Aspirin Bioactivity for Prevention of Cardiovascular Injury in COVID-19

Abstract

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has come to be one of the gravest pandemics of the last two centuries. WHO epidemiological records on COVID-19 outbreak confirmed more than 35 million cases and 1 million deaths worldwide since the disease have originated in Wuhan, China (1, 2). Although clinical treatment of COVID-19 patients focuses on the pulmonary complications and acute respiratory distress syndrome (ARDS), medical reports have also pointed toward the severe deterioration of the patient's state of health due to cardiovascular complications. Furthermore, cardiovascular comorbidities have been determined as key factors of mortality for SARS-CoV-2 infected patients, which present high blood levels of cardiac-specific proteins troponin I and/or T, indicative signs of hypoxia, tachyarrhythmia, myocarditis, and myocardial injury (3–8). Other cardiovascular injuries associated with COVID-19 are venous and arterial thrombosis, and venous thromboembolism (VTE). Case studies performed on COVID-19 patients, and autopsies conducted on those who died due to cardiovascular complications such as stroke and acute coronary syndromes, point to thrombotic disease as a critical factor of mortality in severe cases of COVID-19 (9–12). Severe cases of SARS-COV-2 infected patients experience lymphocytopenia and a high activation of metabolic proinflammatory cytokines mechanisms which leads to an elevated blood concentration of interleukin (IL) 2 (IL-2), IL-6, IL-7, interferon gamma (IFN-γ), macrophage inflammatory protein- 1 alpha (MIP1A), and tumor necrosis factor alpha (TNF-α) pro-inflammatory cytokines (4, 13). This high level of cytokines, known as cytokine storm syndrome (CSS), tends to be a critical factor of morbidity and mortality for COVID-19 patients. CSS contributes to the upregulation of metabolic coagulation pathways resulting in damage to the endothelium, and therefore to the cardiovascular system (14–16). Furthermore, oxygen deprivation seems to mediate the hypercoagulability in COVID-19 (9). Patients with severe COVID-19 pneumonia progress to ARDS, accompanied by disseminated intravascular coagulation (DIC) (17), which may upregulate the coagulation pathways by activation of procoagulant factors, such as tissue factor, leading to both arterial and venous thrombotic disease. These biochemical mechanisms are main factors associated with disturbance of blood coagulation in COVID-19 patients. On the other hand, there is a potential risk of VTE associated with administration of some medications to severe cases of COVID-19 (18). Clinical reports have indicated thrombotic disease in around 25–30% SARS-CoV-2 infected patients, mainly in seriously ill patients (9, 10, 12, 19–22). Therefore, early anticoagulant treatment certainly leads to a better prognosis. In this sense, the antithrombotic properties of aspirin make it a plausible drug for thrombotic disease prevention, the efficacy of which requires to be validated in COVID-19 patients. Acetylsalicylic acid, aspirin, is an antiplatelet drug that inhibits platelet aggregation. The main biochemical mechanism by which aspirin inhibits thrombotic damage is through irreversible inactivation of cyclooxygenase 1 (COX-1) enzyme. In this respect, aspirin acetyl group attaches to the active side of COX-1 at S529, inhibiting the biosynthesis of prostaglandin H2 (PGH2), which is the substrate of thromboxane-A synthase that catalyzes the generation of the prothrombotic eicosanoid thromboxane A2 (TXA2) (Figure 1) suppressing platelet aggregation leading to the prevention of VTE without significant alterations in the endothelial function. On the other hand, aspirin acetylates fibrinogen and other proteins involved in blood coagulation, also preventing thrombus formation. These biochemical mechanisms cause a decrease of dense granule release from platelets (23, 24). Activated platelets and endothelial cells biosynthesize P-selectin, a cell-adhesion glycoprotein that promotes leukocyte and platelet adhesion, and the attachment of leukocytes to the vascular endothelium. Aspirin inhibits P-selectin, which results in the reduction of deep vein thrombosis (DVT) (25). Other antithrombotic mechanism of aspirin involves upregulation of nitric oxide (NO) metabolic production by endothelial cells, through inhibition prostacyclin synthesis, which leads to platelet inactivation (26). Additionally, aspirin prevents the formation of the serine protease enzyme thrombin, which catalyzes the transformation of fibrinogen to fibrin and, hence, leads to the formation of blood clot. Furthermore, thrombin is a potent mediator of platelet activation and aggregation. Thrombin promotes its biosynthesis by feedback activation of prothrombinase complex coenzymes (factors V and VIII). Aspirin inhibits tissue factor (TF): Factor VIIa (FVIIa) complex that catalyzes thrombin formation and, therefore, thrombin-mediated coagulation pathways (24). Figure 1. Putative mechanism of thrombotic disease associated with cytokine storms in COVID-19 patients, and biochemical mechanism of aspirin to prevent arterial/venous thrombosis and thromboembolism. Aspirin is certainly one of the most used drugs in medicine. In addition to its antithrombotic activity, aspirin is very well-known for its antipyretic, antiviral, and analgesic properties (27). Aspirin bioactivity inhibits virus replication such as influenza virus, hepatitis C virus, and flavivirus. Among the reported metabolic mechanisms that produces inhibition is the activation of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase ½ and p38 mitogen-activated protein kinase. Furthermore, an additional mechanism is the inhibition of the proinflammatory transcription factor NF-κB which is relevant for viral genes expression (28). Clinical studies have reported reduction...