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PubMed1988

Fibrinogen Nijmegen: congenital dysfibrinogenemia associated with impaired t-PA mediated plasminogen activation and decreased binding of t-PA.

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.

Blood Coagulation Disorders↗
PubMed2006

Inherited abnormalities of fibrinogen: 10-year clinical experience of an Italian group.

Inherited abnormalities of fibrinogen present a high variability in penetrance and expressivity, and clinical manifestations vary from severe bleeding or thrombosis to asymptomatic This variability makes clinical and genetic counseling more difficult. We report the experience of a clinical group working in specialist centers in Southern Italy on a series of consecutive patients presenting with congenital abnormalities of fibrinogen. Over 10 years, 18 patients were diagnosed to carry a congenital abnormality of fibrinogen. These patients and 26 first-degree relatives were investigated in-depth to fully characterize the nature of their abnormal fibrinogen levels. A gene mutation was identified in 15 patients (four afibrinogenemic patients, three hypofibrinogenemic patients, and eight dysfibrinogenemic patients). A new mutation was found in four of them: Aalpha Arg159Stop in one afibrinogenemic patient, Aalpha Arg104Cys in two hypofibrinogenemic patients, and Aalpha Pro270Thr in one dysfibrinogenemic patient. While all afibrinogenemic patients had clinically important bleeding, participants presenting with hypofibrinogenemia remained asymptomatic. In the presence of the synthesis of an abnormal molecule, the clinical phenotype was not strictly related to plasma fibrinogen levels but was associated with the molecular defect, most carriers remaining asymptomatic. Personal and family histories of bleeding and thrombosis are important for the clinical management of patients presenting with congenital abnormalities of fibrinogen. Biochemical and genetic investigations may be a useful guide for decision-making, providing additional steps in the assessment of the risk of patients presenting with low levels of a normal molecule (hypofibrinogenemia and afibrinogenemia) and with an abnormal molecule (dysfibrinogenemia), respectively.

Adolescent↗
PubMed2005

Fibrinogen Philadelphia, a hypodysfibrinogenemia characterized by abnormal polymerization and fibrinogen hypercatabolism due to gamma S378P mutation.

Fibrinogen Philadelphia, a hypodysfibrinogenemia described in a family with a history of bleeding, is characterized by prolonged thrombin time, abnormal fibrin polymerization, and increased catabolism of the abnormal fibrinogen. Turbidity studies of polymerization of purified fibrinogen under different ionic conditions reveal a reduced lag period and lower final turbidity, indicating more rapid initial polymerization and impaired lateral aggregation. Consistent with this, scanning and transmission electron microscopy show fibers with substantially lower average fiber diameters. DNA sequence analysis of the fibrinogen genes A, B, and G revealed a T>C transition in exon 9 resulting in a serine-to-proline substitution near the gamma chain C-terminus (S378P). The S378P mutation is associated with fibrinogen Philadelphia in this kindred and was not found in 10 controls. This region of the gamma chain is involved in fibrin polymerization, supporting this as the polymerization defect causing the mutation. Thus, this abnormal fibrinogen is characterized by 2 unique features: (1) abnormal polymerization probably due to a major defect in lateral aggregation and (2) hypercatabolism of the mutant protein. The location, nature, and unusual characteristics of this mutation may add to our understanding of fibrinogen protein interactions necessary for normal catabolism and fibrin formation.

Afibrinogenemia↗
PubMed1974

Fibrinogen Philadelphia. A hereditary hypodysfibrinogenemia characterized by fibrinogen hypercatabolism.

