Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An abnormal fibrinogen was discovered in the plasma of a clinically asymptomatic woman. Laboratory evaluation of five members of the affected family showed low fibrinogen values in kinetic assays whereas the fibrinogen levels, tested by immunological procedures were normal. The patient's plasma had an inhibitory effect on the thrombin time of normal plasma. The calcium ions totally corrected the thrombin and reptilase times. Either low or high ionic strength prolonged the thrombin time of the proposita's purified fibrinogen. Kinetic analysis of clotting by monitoring transmission at 350 nm showed abnormally slow clotting with thrombin and reptilase. Assays were preformed in whole plasma as well as in purified fibrinogen. A delay in the rate of polymerization was evident when purified patient monomers were compared with those of normals. Immunoelectrophoretic, chromatofocusing, and isoelectrofusing experiments detected neither structural nor immunological abnormalities of fibrinogen. The rate of release of fibrinopeptide A by thrombin, measured by a specific immunoenzymatic method was also normal. HPLC analysis showed normal liberation of fibrinopeptides after prolonged thrombin action. Cross-linking of fibrin by factor XIII and lysis of fibrinogen by plasmin were normal. In view of these results, the defect of this dysfibrinogenemia, designated as Fibrinogen Oviedo I, probably could be due to conformational modifications in the D section of the molecule.
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PMID:Fibrinogen Oviedo I. A new Spanish dysfibrinogenaemia. 213 36

Activation of plasminogen by tissue-type plasminogen activator (tpA) is potentiated by fibrin. We have demonstrated the role of fibrin polymerization in the potentiating effect of tpA-induced fibrinolysis. Therefore a pathogenic mechanism of thrombotic disorder may be related to an abnormal fibrin polymerization: the abnormal clot being less accessible to fibrinolysis than normal one. This defective lysis may be due to a defective enhancement by the abnormal fibrin of plasminogen activation by tpA, as demonstrated for fibrinogen Dusard, a congenital dysfibrinogenemia associated with a very severe thrombotic disorder. In some other cases, a decrease in the availability of the plasmin cleavage sites in fibrin clot may be involved. On the contrary, some antithrombotic drugs such as pentosane polysulfate in modifying clot structure allow a better degradation of fibrin clot by fibrinolytic enzymes. It is speculated that this enhanced fibrinolysis could explain, almost in part, the antithrombotic action of these drugs.
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PMID:[Importance of the structure of the clot in thrombolysis]. 244 30

A dysfibrinogenemia (fibrinogen Sevilla) was detected in a 64-yr-old woman with no previous history of hemorrhagic diathesis or thrombosis. Thrombin and reptilase times were prolonged. The aggregation of fibrin monomers showed a prolonged latency time with a defective slope although fibrinopeptide release and clot stabilization were found to be normal. Plasmin proteolysis was abnormal with a much slower plasmic degradation in patient's purified fibrinogen. By chromatofocussing the patient's fibrinogen showed an abnormality in pattern elution with a second peak eluting at a pH slightly more basic than the normal one (pH 5.5). Likewise, the isoelectrofocussing of purified non-reduced patient's fibrinogen in agarose gel showed an abnormal distribution in its focussed bands, especially in a group which focussed in a pI-interval between 5.20-5.85. By two-dimensional electrophoresis we did not find any abnormality in the fibrinogen-reduced chains. These results could indicate that the abnormal monomer aggregation, as well as the defective plasmin lysis, could be due to conformational aspects of fibrinogen rather than to structural defects.
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PMID:Fibrinogen Sevilla, a congenital dysfibrinogenemia characterized by an abnormal monomer aggregation and a defective plasmin lysis. 271 97

An abnormal fibrinogen was found in two asymptomatic members (father and daughter) of the same family, originating from northern Italy. Routine coagulation studies revealed prolonged thrombin and reptilase clotting times. Plasma fibrinogen levels, as determined by a functional assay, were markedly diminished, whereas the heat precipitation method indicated normal fibrinogen values. On the basis of these findings, a tentative diagnosis of dysfibrinogenemia was made, and according to the accepted nomenclature, this fibrinogen variant was called "fibrinogen Milano l." The time course of fibrinopeptide A and B release from fibrinogen Milano l was normal, but the aggregation of fibrin monomers was delayed. Two-dimensional electrophoresis of reduced variant fibrinogen chains showed a defective gamma-chain with increased cathodic mobility. An abnormal electrophoretic mobility was observed also for the gamma-chain remnants of fibrinogen fragments D1 and D2 derived from fibrinogen Milano l, whereas the charge anomaly was lost after a further digestion by plasmin to D3, suggesting that the structure abnormality of this variant is situated in the region gamma 303-356. An abnormal peptide was isolated after cyanogen bromide cleavage of intact fibrinogen Milano l. This fragment spans from position gamma 311 to gamma 336. Amino acid analysis of the abnormal peptide showed the presence of valine and a diminished content of aspartic acid. Sequence analysis demonstrated an amino acid exchange Asp----Val in the gamma-chain at position 330.
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PMID:Characterization of fibrinogen Milano I: amino acid exchange gamma 330 Asp----Val impairs fibrin polymerization. 370 59

