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)

Fibrinogen displays a regulation of considerable physiological significance by lowering the Ca2+ requirement for the conversion of the fibrin-stabilizing factor (Factor XIII) zymogen to the range of concentrations of this ion found in plasma. Fibrinogen modulates both Ca2+-dependent steps in the complex process of zymogen activation, involving the heterologous dissociation of subunits of the thrombin-modified zymogen (Factor XIII') species : formula: (see text) and the unmasking of iodoacetamide titratable sites during generation of transamidating activity : formula: (see text). It is interesting that a thrombin-independent pathway of zymogen activation : formula: (see text), which we found to operate at Ca2+ concentrations above 50 mM, is not affected by the presence of fibrinogen. Regulation by fibrinogen thus appears to be specific for controlling only the physiological pathway of zymogen conversion.
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PMID:Ca2+-related regulatory function of fibrinogen. 27 11

Factor XIIIa (active fibrin-stabilizing factor) generated in heat-defibrinated plasma by the addition of thrombin can be measured by 14C-putrescine incorporation into casein. Modification of this assay be substituting 3H-putrescine of high specific activity as the donor amine permits measurement of amine incorporation by plasma even in the absence of added thrombin. Incorporation is calcium dependent, inhibited by iodoacetamide, and absent from congenital factor XIII-deficient plasma and from normal platelets. The transamidating activity detected by radioenzymatic assay catalyzed the formation of gamma-gamma dimers and alpha polymers of fibrin and was thus biologically functional. This fibrin cross-linking activity was absent from factor XIII-deficient plasma. These experiments show (1) some factor XIII is present in plasma as factor XIIIa; (2) this factor XIIIa can cross-link fibrin and thus has biologic activity as well; and (3) this activity is not present in factor XIII-deficient plasma. Factor XIIIa in normal plasma is possibly activated in vivo, perhaps by circulating thrombin, factor Xa, or other proteolytic enzymes.
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PMID:Detection of factor XIIIa (active fibrin-stabilizing factor) in normal plasma. 67 74

A large number of families have now been described in whom affected individuals have within their plasmas an abnormal species of fibrinogen (factor I). These defects, presumably examples of the phenomenon of allotypy--i.e., the synthesis of variant forms of a normal protein--have been inherited as autosomal dominant characteristics. In the great majority of cases, clotting is abnormally slow when thrombin is added to the abnormal plasma. Sometimes this defect appears to reside in impaired release of fibrinopeptides by thrombin. In other cases, fibrinopeptide release proceeds normally, but aggregation of fibrin monomers is impeded. In the latter instance, aggregation may be abnormally slow or, once it begins, it may proceed at a normal rate. Curiously, a bleeding tendency is more likely to occur in patients in whom fibrinopeptide release is impaired, while dehiscence of operative wounds rarely complicates dysfibrinogenemias associated with impaired aggregation of fibrin monomers; thrombosis has been described in both groups of patients. Most of the reported cases may be distinguished by functional criteria and by the physicochemical behavior and biochemical nature of the abnormal protein. Additonally, one family has been described in which plasma clots abnormally rapidly upon addition of thrombin, and two others in which crosslinking of fibrin by fibrin-stabilizing factor (factor XIII) is defective.
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PMID:Criteria for the differentiation of dysfibrinogenemic states. 77 32

A new class of biomaterials, called "bioartificial polymeric materials", was prepared blending a segmented polyurethane (PU) with fibrinogen (FBNG); and poly(acrylic acid) (PAA), poly(acrylamide) (PAAM), poly(vinyl alcohol) (PVAL), with collagen (CLG), respectively. The PU-FBNG material was processed through a spraying, phase-inversion technique to fabricate porous tubular conduits. FBNG was subsequently converted into covalently cross-linked fibrin (FBN) through the action of thrombin (Th), fibrin-stabilizing factor (FSF), and calcium ions. Differential scanning calorimetry (DSC) showed the cross-linked blend was more stable than native cross-linked FBN. Tensile behaviors of the PU-FBN materials closely matched those of a natural artery on varying the ratio PU/FBN. Implantation experiments in the rat model showed a mature internal capsule and good tissue organization of PU-FBN (50%) grafts in the regenerated arterial wall. However, 50% of FBN did not assure adequate mechanical resistance, and aneurysmal changes were seen in some grafts. DSC of CLG-based materials, processed by casting, showed that the synthetic component offered definite advantage compared to the CLG denaturation temperature, particularly noticeable for CLG-PAA and CLG-PVAL blends. Material advantages and drawbacks are discussed.
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PMID:Bioartificial polymeric materials obtained from blends of synthetic polymers with fibrin and collagen. 186 55

