Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent pathogen responsible for the coronavirus disease 2019 (COVID-19). Since its emergence, the novel coronavirus has rapidly achieved pandemic proportions causing remarkably increased morbidity and mortality around the world. A hypercoagulability state has been reported as a major pathologic event in COVID-19, and thromboembolic complications listed among life-threatening complications of the disease. Platelets are chief effector cells of hemostasis and pathological thrombosis. However, the participation of platelets in the pathogenesis of COVID-19 remains elusive. This report demonstrates that increased platelet activation and platelet-monocyte aggregate formation are observed in severe COVID-19 patients, but not in patients presenting mild COVID-19 syndrome. In addition, exposure to plasma from severe COVID-19 patients increased the activation of control platelets ex vivo. In our cohort of COVID-19 patients admitted to the intensive care unit, platelet-monocyte interaction was strongly associated with tissue factor (TF) expression by the monocytes. Platelet activation and monocyte TF expression were associated with markers of coagulation exacerbation as fibrinogen and D-dimers, and were increased in patients requiring invasive mechanical ventilation or patients who evolved with in-hospital mortality. Finally, platelets from severe COVID-19 patients were able to induce TF expression ex vivo in monocytes from healthy volunteers, a phenomenon that was inhibited by platelet P-selectin neutralization or integrin αIIb/β3 blocking with the aggregation inhibitor abciximab. Altogether, these data shed light on new pathological mechanisms involving platelet activation and platelet-dependent monocyte TF expression, which were associated with COVID-19 severity and mortality.

Vascular Manifestations of COVID-19 – Thromboembolism and Microvascular Dysfunction

“…Similar findings were observed when platelets from COVID-19 negative patients were treated with plasma from COVID-19 positive patients (124). Platelets from COVID-19 patients induces ex vivo expression of tissue factor (TF) in monocytes (124), indicating a likely reprogramming event during SARS-CoV-2 infection. Indeed, this hypothesis is supported by pre-publication evidence reporting the presence of SARS-CoV-2 RNA in platelets of COVID-19 patients, which were shown to be hyperactivated and aggregated at a lower threshold of in vitro thrombin stimulation (125).…”

“…Direct activation of platelets by SARS-CoV-2 is a likely pathway for the development of thromboembolism. Hottz et al (124) reported platelet activation and formation of platelet-monocyte aggregates in patients with severe but not in mild COVID-19. Similar findings were observed when platelets from COVID-19 negative patients were treated with plasma from COVID-19 positive patients (124).…”

“…Hottz et al (124) reported platelet activation and formation of platelet-monocyte aggregates in patients with severe but not in mild COVID-19. Similar findings were observed when platelets from COVID-19 negative patients were treated with plasma from COVID-19 positive patients (124). Platelets from COVID-19 patients induces ex vivo expression of tissue factor (TF) in monocytes (124), indicating a likely reprogramming event during SARS-CoV-2 infection.…”

Immune Mechanisms in Cardiovascular Diseases Associated With Viral Infection

“…Like influenza, SARS-CoV-2 infection also activates clotting factors, fibrinolysis proteases, and immunothrombosis that favor coagulopathy in COVID-19 patients. A study has shown that platelet-monocyte aggregates were observed in severely ill COVID-19 patients, associated with tissue factor induction (218). SARS-CoV-2 viral entry decreases the expression of ACE2 that enhances the levels of Angiotensin II (Ang II).…”

Perspectives on Platelet Heterogeneity and Host Immune Response in Coronavirus Disease 2019 (COVID-19)

“…18 An increased cross-talk between platelets and leukocytes has also been linked to other features of hypercoagulability in COVID-19 pathology, where platelet-monocyte aggregates fuel tissue factor (TF) expression, and platelet-neutrophil interactions contribute to microthrombosis and acute respiratory distress syndrome (ARDS). 24,25 Following cytokine storm and exacerbated inflammation, injured tissues may release damage-associated molecular patterns (DAMPs) into circulation, 20 typically including high-mobility group box (HMGB1), S100 family, and histone proteins. DAMPs may be detected by innate immune receptors on platelets, including TLRs, to bring about platelet heterogeneity supporting inflammation, coagulation, and sepsis (►Fig.…”