SARS-CoV-2 Receptors are Expressed on Human Platelets and the Effect of Aspirin on Clinical Outcomes in COVID-19 Patients

Background: Coronavirus disease-2019 (COVID-19) caused by SARS-CoV-2 is an ongoing viral pandemic marked by systemic inflammation and increased risk of thrombotic events including myocardial infarction, stroke, and venous thromboembolism. Despite systemic anticoagulation, thrombotic events may still occur in some patients. Autopsy studies of patients with COVID-19 demonstrated microvascular thrombosis in multiple disparate vascular beds. Platelets, which are hyperreactive in the microcirculation, could be mediators of thrombosis in COVID-19.Methods: Using direct and indirect immunological techniques, we show that known SARS-CoV-2 receptors are expressed in human platelets. We evaluated 22,072 symptomatic patients at two Cleveland Clinic sites who were tested for COVID-19. Patients positive for a SARS-CoV-2 amplicon by reverse transcriptase polymerase chain reaction (RT-PCR) were then stratified into cohorts with thrombotic complications or not. Propensity-matched analyses were performed to determine if treatment with aspirin affected thrombotic outcomes in COVID-19. To distinguish a drug from a class effect, the same analysis was conducted for other non-steroidal anti-inflammatory drugs (NSAIDs).Findings: Both ACE2 and TMPRSS2 are expressed on human platelets and were detected by immunoblotting and confirmed by confocal microscopy. Neither aspirin (OR 0.52, 95% CI: 0.51-1.41; p=0.52) nor NSAIDs (OR 0.97, 95% CI: 0.58-1.62; p=0.90) confer a mortality benefit in COVID-19. However, both aspirin (OR 3.52, 95% CI: 1.48-8.40; p=0.005) and NSAIDs (OR 2.49, 95% CI: 0.58-1.62; p=0.046) are associated with increased combined thrombotic endpoints.Interpretation: While platelets clearly express ACE2-TMPRSS2 receptor-protease axis for SARS-CoV-2 infection, the antiplatelet medication aspirin did not prevent thrombosis and death in patients with COVID-19. These findings suggest platelets may simply be vehicles of dissemination for SARS-CoV-2 or indirect mediators of thrombosis in COVID-19. Antiplatelet medications operating through different pharmacological mechanisms require the rigor of randomized controlled trials in the COVID-19 era.Funding Statement: National Heart, Lung, and Blood Institute, National Institutes of Health, American Heart Association COVID19 Rapid Response AwardDeclaration of Interests: None of the authors have any relevant conflicting financial, personal, or professional relationships.Ethics Approval Statement: Healthy volunteers without any known medical history or on antiplatelet therapy donated blood specimens in accordance with an institutional review board (IRB) approval.Washed platelets from healthy subjects or patients with coronary artery disease (CAD) enrolled at the Cleveland Clinic main campus in Ohio were isolated and proteins separated by SDS-PAGE as we have previously documented and in accordance with IRB protocols (#19-1451 for patients and #20-413 for healthy volunteers).Human placenta lysate was prepared with tissue was normally discarded placentas with intact fetal membranes, and following inclusion in the study no protected health information, identifiers, or clinical data were collected. A waiver of consent was approved by the IRB since the placentas were collected anonymously. Approval by the Cleveland Clinic and MetroHealth IRB (#16–1311 and #16–00335).