Structure functional insights into calcium binding during the activation of coagulation factor XIII A

Singh, Sneha; Dodt, Johannes; Volkers, Peter; Hethershaw, Emma; Philippou, Helen; Ivaškevičius, Vytautas; Imhof, Diana; Oldenburg, Johannes; Biswas, Arijit

doi:10.1038/s41598-019-47815-z

Cited by 68 publications

(49 citation statements)

References 66 publications

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“…Ca 2+ is an important factor in coagulation function ( 17 ), and it was significantly decreased in patients with severe COVID-19 infection. Thus, we examined indicators related to coagulation function in COVID-19 patients.…”

Section: Resultsmentioning

confidence: 99%

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Abnormal Coagulation Function of Patients With COVID-19 Is Significantly Related to Hypocalcemia and Severe Inflammation

Kong

Ding

et al. 2021

Front. Med.

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This study aimed to detect, analyze, and correlate the clinical characteristics, blood coagulation functions, blood calcium levels, and inflammatory factors in patients with mild and severe COVID-19 infections. The enrolled COVID-19 infected patients were from Wuhan Jin Yin-tan Hospital (17 cases, Wuhan, China), Suzhou Infectious Disease Hospital (87 cases, Suzhou, China), and Xuzhou Infectious Disease Hospital (14 cases, Xuzhou, China). After admission, basic information was collected; X-ray and chest CT images were obtained; and data from routine blood tests, liver and kidney function, myocardial enzymes, electrolytes, blood coagulation function, (erythrocyte sedimentation rate) ESR, C-reactive protein (CRP), IL-6, procalcitonin (PCT), calcitonin, and other laboratory tests were obtained. The patients were grouped according to the clinical classification method based on the pneumonia diagnosis and treatment plan for new coronavirus infection (trial version 7) in China. The measurements from mild (56 cases) and severe cases (51 cases) were compared and analyzed. Most COVID-19 patients presented with fever. Chest X-ray and CT images showed multiple patchy and ground glass opacities in the lungs of COVID 19 infected patients, especially in patients with severe cases. Compared with patients with mild infection, patients with severe infection were older (p = 0.023) and had a significant increase in AST and BUN. The levels of CK, LDH, CK-MB, proBNP, and Myo in patients with severe COVID-19 infection were also increased significantly compared to those in patients with mild cases. Patients with severe COVID-19 infections presented coagulation dysfunction and increased D-dimer and fibrin degradation product (FDP) levels. Severe COVID-19 patients had low serum calcium ion (Ca2+) concentrations and high calcitonin and PCT levels and exhibited serious systemic inflammation. Ca2+ in COVID-19 patients was significantly negatively correlated with PCT, calcitonin, D-dimer, PFDP, ESR, CRP and IL-6. D-dimer in COVID-19 patients was a significantly positively correlated with CRP and IL-6. In conclusion, patients with severe COVID-19 infection presented significant metabolic dysfunction and abnormal blood coagulation, a sharp increase in inflammatory factors and calcitonin and procalcitonin levels, and a significant decrease in Ca2+. Decreased Ca2+ and coagulation dysfunction in COVID-19 patients were significantly correlated with each other and with inflammatory factors.

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Section: Resultsmentioning

confidence: 99%

“…Ca 2+ plays an important role in maintaining heart function and coagulation function ( 17 , 40 , 41 ). When testing serum electrolytes, we found that the levels of Na + , K + , and Cl − were all normal in COVID-19 infected patients, although the level of Ca 2+ in patients with severe COVID-19 infection was significantly reduced.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Coagulation Function of Patients With COVID-19 Is Significantly Related to Hypocalcemia and Severe Inflammation

Kong

Ding

et al. 2021

Front. Med.

