Platelets in COVID-19 disease: friend, foe, or both?

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.

Protein disulfide isomerase-A1 regulates intraplatelet reactive oxygen species-thromboxane A2 -dependent pathway in human platelets.

BACKGROUND: Platelet-derived protein disulfide isomerase 1 (PDIA1) regulates thrombus formation, but its role in the regulation of platelet function is not fully understood. AIMS: The aim of this study was to characterize the role of PDIA1 in human platelets. METHODS: Proteomic analysis of PDI isoforms in platelets was performed using liquid chromatography tandem mass spectometry, and the expression of PDIs on platelets in response to collagen, TRAP-14, or ADP was measured with flow cytometry. The effects of bepristat, a selective PDIA1 inhibitor, on platelet aggregation, expression of platelet surface activation markers, thromboxane A2 (TxA2 ), and reactive oxygen species (ROS) generation were evaluated by optical aggregometry, flow cytometry, ELISA, and dihydrodichlorofluorescein diacetate-based fluorescent assay, respectively. RESULTS: PDIA1 was less abundant compared with PDIA3 in resting platelets and platelets stimulated with TRAP-14, collagen, or ADP. Collagen, but not ADP, induced a significant increase in PDIA1 expression. Bepristat potently inhibited the aggregation of washed platelets induced by collagen or convulxin, but only weakly inhibited platelet aggregation induced by TRAP-14 or thrombin, and had the negligible effect on platelet aggregation induced by arachidonic acid. Inhibition of PDIA1 by bepristat resulted in the reduction of TxA2 and ROS production in collagen- or thrombin-stimulated platelets. Furthermore, bepristat reduced the activation of αIIbß3 integrin and expression of P-selectin. CONCLUSIONS: PDIA1 acts as an intraplatelet regulator of the ROS-TxA2 pathway in collagen-GP VI receptor-mediated platelet activation that is a mechanistically distinct pathway from extracellular regulation of αIIbß3 integrin by PDIA3.