Expert Opinion on Investigational Drugs | 2021
Low-dose aspirin for early COVID-19: does the early bird catch the worm?
Abstract
During the ongoing COVID-19 pandemic caused by SARS-CoV -2 virus, the vast majority of patients have a mild to moderate illness that does not necessitate hospitalization and are appropriately treated in an ambulatory setting. Optimization of the outpatient treatment can potentially reduce viral spread and in hospitals reaching full capacity. Steroids, and tocilizumab have been demonstrated to improve outcomes in hospitalized patients with severe disease in the RECOVERY trial. However, an effective treatment for outpatients with mild to moderate disease has remained elusive, and no drug has been demonstrated to be effective in ambulatory setting. The COLCORONA study showed some benefit of colchicine in terms of reducing hospitalization [1], but a significant amount of gastrointestinal side effects can be induced by colchicine knowing that COVID19 is also associated with these side effects [2]. A number of hemostatic and inflammatory changes have been observed in mild COVID-19 that offer a therapeutic target. Necropsies of COVID-19 patients have revealed inflammatory microvascular thrombi containing neutrophils, platelets, and neutrophil extracellular traps (NETs) in the pulmonary, hepatic, renal, and cardiac microvasculature as the hallmark of severe COVID-19 disease and the underlying cause of multiorgan failure [3–5]. Adults with mild to moderate disease also exhibit an increase in plasma D-dimer levels indicative of microvascular thrombosis [6]. Furthermore, thrombotic microangiopathy has been reported in children even when relatively asymptomatic [7]. Progression of pulmonary microvascular thrombosis causes ventilation-perfusion mismatch and leads to hypoxia [8]. Additionally, microvascular thrombosis in the heart and kidneys causes ischemia reperfusion injury and leads to organ dysfunction and failure [3]. Therefore, targeting thromboinflammation in outpatients with mild or moderate COVID-19 can potentially reduce progression of the disease and improve outcomes In the pathogenesis of this thromboinflammatory state, platelets have emerged as key effector cells, evidenced by first, platelet aggregation, adhesion, and spreading; and second, increased surface expression of P-selectin on the platelets with circulating platelet-monocyte, plateletneutrophil, and platelet-T cell aggregates [3,9–11]. Platelet activation in COVID-19 is induced by endothelial damage [9,12]. Thromboxane A2, is generated by and modulates the functions of platelets and endothelial cells in a paracrine manner via the thromboxane prostanoid receptor (TPr) [13]. Thromboxane A2 also stimulates P-selectin expression in platelets, and P-selectin plays a critical role in the initial adhesion and rolling of platelets and leukocytes to areas of injury and inflammation [14,15]. Thromboxane levels in the plasma and in the bronchoalveolar lavage fluid are markedly increased in COVID-19 [9,16]. Thus, use of aspirin to inhibit synthesis of thromboxane A2 has been proposed for early treatment of COVID-19 [17] [see Figure 1]. Aspirin has anti-inflammatory, analgesic, antipyretic, antithrombotic effects, and antiviral properties against RNA viruses [18,19]. Several pharmacological effects of aspirin have been postulated to have clinical applications in the modulation of inflammatory pathways, thrombosis, and viral infectivity. Lowdose aspirin has pleiotropic effects with potential benefits especially early in the course of COVID-19 illness. First, irreversible inhibition COX-1 enzyme inhibits the synthesis of thromboxane A2 in platelets and leads to potent anti-thrombotic action. Second, acetylation of COX-2 enzyme leads to synthesis of resolvins, the anti-inflammatory lipid mediators that promote resolution of inflammation induced by tissue damage and cytokines in COVID-19 [20]. Third, low-dose aspirin stimulates 15-epi-lipoxin A4 synthesis thereby dampening leukocyte/endothelial cell interaction and leukocyte migration [21]. Aspirin may not be sufficient as an anti-thrombotic in hospitalized patients with moderate to severe COVID-19 when anticoagulation with heparin is recommended with optional addition of aspirin as an anti-platelet agent. Low-dose aspirin stimulates the endogenous production of anti-inflammatory and proresolving mediators termed aspirin triggered specialized pro-resolving mediators (AT-SPMs), such as aspirintriggered resolvins (AT-RvDs) and lipoxins (AT-LXs). Additionally, low-dose aspirin stimulates 15-epi-lipoxin A4 synthesis thereby dampening leukocyte/endothelial cell interaction, leukocyte migration, and leukocyte mediated inflammation [21].