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“…Calcium concentration was another important variable impacting peptide incorporation, with increased calcium concentrations being associated with increased peptide incorporation. Calcium binding to sites on FXIII facilitate conformational changes that form substrate-binding pockets and ultimately expose the active site [ 48 ]. The reaction conditions that maximized peptide incorporation were subsequently used for the reactions that functionalized fibrin with the oligo tethers.…”

Section: Discussionmentioning

confidence: 99%

Functionalizing Fibrin Hydrogels with Thermally Responsive Oligonucleotide Tethers for On-Demand Delivery

et al. 2022

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There are a limited number of stimuli-responsive biomaterials that are capable of delivering customizable dosages of a therapeutic at a specific location and time. This is especially true in tissue engineering and regenerative medicine applications, where it may be desirable for the stimuli-responsive biomaterial to also serve as a scaffolding material. Therefore, the purpose of this study was to engineer a traditionally non-stimuli responsive scaffold biomaterial to be thermally responsive so it could be used for on-demand drug delivery applications. Fibrin hydrogels are frequently used for tissue engineering and regenerative medicine applications, and they were functionalized with thermally labile oligonucleotide tethers using peptides from substrates for factor XIII (FXIII). The alpha 2-plasmin inhibitor peptide had the greatest incorporation efficiency out of the FXIII substrate peptides studied, and conjugates of the peptide and oligonucleotide tethers were successfully incorporated into fibrin hydrogels via enzymatic activity. Single-strand complement oligo with either a fluorophore model drug or platelet-derived growth factor-BB (PDGF-BB) could be released on demand via temperature increases. These results demonstrate a strategy that can be used to functionalize traditionally non-stimuli responsive biomaterials suitable for on-demand drug delivery systems (DDS).

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“…The remaining aptamers show no direct specificity for fibrinogen and α2AP binding sites but as our functional data suggests, they might still maintain allosteric control over fibrinogen binding and subsequent cross-linking. These aptamers are observed to bind to counter-surfaces around regions which have been demonstrated to affect substrate binding for e.g., calcium binding sites ( Supplementary Materials, Figure S6 ) [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Functional and Structural Characterization of Nucleic Acid Ligands That Bind to Activated Coagulation Factor XIII

Hamedani

Biswas

Rudan

et al. 2021

JCM

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Coagulation factor XIII (FXIII) is a protransglutaminase which plays an important role in clot stabilization and composition by cross-linking the α- and γ-chains of fibrin and increasing the resistance of the clot to mechanical and proteolytic challenges. In this study, we selected six DNA aptamers specific for activated FXIII (FXIIIa) and investigated the functional characterization of FXIIIa after aptamer binding. One of these aptamers, named FA12, efficiently captures FXIIIa even in the presence of zymogenic FXIII subunits. Furthermore, this aptamer inhibits the incorporation of FXIII and α2-antiplasmin (α2AP) into fibrin(ogen) with IC50-values of 38 nM and 17 nM, respectively. In addition to FA12, also another aptamer, FA2, demonstrated significant effects in plasma-based thromboelastometry (rotational thromboelastometry analysis, ROTEM)-analysis where spiking of the aptamers into plasma decreased clot stiffness and elasticity (p < 0.0001). The structure–function correlations determined by combining modeling/docking strategies with quantitative in vitro assays revealed spatial overlap of the FA12 binding site with the binding sites of two FXIII substrates, fibrinogen and α2AP, while FA2 binding sites only overlap those of fibrinogen. Taken together, these features especially render the aptamer FA12 as an interesting candidate molecule for the development of FXIIIa-targeting therapeutic strategies and diagnostic assays.

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Structure functional insights into calcium binding during the activation of coagulation factor XIII A

Cited by 68 publications

References 66 publications

Abnormal Coagulation Function of Patients With COVID-19 Is Significantly Related to Hypocalcemia and Severe Inflammation

Abnormal Coagulation Function of Patients With COVID-19 Is Significantly Related to Hypocalcemia and Severe Inflammation

Functionalizing Fibrin Hydrogels with Thermally Responsive Oligonucleotide Tethers for On-Demand Delivery

Functional and Structural Characterization of Nucleic Acid Ligands That Bind to Activated Coagulation Factor XIII

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