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PubMed2000

Hypofibrinogenemia in an individual with 2 coding (gamma82 A-->G and Bbeta235 P-->L) and 2 noncoding mutations.

We investigated the molecular basis of hypofibrinogenemia in a man with a normal thrombin clotting time. Protein analysis indicated equal plasma expression of 2 different Bbeta alleles, and DNA sequencing confirmed heterozygosity for a new Bbeta235 P-->L mutation. Protein analysis also revealed a novel gamma(D) chain, present at a ratio of 1:2 relative to the gamma(A) chain. Mass spectrometry indicated a 14 d decrease in the gamma(D)-chain mass, and DNA sequencing showed this was caused by a novel gamma82 A-->G substitution. DNA sequencing established heterozygosity for 2 further mutations: T-->C in intron 4 of the Aalpha gene and A-->C in the 3' noncoding region of the Bbeta gene. Studies on the man's daughter, together with plasma expression levels, discounted both the Aalpha and Bbeta mutations as the cause of the low fibrinogen, suggesting that the gamma82 mutation caused the hypofibrinogenemia. This was supported by analysis of 31 normal controls in whom the Bbeta mutations were found at polymorphic levels, with an allelic frequency of 5% for the Bbeta235 mutation and 42% for the Bbeta 3' untranslated mutation. The gamma82 mutation was, however, unique to the propositus. Residue gamma82 is located in the triple helix that separates the E and D domains, and aberrant packing of the helices may explain the decreased fibrinogen concentration. (Blood. 2000;95:1709-1713)

3' Untranslated Regions↗
PubMed2000

Plasma viscosity, fibrinogen and the metabolic syndrome: effect of obesity and cardiorespiratory fitness.

The association between both plasma viscosity and fibrinogen concentration with clustering of metabolic risk markers was examined within a cross-sectional study of employed middle-aged men. Analyses were performed on a subsample of 629 non-smokers (46.7+/-7.8 years) without diabetes. The effect of obesity and cardiorespiratory fitness on these haemorheological parameters and their association with the metabolic syndrome was also investigated. The cohort was grouped by the number of metabolic markers present. Metabolic markers included high-density lipoprotein-cholesterol (<1.13 mmol/l), triglycerides (> or =1.805 mmol/l), glucose (> or =5.5 mmol/l) and diastolic blood pressure (> or =90 mm Hg). The age-adjusted odds ratio for hyperviscosity (> or =1.67 mPa/s) was 2.08 [95% confidence interval (CI), 1.06-4.05; P = 0.031] for the subjects with the metabolic syndrome (three or more metabolic markers) when compared with those with no metabolic abnormalities. The comparable age-adjusted odds ratio for hyperfibrinogenaemia (> or = 3.47 g/l) was non-significantly higher at 1.69 (95% CI, 0.87-3.27; P = 0.119). The mean age-adjusted plasma viscosity level and the prevalence of hyperviscosity increased significantly from 1.629 to 1.692 mPa/s (P = 0.0005) and from 21.0 to 36.0% with accumulating metabolic markers (P = 0.006). Plasma viscosity and fibrinogen concentration both increased with higher quartiles of skinfolds (P = 0.003 and P = 0.01, respectively) following adjustment for age, lipids and leucocyte count. Plasma viscosity was also significantly lower with higher levels of predicted maximum oxygen consumption (VO2max) (P = 0.0005). The odds ratio for hyperviscosity in subjects with the metabolic syndrome as compared with those with no metabolic markers was attenuated following adjustment for age, sum of skinfolds and predicted maximum oxygen consumption (VO2max) (1.44; 95% CI, 0.72-2.90; P = 0.307). These cross-sectional results suggest that plasma viscosity is associated with increased clustering of metabolic markers in middle-aged men of high socio-economic status. Obesity and poor cardiorespiratory fitness may be important in the development of haemorheological abnormalities associated with the metabolic syndrome.

Adult↗
PubMed2000

A functional assay suggests that heterodimers exist in two C-terminal gamma-chain dysfibrinogens: Matsumoto I and Vlissingen/Frankfurt IV.

