Comprehensive Analysis of the Role of Fibrinogen and Thrombin in Clot Formation and Structure for Plasma and Purified Fibrinogen

Risman, Rebecca A.; Belcher, Heather A.; Ramanujam, Ranjini K.; Weisel, John W.; Hudson, Nathan E.; Tutwiler, Valerie

doi:10.3390/biom14020230

Cited by 4 publications

(2 citation statements)

References 84 publications

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“…The ability of normal fibrinogen [224] and other proteins [225] to convert into a β-sheet-rich form is probably highly relevant. These observations also depend, of course, on a variety of factors such as degree of hydration, initial fibrinogen [226] and thrombin [227] concentrations, levels of small molecules [191,228], of metal and other ions [229][230][231][232], and so on. However, the point of this paragraph is that these are clearly very much larger numbers for the fibre diameters in fibrinaloid microclots than are those seen in classical amyloidoses.…”

Section: Size Of Fibres In Classical Amyloidoses and In Normal And Fi...mentioning

confidence: 99%

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

Kell,

Pretorius

2024

Preprint

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In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils and fibrils exhibiting a cross-β motif of parallel or antiparallel β-sheets oriented perpendicular to the fibre direction. These protofibrils and fibrils can intertwine to form mature amyloid fibres. Similar phenomena occur in blood from individuals with circulating inflammatory molecules (also those originating from viruses and bacteria). In the presence of inflammagens, pathological clotting can occur, that results in an anomalous amyloid form termed fibrinaloid microclots. Previous proteomic analyses of these microclots have shown the presence of non-fibrin(ogen) proteins, suggesting a more complex mechanism than simple entrapment. We provide evidence against a simple entrapment model, noting that clot pores are too large and centrifugation would have removed weakly bound proteins. Instead, we explore whether co-aggregation into amyloid fibres may involve axial (multiple proteins within the same fibril), lateral (single-protein fibrils contributing to a fibre), or both types of integration. Our analysis of proteomic data from fibrinaloid microclots in different diseases shows no significant overlap with the normal plasma proteome and no correlation between plasma protein abundance and presence in microclots. Notably, abundant plasma proteins like α-2-macroglobulin, fibronectin, and transthyretin are absent from microclots, while less abundant proteins such as adiponectin, periostin, and von Willebrand Factor are well represented. Using bioinformatic tools including AmyloGram and AnuPP, we found that proteins entrapped in fibrinaloid microclots exhibit high amyloidogenic tendencies, suggesting their integration as cross-β elements into amyloid structures. This integration likely contributes to the microclots’ resistance to proteolysis. Our findings underscore the role of cross-seeding in fibrinaloid microclot formation and highlight the need for further investigation into their structural properties and implications in thrombotic and amyloid diseases. These insights provide a foundation for developing novel diagnostic and therapeutic strategies targeting amyloidogenic cross-seeding in blood clotting disorders.

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Section: Size Of Fibres In Classical Amyloidoses and In Normal And Fi...mentioning

confidence: 99%

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

Kell,

Pretorius

2024

Preprint

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“…Another acute-phase protein is fibrinogen, the precursor of fibrin, which consists of two subunits with three polypeptide chains of Aalpha, Bbeta, and γ. Levels of fibrinogen variants have been associated with severe forms of SARS-CoV-2 infection [ 26 , 27 ]. This finding was also presented in our previous studies, which included data from patients at the time of admission [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

The Relationship between the Laboratory Biomarkers of SARS-CoV-2 Patients with Type 2 Diabetes at Discharge and the Severity of the Viral Pathology

