Scientific premise for the involvement of neutrophil extracellular traps (NETs) in vaccine-induced thrombotic thrombocytopenia (VITT)

Abstract

Following on from the devastating spread of COVID-19, a major global priority has been the production, procurement, and distribution of effective vaccines to ensure that the global pandemic reaches an end. However, concerns were raised about worrying side effects, particularly the occurrence of thrombosis and thrombocytopenia after administration of the Oxford/AstraZeneca and Johnson & Johnson's Janssen COVID-19 vaccine, in a phenomenon being termed vaccine-induced thrombotic thrombocytopenia (VITT). Similar to heparin-induced thrombocytopenia (HIT), this condition has been associated with the development of anti-platelet factor 4 antibodies, purportedly leading to neutrophil-platelet aggregate formation. Although thrombosis has also been a common association with COVID-19, the precise molecular mechanisms governing its occurrence are yet to be established. Recently, increasing evidence highlights the NLRP3 (NOD-like, leucine-rich repeat domains, and pyrin domain-containing protein) inflammasome complex along with IL-1β and effete neutrophils producing neutrophil extracellular traps (NETs) through NETosis. Herein, we propose and discuss that perhaps the incidence of VITT may be due to inflammatory reactions mediated via IL-1β/NLRP3 inflammasome activation and consequent overproduction of NETs, where similar autoimmune mechanisms are observed in HIT. We also discuss avenues by which such modalities could be treated to prevent the occurrence of adverse events and ensure vaccine rollouts remain safe and on target to end the current pandemic. INTRODUCTIONEver since COVID-19, caused by SARS-CoV-2, was declared by the World Health Organization (WHO) as a global pandemic, the leading global strategy against this disease has been the effective development, procurement, and distribution of vaccines. Indeed, many vaccines have been authorized by global regulatory authorities since December 2020. 1,2 Coronaviruses are large single-stranded positive-sense RNA viruses with a helical nucleocapsid (N) and an envelope composed of matrix protein (M), an envelope protein (E), and spike protein (S). The spike protein is the receptor-binding site for angiotensin-converting enzyme 2 for viral entry into the cell.The developmental stage of the COVID-19 vaccine saw various approaches, all of which utilize S protein as the immunogen: recombinant vaccines using viral vectors; nucleic acid vaccines or mRNA vaccines; inactivated vaccines; nanoparticle or virus-like particle vaccines; protein subunit vaccines; and live attenuated vaccines. 3,4 However, as one would expect from vaccines developed at such an unprecedented pace, several side effects have been reported termed adverse events of special interests (AESI). Variable AESIs observed include acute myocardial infarction, hemorrhagic/nonhemorrhagic stroke, deep vein thrombosis, pulmonary embolism, Bell's palsy,

NET-Mediated Pathogenesis of COVID-19: The Role of NETs in Hepatic Manifestations

“…Collectively, we propose that NETs-observed to be elevated in COVID infection-play principal roles in liver injury in addition to acute lung injury. In support of our findings, serum NET markers are elevated in COVID-19 patients, which correlate with disease severity 70,71 ; well-established inducers of NETosis, such as endothelial cells and proinflammatory cytokine IL-1β, are confirmed to play a major role in COVID-19 pathogenesis 51,55,94 , NETs play key roles in liver disease regardless of etiology 10 , and other, similar, immunerelated diseases feature NETs 12,26,95 , and NETs are consistently detected within pulmonary, 75,96 renal, 16 and cardiac 97 microthrombi in COVID-19 patients.…”

“…The priming stage is constituted by the activation of pattern recognition receptors by DAMPs or pathogen-associated molecular patterns (PAMPs), which induce the activation of NF-κB promoting the gene expression of pro-IL-1β and pro-IL-18 and NOD-like receptor family pyrin domain-containing 3 (NLRP3). [49][50][51] The second activation signal could be provided by several extracellular stimuli, including membrane damage, activation of ion channels, and reactive oxygen species (ROS), all of which promote NLRP3 oligomerization which, along with adaptor protein and caspase-1, forms the inflammasome and cleaves pro-IL-1β and pro-IL-18 into the active IL-1β and IL-18, respectively. 49,52,53 The last step of this process is the caspase-1-mediated cleavage of Gasdermin D (GSDMD), resulting in the formation of pores in the cell membrane to allow for the release of IL-1β and IL-18 as well as inducing cell death by pyroptosis, producing DAMPs.…”

“…3 This process collectively intensifies the immune response but, if not tightly regulated, can lead to massive infiltration of activated neutrophils with subsequent NETosis, activation of macrophages, and an exaggerated cytokine response leading to substantial tissue damage. 51,56,57 In the context of coronaviruses, SARS-CoV directly activates the NLRP3 inflammasomes via its E protein and viroporin 3a. Since significant homology exists between SARS-CoV and SARS-CoV-2, there is likely significant overlap regarding pathophysiology.…”

COVID-19 Vaccine-Related Thrombosis: A Systematic Review and Exploratory Analysis

“…It is also possible that there is a common physiopathological mechanism for COVID-19 infection and VITT or HIT. Some researchers hypothesized an important role of the innate immune system in causing thrombotic events in COVID-19 patients and in cases of VITT or HIT ( 42 ).…”

“…In case of VITT, the certain inflammatory vaccine adjuvants and delivery systems could trigger immune system cells’ recruitment, especially neutrophils, through the activation of NPL3 inflammasome and enhance NET production ( 42 , 51 , 52 ). NETs’ components by binding to PF-4 determine the production of antibodies against PF-4 polyanionic complexes.…”