A study is presented of 63 patients with pulmonary tuberculosis suffering of chronic alcoholism. Examination of the activated recalcification time, thrombin and prothrombin time, plasma fibrinogen level, fibrinolytic activity of the blood, ethanol and protaminsulfate tests, fibrin-stabilizing factor, autocoagulation test revealed in most of these patients significant disorders of the coagulation activity suggesting predisposition to intravascular blood coagulation.
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PMID:[Blood coagulation and fibrinolysis in patients with pulmonary tuberculosis suffering from chronic alcoholism]. 258 27

Thrombin-catalyzed release of activation peptide (AP) from plasma factor XIII was studied to characterize the regulation of this initial step in the activation of factor XIII zymogen (fibrin-stabilizing factor). High-performance liquid chromatography was used to monitor the kinetics of release of AP. Non-cross-linked polymeric fibrins I and II (polymerized des-A- and des-A,B-fibrinogens), physiological substrates of factor XIIIa, were shown to be potent promoters of thrombin-catalyzed release of activation peptide from factor XIII. These promoters are proposed to act by complexing factor XIII and reducing the apparent Km for thrombin-catalyzed release of AP. Since thrombin-catalyzed release of AP is inefficient in the absence of polymerized fibrin, this mode of regulation should minimize formation of factor XIIIa prior to the formation of its fibrin substrates. The promoting activity of polymeric fibrin was rapidly lost when catalytically competent factor XIIIa was allowed to form. This observation suggested the possibility that factor XIIIa catalyzed cross-linking of fibrin inactivates fibrin as a promoter for the thrombin-catalyzed release of AP from factor XIII. Consistent with this view, the thiol reagent S-methyl methanethiosulfonate inactivated factor XIIIa, blocked cross-linking of fibrin, and protected against loss of its promoter activity. This mode of feedback regulation of the activation process by catalytically active factor XIIIa may serve to ensure against continued generation of factor XIIIa after its fibrin substrates have been cross-linked.
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PMID:Regulation of formation of factor XIIIa by its fibrin substrates. 286 98

We have determined the primary structure of human placental factor XIIIa, an enzyme [fibrinoligase, transglutaminase, fibrin-stabilizing factor, EC 2.3.2.13 (protein-glutamine:amine gamma-glutamyltransferase)] that forms intermolecular isopeptide bonds between fibrin molecules as the last step in blood coagulation. Placental factor XIIIa is an unglycosylated polypeptide chain of 730 amino acid residues (Mr = 83,005) that appears to be identical to the a subunit of the plasma zymogen factor XIII. Ca2+-dependent activation of factor XIIIa by thrombin removes a blocked amino-terminal peptide and unmasks a reactive thiol group at Cys-314. A second specific cleavage after Lys-513 by thrombin inactivates factor XIIIa and produces an amino-terminal 56-kDa fragment and a 24-kDa fragment. The amino acid sequence of factor XIIIa is unique and does not exhibit internal homology, but its active center is similar to that of the thiol proteases. The probable Ca2+-binding site of factor XIIIa has been identified by homology to the high-affinity sites in calmodulins. Knowledge of the primary structure of factor XIIIa will aid elucidation of the mechanism of its enzymatic action and that of the many tissue transglutaminases of which it is the prototype. This will also facilitate production of factor XIIIa by recombinant DNA technology for use in treatment of congenital factor XIII deficiencies and in the postoperative healing of wounds.
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PMID:Primary structure of blood coagulation factor XIIIa (fibrinoligase, transglutaminase) from human placenta. 287 56

