The Polymerization of Fibrinogen Dusart (Aα 554 Arg→Cys) After Removal of Carboxy Terminal Regions of the Aα-Chains

Document Type

Article

Publication Date

2-1993

Publisher

Lippincott Williams & Wilkins

Source Publication

Blood Coagulation and Fibrinolysis

Source ISSN

0957-5235

Original Item ID

DOI: 10.1097/00001721-199302000-00010

Abstract

The six polypeptide chains of normal fibrinogen are covalently linked by interchain disulphide bonds, and there are no free sulphhydryl groups. Fibrinogen Dusart is a congenital fibrinogen variant in which Aα 554 Arg is replaced by Cys; albumin is disulphide linked to these fibrinogen molecules, possibly at Aα 554 Cys. Functionally, Dusart fibrinogen displays markedly abnormal fibrin polymerization, characterized by delayed lateral fibril association and matrix fibre bundles that are thinner than normal fibrin bundles. These observations are consistent with experiments suggesting that the carboxy terminal region of the Aα-chain contains a polymerization domain that participates in lateral fibril associations. In order to investigate the location and the effect of albumin binding to Dusart fibrinogen, we examined the fibrinogen by electron microscopy, and compared the polymerization and ultrastructure of fibrin prepared from normal fibrinogen containing intact Aα-chains (fraction I-2) or plasmin degraded fibrinogen molecules lacking carboxy terminal regions of Aα-chains (fraction I-9D), with fibrin prepared from Dusart fraction I-2 and I-9D. Most bound albumin was released from Dusart fibrinogen by plasmin degradation involving the Aα-chains. Nevertheless, we were able to visualize albumin molecules remaining covalently bound to Dusart I-9D as well as to Dusart I-2 fibrinogen, as distinct globular domains situated near the fibrinogen D domain. The presence of albumin in these fractions was confirmed by Western blotting using anti-albumin. Dusart fibrin polymerized much more slowly than normal I-2, as previously reported, whereas polymerization of Dusart I-9D fibrin was faster than Dusart I-2 and nearly the same as normal I-9D fibrin. The ultrastructure of the Dusart I-9D fibrin matrix was indistinguishable from that of normal I-9D; both contained intensely striated thick fibres. In contrast, Dusart I-2 fibrin had thinner, more highly branched fibres with few striations. These results indicate; (1) most albumin bound to fibrinogen Dusart is removed by release of the carboxyl-terminal region of the Aα-chain, suggesting that at least 90% of the albumin is bound at Aα 554 Cys; (2) removal of the carboxyl-terminal region of the fibrinogen (I-9D) normalizes its polymerization properties relative to normal I-9D.

Comments

Blood Coagulation and Fibrinolysis, Vol. 4, No. 1 (February 1993): 61-65. DOI.

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