Fibrinogen Seattle Releases Half the Normal Amount of Fibrinopeptide B

Summary. We found two heterozygous dysfibrinogenemias, designated fibrinogen Kosai and fibrinogen Ogasa. Kosai was associated with arteriosclerosis obliterans but Ogasa showed no bleeding or thrombotic tendencies. The plasma fibrinogen concentrations from the two propositi (Ogasa and Kosai) were much lower when determined by the thrombin-time method (0.94 and 1.06 g L À1, respectively) than when determined by the immunological method (2.87 and 2.72 g L À1 , respectively). We performed DNA sequencing and functional analyses to clarify the relationship between the structural and functional abnormalities. Genetic analysis of PCR-amplified DNA from the propositi identified the heterozygous substitution Bb15Gly!Cys (GGT!TGT). Western blotting analysis of purified fibrinogen revealed the existence of albumin-fibrinogen complexes. Functional analyses indicated that compared with the normal control, the propositi's fibrinogen released only half the normal amount of fibrinopeptide B and showed markedly impaired polymerization. In addition, the observation of thinner fibers in fibrin clots (by scanning electron microscopy) indicated markedly defective lateral aggregation in the variant fibrinogens. The impaired functions may be due to the substitution of Cys for Bbo15Gly plus the existence of some additional disulfide-bonded forms.

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“…Similar results have been reported for the Bβ14 Arg→Cys variant, i.e. 14Cys‐15Gly bonding was not cleaved either [17,19,24].…”

Section: Discussionsupporting

confidence: 86%

Fibrinogens Kosai and Ogasa: Bβ15Gly→Cys (GGT→TGT) substitution associated with impairment of fibrinopeptide B release and lateral aggregation

Hirota-Kawadobora

Terasawa

Yonekawa³

et al. 2003

Journal of Thrombosis and Haemostasis

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“…There are a number of reports in unrelated families of dysfibrinogenaemia due to heterozygosity for BbArg14Cys; a missense mutation affecting the fibrinopeptide B thrombin cleavage site [31,[61][62][63][64][65][66]. These variants typically had mild thrombin and reptilase time prolongation and were associated with a thrombotic tendency, with one published exception, in which the patient was asymptomatic [61].…”

Section: Dysfibrinogenaemia Variants Associated With Thrombosismentioning

confidence: 99%

“…There are a number of reports in unrelated families of dysfibrinogenaemia due to heterozygosity for BβArg14Cys; a missense mutation affecting the fibrinopeptide B thrombin cleavage site [31,61–66]. These variants typically had mild thrombin and reptilase time prolongation and were associated with a thrombotic tendency, with one published exception, in which the patient was asymptomatic [61]. Although the mechanism underlying thrombosis in this variant has not been confirmed, functional studies of the Fibrinogen Ijmuiden (BβArg14Cys) variant [63] observed that the free cysteine residue in this variant may lead to disulphide linked complexes to other proteins, predominantly albumin and suggested this may be more functionally significant than an effect on the Bβ thrombin cleavage site.…”

Section: Clinical Features Of Dysfibrinogenaemiamentioning

confidence: 99%

Diagnosis, clinical features and molecular assessment of the dysfibrinogenaemias

Hill

Dolan

2008

Haemophilia

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Hereditary dysfibrinogenaemia is characterized by the presence of functionally abnormal plasma fibrinogen. Dysfibrinogenaemia is a heterogeneous disorder associated with different mutations throughout the three genes that code for the fibrinogen sub-units, affecting many different aspects of fibrinogen/fibrin activity. Dysfibrinogenaemia may be discovered during the investigation of individuals who present with bleeding or thombosis, or may be found in individuals during routine coagulation screening. More specialized coagulation tests may confirm the diagnosis of dysfibrinogenaemia but do not reliably distinguish between the different fibrinogen variants and are not usually useful in predicting bleeding or thrombotic risk. Advances in molecular diagnostics have facilitated the investigation of the molecular causes of fibrinogen disorders. Several 'hot spot' areas have been identified where mutations causing a high proportion of cases of dysfibrinogenaemia are found (AalphaArg16 and gammaArg275). Molecular diagnostics have also shown that many fibrinogen variants share the same causative mutation. There is a discrepancy between the quality of the molecular and functional data available for each mutation and the clinical information on individuals and their family members. However, there are accumulating data that the 'hot spot' mutations accounting for 60-80% of cases of dysfibringenaemia are not associated with a significant bleeding or thrombosis in the absence of other risk factors. Rapid screening for these mutations may provide reassurance for patients in the presurgical setting.

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“…Fibrinogen Christchurch II (11), fibrinogen Seattle I (12,13), and fibrinogen IJmuiden (14) have a mutation from Arg to Cys at residue 14 of the B␤ chain. Dysfibrinogenemia with prolonged thrombin and reptilase times has been attributed to the impaired release of FPB from abnormal fibrinogen molecules by thrombin due to this Arg to Cys substitution.…”

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confidence: 99%

An Abnormal Fibrinogen Fukuoka II (Gly-Bβ 15 → Cys) Characterized by Defective Fibrin Lateral Association and Mixed Disulfide Formation

Kamura

Tsuda

Yae

et al. 1995

Journal of Biological Chemistry

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A dysfibrinogenemia was attributable to a single amino acid substitution from glycine to cysteine at residue 15 of the B beta chain in a fibrinogen molecule designated as fibrinogen Fukuoka II. The fibrinogen Fukuoka II showed prolonged thrombin and reptilase times and impaired fibrinopeptide B release by thrombin, resulting in abolition of fibrin monomer repolymerization under physiological conditions. Repolymerization of the des-(B beta 1-42)-fibrin monomers, however, was not distinguished from the normal pattern of des-(B beta 1-42)-fibrin monomers, suggesting that no other abnormality existed in fibrinogen Fukuoka II. Although an additional cysteine was substituted at residue 15 of the B beta chain, fibrinogen Fukuoka II had no free sulfhydryl group within the molecule. Instead, fibrinogen Fukuoka II formed a disulfide bond with cysteine, albumin, another mutated B beta chain within the same molecule, or intermolecular dimeric fibrinogen Fukuoka II. The mutation in fibrinogen Fukuoka II was the same as that in fibrinogen Ise published previously (Yoshida, N., Wada, H., Morita, K., Hirata, H., Matsuda, M., Yamazumi, K., Asakura, S., and Shirakawa, S. (1991) Blood 77, 1958-1963). Fibrinogen Ise, however, has been described as having prolonged thrombin time but normal reptilase time. Reasons for the discrepancy were not clear. Analysis of the B beta 1-42 fragment showed that fibrinogen was heterogeneous at position 31 of the B beta chain with respect to proline or hydroxyproline.

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Fibrinogen Seattle Releases Half the Normal Amount of Fibrinopeptide B

Cited by 12 publications

References 20 publications

Fibrinogens Kosai and Ogasa: Bβ15Gly→Cys (GGT→TGT) substitution associated with impairment of fibrinopeptide B release and lateral aggregation

Fibrinogens Kosai and Ogasa: Bβ15Gly→Cys (GGT→TGT) substitution associated with impairment of fibrinopeptide B release and lateral aggregation

Diagnosis, clinical features and molecular assessment of the dysfibrinogenaemias

An Abnormal Fibrinogen Fukuoka II (Gly-Bβ 15 → Cys) Characterized by Defective Fibrin Lateral Association and Mixed Disulfide Formation

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