Studies of platelet fibrinogen from a subject with a congenital plasma fibrinogen abnormality (fibrinogen Paris I).
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Autoradiography↗
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Comparative studies on the structures of the carbohydrate moieties of human fibrinogen and abnormal fibrinogen Nagoya.
Human fibrinogen contains four asparagine-linked sugar chains in one molecule. All B beta and gamma subunits obtained from both normal fibrinogen and abnormal fibrinogen Nagoya contain 1 mol each of an asparagine-linked sugar chain. The sugar chains were quantitatively liberated as radioactive oligosaccharides from the polypeptide portion by hydrazinolysis followed by N-acetylation and NaB3H4 reduction. By the combination of sequential exoglycosidase digestion and methylation analysis, the structures of the sugar chains of human fibrinogen were elucidated to be NeuAc alpha 2 leads to 6Gal beta 1 leads to 4GlcNAc beta 1 leads to 2Man alpha 1 leads to 6(NeuAc alpha 2 leads to 6Gal beta 1 leads to 4GlcNac beta 1 leads to 2Man alpha 1 leads to 3)Man beta 1 leads to 4GlcNAc beta 1 leads to 4GlcNAc and Gal beta 1 leads to 4GlcNAc beta 1 leads to 2Man alpha 1 leads to 6(NeuAc alpha 2 leads to 6Gal beta 1 leads to 4GlcNAc beta 1 leads to 2Man alpha 1 leads to 3)Man beta 1 leads to 4GlcNAc beta 1 leads to 4GlcNAc. Neither quantitative nor qualitative differences were found between the sugar chain moieties of normal fibrinogen and fibrinogen Nagoya, indicating that the molecular basis of the abnormality in the latter may reside in its polypeptide moieties.
Asparagine↗
Fibrinogen Copenhagen; an abnormal fibrinogen with defective polymerization and release of fibrinopeptide A, but normal adsorption of plasminogen.
A qualitatively abnormal fibrinogen was detected in the plasma of a 53 year old woman with severe arterial thrombotic disease. The concentrations of plasma fibrinogen and serum fibrinogen related material were normal. The abnormal fibrinogen was electrophoretically normal. The defects detected were an abnormality of polymerization of fibrin monomers and a decreased rate of release of fibrinopeptide A. The absorption of radiolabelled partially degraded plasminogen on to fibrin prepared from purified fibrinogen Copenhagen was normal.
Adsorption↗
Fibrinogen Guarenas, an abnormal fibrinogen with an Aalpha-chain truncation due to a nonsense mutation at Aalpha 467 Glu (GAA)-->stop (TAA).
Fibrinogen Guarenas is a dysfibrinogenemia with a nonsense mutation at G4731T that causes an Aalpha-chain truncation at Ser 466. This abnormal fibrinogen is associated with a bleeding diathesis, severe in the proposita and mild in one brother, even though the fibrinogen levels in plasma are normal. All other family members are asymptomatic. Fibrinogens from the proposita and one family member, the mother of the proposita, both heterozygous for the mutation, were studied. Turbidity curves of fibrin polymerization showed that the lateral association of protofibrils was impaired and the maximum rate of polymerization was slightly diminished. The binding of albumin to fibrinogen was increased compared to control due to the presence of a free sulfhydryl group because of the missing disulphide bridge between Aalpha-Cys 442-472 in the mutated molecules. The abnormal fibrinogen formed much less alpha-polymer, and gamma-dimer formation was delayed compared to the control. Plasminogen activation by t-PA in the presence of fibrin was decreased. When Guarenas clots were perfused with fibrinolytic enzymes, clot degradation was retarded. Clot structure studied by confocal 3D microscopy showed that the fibrin network was dense, made up of thin and highly branched fibers, which accounted for the decreased flow rates by buffer permeation and increased rigidity of the fibrin clots, measured using a torsion pendulum. It seems that the increased clot rigidity, decreased porosity, hypofibrinolysis and t-PA induced fibrinolysis, by itself are not necessarily associated with thrombotic disorders in dysfibrinogenemia.
