Influence of γ′ Fibrinogen Splice Variant on Fibrin Physical Properties and Fibrinolysis Rate

Abstract

Objective— A splice variant of fibrinogen, γ′, has an altered C-terminal sequence in its gamma chain. This γA/γ′ fibrin is more resistant to lysis than γA/γA fibrin. Whether the physical properties of γ′ and γA fibrin may account for the difference in their fibrinolysis rate remains to be established. Methods and Results— Mechanical and morphological properties of cross-linked purified fibrin, including permeability (Ks, in cm 2 ) and clot stiffness (G′, in dyne/cm 2 ), were measured after clotting γA and γ′ fibrinogens (1 mg/mL). γ′/γ′ fibrin displayed a non-significant decrease in the density of fibrin fibers and slightly thicker fibers than γA/γA fibrin (12±2 fiber/10 −3 nm 3 versus 16±2 fiber/10 −3 nm 3 and 274±38 nm versus 257±41 nm for γ′/γ′ and γA/γA fibrin, respectively; P =NS). This resulted in a 20% increase of the permeability constant (6.9±1.7 10 −9 cm 2 versus 5.5±1.9 10 −9 cm 2 , respectively; P =NS). Unexpectedly, γ′ fibrin was found to be 3-times stiffer than γA fibrin (72.6±2.6 dyne/cm 2 versus 25.1±2.3 dyne/cm 2 ; P <0.001). Finally, there was a 10-fold decrease of the fibrin fiber lysis rate. Conclusions— Fibrinolysis resistance that arises from the presence of γA/γ′ fibrinogen in the clot is related primarily to an increase of fibrin cross-linking with only slight modifications of the clot architecture.