Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability and resistance to fibrinolysis

Fibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen α-chain (αC-region) is composed of an αC-domain and αC-connector. Two recombinant fibrinogen variants (α390 and α220) were produced to investigate the role of subregions in modulating clot stability and resistance to lysis. The α390 variant, truncated before the αC-domain, produced clots with a denser structure and thinner fibres. In contrast, the α220 variant, truncated at the start of the αC-connector, produced clots that were porous with short, stunted fibres and visible fibre ends. These clots were mechanically weak and susceptible to lysis. Our data demonstrate differential effects for the αC-subregions in fibrin polymerisation, clot mechanical strength, and fibrinolytic susceptibility. Furthermore, we demonstrate that the αC-subregions are key for promoting longitudinal fibre growth. Together, these findings highlight critical functions of the αC-subregions in relation to clot structure and stability, with future implications for development of novel therapeutics for thrombosis.

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Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability and resistance to fibrinolysis

10.1101/2021.05.07.443174 ◽

2021 ◽

Author(s):

Helen McPherson ◽

Cedric Duval ◽

Stephen R Baker ◽

Matthew S Hindle ◽

Lih T Cheah ◽

...

Keyword(s):

Mechanical Strength ◽

Blood Coagulation ◽

Mechanical Stability ◽

Blood Clot ◽

C Terminus ◽

Fibre Growth ◽

Clot Structure ◽

Clot Stability ◽

Longitudinal Fibre

Fibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen α-chain (αC-region) is composed of an αC-domain and αC-connector. Two recombinant fibrinogen variants (α390 and α220) were produced to investigate the role of subregions in modulating clot stability and resistance to lysis. The α390 variant, truncated before the αC-domain, produced clots with a denser structure and thinner fibres. In contrast, the α220 variant, truncated at the start of the αC-connector, produced clots that were porous with short stunted fibres and visible fibre ends. These clots were mechanically weak and susceptible to lysis. Our data demonstrate differential effects for the αC-subregions in fibrin polymerisation, clot mechanical strength, and fibrinolytic susceptibility. Furthermore, we demonstrate that the αC-subregions are key for promoting longitudinal fibre growth. Together, these findings highlight critical functions of the αC-subregions in relation to clot structure and stability, with future implications for development of novel therapeutics for thrombosis.

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A Re-Appraisal of the Role of Blood Coagulation and Platelets in the Generalized Shwartzman Phenomenon

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649455 ◽

1966 ◽

Vol 15 (03/04) ◽

pp. 519-538 ◽

Cited By ~ 10

Author(s):

J Levin ◽

E Beck

Keyword(s):

Blood Coagulation ◽

The State ◽

Coagulation System ◽

Renal Lesions ◽

Intravascular Coagulation ◽

Renal Glomeruli ◽

Coagulation Mechanism ◽

Shwartzman Phenomenon ◽

Do So

SummaryThe role of intravascular coagulation in the production of the generalized Shwartzman phenomenon has been evaluated. The administration of endotoxin to animals prepared with Thorotrast results in activation of the coagulation mechanism with the resultant deposition of fibrinoid material in the renal glomeruli. Anticoagulation prevents alterations in the state of the coagulation system and inhibits development of the renal lesions. Platelets are not primarily involved. Platelet antiserum produces similar lesions in animals prepared with Thorotrast, but appears to do so in a manner which does not significantly involve intravascular coagulation.The production of adrenal cortical hemorrhage, comparable to that seen in the Waterhouse-Friderichsen syndrome, following the administration of endotoxin to animals that had previously received ACTH does not require intravascular coagulation and may not be a manifestation of the generalized Shwartzman phenomenon.

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Factor Xa Enhances the Binding of Tissue Factor Pathway Inhibitor to Acidic Phospholipids

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650369 ◽

1996 ◽

Vol 75 (05) ◽

pp. 796-800 ◽

Cited By ~ 10

Author(s):

Sanne Valentin ◽

Inger Schousboe

Keyword(s):

Tissue Factor ◽

Tissue Factor Pathway Inhibitor ◽

Factor Xa ◽

Microtitre Plate ◽

C Terminus ◽

Microtitre Plate Assay ◽

Kunitz Domain ◽

Tissue Factor Pathway ◽

Acidic Phospholipids

SummaryIn the present study, the interaction between tissue factor pathway inhibitor (TFPI) and phospholipids has been characterized using a microtitre plate assay. TFPI was shown to bind calcium-independently to an acidic phospholipid surface composed of phosphatidylserine, but not a surface composed of the neutral phosphatidylcholine. The interaction was demonstrated to be dependent on the presence of the TFPI C-terminus. The presence of heparin (1 U/ml, unfractionated) was able to significantly reduce the binding of TFPI to phospholipid. The interaction of TFPI with phosphatidylserine was significantly decreased in the presence of calcium, but this was counteracted, and even enhanced, following complex formation of TFPI with factor Xa prior to incubation with the phospholipid surface. Moreover, a TFPI variant, not containing the third Kunitz domain and the C-terminus, was unable to bind to phospholipid. However, following the formation of a TFPI/factor Xa-complex this TFPI variant was capable of interacting with the phospholipid surface. This indicates that the role of factor Xa as a TFPI cofactor, at least in part, is to mediate the binding of TFPI to the phospholipid surface.