Afibrinogenemia↗
Fibrinogen ""New York"--an abnormal fibrinogen associated with thromboembolism: functional evaluation.
A 54-yr-old woman presented with a 23-yr history of repeated life-threatening thromboembolism. The presence of a qualitatively abnormal fibrinogen was suggested by the demonstration of delayed and incomplete coagulation of plasma or partially purified fibrinogen by thrombin or Reptilase. Two brothers showed a similar in vitro defect but were clinically not affected. The plasma fibrinogen concentration was 0.50-1.64 mg/ml when estimated by heat turbidity, clottability, or immunologic techniques. The serum contained 80-820 mug/ml of unclottable fibrinogen-related materials even after 24 hr exposure to thrombin. The fibrinogen-related material in the serum showed faster anodal mobility an immunoelectrophoresis than that of normal plasma. Immunodiffusion studies with rabbit antihuman fibrinogen antiserum showed lines of identity between control plasma and the patient's plasma and serum. Studies of the kinetics of thrombin action on fibrinogen demonstrated impaired release of fibrinopeptide A and B and defective polymerization of preformed fibrin monomers. The maximum amount of fibrinopeptide A released by exhaustive treatment with thrombin was similar (per milligram protein) for both the patient's and control fibrinogen. This abnormal fibrinogen varient is tentatively designated fibrinogen "New York"; its possible identity with one of the previously described abnormal fibrinogens has not been excluded.
Aprotinin↗
Fibrinogen Kawaguchi: an abnormal fibrinogen characterized by defective release of fibrinopeptide A.
A congenital dysfibrinogenemia was found in a 32-year-old asymptomatic female and her immediate family. The propositus, apparently a heterozygote for the abnormality, characteristically showed defective release of fibrinopeptide A from half of her fibrinogen molecules. No fibrinopeptide A was cleaved off from the isolated abnormal molecule by thrombin or snake venoms (Reptilase and Ancrod) as evidenced by radioimmunoassay, high performance liquid chromatography and determination of the NH2-terminal amino acids. The abnormal fibrinogen formed a solid gel solely by the release of fibrinopeptide B upon incubation with thrombin. We provisionally designate this abnormal fibrinogen as "Fibrinogen Kawaguchi", although possible identity with other abnormal fibrinogens is not excluded.
Adult↗
[Fibrinogen "Hannover", a further abnormal fibrinogen].
Another abnormal fibrinogen--"fibrinogen Hannover"--is reported. As known from most dysfibrinogenemias the clottability is poor, while immunologic test, heat precipitating test and the staphylococcal clumping test give normal fibrinogen concentrations. The clotting time when using thrombin or thrombin like enzymes is prolonged, it can be corrected with high thrombin concentration or thrombin combined with calcium inons, but not with thrombin like enzymes combined with calcium ions. The mild bleeding diathesis was first noted when the patient underwent an operation.
Adult↗
Fibrinogen Longmont. A heterozygous abnormal fibrinogen with B beta Arg-166 to Cys substitution associated with defective fibrin polymerization.
B beta Arg166 to Cys substitution was identified in an abnormal fibrinogen named fibrinogen Longmont. The proband, a young woman, and her mother were heterozygous; both experienced episodes of severe hemorrhage at childbirth. The neo-Cys residues were found to be disulfide-bridged to either an isolated Cys amino acid or to the corresponding Cys residue of another abnormal fibrinogen molecule, forming dimers. Thrombin and batroxobin induced fibrin polymerization were impaired, despite normal release of fibrinopeptides A and B. Moreover, the polymerization defect was not corrected by removing the dimeric species or adding calcium. Fibrinogen Longmont had normal polymerization site a, as evidenced by normal GPRP-peptide binding. Thus, the sites A and a can interact to form protofibrils, as evidenced by dynamic light scattering measurements. These protofibrils, however, do not associate laterally in a normal manner, leading to an abnormal clot formation.
Biopolymers↗
Fibrinogen Cleveland II. An abnormal fibrinogen with defective release of fibrinopeptide A.
