C oronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by the respiratory symptoms implicit in the name severe acute respiratory syndrome. Still, with the increasing number of cases, it has also been linked to nonpulmonary targets, including cardiac, gastrointestinal, skin, renal, and neurologic manifestations (1-5). Venous thromboembolism has also been shown to be an important cause of morbidity and mortality in patients with COVID-19, both in the general inpatient and in the intensive care unit (ICU) setting, and even in patients receiving therapeutic anticoagulation (6-8). For example, in one autopsy series, unsuspected deep vein thrombosis was found in the majority of patients with COVID-19, and pulmonary embolism was the cause of death in one-fourth of these patients (9). Arterial thrombosis has also been reported within coronary arteries (6,10) and within the brain (6,11) in patients with COVID-19. There have also been case reports regarding mesenteric (12-14) and aortoiliac (6,12) thrombosis. In our practice, in a COVID-19 hotspot, where at its peak (April 12, 2020) our hospital system had 1194 inpatients with diagnosed COVID-19, we have observed an increased number of patients presenting with lowerextremity ischemia and extensive arterial thromboses during the current pandemic. These patients typically presented to the emergency department with new symptoms of leg pain, coldness, discoloration, and ulceration, and they underwent lower-extremity CT angiography. Diagnostic work-ups in many of these patients showed them to be positive for the SARS-CoV-2 virus. With growing evidence of coagulopathy or vasculopathy (15) in patients with COVID-19, we investigated whether these cases were also due to COVID-19-related thrombosis. The goal of

Background and Purpose: We sought to determine if biomarkers of inflammation and coagulation can help define coronavirus disease 2019 (COVID-19)–associated ischemic stroke as a novel acute ischemic stroke (AIS) subtype. Methods: We performed a machine learning cluster analysis of common biomarkers in patients admitted with severe acute respiratory syndrome coronavirus 2 to determine if any were associated with AIS. Findings were validated using aggregate data from 3 large healthcare systems. Results: Clustering grouped 2908 unique patient encounters into 4 unique biomarker phenotypes based on levels of c-reactive protein, D-dimer, lactate dehydrogenase, white blood cell count, and partial thromboplastin time. The most severe cluster phenotype had the highest prevalence of AIS (3.6%, P <0.001), in-hospital AIS (53%, P <0.002), severe AIS (31%, P =0.004), and cryptogenic AIS (73%, P <0.001). D-dimer was the only biomarker independently associated with prevalent AIS with quartile 4 having an 8-fold higher risk of AIS compared to quartile 1 ( P =0.005), a finding that was further corroborated in a separate cohort of 157 patients hospitalized with COVID-19 and AIS. Conclusions: COVID-19–associated ischemic stroke may be related to COVID-19 illness severity and associated coagulopathy as defined by increasing D-dimer burden.

The publication of this Accepted Manuscript is provided to give early visibility to the contents of the article, which will undergo additional copyediting, typesetting, and review before it is published in its final form. During the production process, errors may be discovered that could affect the content of the Accepted Manuscript. All legal disclaimers that apply to the journal pertain. The reader is cautioned to consult the definitive version of record before relying on the contents of this document.