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Haemostasis
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
In the final common pathway, activated factor X together with factor V, calcium and platelet factor 3 convert prothrombin (II) to thrombin (IIa). Thrombin hydrolyses the arginine–glycine bonds of fibrinogen to fibrinopeptide A and B to form fibrin monomers. Hydrogen bonds link fibrin monomers to form a loose, insoluble fibrin polymer. Factor XIII activated by thrombin and calcium stabilize the fibrin polymers via covalent bond cross-links.
Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
The transformation of blood from fluid state into gel is connected with the production of an interwoven network of insoluble fibrin from fibrinogen. Human fibrinogen is a dimer protein constituted from three pairs of chains joined by disulfide bridges316 with a molecular weight approximating 340,000 Da and a structure described as (Aα, Bβ, γ)2 where Aα, Bβ, and γ represent fibrinopeptides A, B, and C, respectively. The stability of fibrinogen is associated with the negatively charged amino terminal regions of the Aa and Bp chains. The coagulation takes place in two distinct stages.105,293 The first stage is enzymatic, thrombin cleaves four arginyl-glycine bonds of fibrinogen and by releasing fibrinopeptides, fibrin is formed that can be represented by the formula (αβγ)2. Two other peptides are also released, AP and Y; these are analogs to fibrinopeptide A. Peptides released from fibrinogen, particularly fibrinopeptide B, enhance the response of smooth muscle to various stimuli. The second stage is the polymerization of fibrin.43 During this stage, fibrin monomers aggregate to form the matrix of the clot. Fibrinopeptide A is necessary for the initiation of polymerization, and it is released more rapidly than fibrinopeptide B. The release of the latter takes place simultaneously with polymerization.
Predisposition to Thrombotic Complications in Diabetes Mellitus
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
These data clearly indicate that a hypercoagulable state favors the thrombotic aspects of atherosclerosis in diabetic patients. To confirm that this activation exists, assessment was made of plasma concentrations of fibrinopeptide A, an indicator of fibrinogen activation by thrombin, and thrombin-antithrombin III complex (TAT), a sensitive and specific method for detecting latent clotting activation and a good indicator of in vivo generation of thrombin. High fibrinopeptide A levels found in diabetic patients, regardless of type, correlated with glycosylated hemoglobin, suggesting that poor glycemic control is associated with enhanced thrombin activity.65-67 Likewise, plasma levels of TAT were also found to be significantly elevated in diabetic patients.68,69 Interestingly, in patients with coronary artery disease the levels of TAT were higher in those with diabetes.70 These findings suggest a dynamic activation of coagulation occurring in patients with diabetes mellitus.
Demonstration of ultrasound-mediated therapeutic delivery of fibrin-targeted pioglitazone-loaded echogenic liposomes into the arterial bed for attenuation of peri-stent restenosis
Published in Journal of Drug Targeting, 2023
Melvin E. Klegerman, Melanie R. Moody, Shao-Ling Huang, Tao Peng, Susan T. Laing, Vijay Govindarajan, Delia Danila, Amirali Tahanan, Mohammad H. Rahbar, Deborah Vela, Curtis Genstler, Kevin J. Haworth, Christy K. Holland, David D. McPherson, Patrick H. Kee
In this study, we confirmed fibrin expression after balloon injury to the arterial wall. We used a peptide containing the fibrin-binding tripeptide glycyl-L-prolyl-L-arginine (GPR) to develop atheroglitatide. This peptide was first described [17] as the amino acid sequence exposed in the fibrinogen α-chain amino terminal knob after removal of fibrinopeptide A by thrombin. The sequence then binds to ‘holes’ in the γ-chain globular carboxy region of fibrin to contribute to formation of fibrin protofibrils. Others later demonstrated that addition of two carboxy-terminal prolines strengthened and stabilised the fibrinogen binding [35]. The nonapeptide used in this formulation, with the addition of a tri-glycyl spacer and amino terminal L-cysteine for thioether linkage, binds to both fibrinogen and fibrin. For our purposes, local arterial injection minimises cross-reactivity with circulating fibrinogen. This peptide is thus translatable for use in patients.