Because it contains three pairs of polypeptides, fibrinogen isolated from heterozygous individuals is expected to be a mixture of homodimers and heterodimers. Nevertheless, heterozygous individuals with only homodimers have been identified. We synthesized two recombinant fibrinogens with the mutations from fibrinogen Vlissingen/ Frankfurt IV (gamma(delta)319, 320) and Matsumoto I (gammaD364H), both identified in heterozygous individuals. We found that polymerization of these fibrinogens was undetectable in 30 min; polymerization of a 1:1 mixture of variant and normal fibrinogen was the same as polymerization of a 1:1 mixture of buffer and normal fibrinogen; polymerization of either plasma fibrinogen was markedly impaired when compared to the 1:1 mixture of the respective variant and normal fibrinogens. We conclude that each plasma fibrinogen is a mix of homodimers and heterodimers, such that the incorporation of heterodimers into the fibrin clot impairs polymerization. We suggest that incorporation of heterodimers can induce clinical symptoms.

Afibrinogenemia↗
PubMed1976

Aspects of obstetrical defibrination in West Malaysia.

Five patients illustrate various aspects of obstetrical defibrination in West Malaysia, resulting from exaggeration of changes in fibrinolytic-coagulation equilibrium that occur at delivery. Hypofibrinogenaemia and fibrinolysis may occur in association or either feature predominate. These patients are from a population in which a variety of genetic and environmental factors may interact, e.g. abnormal haemoglobins, cold agglutinins, viral and other infections, introducing additional complications.

Abortion, Spontaneous↗
PubMed2000

Hypofibrinogenaemia with compound heterozygosity for two gamma chain mutations - gamma 82 Ala-->Gly and an intron two GT-->AT splice site mutation.

We investigated the molecular basis of hypofibrinogenaemia in a woman with a history of recurrent, pregnancy-associated bleeding, and miscarriage. She had a Clauss fibrinogen of 0.9 mg/ml and SDS PAGE of purified fibrinogen showed a normal pattern of chains. However careful inspection of reverse phase chain separation profiles showed apparent homozygosity for a more hydrophilic form of the gamma chain. DNA Sequencing showed only heterozygosity for a CGT-->GGT (Ala-->Gly) mutation at codon gamma82, but further sequencing showed an additional GT splice sequence mutation at the 5' end of intron 2 of the gamma gene. Translation of mRNA containing this intron would result in premature truncation explaining the phenotypic homozygosity of the gamma82 Ala-->Gly substitution. The patient's sister had a mild bleeding disorder with hypofibrinogenaemia and she too was a compound heterozygote for the y mutations. Her nephew had only the novel splice site mutation, while her mother and daughter inherited only the gamma82 Ala-->Gly substitution.

Adult↗
PubMed2000

Fibrinogen Alès: a homozygous case of dysfibrinogenemia (gamma-Asp(330)-->Val) characterized by a defective fibrin polymerization site "a".

Congenital homozygous dysfibrinogenemia was diagnosed in a man with a history of 2 thrombotic strokes before age 30. His hemostatic profile was characterized by a dramatically prolonged plasma thrombin clotting time, and no clotting was observed with reptilase. Complete clotting of the abnormal fibrinogen occurred after a prolonged incubation of plasma with thrombin. The release of fibrinopeptides A and B by thrombin and of fibrinopeptide A by reptilase were both normal. Thrombin-induced fibrin polymerization was impaired, and no polymerization occurred with reptilase. The polymerization defect was characterized by a defective site "a," resulting in an absence of interaction between sites A and a, indicated by the lack of fragment D(1) (or fibrinogen) binding to normal fibrin monomers depleted in fibrinopeptide A only (Des-AA fm). By SDS-PAGE, the defect was detected on the gamma-chain and in its fragment D(1). The molecular defect determined by analysis of genomic DNA showed a single base change (A-->T) in exon VIII of the gamma-chain. The resulting change in the amino acid structure is gamma 330 aspartic acid (GAT) --> valine (GTT). It is concluded that the residue gamma-Asp(330) is essential for the normal functioning of the polymerization site a on the fibrinogen gamma-chain.

Adult↗
PubMed1979

Coagulation abnormalities induced by Russell's viper venom in the rhesus monkey.