A new, autosomally inherited abnormal fibrinogen associated with hypofibrinogenemia has been described in several members of a family. Plasma fibrinogen measured either as thrombin-clottable protein or by immunodiffusion revealed a fibrinogen level ranging between 60 and 90 mg/100 ml. The thrombin time of plasma or purified fibrinogen was prolonged and only partially corrected by the addition of calcium. Purified fibrinogen prolonged the thrombin time of normal plasma. Fibrinopeptide release by thrombin was normal in rate and amount, but fibrin monomer aggregation was grossly disturbed, especially in a high ionic strength medium. We have designated this fibrinogen "fibrinogen Philadelphia." Acrylamide gel electrophoresis of mixtures of [121I]normal and [125I]abnormal fibrinogens revealed a slight increase in the anodal mobility of fibrinogen Philadelphia. Similarly, DEAE-cellulose chromatography showed slightly stronger binding of fibrinogen Philadelphia than normal. To elucidate the mechanism responsible for the low plasma fibrinogen concentration, simultaneous metabolic studies of autologous (patient) and homologous (normal) fibrinogen, labeled with 125I and 121I, respectively, were performed in two affected subjects. Autologous fibrinogen half-life was short and the fractional catabolic rate was markedly increased in both family members. In contrast, homologous fibrinogen half-life and fractional catabolic rate were normal. These metabolic studies demonstrate that rapid degradation of fibrinogen Philadelphia is largely responsible for the depressed levels of a plasma fibrinogen. This represents the first example of a mutant plasma protein in which the molecular defect is associated with an altered catabolism.

Adolescent↗
PubMed1985

[Hemostatic studies on acquired abnormal fibrinogenemia in severe liver diseases and umbilical cord blood].

An abnormal fibrinogen in patients with liver diseases, especially liver cirrhosis and hepatocellular carcinoma was examined. In these patients, delayed polymerization of fibrin monomer, which was useful for detecting abnormal fibrinogen in plasma and also detecting one of liver dysfunctions, was observed. Same results were found by using purified abnormal fibrinogen from these patients. However, according to electrophoretic and immunochemical studies, no difference were shown between purified abnormal fibrinogen and purified normal fibrinogen. The total content of sialic acid in purified abnormal fibrinogen was markedly increased as compared to that in purified normal fibrinogen. When coagulation time was examined by using asialofibrinogen treated with neuraminidase, the prolonged coagulation time was partially normalized even in patients with liver cirrhosis. These findings suggested that sialic acid might affect the polymerization of fibrin monomer. It was reported by Harvey (1978) that an abnormal fibrinogen in liver diseases was similar to the fetal fibrinogen in the content of sialic acid and prolongation of thrombin time. Therefore, purified fibrinogen from umbilical cord blood was also investigated by similar methods. Consequently, it was suggested that a dysfunction of fibrinogen in umbilical cord blood was not related to molecular abnormality, but some inhibitory mechanisms which caused the abnormal pattern of coagulation might be existed.

Fetal Blood↗
PubMed1994

Fibrinogen New Britain: characterization of an A alpha Arg 16-->His variant human fibrinogen.

Routine laboratory screening identified an abnormal fibrinogen in an asymptomatic patient from New Britain, Connecticut. This paper reports the characterization of the abnormal fibrinogen. Clinical clotting studies showed marked prolongation of both the thrombin and Reptilase times. A discrepancy was noted between the fibrinogen concentration as determined by a rate-dependent clotting assay (0.73 milligrams) vs immunological determination (2.27 milligrams). Polymerase chain reaction (PCR) based DNA sequencing was used to identify the underlying molecular defect. Fibrinogen New Britain was found to have a point mutation in exon 2 of the A alpha chain. This mutation results in the amino acid substitution Arg-->His at position 16 of the A alpha chain, the site of thrombin cleavage. The substitution results in delayed polymerization of fibrin clot due to impaired release of fibrinopeptide A by thrombin. Studies of fibrin fibre dimensions and structure showed New Britain fibrin fibres to have a larger mean diameter and an increased mass/length ratio when compared with normal fibrin fibres formed under the same conditions.

Amino Acid Sequence↗
PubMed1985

Fibrinogen Seattle II: defective release of fibrinopeptide A in a slow clotting fibrinogen.

