Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.5 (thrombin)
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Dysfibrinogenemia is a coagulation disorder caused by a variety of structural abnormalities in the fibrinogen molecule that result in abnormal fibrinogen function. It can be inherited or acquired. The inherited form is associated with increased risk of bleeding, thrombosis, or both in the same patient or family. Traditionally, dysfibrinogenemia is diagnosed by abnormal tests of fibrin clot formation; the thrombin time and reptilase time are the screening tests, and the fibrinogen clotting activity-antigen ratio is the confirmatory test. The inherited form is diagnosed by demonstrating similar laboratory test abnormalities in family members, and if necessary by analysis of the fibrinogen protein or fibrinogen genes in the patient. The acquired form is diagnosed by demonstrating abnormal liver function tests and by ruling out dysfibrinogenemia in family members. This article reviews the laboratory testing of dysfibrinogenemia and presents an algorithm for sequential test selection that can be used for diagnosis.
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PMID:Laboratory diagnosis of dysfibrinogenemia. 1190 May 86

The effects of elevated fibrinogen on thrombin and reptilase times have not been well documented. High fibrinogen levels are common (38% of specimens submitted to our coagulation laboratory). Among 102 patients in the present study, an endogenously elevated fibrinogen level was significantly associated, as follows, with prolonged reptilase times: 1 (4%) of 28 with normal fibrinogen levels, 6 (20%) of 30 with levels in the 400 to 700 mg/dL (4.0-7.0 g/L) range, 10 (34%) of 29 with levels in the 700 to 1,000 mg/dL (7.0-10.0 g/L) range, and 7 (47%) of 15 with fibrinogen levels greater than 1,000 mg/dL (10.0 g/L). This association was independent of patient age and fibrin degradation product titer. In contrast, thrombin time was not altered notably by elevated fibrinogen levels. In 4 patients studied further, the prolonged clotting times could be corrected or nearly corrected by adding calcium chloride or albumin, whereas no such corrections were demonstrable in samples from several hereditary dysfibrinogenemia control subjects. An elevated fibrinogen level is common and is associated with reptilase time prolongations. For patients with prolonged reptilase times, a fibrinogen assay is suggested before establishing a diagnosis of dysfibrinogenemia.
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PMID:Elevated fibrinogen in an acute phase reaction prolongs the reptilase time but typically not the thrombin time. 1216 88

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

This paper reports a new dysfibrinogenemia with an unusual pattern of laboratory assays. The patient, a 51-year-old female with a lifelong moderate bleeding history, was initially diagnosed with von Willebrand disease based on routine coagulation assays and the clinical bleeding presentation. During recent testing as part of a preoperative screen and without any current history of treatment, levels of von Willebrand factor (VWF) antigen, VWF activity, and factor VIII activity were all significantly elevated, which was unexpected given her previous diagnosis. Additional testing was performed looking for other heritable causes for her considerable bleeding tendency. Interestingly, the patient had a significantly prolonged Reptilase time, minimally short thrombin time, and an abnormal fibrinogen-crossed immunoelectrophoresis pattern. Clearly, this patient had a fibrinogen abnormality that had been missed when only routine coagulation screening assays were performed. A brief review of the fibrinogen literature revealed no other dysfibrinogenemias reported with a similar pattern of test results, and thus this defect was designated fibrinogen Denver.
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PMID:Fibrinogen Denver: a dysfibrinogenemia associated with an abnormal Reptilase time and significant bleeding. 1683 39

An asymptomatic, 29-year-old woman was referred to our hospital before surgery because in the basic study of hemostasis she showed a prolonged thrombin time (TT) and a normal reptilase time (RT). She had not received any anticoagulants so, to account for these abnormal results the presence of an inhibitor or a dysfibrinogenemia was suspected. A 1:1 mixture of the patient's plasma with control plasma did not correct the TT. Dysfibrinogenemia was excluded because the defibrinated plasma retained the inhibitory activity when mixed with normal plasma. When 0.02 mg/ml of Protamine Sulphate (a concentration that neutralizes 1 U/mL of heparin in normal plasma) was added to the patient's plasma, the inhibitory activity did not disappear. IgG from the patient and from normal serum was isolated. The patient's IgG was able to prolong the TT of a normal plasma and of a purified fibrinogen. The patient IgG did not impair the catalytic activity of thrombin, because no difference was observed in the hydrolysis of S-2238 by 1 U NIH human thrombin with normal or patient IgG. The time course of the thrombin-mediated fibrinopeptide-release from normal fibrinogen with the patient's IgG, showed a delay in the fibrinopeptide B (FPB) release without affecting the fibrinopeptide A (FPA) release. This patient has an IgG antibody that delays fibrinopeptide B release of fibrinogen.
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PMID:An acquired inhibitor that produced a delay of fibrinopeptide B release in an asymptomatic patient. 1740 47

