Platelet-monocyte interaction amplifies thromboinflammation through tissue factor signaling in COVID-19

Abstract

Accumulating evidence into the pathogenesis of COVID-19 highlight a hypercoagulability state with high risk of life-threatening thromboembolic complications. However, the mechanisms of hypercoagulability and their link to hyperinflammation remain poorly understood. Here we investigate functions and mechanisms of platelet activation and platelet-monocyte interactions in inflammatory amplification during SARS-CoV2 infection. We used a combination of immunophenotyping, single cell analysis, functional assays and pharmacological approaches to gain insights on mechanisms. Critically ill COVID-19 patients exhibited increased platelet-monocyte aggregates formation. We identified a subset of inflammatory monocytes presenting high CD16 and low HLA-DR expression as the subset mainly interacting with platelets during severe COVID-19. Single cell RNAseq analysis indicated enhanced fibrinogen receptor Mac-1 in monocytes from severe COVID-19 patients. Monocytes from severe COVID-19 patients displayed increased platelet binding and hyperresponsiveness to P-selectin and fibrinogen with respect to TFN-α and IL-1β secretion. Platelets were able to orchestrate monocyte responses driving TF expression, inflammatory activation and inflammatory cytokines secretion in SARS-CoV-2 infection. Platelet-monocyte interactions ex-vivo and in SARS-CoV-2 infection model in vitro reciprocally activated monocytes and platelets, inducing the heightened secretion of a wide panel of inflammatory mediators. We identified platelet adhesion as a primary signaling mechanism inducing mediator secretion and TF expression, while TF signaling played major roles in amplifying inflammation by inducing proinflammatory cytokines, especially TNF-α and IL-1β. Our data identify platelet-induced TF expression and activity at the crossroad of coagulation and inflammation in severe COVID-19.

Platelet‐leukocyte interactions in COVID‐19: Contributions to hypercoagulability, inflammation, and disease severity

“… 19 Platelets activated by SARS‐CoV‐2 Spike protein also bind to monocytes through P‐selectin and CD40‐L, and signal proinflammatory monocyte activation with high IL‐1β expression 43 . Similarly, results from our group show that platelets from COVID‐19 patients or in vitro‐infected platelets also induce a proinflammatory program in monocytes, which is induced by P‐selectin and integrin α IIb /β 3 binding and is amplified by TF signaling 46 . Platelet activation and monocyte TF expression positively correlate with plasma levels of D‐dimers, supporting a role in hypercoagulability 19 .…”

“…43 Similarly, results from our group show that platelets from COVID-19 patients or in vitro-infected platelets also induce a proinflammatory program in monocytes, which is induced by P-selectin and integrin α IIb /β 3 binding and is amplified by TF signaling. 46 Platelet activation and monocyte TF expression positively correlate with plasma levels of D-dimers, supporting a role in hypercoagulability. 19 In addition, increased platelet activation and monocyte TF expression at admission were predictive of patients' poor outcomes, including the requirement of mechanical ventilation and mortality.…”

Ischemic Stroke and SARS-CoV-2 Infection: The Bidirectional Pathology and Risk Morbidities

“…However, this remains debatable given that viral particles seen in electron microscopy of kidney vessel endothelium may have been normal structures or artefacts [ 69 , 70 ]. Recently, Hottz et al [ 71 ] identified a subset of inflammatory monocytes presenting high CD16 and low HLA-DR expression as the subset mainly interacting with platelets during severe COVID-19. Although no pathological tests were performed, some case reports suggested that multifocal ischemic and hemorrhagic lesions could be associated with endothelial implication, microthrombosis, or vasculitis in small vessels [ 72 , 73 ].…”

Increased platelet activation and platelet-inflammasome engagement during chikungunya infection

“…P-selectin and PF-4 are also important markers of platelet activation in other viral infections such as SARS-CoV-2 and HIV. In COVID-19 it has been shown that P-selectin is essential for platelet-monocyte binding and consequent tissue factor expression, leading to a amplification of thromboinflammatory response ( 39 , 40 ). Also in COVID-19, several studies have shown a correlation between increase PF-4 levels and severe cases, as well as in cases of post-vaccine thrombosis ( 40 , 49 ).…”