island between March 15, 2020, and April 19, 2020. The primary inclusion criterion was hospital admission for stroke, confirmed by brain imaging. Patients were subsequently divided into three distinct groups: those with ischemic stroke and a confirmed COVID-19 diagnosis; contemporary control patients with stroke but without COVID-19; and patients with ischemic stroke and without COVID-19 from the identical time period in 2019.

Imaging and laboratory variables were evaluated to compare characteristics and subtypes of the stroke cases. These variables included cardiac troponin level (upon admission), C-reactive protein (closest to the time of the stroke), erythrocyte sedimentation rate (closest to the time of the stroke), and D-dimer level (highest level and closest to the time of the stroke).

Among the initial findings was a lower overall number of admissions for stroke during the 2020 COVID-19 pandemic trial period than during the corresponding period of 2019. “This finding aligns with anecdotal reports of patients avoiding hospitals, in spite of stroke symptoms, for fear of contracting COVID-19,” says study co-author Jennifer A. Frontera, MD, professor in the Department of Neurology.

The actual number of imaging-confirmed ischemic strokes among patients with confirmed COVID-19 was also low: 32 of 3,556 patients studied, or 0.9 percent—though the researchers acknowledge that the number could underrepresent actual patients, since some may have been physically unfit to receive the confirming brain scan.

Lower Conventional Risk, Higher Coagulability

Notably, in patients with COVID-19 and ischemic stroke, a majority of strokes were classified as cryptogenic—possibly related to an acquired hypercoagulability—and were associated with increased mortality. These patients were found to have elevated clotting factors, suggesting that one of the causes or triggers of their stroke was related to increased clotting in the setting of COVID-19.

Among those 32 patients with both confirmed stroke and positive COVID-19 status, stroke was the reason for admission in 43.8 percent, and COVID-19 symptoms were the reason for admission in 56.2 percent, with index stroke occurring during the hospital stay. The majority of these strokes—65 percent—were found to be of unknown cause. The patients tended to be younger, with a median age of 63, and were notably less likely to have conventional risk factors, such as hypertension or prior stroke.

“The younger median age could simply reflect that older populations are more susceptible to the competing deleterious effects of COVID-19 and become gravely ill or die from a separate factor before the onset of a stroke,” says Dr. Yaghi.

A Pathway for Stroke Prevention

As care teams urgently seek therapeutic protocols to treat and prevent complications arising from COVID-19, Dr. Yaghi and his colleagues note that the identification of higher laboratory hypercoagulability factors, including elevated D-dimer levels, suggests the use of therapeutic anticoagulation could be beneficial in preventing stroke in these patients.

“Our study appears to confirm that this patient population experiences higher rates of thrombotic complications such as ischemic stroke, heart attack, and blood clots,” notes Dr. Frontera. “Since these patients also have a significantly higher rate of mortality than the historical and contemporary controls, more research is needed to test the use of anticoagulant protocols to prevent clotting and improve outcomes.”

With a therapeutic anticoagulation protocol initiated across NYU Langone in early April, more research is underway to test the safety and efficacy of therapeutic versus prophylactic anticoagulation in patients with COVID-19 infection and mild to moderate elevation in D-dimer levels. As additional data inform our understanding of the role of anticlotting medications in COVID-19 care protocols, the new research has immediate implications for the evaluation and care of these patients. “Patients and healthcare workers alike should be aware of the threat of stroke with COVID-19 infection and respond quickly to symptoms of stroke, even in young patients who are not normally at risk,” adds Dr. Frontera.