A new case of congenital dysfibrinogenemia, in which the patient has severe thrombotic disease, is reported. The abnormal fibrinogen molecules are characterized by normal fibrinopeptide release with thrombin and defective polymerization in the formation of fibrin. Clotting times with ancrod and reptilase are significantly prolonged. All other coagulation tests (except those for fibrinogen function) are normal, and the patient has no other underlying disease. The apparent paradox of defective fibrinogen, which clots abnormally and is yet associated with thrombotic disease, can be explained by further analysis of the patient's fibrinogen. The two important functional properties of this fibrinogen are: (1) it forms fibrin gels that are extremely rigid, and (2) the fibrin is highly resistant to lysis by plasmin. Thus, although the abnormal fibrinogen forms defective clots, the fibrin that is formed cannot be removed by the fibrinolytic system. These results provide a molecular explanation for the thrombotic disease in this patient. This abnormal fibrinogen appears to have unique characteristics and has been designated as fibrinogen Chapel Hill Ill.
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PMID:Hereditary dysfibrinogenemia in a patient with thrombotic disease. 619 1

Fibrinogen Cedar Rapids is a heterozygous dysfibrinogenemia (gammaR275C) that was associated with thromboembolism during and following pregnancy in three second-generation family members who also were heterozygotic for factor V Leiden (V R506Q). Like other dysfibrinogenemias with substitutions at position 275 of the gamma-chain, fibrinogen Cedar Rapids is characterized by defective end-to-end intermolecular fibrinogen and fibrin 'D : D' associations, a fibrin network structure that is composed of thicker and more highly branched fibers, normal fibrin 'D: E' associations, and normal factor XIII-mediated crosslinking of fibrinogen and fibrin. In addition, Cedar Rapids fibrinogen and fibrin displayed delayed plasmin lysis rates. Compared with normal fibrinogen, platelet aggregation or platelet fibrinogen receptor clustering was defective in the presence of fibrinogen Cedar Rapids. Most subjects with gammaR275 mutations do not experience clinical thrombotic disorders, suggesting that the combination of a factor V Leiden defect and a gammaR275C dysfibrinogenemia predisposes to thromboembolic disease.
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PMID:Coexisting dysfibrinogenemia (gammaR275C) and factor V Leiden deficiency associated with thromboembolic disease (fibrinogen Cedar Rapids). 1087 Aug 10

Congenital dysfibrinogenemia is a rare cause of unexplained thrombosis. However, most individuals with dysfibrinogenemia are asymptomatic, suggesting that co-morbid factors contribute to thrombo-embolic events. The potential roles of additional genetic or acquired prothrombotic risk factors are poorly understood because detailed family studies are lacking. Herein, we describe a family whose propositus was a young Caucasian man with recurrent venous thrombo-emboli and dysfibrinogenemia due to heterozygosity for an Arg-->Cys substitution at residue 275 in the gamma-chain. The only additional thrombophilic abnormality found in the proband was heterozygosity for a G/A transition at position -455 in the fibrinogen beta-chain promoter; a genotype associated with high acute phase levels of fibrinogen. The proband's father, who died of a cerebral artery thrombosis, carried the gammaR275C substitution but not the beta-promoter -455 variant. Among 14 living relatives, eight were heterozygous for one or the other mutation and only one, a 21-year-old niece, was dually affected. None had suffered bleeding or thrombosis. In vitro studies of the proband's purified fibrinogen revealed markedly abnormal thrombin-catalyzed polymerization and delayed fibrin clot lysis by tPA-activated plasmin. We hypothesize that the gammaR275C substitution predisposes to thrombosis by generating clots that are relatively resistant to fibrinolysis. The clinical risk is low, however, in the absence of an additional thrombophilic mutation. The beta-promoter variant could, theoretically, contribute to this risk by augmenting expression of the dysfibrinogen under conditions of stress. Like the common hereditary thrombophilias, heterozygous familial dysfibrinogenemia induces thrombosis in the setting of multiple prothrombotic influences.
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PMID:Fibrinogen bellingham: a gamma-chain R275C substitution and a beta-promoter polymorphism in a thrombotic member of an asymptomatic family. 1091 75

