Neuroinflammation in COVID-19: Fibrinogen (fibrin), a potential culprit!

Dear Editor,

Ahead of the unprecedented challenges presented by the coronavirus disease 2019 (COVID-19) pandemic, there is an ongoing need to reflect upon the perturbing long-lasting neurological complications of the disease. Despite of the anticipated “wave” of neurocognitive decline in the COVID-19 survivors,¹ discerning the intriguing neurobiology of long COVID continues to be peculiarly difficult.² In this context, there has been a heightened emphasis on the role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered neuroinflammation, particularly in reference to the factors which may trigger and in turn, maintain a neuroinflammatory milieu.1, 2, 3

Within the purview of a multifaceted neurobiology of long COVID,² coagulopathy which is frequently associated with an underlying COVID-19 infection, only appears to be far from benign when staging a discussion on neuroinflammation. Meanwhile independent researchers identify microclot formation as a plausible cause of persistent neurological decline in COVID-19,² the elevated fibrinogen levels in COVID-19 thrombosis merit an individualized attention.³ Fibrinogen, a pleiotropic circulating protein, is intricately connected to the inflammatory responses, given its’ positive acute phase reactant nature. Beyond the links with acute inflammatory responses, studies exist to relate higher plasma fibrinogen with cognitive impairment following stroke, propounding an exaggerated neuroinflammation at the heart of a disrupted synaptic plasticity.^3,4

The fibrinogen leaking in through a disrupted blood–brain barrier gets converted to the insoluble fibrin deposits which subsequently induces microglial activation, cytokine secretion, leukocyte recruitment and oxidative injury with the latter further potentially protracting the neuroinflammatory insult sustained.^3,4 Much on the lines of the pathophysiology outlined, Li et al highlight that the inhibition of the fibrin formation from fibrinogen in hirudin treated mice ameliorates neuroinflammation, leading to markedly improved long-term neurological outcomes post-intracerebral hemorrhage.⁴ Quite notably, fibrinogen-fibrin depositions have been reported in the brains of patients across inflammatory neurodegenerative diseases as Alzheimer's disease, multiple sclerosis and traumatic brain injury.⁵ A systematic review and meta-analysis by Zhou et al also delineates plasma fibrinogen as a prominent risk factor for all-cause dementia.⁶

Specific to neurological outcomes in COVID-19, Saxena et al recently demonstrate significantly higher fibrinogen levels in intensive care unit (ICU) patients with an altered cognitive state in contrast to those without any cognitive decline [7.19 (6.58–8.30) and 6.63 (5.41–7.77) g/L respectively, Wilcoxon p-value = 0.026].³ Amidst the plasma fibrinogen emerging as the sole neuroprognostic inflammatory marker in their setting, the group realizes the possibility of the former being “an important piece of the COVID-19 delirium puzzle” and proffer the ICU admission plasma fibrinogen as a predictor of cognitive impairment in the mechanically ventilated acute respiratory distress syndrome (ARDS) COVID-19 patients.³ It is worth mentioning here that fibrinogen emerges as a unique blood-factor given its’ multiple non-overlapping binding domains that facilitate interactions with both the integrin and nonintegrin receptors expressed on a wide range of cells of the hematopoietic, immune and simultaneously, the central nervous system (CNS).⁷ Fibrinogen within the CNS, as elucidated above leads to microglial activation through the CD11b/CD18 pathway, with the activated microglia releasing interleukins and growth factors such as interleukin-1β (IL-1 β) and vascular endothelial growth factor (VEGF), thereby increasing the permeability of the blood–brain barrier.^3,8

Furthermore, Kell et al strongly propose fibrin-amyloid microclots or, fibrinaloids (as coined by them) as inevitable accompaniments and likely perpetuators of the long COVID syndrome or the multifaceted Post-Acute sequelae of COVID-19 (PASC) symptomatology.⁹ At the same time, Kruger et al demonstrate the presence of entrapped proinflammatory molecules in their proteomic analysis of these fibrin-amyloid microclots, which additionally contribute to a failed fibrinolytic system.¹⁰ Moreover, the solubilized fibrinolytic resistant microclots in long COVID or PASC patients manifesting a considerable increase in the entrapped α(2)-antiplasmin (α2AP) when compared to the controls and those with an acute illness, again substantiates a potential role of fibrin (fibrinogen) mediated-maintained neuroinflammation in COVID-19.¹¹

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The authors have none to declare.