A functionally abnormal fibrinogen was detected in a 27-year-old woman with no prior history of bleeding. Investigation of the defect revealed abnormal release of fibrinopeptide A and incomplete polymerization of fibrin monomers. Crosslinking of polymerized fibrin by Factor XIII was normal. To further characterize the dysfibrinogen, the increase in mechanical impedance during clot development was measured. Fibrinogen Seattle II showed several differences from normal fibrinogen: delayed onset of clotting, decreased rate of clot formation, and lower final clot impedance. Taken cumulatively, these data are consistent with an amino acid substitution at or near residue 16 in one of the A alpha chains, the point at which thrombin cleaves.

Adult↗
PubMed1983

Hereditary dysfibrinogenemia in a patient with thrombotic disease.

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.

Adolescent↗
PubMed1988

A new genetic fibrinogen variant (fibrinogen Erfurt I). Structurally characterized by an abnormal B beta-chain and present both in plasma and platelets.

An abnormal fibrinogen was discovered in the plasma of a clinically asymptomatic woman. This fibrinogen variant was analyzed by high resolution two-dimensional gel electrophoresis and its molecular abnormality established consisting in a slight decrease in molecular mass of the B beta-chains. Analysis of fibrin revealed that cleavage of fibrinopeptide B by thrombin is normal, the molecular defect being confined to the beta-portion of the B beta-chain. The same fibrinogen variant was detected in the blood platelets of the proposita. This finding supports the assumption of a common origin of plasma and platelet fibrinogen pools. Family studies revealed the presence of the abnormal fibrinogen in a brother of the proposita, thus confirming the genetic nature of the observed variant. The underlying mutant gene occurs in both carriers in heterozygous state.

Adult↗
PubMed1986

Fibrinogen Milano II: a congenital dysfibrinogenaemia associated with juvenile arterial and venous thrombosis.

A congenitally abnormal fibrinogen was isolated from blood of a young man with deep-vein thrombosis. Two other affected members of his family had three episodes of severe arterial thrombosis. The fibrinogen showed a delayed clotting by thrombin, but a normal clotting by Arvin, Reptilase, and prothrombin-staphylocoagulase complex. Analysis of the fibrinopeptides A and B by High Performance Liquid Chromatography did not reveal an abnormal peptide structure. The rate of release of A and B peptides by thrombin was strongly delayed, whereas the rate of release of fibrinopeptide A by Arvin appeared to be normal. The fibrin polymerization rate was normal. Interactions between the abnormal fibrinogen, platelets and the fibrinolytic system were also normal. Evidence is presented that the defective interaction between fibrinogen Milano II and thrombin is associated with a defective binding of thrombin to the fibrin moiety of the abnormal fibrinogen.

Adult↗
PubMed1982

An abnormal inherited fibrinogen (fibrinogen Genova) with delayed fibrin aggregation.

A new autosomally inherited dysfibrinogenaemia was recognized in 3 members of an Italian family. No bleeding tendency or thrombotic disease in any of the affected members were demonstrated. Coagulation tests revealed prolonged prothrombin, thrombin and Reptilase times. Plasma fibrinogen levels were normal with immunologic method and slightly reduced with chronometric assay: the other blood coagulation factors were normal. In addition, cross-immunoelectrophoresis performed on patients' plasma was indistinguishable from the normal. Dysfibrinogenaemia was confirmed by studying the purified fibrinogen. The fibrin polymerization curve, measured spectrophotometrically, showed a lower slope than the normal. A delay in fibrin monomer aggregation was revealed when compared to the normal at an equal concentration. The release of fibrinopeptides was normal. SDS polyacrylamide gel electrophoresis, isoelectric focusing and cross-immunoelectrophoresis of purified fibrinogen were not able to demonstrate any structural abnormality. The fibrinogen was named fibrinogen Genova.

Blood Coagulation Disorders↗
PubMed2003

Axillary vein thrombosis and congenital dysfibrinogenemia in a commercial pilot: a case report.