Human fibrin-stabilizing factor (Factor XIII) has been studied immunologically by the preparation of specific anti-Factor XIII antiserum in rabbits. On immunodiffusion it was found that normal plasma produced two precipitin lines. One of the precipitin lines was identical with that present in soluble platelet extract (the alpha-component), the other with that present in normal serum (beta-component). Plasma and serum of patients with congenital Factor XIII deficiency contained only the beta-component. By adsorption it was possible to prepare a second antiserum with solely anti-alpha-activity that did not react with the serum or plasma of XIII-deficient patients. Both antisera neutralized the clot-stabilizing activity of normal plasma. The action of thrombin on fibrinogen-free plasma or platelet extract abolished the immunoprecipitin alpha-line but did not reduce the capacity to neutralize antibody as measured by clot stabilization. It is concluded that the plasma Factor XIII molecule consists of two immunologically identifiable components, alpha and beta. The clot-stabilizing activity and thrombin-reactive site are situated on the alpha-component. Patients with congenital Factor XIII deficiency are devoid of immunologically identifiable or functional alpha-component but retain immunologically identifiable beta-component. It is this beta-component that accounts for the observed immunologically detectable Factor XIII in those patients devoid of clot-stabilizing activity.
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PMID:Immunological studies of coagulation factor XIII. 419 4

Fibrin formed in response to ancrod, reptilase, or thrombin was reduced by beta-mercaptoethanol and examined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. It was found that ancrod progressively and totally digested the alpha-chains of fibrin monomers at sites different than plasmin; however, further digestion of fibrin monomers by either reptilase or thrombin was not observed. Highly purified ancrod did not activate fibrin-stabilizing factor (FSF); however, the reptilase preparation used in these experiments, like thrombin, activated FSF and thereby promoted cross-link formation. Fibrin, formed by clotting purified human fibrinogen with ancrod, reptilase, or thrombin for increasing periods of time in the presence of plasminogen, was incubated with urokinase and observed for complete lysis. Fibrin formed by ancrod was strikingly more vulnerable to plasmin digestion than was fibrin formed by reptilase or thrombin. The lysis times for fibrin formed for 2 hr by ancrod, reptilase, or thrombin were 18, 89, and 120 min, respectively. Evidence was also obtained that neither ancrod nor reptilase activated human plasminogen. These results indicate that fibrin formed by ancrod is not cross-linked and has significantly degraded alpha-chains: as expected, ancrod-formed fibrin is markedly susceptible to digestion by plasmin.
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PMID:Mechanism of ancrod anticoagulation. A direct proteolytic effect on fibrin. 426 97

Fibrinoligase, the fibrin cross-linking enzyme, transiently appearing during the course of coagulation in normal blood, was shown to catalyze the incorporation of a fluorescent amine, monodansylcadaverine [or N-(5-aminopentyl)-5-dimethylamino-1-naphthalene-sulfonamide] into casein. The reaction provided the basis of a sensitive fluorimetric method for measuring the activity of the enzyme (and also of similar other transpeptidases, such as transglutaminase). In tests involving plasma, certain difficulties had to be overcome which were mainly due to the fact that the enzyme itself does not occur in citrated plasma. Only its precursor (fibrin-stabilizing factor or factor XIII) is present, still requiring limited proteolytic activation by thrombin. Thus, in order to measure amine incorporation with plasma as a source of the factor, thrombin must be added. This necessitated a differential desensitization of the intrinsic fibrinogen so that the latter could not clot and could not thereby interfere with amine incorporation. Also, the thrombin-inactivating capacity of plasma had to be saturated to enable full conversion of the factor to the transpeptidase. Concentrations of casein, monodansylcadaverine, calcium, and hydrogen ions were chosen to permit almost maximal velocity of amine incorporation. A linear relationship with regard to plasma concentration could be obtained only under such conditions. No similar assay is presently available for quantitatively evaluating fibrin-stabilizing factor levels in plasma.The amine incorporation test was applied to a clinical case of hereditary total fibrin-stabilizing factor deficiency. The effect of transfusion therapy was studied, and some of the patient's relatives were examined. Whereas a paternal aunt and uncle gave values well within the normal range, a brother and the mother proved to be partially deficient and could be considered as heterozygous carriers. The father appeared to have a reduced level of fibrin-stabilizing factor, though not quite as low as the other two relatives. Two infusions (1 liter each) of fresh normal plasma, administered about 26 hr apart, brought levels in the patient's plasma close to those found in the mother and brother. The corrective power of the transfusions, however, rapidly declined within 5-6 days. Futility of the last transfusion could be ascribed to the appearance of a neutralizing antibody directed against the precursor stabilizing factor, a serious complication. General diagnostic versatility and potential of the quantitative amine incorporation assay with plasma is discussed.
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PMID:Diagnostic and genetic studies on fibrin-stabilizing factor with a new assay based on amine incorporation. 497 30


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