SummaryγA/γ’ fibrinogen is a fibrinogen isoform that constitutes about 15% of total plasma fibrinogen. This isoform contains an additional binding site for zymogen factor XIII and for active thrombin, and forms fibrin clots that are resistant to fibrinolysis in vitro. Little is known about the variability of γA/γ’ fibrinogen levels in human populations, whereas total fibrinogen levels are known to increase with age and are higher in women than in men. In this report, evidence is presented that, in contrast to total fibrinogen levels, γA/γ’ fibrinogen levels showed no significant association with age or gender in a population of normal blood donors. A study of γA/γ’ fibrinogen levels in patients undergoing coronary angiography also showed that γA/γ’ fibrinogen levels were higher on average in coronary artery disease patients than in patients without coronary artery disease, and that this association was independent of total fibrinogen levels.

Summary. A high-affinity thrombin-binding site in an alternately processed fibrinogen variant, the gA/g 0 isoform, is characterized in this report. The binding site has been shown to be situated between g 0 414 and 427, and Tyr418 and 422 in this part of the g 0 chain are known to be sulfated. A synthetic peptide corresponding to the g 0 chain carboxyl terminus is shown to bind thrombin with abinding of this peptide requires negative charges on Tyr418 and 422. Competitive binding studies with hirudin peptides, heparin and DNA aptamers specific for thrombin exosites I or II indicate thrombin binds to the g 0 peptide via exosite II. Thus, thrombin binding to the g 0 chain leaves exosite I and the active site accessible to substrates. This may explain why fibrin-bound thrombin can retain enzymatic activity, and why fibrin-bound thrombin is heparin-resistant.

Summary. Background: Fibrinogen c¢, a fibrinogen c-chain variant generated via alternative mRNA processing, has been associated with susceptibility to thrombotic disease. Objective: The present case-control study searched for potential determinants of the plasma fibrinogen c¢ concentration and examined the relationship between this variant and risk of myocardial infarction (MI). Patients and methods: The Stockholm Coronary Artery Risk Factor study, comprising 387 postinfarction patients and 387 healthy individuals, was employed. The fibrinogen gamma (FGG) 9340T > C [rs1049636], fibrinogen alpha (FGA) 2224G > A [rs2070011] and fibrinogen beta (FGB) 1038G > A [rs1800791] polymorphisms were determined. The plasma fibrinogen c¢ concentration was measured by enzyme-linked immunosorbent assay. The multifactor dimensionality reduction method was used for interaction analyses on risk of MI. Results: The FGG 9340T > C and FGA 2224G > A polymorphisms, total plasma concentrations of fibrinogen, insulin and high-density lipoprotein, and gender appeared to be independent determinants of plasma fibrinogen c¢ concentration in patients, and the corresponding determinants in controls included FGG 9340T > C and FGA 2224G > A polymorphisms and plasma fibrinogen concentration. An elevated plasma fibrinogen c¢ concentration proved to be an independent predictor of MI [adjusted odds ratio (OR) (95% CI): 1.24 (1.01, 1.52)]. The plasma fibrinogen c¢ concentration was involved in a high-order interaction with total plasma fibrinogen and the FGG 9340T > C and FGA 2224G > A polymorphisms, associated with a further increased risk of MI [OR (95% CI): 3.22 (2.35, 4.39)]. Conclusions: Plasma fibrinogen c¢ concentration influences the risk of MI, and this relationship seems to be strengthened by the presence of an elevated total plasma fibrinogen concentration and the FGG 9340T and FGA 2224G alleles.

BACKGROUND:Studies of disease associations with ␥Ј fibrinogen, a newly emerging risk factor for cardiovascular disease, have been hampered by the lack of a standardized and well-characterized assay.

Summary The minor γA/γ′ isoform of fibrinogen contains a high affinity binding site for thrombin exosite II that is lacking in the major fibrinogen isoform, γA/γA fibrinogen. The biological consequences of γ′ chain binding to thrombin were therefore investigated. Coagulation assays, thrombin activity assays, and a primate thrombosis model were used to characterize the biological effects of the γ′ 410–427 peptide. The γ′ peptide had little effect on thrombin cleavage of the small peptidyl substrate tosyl‐glycyl‐prolyl‐arginine‐4‐nitranilide acetate. However, in vitro assays demonstrated that the γ′ peptide inhibited thrombin cleavage of larger proteinaceous substrates, including fibrinogen and factor VIII. The γ′ peptide inhibited the activated partial thromboplastin time in plasma and showed greater inhibition of activated partial thromboplastin time assays than prothrombin time assays, consistent with the inhibition of factor VIII cleavage. Studies in a baboon thrombosis model showed that the γ′ 410–427 peptide inhibited fibrin‐rich thrombus formation (typical of venous thrombi) and, to a lesser extent, platelet‐rich thrombus formation (typical of arterial thrombi). These results indicate that binding of thrombin exosite II by the γ′ peptide has selective effects on the intrinsic pathway.