Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital dysfibrinogenemia was found in a patient with venous thrombosis. Blood clot lysis was prolonged and suggested an impairment of fibrinolysis. We investigated whether this was related to the fibrinogen abnormality. Fibrinopeptide release was normal but fibrin polymerization was defective in the patient. The stimulating effect of the patient's fibrin on t-PA mediated plasminogen activation was impaired. This could not be attributed to defective binding of plasminogen. However, the binding of t-PA to the patient's fibrin was about 16% less than to normal fibrin. A variant t-PA (G K1 K2 P), which contained only one of the two fibrin binding sites, i.e. the kringle-2 domain, was bound to the abnormal fibrin for only 50% of normal. We conclude that the prolongation of blood clot lysis and the impaired stimulation of t-PA mediated plasminogen activation are related to the defective binding of the kringle-2 domain of t-PA onto the fibrin moiety of the abnormal fibrinogen. The impairment of fibrinolysis might explain the occurrence of thrombosis in the patient.
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PMID:Fibrinogen Nijmegen: congenital dysfibrinogenemia associated with impaired t-PA mediated plasminogen activation and decreased binding of t-PA. 314 89

Congenital dysfibrinogenaemia was found in three non-related patients. None of them had a haemorrhagic tendency, but one gave a thrombotic history. When their fibrinogens were treated with thrombin, they released fibrinopeptides A and B at normal rates, but the resultant fibrin monomers produced exhibited abnormal polymerization curves. This abnormality was more marked in fibrinogen Villajoyosa than in Barcelonas III and IV. Plasminogen and t-PA binding to fibrin monomers from the three dysfibrinogenaemias was similar to that of normal fibrin monomers. The gamma chain was purified from the three fibrinogens, treated with CNBr and the peptides produced were separated by reversed-phase HPLC. Chromatograms of digested fibrinogens showed an abnormal peak that was not present in the normal gamma chain. Amino acid sequence analysis of abnormal peptides and genomic DNA sequencing revealed that the gamma arginine 275 had been changed in the three fibrinogens; in two cases it was substituted by histidine, and in the third by cysteine. The altered properties observed in fibrin monomers produced from fibrinogen with the gamma Arg 275-->His or gamma Arg 275-->Cys substitution, suggests that this amino acid is important in maintaining the protein structure necessary for normal polymerization, but is not essential for the binding of t-PA or plasminogen to fibrin. It also suggests that the change Arg-->Cys produces more severe alterations in the functions of fibrinogen than the substitution Arg-->His.
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PMID:Abnormal polymerization and normal binding of plasminogen and t-PA in three new dysfibrinogenaemias: Barcelona III and IV (gamma Arg 275-->His) and Villajoyosa (gamma Arg 275-->Cys). 765 33