Are Aspirin and Apixaban Sufficient to Prevent Immunothrombosis in COVID-19?

Abstract

Severe COVID-19 disease is associated with respiratory and vascular injury and microvascular immunothrombosis mediated by complement activation, inflammatory lipid storm, platelet activation, platelet-leukocyte adhesion and activation of coagulation cascade. Amongst the inflammatory lipids, thromboxane A2 (TxA2) is a known key mediator of microvascular thrombosis. The levels of TxB2, a stable metabolite of TxA2 are markedly increased in the bronchoalveolar lavage fluid and plasma in severe COVID-19 patients. Low-dose aspirin mitigates the generation of prostanoids including TxA2 by irreversible inactivation of the constitutive enzyme cyclooxygenase (COX)-1. The anti-thrombotic action of aspirin is currently being investigated in outpatient and hospitalized COVID-19 patients in the global RECOVERY and ACTIV-4 clinical trials. Several lines of investigations suggest that COX-2 plays an important and critical role in the immunothrombotic effects mediated by COVID-19. Pharmacologic inhibition of either COX-1 or COX-2 can prevent a plethora of lipid mediators of inflammation that are both pro- and anti-inflammatory in function. Thus, a more definitive approach to prevent immunothrombotic events in COVID-19 will be to directly block the prothrombotic effects of TxA2. Although thromboxane synthase (TS) inhibitors suppress TxA2 formation, accumulation of the substrate PGH2 is known to interact with the platelet and vessel wall TxA2 prostanoid receptor (TPR), thus reducing the antiplatelet effects of TS inhibitors. TPR antagonists block the activity of both TxA2 and PGH2 on platelets and vessels but do not block TxA2 production, which leads to increased generation of 11-dehydro-thromboxane B2, a stable metabolite of TxA2, and a potent agonist of the DP2 (CRTH2) receptor for prostaglandin D2 (PGD2). PGD2/DP2 receptor signaling has been implicated in immune dysregulation in viral infections including COVID-19. Ramatroban, an orally bioavailable, potent, dual TxA2/TP and PGD2/DP2 receptor antagonist, has demonstrated efficacy in a variety of animal models of atherosclerosis, thrombosis and sepsis. Ramatroban has a proven safety profile, having been used in Japan over the past 20 years as a treatment of allergic rhinitis and therefore, merits investigation as a promising antithrombotic and immunomodulator agent for chemoprophylaxis and treatment in COVID-19 patients.