Reștea,

Țigan,

Vicaș

et al. 2024

JPM

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In this study, we evaluated the discharge status of patients with type 2 diabetes mellitus and SARS-CoV-2 infection, focusing on the inflammatory profile through biomarkers such as procalcitonin, CRP, LDH, fibrinogen, ESR, and ferritin, as well as electrolyte levels and the prior diagnosis of diabetes or its identification at the time of hospitalization. We assessed parameters at discharge for 45 patients admitted to the Clinical Hospital “Gavril Curteanu” Oradea between 21 October 2021, and 31 December 2021, randomly selected, having as the main inclusion criteria the positive RT-PCR rapid antigen test for viral infection and the diagnosis of type 2 diabetes. At discharge, patients with type 2 diabetes registered significantly lower mean procalcitonin levels among those who survived compared to those who died from COVID-19. In our study, ferritin and hemoglobin values in individuals with type 2 diabetes were outside the reference range at discharge and correlated with severe or moderate forms of COVID-19 infection. Additionally, elevated ferritin levels at discharge were statistically associated with hypokalemia and elevated levels of ESR at discharge. Another strong statistically significant correlation was identified between high CRP levels at discharge, strongly associated (p < 0.001) with elevated LDH and fibrinogen levels in patients with type 2 diabetes and SARS-CoV-2 viral infection. The increase in CRP was inversely statistically associated with the tendency of serum potassium to decrease at discharge in patients with type 2 diabetes and COVID-19. Identifying type 2 diabetes metabolic pathology at the time of hospitalization for SARS-CoV-2 infection, compared to pre-infection diabetes diagnosis, did not significantly influence the laboratory parameter status at the time of discharge. At the discharge of patients with type 2 diabetes and viral infection with the novel coronavirus, procalcitonin was significantly reduced in those who survived COVID-19 infection, and disease severity was significantly correlated with hyperferritinemia and decreased hemoglobin at discharge. Hyperferritinemia in patients with type 2 diabetes and COVID-19 at discharge was associated with hypokalemia and persistent inflammation (quantified by ESR at discharge). The low number of erythrocytes at discharge is associated with maintaining inflammation at discharge (quantified by the ESR value).

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A hybrid construct of decellularized matrix and fibrin for differentiating adipose stem cells into insulin‐producing cells, an optimized in vitro assessment

Bozorgi,

Khazaei,

Bozorgi

et al. 2024

Cell Biochemistry & Function

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The generation of insulin‐producing cells (IPCs) is an attractive approach for replacing damaged β cells in diabetic patients. In the present work, we introduced a hybrid platform of decellularized amniotic membrane (dAM) and fibrin encapsulation for differentiating adipose tissue‐derived stem cells (ASCs) into IPCs. ASCs were isolated from healthy donors and characterized. Human AM was decellularized, and its morphology, DNA, collagen, glycosaminoglycan (GAG) contents, and biocompatibility were evaluated. ASCs were subjected to four IPC differentiation methods, and the most efficient method was selected for the experiment. ASCs were seeded onto dAM, alone or encapsulated in fibrin gel with various thrombin concentrations, and differentiated into IPCs according to a method applying serum‐free media containing 2‐mercaptoethanol, nicotinamide, and exendin‐4. PDX‐1, GLUT‐2 and insulin expression were evaluated in differentiated cells using real‐time PCR. Structural integrity and collagen and GAG contents of AM were preserved after decellularization, while DNA content was minimized. Cultivating ASCs on dAM augmented their attachment, proliferation, and viability and enhanced the expression of PDX‐1, GLUT‐2, and insulin in differentiated cells. Encapsulating ASCs in fibrin gel containing 2 mg/ml fibrinogen and 10 units/ml thrombin increased their differentiation into IPCs. dAM and fibrin gel synergistically enhanced the differentiation of ASCs into IPCs, which could be considered an appropriate strategy for replacing damaged β cells.

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Comprehensive Analysis of the Role of Fibrinogen and Thrombin in Clot Formation and Structure for Plasma and Purified Fibrinogen

Cited by 4 publications

References 84 publications

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

The Relationship between the Laboratory Biomarkers of SARS-CoV-2 Patients with Type 2 Diabetes at Discharge and the Severity of the Viral Pathology

A hybrid construct of decellularized matrix and fibrin for differentiating adipose stem cells into insulin‐producing cells, an optimized in vitro assessment

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