Coagulation studies were carried out in a group of non-human primates (rhesus monkeys) following envenomation with lethal and sublethal doses of Russell's viper venom. The envenomated animals showed significant fibrinogenopenia in association with or without disseminated intravascular coagulation. The findings offer a rational explanation for the bleeding manifestations seen in clinical cases of Russell's viper bite.

Afibrinogenemia↗
PubMed1975

A case against heparin therapy of intravascular coagulation.

Administration of a potentially dangerous drug like heparin should not be based on theroretical considerations and innumerable case reports but 1) on a firm diagnosis and 2) on a critical evaluation of the clinical benefit. The validity of criteria for the diagnosis of intravascular coagulation (IC) is discussed. It is emphasized in particular that loss of fibrinogen into extravascular spaces can only be excluded by assays of the level and disappearance rate of serum proteins not subject to the proteolytic action of thrombin or plasmin. Even when the diagnosis can be reasonably established, heparin therapy in a particular condition should only be advocated if its clinical benefit has been demonstrated in controlled clinical trails. Our conviction that heparin has as yet a small if any place in the management of patients with so-called intravascular coagulations is based mainly on two sets of arguments, one stemming from a critique of the diagnosis of IC, the other from a general attitude in the evaluation of therapeutic procedures.

Afibrinogenemia↗
PubMed2001

Hypofibrinogenemia due to novel 316 Asp --> Tyr substitution in the fibrinogen Bbeta chain.

We investigated the molecular basis of hypofibrinogenemia in a woman with a plasma fibrinogen of 1.0 mg/mL. After sequencing the coding region and intronic boundaries of all three fibrinogen genes a single heterozygous GAC-->TAC mutation was identified at codon 316 of the Bbeta gene. This Asp-->Tyr substitution segregated with the hypofibrinogenemia in the only other affected family member. Examination by SDS-PAGE, isoelectric focussing, reverse phase chromatography and electrospray ionisation (ESI) mass spectrometery, failed to detect expression of the new Bbeta chain in purified plasma fibrinogen. The absence of the variant chain was confirmed by ESI tryptic mapping; while the [M + 1 H] and [M + 2 H] ions of the affected peptide (MGPTELLIEMEDWK) were clearly visible at 1,692 and 847 m/z, there were no new signals (1,741 or 871 m/z) that would at indicate expression of the variant in plasma. Asp 316 and its gamma chain homologue (Asp 252) are conserved in all known species and this is the first report of a mutation at either of these. The residue appears to be critical in maintaining the structure of the five stranded sheet that forms the dominant structural feature of the D domains.

Adult↗
PubMed2001

Genetic interactions between the coagulation and fibrinolytic systems.

Nearly all of the genes encoding the established coagulation and fibrinolytic factors have been successfully altered or disrupted in transgenic mice. Although comprehensive studies of each of these gene-targeted mouse lines are still ongoing, the initial findings have significantly refined our understanding of the roles of selected hemostatic factors in vivo, and occasionally altered long-standing concepts. This review summarizes some of the progress that has been made in the generation and phenotypic characterization of mice lacking key hemostatic factors, including coagulation, fibrinolytic, platelet and endothelial cell-associated factors. New insights regarding the role(s) and interplay of hemostatic factors that have emerged from detailed studies of mice carrying multiple deficits in coagulation and fibrinolytic system components are highlighted.

Afibrinogenemia↗
PubMed2001

The molecular basis of inherited afibrinogenaemia.

This article reviews the substantial progress made in understanding the molecular basis of inherited afibrinogenaemia (or congenital afibrinogenaemia), an autosomal recessive disorder characterised by the complete absence of detectable fibrinogen. The identification in 1999 of the first genetic defect, recurrent homozygous deletions of approximately 11 kb of the fibrinogen alpha-chain (FGA) gene, revealed that the disease was caused by defective fibrinogen synthesis, and led to the subsequent analysis of the three fibrinogen genes in other affected individuals with the identification of numerous causative mutations. Combined analyses of more than thirty unrelated afibrinogenaemia families from various ethnic groups have shown that the majority of patients have truncating mutations in the FGA gene although intuitively all three fibrinogen genes might be equally implicated. These results will facilitate molecular diagnosis of the disorder, permit prenatal diagnosis for families who so desire, and pave the way for new therapeutic approaches such as gene therapy.

Afibrinogenemia↗