An abnormal fibrinogen (fibrinogen Cleveland II) was detected in the plasma of a 23-yr-old white man with a mild bleeding diathesis. The one-stage prothrombin time, thrombin time, and Reptilase time were all prolonged. 16 of 24 tested relatives had the defect, which appeared to be transmitted as an autosomal dominant characteristic. The thrombin time of normal plasma was slightly inhibited by the proband's plasma. The abnormally long thrombin time of fibrinogen Cleveland II was partially corrected by addition of calcium ions. Fibrinogen Cleveland II was indistinguishable from normal fibrinogen by immunoelectrophoresis, DEAE-cellulose column chromatography, or polyacrylamide gel electrophoresis of reduced fibrinogen in sodium dodecyl sulfate. The major defect detected appeared to be impaired release of fibrinopeptide A when fibrinogen Cleveland II was incubated with thrombin. This defect was localized to the NH(2)-terminal disulfide knot portion of the molecule. An abnormality of polymerization of fibrin monomers was also present, but the abnormal fibrin demonstrated relatively normal crosslinking. Despite these defects, fibrinogen Cleveland II achieved a degree of coagulability similar to normal fibrinogen and appeared to incorporate some molecules of fibrin with intact fibrinopeptide A into the clot. The fibrin clot that was formed appeared to be abnormal by electron microscopy. These functional defects and other descriptive characteristics appear to distinguish fibrinogen Cleveland II from other inherited abnormal fibrinogens.
Adult↗
Fibrinogen Caracas V, an abnormal fibrinogen with an Aalpha 532 Ser-->Cys substitution associated with thrombosis.
A new dysfibrinogenemia associated with thrombophilia has been identified in a Venezuelan kindred. Thrombin and Reptilase times were prolonged and the accelerating capacity of the patient's fibrin on the t-PA-induced plasminogen activation was decreased. In addition the affinity of fibrinogen for plasminogen was diminished. Permeability and electron microscopy studies revealed that the abnormal clot was made up of thin and densely packed fibres giving rise to a reduced fibrin gel porosity. This was confirmed by turbidity studies showing a decreased fibre mass/length ratio. Affected members were heterozygous for an Aalpha 532 Ser-->Cys mutation as demonstrated by genetic analyses. This abnormal fibrinogen has been designated as Fibrinogen Caracas V. The family study showed a convincing association between the mutation and thrombotic manifestations. The thrombotic tendency may be ascribed to lack of accelerating capacity of fibrin to induce fibrinolysis caused by an abnormal clot structure with thin fibres and reduced porosity.
Adolescent↗
"Fibrinogen Tokyo II". An abnormal fibrinogen with an impaired polymerization site on the aligned DD domain of fibrin molecules.
A hereditary dysfibrinogenemia associated with defective aggregation of fibrin monomers was found in a 39-yr-old female and in the members of her immediate family, who had all been asymptomatic. The abnormality was probably due to an impaired polymerization site exposed in the DD domain of two adjacent fibrin molecules, because plasmic fragment DD derived from the propositus' cross-linked fibrin bound far less tightly to insolubilized normal fragment E than that from the normal one. Its complementary polymerization site in the E domain of fibrin, which was exposed by thrombin cleavage, and the polymerization site in the D domain of fibrinogen, which was available without activation by thrombin, were both found to be normal. More anodal migration of the abnormal fragment DD than the normal one, as shown by immunoelectrophoresis, seemed to support our concept that the mutation most likely resides in the D domain of the abnormal fibrinogen molecule at or near a region closely related to the polymerization site that is exposed when two fibrin molecules are linearly aligned. The work of others on the polymerization of normal fibrin with different techniques yielded results consistent with our conclusions. We tentatively designate this type of abnormal fibrinogen "fibrinogen Tokyo II," but its possible identity with other abnormalities of fibrinogen reported heretofore is not excluded.
Adult↗
Fibrinogen Detroit - an abnormal fibrinogen with non-functinal NH2-terminal polymerization domain.
