Self-Assembly of Human Fibrinogen into Microclot-Mimicking Antifibrinolytic Amyloid Fibrinogen Particles

Dec 26, 2024ACS applied bio materials

Human Fibrinogen Forms Clot-Like Particles That Resist Breakdown

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Abstract

Amyloid fibrinogen particles (AFPs) can be prepared in vitro, resembling microclots found in Long COVID patients.

Mimetic microclots exhibit structural characteristics similar to those observed in patients with Long COVID.
Amyloid transition of fibrinogen occurs at acidic pH levels between 2.3 and 3.2.
Well-dispersed amyloid oligomers of fibrinogen, sized 1 to 5 μm, can be generated at pH 2.8 after 1 hour.
Amyloid oligomers self-assemble into well-ordered nanodomains that grow perpendicular to the fibrinogen monomer's axis.
AFPs show positive staining in thioflavin T assays and are resistant to breakdown by fibrinolysis.
Proteomic analysis indicates AFPs interact with various plasma components, notably having increased binding affinity for complement C3.

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Recent clinical studies have highlighted the presence of microclots in the form of amyloid fibrinogen particles (AFPs) in plasma samples from Long COVID patients. However, the clinical significance of these abnormal, nonfibrillar self-assembly aggregates of human fibrinogen remains debated due to the limited understanding of their structural and biological characteristics. In this study, we present a method for generating mimetic microclots in vitro. Using this approach, the self-assembly process, structural organization of AFPs, and their interactions with human plasma components were elucidated. The amyloid transition of fibrinogen occurs under acidic conditions within a pH range of 2.3-3.2. Well-dispersed amyloid oligomers of fibrinogen, ranging in size from 1 to 5 μm, can be prepared at pH 2.8 after 1 h of incubation. We tracked the dynamic self-assembly process at the single-molecule level using high-speed atomic force microscopy (HS-AFM). The arrangement of amyloid oligomers manifests as well-ordered, stacked nanodomains with striped patterns, growing perpendicular to the primary axis of the fibrinogen monomer. Upon transfer to physiological solution conditions or human plasma, these amyloid oligomers further aggregate into nonfibrillar structures at the micrometer scale, resembling the microclots observed in the bloodstream of Long COVID patients. Notably, these AFPs exhibit characteristics consistent with microclots, including positive staining in thioflavin T (ThT) assays and resistance to fibrinolysis. Proteomic analysis suggests that AFPs interact with various components of human plasma and have an enhanced binding affinity with complement C3 compared to native fibrinogen. This study enables the in vitro preparation of mimetic microclots exhibiting amyloid features. It is anticipated to facilitate further researches on the mechanisms, detection, and treatment of diseases associated with fibrinogen amyloidogenesis.

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Self-Assembly of Human Fibrinogen into Microclot-Mimicking Antifibrinolytic Amyloid Fibrinogen Particles

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