Plasma fibrinogen γ′ chain content in the thrombotic microangiopathy syndrome

Abstract

Background: Human fibrinogen γ chain variants, termed γ′ chains, contain a unique 20-residue sequence after γ chain residue 407 that ends at γ′427, and is designated γ′427L. Full-length (FL) γ′427L chains are constituents of a fibrin-dependent thrombin inhibitory system known as antithrombin I, whereas a γ′ chain processed in vivo, termed γ′423P, lacks the C-terminal tetrapeptide EDDL, and does not bind thrombin. Together, the γ′423P and γ′427L chains comprise the total plasma fibrinogen γ′ chain content. Objectives: Lowered plasma γ′ chain content (i.e. γ′ chain-containing fibrinogen/total fibrinogen ratio) has been shown to correlate with susceptibility to venous thrombosis, thus prompting this study on the total and FL γ′ chain content in 45 subjects with thrombotic microangiopathy (TMA), a disorder characterized by microvascular thrombosis. Methods: We measured by enzyme-linked immunosorbent assay the total γ′ chain-containing fibrinogen/total fibrinogen (Total γ′-fgn/Total fgn) ratio and the FL γ′ chain-containing fibrinogen/total fibrinogen (FL γ′-fgn/Total fgn) ratio in these plasmas and in healthy subjects (n = 87). Results: In healthy subjects, the mean Total γ′-fgn/Total fgn ratio was 0.127, whereas the FL γ′-fgn/Total fgn ratio was somewhat lower at 0.099 (P < 0.0001), a difference reflecting the presence of γ′423P chains. In TMA plasmas, both the Total γ′-fgn and FL γ′-fgn/Total fgn ratios (0.099 and 0.084, respectively) were lower than those of their healthy subject counterparts (P < 0.0001). Conclusions: These findings in TMA suggest that reductions in the γ′ chain content indicate reduced antithrombin I activity that may contribute to microvascular thrombosis in TMA. © 2007 International Society on Thrombosis and Haemostasis.