Fibrinogen Bern I: A Hereditary Fibrinogen Variant With Defective Conformational Stabilization By Calcium Ions

Abstract

Inherited hypodysfibrinogenemia (fibrinogen Bern I) was found in four members (two generations) of a family with no haemorrhagic or thrombotic history. Fibrin aggregation curves (350 nm, 37°C) with patient plasma or purified fibrinogen Bern I, after addition of thrombin, were normal at high calcium concentrations (5mM) but delayed at lower calcium concentrations (≤0.lmM). The release of fibrinopeptide A was normal. Whereas the polypeptide chains of fibrinogen Bern I were indistinguishable from normal fibrinogen by SDS-gel-electrophoresis, an abnormal γ-chain with a decreased negative charge was found by isoelectric focussing.Plasmic degradation o| normal fibrinogen, in the presence of calcium (≥ImM), results in only one terminal D fragment which is stabilized by calcium against further degradation of γ-chains. In contrast, degradation of fibrinogen Bern I, under the same conditions, yielded at least two additional smaller D fragments. In conclusion, fibrinogen Bern I is characterized by defective calcium binding in the D domain of the γ-chain.

Fibrinogen Nijmegen : Congenital Dysfibrinogenemia Associated with Impaired t-PA Mediated Plasminogen Activation and Decreased Binding of t-PA

“…Several members of his family from two generations had prolonged thrombin clotting times and are likely to have inherited the abnormality. The pattern of inheritance observed in this family is consistant with an autosomal dominant mode, os has also been reported for other dysfibrinogenemias (1). Thrombinand reptilase clotting times in the affected individuals were prolonged to the same degree as found in the proband and his sister.…”

Fibrinogen Baltimore II: congenital hypodysfibrinogenemia with delayed release of fibrinopeptide B and decreased rate of fibrinogen synthesis.

“…However, the structure of the abnormal fibrin polymer may well be different from normal, as evidenced by the divergence in solution turbidity at later time points (Fig. 4) Congenital hypodysfibrinogenemia has been described in six families in addition to that reported here (44)(45)(46)(47)(48)(49). Fibrinogen Bethesda II (44), which manifests a slight delay in total fibrinopeptide release, also exhibits a major delay in fibrin monomer polymerization and is therefore dissimilar to fibrinogen Baltimore II.…”

“…Fibrinogen Bethesda II (44), which manifests a slight delay in total fibrinopeptide release, also exhibits a major delay in fibrin monomer polymerization and is therefore dissimilar to fibrinogen Baltimore II. The remaining proteins (45)(46)(47)(48)(49) are delayed only in the polymerization phase of coagulation. Thus, fibrinogen Baltimore II is readily distinguished from the other hypodysfibrinogens on the basis of its functional defect, a delay in fibrinopeptide B release.…”

A New Genetic Fibrinogen Variant (Fibrinogen Erfurt I) Structurally Characterized by an Abnormal Bβ-Chain and Present both in Plasma and Platelets

“…Hereditary abnormalities of the fibrinogen molecule have been detected in more than 120 families (1). In most cases functional defects of the fibrinogen variants at different stages of clot formation were shown by in vitro tests (1,2).…”

“…Hereditary abnormalities of the fibrinogen molecule have been detected in more than 120 families (1). In most cases functional defects of the fibrinogen variants at different stages of clot formation were shown by in vitro tests (1,2). Clinical manifesta tion with a bleeding tendency or thromboembolism of the mostly heterozygous carriers of the underlying abnormal gene is not the rule (1,2).…”