Disorders of fibrinogen are usually caused by genetic mutations that result in low protein levels (hypofibrinogenemia) or an abnormal molecule (dysfibrinogenemia). However, environmental and plasma factors can have an acquired effect on its expression or function. For example, antibodies can bind fibrinogen and/or fibrin to interfere with polymerization and inhibit coagulation. The objective here was to determine the cause of dysfibrinogenemia in a 63-year-old man. Despite a low functional fibrinogen concentration and prolonged thrombin time, no inherited fibrinogen abnormality could be detected after extensive protein analysis and gene sequencing. Thus, electrophoresis methods and fibrinogen binding studies were used to establish the cause of the acquired dysfibrinogenemia. An immunoglobulin lambda light chain was found to bind fibrinogen as a monomer. It had no significant effect on fibrinopeptide release, but caused substantial defects in all other stages of thrombin-catalyzed fibrin polymerization. Binding to fibrinogen also seemed to prevent the light chain from being filtered through the kidneys, causing only low levels of it in the urine. Once in the urine, the lambda chain lost its anti-fibrinogen activity, apparently due to dimerization. The 63-year-old patient acquired dysfibrinogenemia from a monoclonal production of lambda light chain that bound and inhibited the function of fibrinogen. At age 64.5 he was diagnosed with monoclonal gammopathy of undetermined significance, explaining the abnormal immunoglobulin chain production. This case was particularly unusual in that the inhibition of fibrin polymerization was caused by a single immunoglobulin light chain, rather than by a whole antibody molecule.
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PMID:Acquired dysfibrinogenemia caused by monoclonal production of immunoglobulin lambda light chain. 1802 87

A 5-year-old boy was hospitalized for acute appendicitis. Routine preoperative hemostasis screening resulted in a diagnosis of dysfibrinogenemia. Fifteen days after the operation the patient was re-hospitalized for deep vein thrombosis. Genetic analysis of the fibrinogen genes revealed a novel missense mutation in exon 8 of fibrinogen gamma-chain gene (FGG): c.1031A>T, p.Asp344Val (p.Asp318Val in the mature chain) in heterozygosity. Interestingly, this same residue in the fibrinogen gamma chain was previously found to be mutated to a glycine (fibrinogen Giessen IV) in another young dysfibrinogenemia patient with thrombosis. The side chain of Asp344 (or Asp318) in the gamma chain is directly involved in binding to calcium. Abnormal polymerization of fibrin in fibrinogen Giessen IV and in the novel fibrinogen Caen described here could lead to the formation of abnormal clots leading to thrombosis, in addition to abnormal thrombin binding and decreased fibrinolysis.
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PMID:A novel Asp344Val substitution in the fibrinogen gamma chain (fibrinogen Caen) causes dysfibrinogenemia associated with thrombosis. 1883 13

Dengue virus is a mosquito-borne human viral pathogen that has recently become a major public health concern particularly in tropical and subtropical countries, predominantly in urban and periurban areas. Plasma from five patients infected by the virus was selected since they have in different degrees prolonged thrombin times: +2.1, +3.4, +5.7, +7.1 and +18.5 s, like a transitory acquired dysfibrinogenemia. The serotype could be determined in only two patients, being DEN-1 and DEN-3. The fibrinogen concentration was normal ranging from 2.5 to 3.2 g/l. In general, the fibrin degradation products of the patients were high, reaching values of 6000 ng/ml. The polymerization process was quite similar to that of the control, except in two cases where the final turbidity was almost half the control value. In one of these patients, the fibrinogen was purified and mixed with normal fibrinogen (v: v); the patients' fibrinogen impaired normal fibrin polymerization. Studies of the fibrinolytic process revealed that clots from dengue patients started to lyze before they have reached the maximum turbidity, although this was not reflected in the time needed for complete clot dissolution, which was similar to that of the control for all the patients. Fibrinolysis of clots made by mixing normal and patient purified fibrinogen (2.5: 1) was impaired. Clot images obtained by scanning electron microscopy showed that the patients' fibrin network had some degree of degradation and the fibers were thicker than those of the control (P < 0.05). This preliminary study seems to indicate that the dengue virus infection modifies the balance of coagulation-fibrinolysis toward hyperfibrinolysis and could modify the normal fibrinogen molecule.
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PMID:Fibrin formation and lysis studies in dengue virus infection. 1964 59

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

The most widely used technique for determination of fibrinogen concentration is the Clauss fibrinogen (FIB(Clauss)) assay, which measures the clotting time of plasma after addition of excess thrombin. More recently, the PT-derived fibrinogen (FIB(PT)) assay has been developed, based on the relationship between fibrinogen concentration and the kinetics of clot formation during the prothrombin time. The objective of this study was to compare the fibrinogen concentration determined by the FIB(Clauss) and FIB(PT) assays in citrated plasma samples from healthy dogs (n = 40), monkeys (n = 40), rabbits (n = 26), and rats (n = 58) by using an automated coagulation analyzer. Results of a t test analysis indicated that the mean plasma fibrinogen concentrations measured by the 2 assays for all 4 species were significantly different. According to Pearson correlation coefficients, the FIB(PT) assay displayed a high correlation (0.93 to 0.98) with the FIB(Clauss) assay for all species. When the FIB(PT) and FIB(Clauss) assays were compared by using Deming regression, positive or negative constant and proportional biases emerged for all species. Intra- and interassay coefficients of variation for the FIB(PT) and FI(BClauss) assays were 0.8% to 2.3% and 1.8% to 7.4%, respectively. In conclusion, the FIB(PT) assay is a rapid and economical method for estimating fibrinogen concentration in plasma samples from dogs, monkeys, rabbits, and rats. However, it should not be used without restriction. Further studies are required to investigate the performance of this assay in animals with various pathologic states, including coagulopathy, dysfibrinogenemia, and hypo- or hyperfibrinogenemia.
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PMID:Determination of plasma fibrinogen concentrations in beagle dogs, cynomolgus monkeys, New Zealand white rabbits, and Sprague-Dawley rats by using Clauss and prothrombin-time-derived assays. 2233 Jul 78


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