Platelet NO/ROS Equilibrium—A Novel Mechanism for COVID-19 Related Thrombotic Events?

COVID-19 infection, especially in its severe presentations, has been associated with high incidence of venous and arterial thrombotic complications, mainly venous thromboembolism, myocardial infarction, and ischemic stroke.[1] [2] Several mechanisms have been proposed for the elevated risk of thrombotic events including an excessive inflammatory response, platelet activation, intravascular coagulopathy, marked endothelial dysfunction, and stasis.[1] Virus-induced as well as cytokine-induced platelet, neutrophil, and endothelial cell activation have all been shown to be triggers of a pronounced thrombo-inflammatory cycle leading to the thrombotic events.[2] Research of the pathways leading to platelet hyper-reactivity in COVID-19 has focused on virus- and cytokine-induced platelet activation, immune complex mediated activation, as well as augmented release of immature hyper-reactive platelets from megakaryocytes.[2] [3]

In the current issue of Thrombosis and Haemostasis, Petito et al describe a novel platelet mechanism contributing to the elevated risk of thrombotic complications in COVID-19.[4] Platelets from COVID-19 patients showed a defective balance of nitric oxide (NO)/reactive oxygen species (ROS) production with reduced NO and increased ROS production, compared with healthy controls and ICU patients without COVID-19.[4] Furthermore, reduced platelet NO was associated with thrombotic events during hospitalization in COVID-19 patients.[4] Importantly, impaired platelet NO generation and increased platelet-derived ROS have been associated with platelet activation and enhanced oxidative stress in COVID-19 (current study) as well as other infectious and inflammatory disorders.

The finding that platelet NO/ROS production imbalance contributes to the elevated risk of thrombotic events in COVID-19 has important clinical implications. Restoration of platelet NO production, as well as attenuation of ROS production by antioxidants, NO donors, NADPH oxidase inhibitors, or statins (shown to increase endothelial NO production), may all improve the NO/ROS equilibrium in patients with COVID-19 and prevent thrombotic complications. Thus, the platelet may be a key therapeutic target in COVID-19 beyond anti-thrombotic treatment.

Publication History

Received: 31 March 2025

Accepted: 01 April 2025

Article published online:
21 April 2025

• References

• 1 Bikdeli B, Madhavan MV, Jimenez D. et al; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol 2020; 75 (23) 2950-2973
• 2 Violi F, Harenberg J, Pignatelli P, Cammisotto V. COVID-19 and long-COVID thrombosis: from clinical and basic science to therapeutics. Thromb Haemost 2024; 124 (04) 286-296
• 3 Sevilya Z, Kuzmina A, Cipok M. et al. Differential platelet activation through an interaction with spike proteins of different SARS-CoV-2 variants. J Thromb Thrombolysis 2023; 56 (04) 538-547
• 4 Petito E, Guglielmini G, De Robertis D. et al. Platelets from COVID-19 show an altered nitric oxide/reactive oxygen species production balance. Thromb Haemost 2025