A novel fibrinogen γ chain frameshift deletion (c.637delT) in a patient with hypodysfibrinogenemia associated with thrombosis
Vytautas IvaškevičiusA. ThomasArijit BiswasHans Juergen EnsikatUlrich SchmittS. HorneffA. PavlovaBernd PoetzschJohannes Oldenburg
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Inherited fibrinogen (FG) disorders are rare and result in quantitative or/and qualitative FG deficiency. While the majority of patients with clinically relevant FG deficiencies demonstrate a bleeding phenotype, a subset of patients are at increased risk of thrombosis.We report a 54-years old man presenting with a thrombophilic phenotype characterized by two episodes of unprovoked venous thrombosis and a deep vein thrombosis several weeks after myocardial infarction. Recently, he developed A. carotis communis thrombosis and died. Coagulation tests were done using standard procedures. FG genes were screened using direct sequencing. Effect on fibrin clot structure was analyzed by scanning electron microscopy (SEM) and FG chain polymerization was analysed using SDS-PAGE.While thrombophilia testing was negative, we found a decreased concentration of clottable FG (126-148 mg/dl) compared to FG antigen (182-194 mg/dl of normal). The thrombin time was slightly prolonged, while aPTT and reptilase time were within the normal range. A novel deletion in FGG gene (c.637delT) resulting in a frameshift and the premature termination of the γ chain at amino acid position p.228 was identified. SDS-PAGE showed a time-shift in γ-γ and α-α cross linking. SEM showed no statistically significant differences between the patient´s and a healthy control´s fibrin clot structure.In addition to the reduction of FG concentration expected by the nature of the mutation also a functional defect (hypodysfibrinogenemia) was found. Moreover this mutation seems to increase the risk of thrombosis warranting long term anticoagulation possibly in a combination with antiplatelet drugs.Cite
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Fibrin stabilizing factor (FSF) catalyzed intermolecular crosslinking of fibrinogen. Differing from the known zero-order relationship in fibrin crosslinking, the rate of crosslinking of fibrinogen depended on its concentration (first-order). When the concentraction was extremely high, FSF rapidly catalyzed crosslinking to produce gelation of fibrinogen. This observation suggests that filtrational condensation of fibrinogen may contribute to deposition of insoluble fibrinogen in atheromatous tissue.In studies on mixtures of fibrinogen and fibrin, FSF showed almost equal affinities to both substrates; and, a) at low concentration of fibrinogen, in which crosslinking of fibrinogen proceeded very slowly compared to fibrin, fibrinogen inhibited the stabilization of fibrin clots by competitively binding to FSF.b) at high concentration of fibrinogen, in which fibrinogen could solubilize small amount of fibrin by forming the soluble fibrinogen-fibrin complex and inhibit fibrin clot formation, stabilization of soluble fibrinogen-fibrin complex by FSF added further inhibition of stabilization of fibrin clots. These findings may suggest the mechanism in which fibrinogen inhibit both polymerization and crosslinking of fibrin being produced in the circulating blood.
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Fibrinogen altered by thrombin-catalyzed liberation of fibrinopeptide A was found to combine with native fibrinogen to form a cold-precipitable complex we have called "cryoprofibrin." The altered fibrinogen lacking fibrino-peptide A polymerized into fibrin, but not until conditions for equilibrium between its incorporation into both cryoprofibrin and fibrin were satisfied. At equilibrium, the concentration of cryoprofibrin was maintained at a threshold proportional to the concentration of fibrinogen. When the concentration of cryoprofibrin was below threshold, fibrin could be depolymerized and solubilized by fibrinogen with resultant formation of cryoprofibrin. Since threshold concentrations of cryoprofibrin appear necessary for precipitation of fibrin, the concentration of cryoprofibrin in plasma provides a basis for determining intravascular deposition of fibrin. Intravascular deposition of fibrin does not appear to occur normally in rabbits, because the concentration of cryoprofibrin in plasma from normal rabbits is far below the threshold for precipitation of fibrin. The applicability of cryoprofibrin as an indicator of fibrin deposition is demonstrated by the occurrence of levels of cryoprofibrin approaching the threshold for precipitation of fibrin in plasma from endotoxin-treated rabbits. The current concept that the fibrinogen molecule can dissociate into subunits can be used to explain the conversion of fibrinogen to cryoprofibrin. As one possibility, the two residues of fibrinopeptide A contained in fibrinogen may be located on two separate subunits of the molecule; cryoprofibrin is produced when one of these subunits is replaced by a subunit altered by loss of fibrinopeptide A. Recombination of native subunits with subunits altered by loss of A would counter dissociation of cryoprofibrin and inhibit polymerization of subunits lacking fibrinopeptide A. As an alternate mechanism, two residues of A may be liberated concurrently from a single subunit. Cryoprofibrin would then correspond to a fibrinogen molecule, containing a subunit with two residues of A, in combination with an altered molecule containing a subunit lacking two residues of A. Liberation of fibrinopeptide B did not contribute measurably to production of fibrin resulting from limited action of thrombin on rabbit fibrinogen. Both fibrin containing B but not A, and fibrin containing neither B nor A, as is produced by extensive action of thrombin, could be solubilized by fibrinogen. Thrombin, or another enzyme utilizing tosyl-L-arginine methyl ester as substrate, appeared reversibly to inhibit polymerization of fibrin containing fibrinopeptide B. This enzyme and fibrinogen were the only proteins appearing to inhibit polymerization in plasma from normal rabbits.
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The Amount of Fibrin Necessary to Give a Positive Ethanol Gelation Test at Various Fibrinogen Levels
The minimum fibrin‐fibrinogen ratio (f‐F ratio) required to give a positive ethanol gelation test at various fibrinogen concentrations was studied. Due to the fact that quantitation of soluble fibrin in plasma is difficult, highly purified fibrinogen was used. However, since a plasma milieu is required to achieve clear cut results with ethanol gelation (with purified fibrinogen alone, precipitation occurs), heat‐defibrinated, dialysed and lyophilized normal plasma was added. With this artificial plasma, which in all relevant respects proved very similar to plasma obtained from healthy donors, ethanol gelation was not observed at the highest attainable fibrinogen concentration (1150 mg/100 ml). At fibrinogen levels down to 5–600 mg%, the minimum f‐F ratio remained almost constant, but increased gradually by further lowering the fibrinogen concentration. At fibrinogen levels around 50 mg%, the ethanol gelation test remained negative, even in samples saturated with soluble fibrin, i.e. those containing visible fibrin threads.
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The effect of fibrinogen on the two steps of polymerization of two fibrin forms differing in the set of polymerization sites (fibrin-desAA and fibrin-desAABB) was studied. It was shown that fibrinogen inhibited the protofibril growth and fibril formation at the stage of lateral aggregation more effectively with fibrin-desAABB than with fibrin desAA. When the fibrinogen D2-site was blocked by tetrapeptide Gly-His-Arg-Pro, the key structure of the E2-site, the inhibitory activity of fibrinogen diminished. A conclusion is drawn that the high susceptibility of fibrin-desAABB to fibrinogen is due to the interaction of the E2-active site with the D2-site of the fibrinogen molecule. The concentration dependence of the tetrapeptide Gly-His-Arg-Pro-induced inactivation of fibrinogen and the effects of temperature and Ca2+ on the tetrapeptide interaction with fibrinogen were investigated.
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