Differential expression of Lumican, Mimecan, Annexin A5 and Serotransferrin in ectopic and matched eutopic endometrium in ovarian endometriosis: a case-control study
Published in Gynecological Endocrinology, 2021
Tahreem Sahar, Aruna Nigam, Shadab Anjum, Farheen Waziri, S. K. Jain, Saima Wajid
The LC instrumentation used was Nano ACQUITY UPLC (Waters, Milford, MA) coupled to SYNAPT G2-S HDMS mass spectrometer (Waters, Milford, MA). For peptide trapping, we used Nano ACQUITY UPLC Symmetry C18 trap column (180 μm × 20 mm, 5 μm, Waters, Milford, MA) and for analytical separation Nano ACQUITY UPLC BEH130 C18 (75 μm × 150 mm, 1.7 μm, Waters, Milford, MA) column. The probability of ≥95% and good peptide identification (Ok designation in ProteinLynx Global SERVER (PLGS)) were required for protein quantification. Peptides were suspended to 80 μl of 3% acetonitrile in 0.1% formic acid. Five microliters of E. coli enolase standard loading control (Waters, Milford, MA) was added to 10 μl samples and from this mix 4 μl was loaded per injection. Data normalization was done based on internal standard (enolase) that was added to each sample. Glu-fibrinopeptide B was used as a lock mass (reference) compound. Mass accuracy was maintained by infusing this reference compound using lockspray throughout the analysis and scanning was done after every 30 s. Protein quantification was done with reference to E. coli enolase concentration in the sample by PLGS Expression-E software (Waters, Milford, MA).
Determination of variability due to biological and technical variation in urinary extracellular vesicles as a crucial step in biomarker discovery studies
Published in Journal of Extracellular Vesicles, 2019
Eline Oeyen, Hanny Willems, Ruben ’T Kindt, Koen Sandra, Kurt Boonen, Lucien Hoekx, Stefan De Wachter, Filip Ameye, Inge Mertens
The purified peptides were vacuum dried and dissolved in mobile phase A, containing 2% acetonitrile and 0.1% formic acid to a final concentration of 1 µg/µL, and spiked with 20 fmol Glu-1-fibrinopeptide B (Glu-fib, Protea biosciences, Morgantown, WV). Samples were analysed in random order. A total of 2 µg of protein was loaded on the column and the peptide mixture was separated by reversed-phase chromatography using an nanoACQUITY UPLC Symmetry C18 Trap Column (100Å, 5 µm, 180 µm x 20 mm, 2G, V/M, 1/pkg) (Waters, Milford, MA) connected to an ACQUITY UPLC PST C18 nanoACQUITY Column (10K psi, 130Å, 1.7 µm, 100 µm X 100 mm, 1/pkg) (Waters). A linear gradient of mobile phase B (0.1% formic acid in 98% acetonitrile) from 1% to 45% in 95 min followed by a steep increase to 90% mobile phase B in 10 min. A steep decrease to 1% mobile phase B is achieved in 5 min and 1% mobile phase B is maintained for 5 min. The flow rate is 400 nL per minute. Liquid chromatography was followed by tandem MS (LC-MS/MS) and was performed on a Q-Exactive plus MS (Thermo Fisher Scientific). A nanospray ion source (Thermo Fisher Scientific) was used. Full-scan spectrum (350 to 1850 m/z, resolution 70,000, automatic gain control 3E6, maximum injection time 100 ms) was followed by high-energy collision-induced dissociation (HCD) tandem mass spectra with a run time of 90 min. Peptide ions were selected for fragmentation by tandem MS as the 10 most intense peaks of a full-scan mass spectrum. HCD scans were acquired in the Orbitrap (resolution 17,500, automatic gain control 1E5, maximum injection time 80 ms).