Immuno-thrombosis of COVID-19 results in the activation of platelets and coagulopathy. Antiplatelet therapy has been widely used in COVID-19 patients to prevent thrombotic events. However, recent analysis of clinical trials does not support the major effects of antiplatelet therapy on mortality in hospitalized COVID-19 patients, despite the indisputable evidence for an increased risk of thrombotic complications in COVID-19 disease. This apparent paradox calls for an explanation. Platelets have an important role in sensing and orchestrating host response to infection, and several platelet functions related to host defense response not directly related to their well-known hemostatic function are emerging. In this paper, we aim to review the evidence supporting the notion that platelets have protective properties in maintaining endothelial barrier integrity in the course of an inflammatory response, and this role seems to be of particular importance in the lung. It might, thus, well be that the inhibition of platelet function, if affecting the protective aspect of platelet activity, might diminish clinical benefits resulting from the inhibition of the pro-thrombotic phenotype of platelets in immuno-thrombosis of COVID-19. A better understanding of the platelet-dependent mechanisms involved in the preservation of the endothelial barrier is necessary to design the antiplatelet therapeutic strategies that inhibit the pro-thrombotic activity of platelets without effects on the vaso-protective function of platelets safeguarding the pulmonary endothelial barrier during multicellular host defense in pulmonary circulation.