Elevated plasma homocysteine is associated with an increased risk of atherosclerosis and thrombosis. However, the mechanisms by which homocysteine might cause these events are not understood. We hypothesized that hyperhomocysteinemia might lead to modification of fibrinogen in vivo, thereby causing altered fibrin clot structure. New Zealand White rabbits were injected intraperitoneally (i.p.) every 12 h through an indwelling catheter with homocysteine or buffer for 8 weeks. This treatment raised the plasma homocysteine levels to about 30 micro mol L(-1) compared with 13.5 micro mol L(-1) in control rabbits by the end of the treatment period. The fibrinogen levels were 3.2 +/- 0.6 in homocysteine-treated and 2.5 +/- 1.1 mg mL(-1) in control rabbits. The reptilase time was prolonged to 363 +/- 88 for plasma from homocysteine-treated rabbits compared with 194 +/- 48 s for controls (P < 0.01). The thrombin clotting time (TCT) for the homocysteine-treated rabbits was significantly shorter, 7.5 +/- 1.7 compared with 28.6 +/- 18 s for the controls (P < 0.05). The calcium dependence of the thrombin clotting time was also different in homocysteinemic and control plasmas. Clots from plasma or fibrinogen of homocysteinemic rabbits were composed of thinner fibers than control clots. The clots formed from purified fibrinogen from homocysteine-treated rabbits were lyzed more slowly by plasmin than comparable clots from control fibrinogen. Congenital dysfibrinogenemias have been described that are associated with fibrin clots composed of thin, tightly packed fibers that are abnormally resistant to fibrinolysis, and recurrent thrombosis. Our results suggest that elevated plasma homocysteine leads to a similar acquired dysfibrinogenemia. The formation of clots that are abnormally resistant to fibrinolysis could directly contribute to the increased risk of thrombosis in hyperhomocysteinemia.
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PMID:Elevated plasma homocysteine leads to alterations in fibrin clot structure and stability: implications for the mechanism of thrombosis in hyperhomocysteinemia. 1287 4

We have previously shown functional differences in fibrinogen from hyperhomocysteinemic rabbits compared to that in control rabbits. This acquired dysfibrinogenemia is characterized by fibrin clots that are composed of abnormally thin, tightly packed fibers with increased resistance to fibrinolysis. Homocysteine thiolactone is a metabolite of homocysteine (Hcys) that can react with primary amines. Recent evidence suggests that Hcys thiolactone-lysine adducts form in vivo. We now demonstrate that the reaction of Hcys thiolactone with purified fibrinogen in vitro produces fibrinogen (Hcys fibrinogen) with functional properties that are strikingly similar to those we have observed in homocysteinemic rabbits. Fibrinogen purified from homocysteinemic rabbits and Hcys fibrinogen are similar in that (1) they both form clots composed of thinner, more tightly packed fibers than their respective control rabbit and human fibrinogens; (2) the clot structure could be made to be more like the control fibrinogens by increased calcium; and (3) they both form clots that are more resistant to fibrinolysis than those formed by the control fibrinogens. Further characterization of human fibrinogens showed that Hcys fibrin had similar plasminogen binding to that of the control and an increased capacity for binding tPA. However, tPA activation of plasminogen on Hcys fibrin was slower than that of the control. Mass spectrometric analysis of Hcys fibrinogen revealed twelve lysines that were homocysteinylated. Several of these are close to tPA and plasminogen binding sites. Lysines are major binding sites for fibrinolytic enzymes and are also sites of plasmin cleavage. Thus, modification of lysines in fibrinogen could plausibly lead to impaired fibrinolysis. We hypothesize that the modification of lysine by Hcys thiolactone might occur in vivo, lead to abnormal resistance of clots to lysis, and thereby contribute to the prothrombotic state associated with homocysteinemia.
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PMID:Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism of the thrombotic tendency in hyperhomocysteinemia. 1648 40

We found a heterozygous dysfibrinogenemia caused by the substitution of BbetaGly15Cys and designated it fibrinogen Hamamatsu II (H-II). Although the propositus suffered an infarction of the medulla oblongata, other thrombotic risk factors, paradoxical cerebral infarction, and arterial dissection were not found. To determine whether the delayed lysis of fibrin clots or not in the context of the BbetaGly15Cys substitution, we examined the clot lysis and plasmin generation of propositus' fibrinogen. Fibrinogen was purified from the propositus' and normal control plasma by immunoaffinity chromatography and was used for the following experiments: sodium dodecyl sulfate-polyacrylamide gel electrophoresis, fibrin polymerization, scanning electron microscopic observation of fibrin clot and fibers, clot lysis, and tissue-type plasminogen activator-mediated plasminogen activation. The H-II plasma fibrinogen showed the presence of albumin-binding variant forms, a dimeric molecule of variant fibrinogen, and impairment of lateral aggregation during fibrin polymerization. The H-II fibrin clot showed lower density of bundles and thinner diameters of fibers than in the normal fibrin clot. In the clot lysis experiments with overlaid plasmin, H-II fibrin showed a similar lysis period and lysis rate to the normal control. Moreover, plasmin generation from a mixture of thrombin, tissue-type plasminogen activator, plasminogen, and H-II fibrinogen also showed a similar rate to normal fibrinogen. Although the propositus suffered an infarction, the present study did not observe delayed clot lysis, that is, the clot was not resistant to plasmin degradation. Therefore, we did not clarify an association between the BbetaGly15Cys dysfibrinogenemia and arterial thrombosis.
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PMID:Analysis of plasmin generation and clot lysis of plasma fibrinogen purified from a heterozygous dysfibrinogenemia, BbetaGly15Cys (Hamamatsu II). 1980 4


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