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THE RÔLE OF CEPHALIN IN BLOOD COAGULATION

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)85936-1 ◽

1922 ◽

Vol 50 (2) ◽

pp. 455-462

Author(s):

André Gratia ◽

P.A. Levene

Keyword(s):

Blood Coagulation

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Mechanical Behavior of Hydroxyapatite-Chitosan Composite: Effect of Processing Parameters

Minerals ◽

10.3390/min11020213 ◽

2021 ◽

Vol 11 (2) ◽

pp. 213

Author(s):

Hamid Ait Said ◽

Hassan Noukrati ◽

Hicham Ben Youcef ◽

Ayoub Bayoussef ◽

Hassane Oudadesse ◽

...

Keyword(s):

Molecular Weight ◽

Compressive Strength ◽

Mechanical Strength ◽

Bone Repair ◽

Mechanical Stability ◽

Three Dimensional ◽

Processing Parameters ◽

Composite Effect ◽

Solid Liquid ◽

The Impact

Three-dimensional hydroxyapatite-chitosan (HA-CS) composites were formulated via solid-liquid technic and freeze-drying. The prepared composites had an apatitic nature, which was demonstrated by X-ray diffraction and Infrared spectroscopy analyses. The impact of the solid/liquid (S/L) ratio and the content and the molecular weight of the polymer on the composite mechanical strength was investigated. An increase in the S/L ratio from 0.5 to 1 resulted in an increase in the compressive strength for HA-CSL (CS low molecular weight: CSL) from 0.08 ± 0.02 to 1.95 ± 0.39 MPa and from 0.3 ± 0.06 to 2.40 ± 0.51 MPa for the HA-CSM (CS medium molecular weight: CSM). Moreover, the increase in the amount (1 to 5 wt%) and the molecular weight of the polymer increased the mechanical strength of the composite. The highest compressive strength value (up to 2.40 ± 0.51 MPa) was obtained for HA-CSM (5 wt% of CS) formulated at an S/L of 1. The dissolution tests of the HA-CS composites confirmed their cohesion and mechanical stability in an aqueous solution. Both polymer and apatite are assumed to work together, giving the synergism needed to make effective cylindrical composites, and could serve as a promising candidate for bone repair in the orthopedic field.

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Role of Lime-Fibre on Mechanical Strength and Resilient Characteristics of Pond Ash

Transportation Infrastructure Geotechnology ◽

10.1007/s40515-021-00149-8 ◽

2021 ◽

Author(s):

Sudhakar Mogili ◽

Heeralal Mudavath ◽

Kalyan Kumar Gonavaram

Keyword(s):

Mechanical Strength ◽

Pond Ash

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A CACNA1A variant associated with trigeminal neuralgia alters the gating of Cav2.1 channels

Molecular Brain ◽

10.1186/s13041-020-00725-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Eder Gambeta ◽

Maria A. Gandini ◽

Ivana A. Souza ◽

Laurent Ferron ◽

Gerald W. Zamponi

Keyword(s):

Trigeminal Neuralgia ◽

Missense Mutation ◽

Neurotransmitter Release ◽

Trigeminal System ◽

Wild Type ◽

Calcium Dependent ◽

Whole Cell Patch Clamp ◽

C Terminus ◽

Dependent Inactivation

AbstractA novel missense mutation in the CACNA1A gene that encodes the pore forming α1 subunit of the CaV2.1 voltage-gated calcium channel was identified in a patient with trigeminal neuralgia. This mutation leads to a substitution of proline 2455 by histidine (P2455H) in the distal C-terminus region of the channel. Due to the well characterized role of this channel in neurotransmitter release, our aim was to characterize the biophysical properties of the P2455H variant in heterologously expressed CaV2.1 channels. Whole-cell patch clamp recordings of wild type and mutant CaV2.1 channels expressed in tsA-201 cells reveal that the mutation mediates a depolarizing shift in the voltage-dependence of activation and inactivation. Moreover, the P2455H mutant strongly reduced calcium-dependent inactivation of the channel that is consistent with an overall gain of function. Hence, the P2455H CaV2.1 missense mutation alters the gating properties of the channel, suggesting that associated changes in CaV2.1-dependent synaptic communication in the trigeminal system may contribute to the development of trigeminal neuralgia.

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