Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of organophosphorus inhibitors of serine esterases (proteases) on secretion from washed rabbit platelets was examined. Five noncytotoxic stimuli were employed: collagen, thrombin, heterologous anti-platelet antibody (in the absence of complement), rabbit C3 bound to zymosan, and platelet activating factor derived from antigen-stimulated, IgE-sensitized rabbit basophils. Diisoprophyl phosphofluoridate, three series of p-nitrophenyl ethyl phosphonates, and a series of cyclohexyl phenylalkylphosphonofluridates were all found to be inhibitory to the platelet secretion. These are irreversible inhibitors of serine proteases but in this system were only inhibitory if added to the platelets concurrently with the stimuli. Pretreatment of either the platelets or the stimuli with the inhibitors followed by washing, was without effect on the subsequent reaction. This suggested the involvement of stimulus-activatable serine proteases in the secretory process. The concept was supported by finding that nonphosphorylating phosphonates or hydrolyzed phosphonates or phosphonofluoridates were without inhibitory action. The effect of a series of phosphonates or phosphonoflouridates in inhibiting each stimulus exhibited a unique activity-structure profile. The demonstration of such unique profiles with four series of inhibitors for each of the five stimuli was interpreted as demonstrating that a specific activatable serine protease was involved in the platelet secretory response to each stimulus.
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PMID:Activation of stimulus-specific serine esterases (proteases) in the initiation of platelet secretion. I. Demonstration with organophosphorus inhibitors. 100 7

In isolated rabbit lungs standardized amounts of edema were induced. Stimulation with the Ca ionophore A23187, leukotriene C4, Pseudomonas aeruginosa cytotoxin and human serum (activated complement) all resulted in protein leakage into the alveolar space with no change in the total phospholipid content. The pressure-volume characteristics of the lungs and the characteristics of the lavage surfactant (Wilhelmy balance) were markedly altered, correlating to the lavage protein content. The surfactant alterations were reproduced by addition of perfusion fluid protein to control surfactant in vitro. All changes were far less expressed or even missing in isolated lungs developing the same amount of edema due to omittance of proteins from the perfusion liquid. Different proteins added to control surfactant in the Wilhelmy balance showed a marked rank order of potency in interfering with surfactant function: immunoglobulins G and M and elastin less than albumin less than fibrinogen less than fibrin monomers. The fibrin monomer effect was reproduced by addition of thrombin to a surfactant fibrinogen mixture and was partly reversed by subsequent incubation with plasmin. In conclusion, high-permeability edema induced by different means results in alterations of lung mechanics and surface activity of lavaged surfactant, presumably due to protein surfactant interaction. Among different proteins, fibrin monomers are especially effective in interfering with surfactant function.
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PMID:Alteration of surfactant function due to protein leakage: special interaction with fibrin monomer. 383 43

People deficient in C1-INH present recurrent angioedema localized to subcutaneous or mucous tissues. The defect can be caused by impaired synthesis, due to a genetic defect (hereditary angioedema), or by increased catabolism (acquired angioedema). In our experience the majority of patients with acquired angioedema (16 of 18) have autoantibodies to C1-INH in their serum. These autoantibodies bind to C1-INH with different and generally low affinity. The vasopermeability mediator responsible for attacks is still undefined: bradykinin (derived from cleavage of high molecular weight kininogen) and a kinin-like peptide (derived from the second component of complement) still remain the two primary candidates. We examined the systems controlled by C1-INH (complement, contact system, fibrinolysis and coagulation) and found that all of them are activated during angioedema attacks. Activation of the coagulation leads to generation of thrombin whose vasoactive effect can thus influence edema formation. Treatment of severe angioedema attacks is satisfactorily performed with C1-INH plasma concentrate although patients with an acquired defect frequently need very high doses. Attenuated androgens effectively prevent attacks in hereditary angioedema, but their safety, on the very long-term, needs to be further assessed. Acquired angioedema generally fail to respond to these drugs, but can be treated prophylactically with antifibrinolytic agents.
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PMID:Pathogenetic and clinical aspects of C1 inhibitor deficiency. 977 20

In vitro testing of blood contacting materials before clinical application is generally advisable. Four heparin coatings from different manufacturers were tested for adsorbed proteins and soluble activation markers. The surface with the highest antithrombin, thrombin, high-molecular-weight-kininogen (HMWK) and the lowest fibrinogen binding capacity (Carmeda, Medtronic) showed significantly lower levels of granulocytes and platelet activation (beta-TG, PMN-elastase release). No statistically significant differences in soluble markers of the coagulation system could be detected (F1 + 2, TAT). Interestingly, complement activation (TCC) was significantly reduced within the group of the lowest adsorption of the complement factor C3. Our data demonstrate that there is a relation between the binding affinity of proteins (C1-inhibitor, C3-complement) and the consecutive changes in complement activation (TCC). Therefore, measuring adsorbed proteins on artificial surfaces is a suitable, sensitive and very reproducible method for assessing the thrombogenicity of biomaterials.
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PMID:Quality assessment of heparin coatings by their binding capacities of coagulation and complement enzymes. 1097 57

Some strains of the bacterial pathogen Streptococcus pyogenes secrete protein SIC (streptococcal inhibitor of complement), including strains of the clinically relevant M1 serotype. SIC neutralizes the effect of a number of antimicrobial proteins/peptides and interferes with the function of the host complement system. Previous studies have shown that some S. pyogenes proteins bind and modulate coagulation and fibrinolysis factors, raising the possibility that SIC also may interfere with the activity of these factors. Here we show that SIC interacts with both human thrombin and plasminogen, key components of coagulation and fibrinolysis. We found that during clot formation, SIC binds fibrin through its central region and that SIC inhibits fibrinolysis by interacting with plasminogen. Flow cytometry results indicated that SIC and plasminogen bind simultaneously to S. pyogenes bacteria, and fluorescence microscopy revealed co-localization of the two proteins at the bacterial surface. As a consequence, SIC-expressing bacteria entrapped in clots inhibit fibrinolysis, leading to delayed bacterial escape from the clots as compared with mutant bacteria lacking SIC. Moreover, within the clots SIC-expressing bacteria were protected against killing. In an animal model of subcutaneous infection, SIC-expressing bacteria exhibited a delayed systemic spread. These results demonstrate that the bacterial protein SIC interferes with coagulation and fibrinolysis and thereby enhances bacterial survival, a finding that has significant implications for S. pyogenes virulence.
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PMID:Streptococcal inhibitor of complement (SIC) modulates fibrinolysis and enhances bacterial survival within fibrin clots. 3000 22