The Ultrastructure of Fibrin Prepared from Fibrinogen Haifa (γ₂₇₅ Arg→His)

Abstract

Fibrinogen is composed of six polypeptide chains, 2 Aα, 2 Bβ and 2 γ chains, covalently linked at their amino termini by disulfide bonds. Fibrinogen is activated to α,β-fibrin by thrombin which cleaves 2 A (FPA) and 2B (FPB) fibrinopeptides from the N-termini. Release of FPA and FPB exposes'A'and'B' polymerization sites, respectively. The resulting fibrin self-associates into a branched 3-dimensional matrix. Two other types of fibrin can be formed in vitro: ct-fibrin [FPA release]and β-fibrin [FPB reelease). Fibrinogen Haifa is a congenital abnormal fibrinogen variant characterized by normal fibrinopeptide release, abnormal fibrin polymerization and replacement of γ275 Arg by His. The propositus has experienced thrombotic episodes. In this study the ultrastructure of fibrin formed from fibrinogen Haifa was compared to that of normal fibrin in order to better define the effect of the γ275 Arg → His substitution on its molecular function.

Heterozygous Abnormal Fibrinogen Osaka III with the Replacement of γ Arginine-275 by Histidine Has an Apparently Higher Molecular Weight γ-Chain Variant

“…The reason for such a difference observed in the same type of γchain variants is not known but might be caused by the differences of experimental conditions including the method of fibrinogen purification. It was suggested from ultrastructural studies of fibrin and impaired fibrin polymerization by copperhead venom procoagulant enzyme that the COOH-terminal "b" polymerization site to which NH 2 -terminus of ß-chain binds is impaired in fibrinogen Haifa (30). We do not know the mechanism by which impaired "b" site causes reptilase-induced polymerization of fibrinogen Haifa with a shorter lag time and a greater initial slope, while thrombin-induced polymerization is clearly defective (23,30).…”

“…Recently the polymerization profile of fibrin by the addition of reptilase to fibrinogen Haifa in the absence of calcium has been reported to have a shorter lag time and a greater initial slope than that of normal (30). This can imply at least almost normal reptilase time and will be at variance with the prolonged reptilase time in fibrinogens Haifa (23), Bergamo II, Essen, Perugia (3), Saga (14) and Osaka III (Table 1) and with markedly defective polymerization of preformed reptilase-fibrin (Fig.…”

New molecular defects in the γ subdomain of fibrinogen D-domain in four cases of (hypo)dysfibrinogenemia: fibrinogen variants Hannover VI, Homburg VII, Stuttgart and Suhl

“…The three fg variants Suhl, Homburg VII and Hannover VI were found in rather young patients with venous thromboembolism. A number of γ dysfibrinogenemias are reportedly associated with thromboembolism, especially defects affecting D-D interaction (31)(32)(33) and Ca 2+ -binding (31,34). However, a causal relation between the dysfibrinogenemia and the clinical state is not apparent in most of the reported cases.…”

Dysfibrinogenemia and Thrombosis

“…Of the numerous dysfibrinogenemic families that are characterized by an amino acid substitution at posi tion 275R of the normal γ chain, either R to C, R to H, or R to S, 1,59,[82][83][84][85][86][87][88][89][90] all but five are asymptomatic. Of the fam ilies reporting thrombophilia, there are two with 7R275C, Bologna I 2 and Cedar Rapids, 84 and three with γR275H substitutions.…”