A 34-yr-old male commercial pilot developed a painful swollen right upper arm following an episode of trauma. Venography confirmed the clinical diagnosis of a right axillary deep venous thrombosis. Magnetic resonance imaging suggested the presence of a fibrous tissue band overlying the junction of the right subclavian and innominate veins, potentially creating a thoracic outlet syndrome. A thrombophilia screen revealed an abnormal fibrinogen variant consistent with a diagnosis of congenital dysfibrinogenemia. The pilot was treated with anticoagulant therapy for 4 mo. There were diagnostic difficulties in determining the definitive etiology of the axillary vein thrombosis. Congenital dysfibrinogenemia is a rare condition, which is asymptomatic in the majority, but may manifest with hemorrhage or thrombosis in up to 45% of cases. The clinical management of the pilot and the aeromedical implications of the diagnosis are discussed.

Adult↗
PubMed1997

Congenital dysfibrinogenemia.

Fibrinogen abnormalities can be classified as congenital or acquired. Each class manifests quantitative or qualitative alterations; the latter are known as dysfibrinogenemias. In dysfibrinogenemias, structural defects cause alterations in the conversion of fibrinogen to fibrin. Approximately 300 abnormal fibrinogens have been reported, and about 83 structural defects have been identified. The most common structural defect involve the fibrinopeptides and their cleavage sites, and the second most common involves the gamma-chain polymerization region. Approximately half of the mutants are clinically silent, whereas hemorrhage and thrombosis occur in almost equal numbers of cases. Study of the abnormal fibrinogens has provided insight into fibrinogen structure and fibrin formation and dissolution. Some of the structural abnormalities exhibit defective assembly and activation of components of the fibrinolytic system on the abnormal fibrin, resulting in impaired dissolution of fibrin, clinically associated with thrombosis.

Afibrinogenemia↗
PubMed1996

The relationship between the fibrinogen D domain self-association/cross-linking site (gammaXL) and the fibrinogen Dusart abnormality (Aalpha R554C-albumin): clues to thrombophilia in the "Dusart syndrome".

Cross-linking of fibrinogen at its COOH-terminal gamma chain cross-linking site occurs in the presence of factor XIIIa due to self-association at a constitutive D domain site ("gammaXL"). We investigated the contribution of COOH-terminal regions of fibrinogen Aalpha chains to the gammaXL site by comparing the gamma chain cross-linking rate of intact fibrinogen (fraction I-2) with that of plasma fraction I-9, plasmic fraction I-9D, and plasmic fragment D1, which lack COOH-terminal Aalpha chain regions comprising approximately 100, approximately 390, and 413 residues, respectively. The cross-linking rates were I-2 > I-9 > 1-9D = D1, and indicated that the terminal 100 or more Aalpha chain residues enhance gammaXL site association. Fibrinogen Dusart, whose structural abnormality is in the COOH-terminal "alphaC" region of its Aalpha chain (Aalpha R554C-albumin), is associated with thrombophilia ("Dusart Syndrome"), and is characterized functionally by defective fibrin polymerization and clot structure, and reduced plasminogen binding and tPA-induced fibrinolysis. In the presence of XIIIa, the Dusart fibrinogen gamma chain cross-linking rate was about twice that of normal, but was normalized in proteolytic fibrinogen derivatives lacking the Aalpha chain abnormality, as was reduced plasminogen binding. Electron microscopy showed that albumin-bound Dusart fibrinogen "alphaC" regions were located in the vicinity of D domains, rather than at their expected tethered location near the fibrinogen E domain. In addition, there was considerable fibrinogen aggregation that was attributable to increased intermolecular COOH-terminal Aalpha chain associations promoted by untethered Dusart fibrinogen aC domains. We conclude that enhanced Dusart fibrinogen self-assembly is mediated through its abnormal alphaC domains, leads to increased gammaXL self-association and gamma chain cross-linking potential, and contributes to the thrombophilia that characterizes the "Dusart Syndrome."

Dextrans↗