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Animals↗
Hypofibrinogenaemia is the commonest congenital fibrinogen abnormality in north India.
Congenital abnormalities of fibrinogen are rare disorders and all the cases reported in the literature indicate that the incidence of afibrinogenaemia is much higher than hypofibrinogenaemia. Of the total of 20 cases reported from other parts of India only one was congenital hypofibrinogenaemia. In contrast, the present study showed eight patients with congenital hypofibrinogenaemia among a total of nine unrelated North Indian patients with a fibrinogen abnormality. This disproportionately high incidence of hypofibrinogenaemia suggests the existence of a distinct genetic defect in the North Indian population.
Adolescent↗
[Fibrinogen (factor I) and abnormal fibrinogen].
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Adolescent↗
A correlation between thrombotic disease and a specific fibrinogen abnormality (A alpha 554 Arg-->Cys) in two unrelated kindred, Dusart and Chapel Hill III.
For the first time, a correlation between a specific fibrinogen abnormality and the clinical symptoms of thrombosis has been found in unrelated families. These abnormal fibrinogens have been designated Dusart and Chapel Hill III. The abnormal fibrinogen Chapel Hill III was identified previously in a patient with thrombotic disease. We purified fibrinogen from small aliquots of patient and normal plasmas by a simple, rapid procedure. Coomassie stained sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis demonstrated that fibrinogen Chapel Hill III contained several high molecular weight forms in addition to the two forms seen with normal fibrinogen. Immunoblot analysis of Chapel Hill III fibrinogen demonstrated that essentially all the high molecular weight forms react with antiserum to albumin. Immunoblot analysis of plasmin digests of Chapel Hill III fibrinogen demonstrated that albumin is linked to the C-terminus of the A alpha chain. Using DNA analysis, we found that the patient is heterozygous for a single base change, resulting in the substitution A alpha Arg 554-->Cys. This is the same change identified in fibrinogen Dusart. The Dusart family members who are heterozygous for this substitution also suffer from recurrent thrombotic disorders.
Afibrinogenemia↗
Congenital abnormal fibrinogens.
Congenital and hereditary abnormal fibrinogen is the most common of the inherited disorders of fibrinogen. There is no uniform clinical pattern which characterizes the disease and the diagnosis is evoked on the results of laboratory tests which show an abnormal conversion of fibrinogen to fibrin. This abnormality should be confirmed on the purified defective fibrinogen. Characterization of the abnormality includes physical, immunological, functional and structural analyses. Studies related to fibrinogen behavior upon plasmin digestion and those related to polymerization also provide useful information. Recognition of the specific nature of the molecular defect is dependent on molecular analysis. A single distinctive amino acid substitution is currently recognized for Fibrinogen Detroit, Lille and München.
Blood Coagulation Disorders↗
Fibrinogen Irvine: a qualitatively abnormal fibrinogen associated with the predisposition to recurrent visceral and peripheral venous thrombosis.
A slow clotting dysfibrinogen with delayed anodal immunoelectrophoretic mobility and impaired fibrinopeptide A release has been identified in a patient with recurrent portal vein and deep venous thrombosis. Affected family members tested in the initial screening were asymptomatic. The proband's father died of pulmonary embolism at age 44 years and had mesenteric thrombosis at necropsy. The association of a plasma protein abnormality with visceral thrombosis is unusual and has never been observed previously with a dysfibrinogen. The qualitative abnormality is transmitted as an autosomal codominant and is tentatively designated, fibrinogen Irvine.
Adult↗
Fibrinogen Seattle: a qualitatively abnormal fibrinogen in a patient with tetralogy of Fallot.
A dysfibrinogen was detected in the plasma of a 14-year-old asymptomatic Caucasian boy who had tetralogy of Fallot. The mutant molecular species could be traced through four generations in an autosomal dominant type of inheritance pattern. Nine of 14 family members were found to have the coagulopathy. Following laboratory and clinical evaluation, the proband underwent radical repair of the cardiac defect without incident. This variant is tentatively designated fibrinogen Seattle pending further characterization.
Adolescent↗