Influence of γ′ fibrinogen splice variant on fibrin physical properties and fibrinolysis rate

Objective-A splice variant of fibrinogen, gamma', has an altered C-terminal sequence in its gamma chain. This gammaA/gamma' fibrin is more resistant to lysis than gammaA/gammaA fibrin. Whether the physical properties of gamma' and gammaA 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 gammaA and gamma' fibrinogens (1 mg/mL). gamma'/gamma' fibrin displayed a non-significant decrease in the density of fibrin fibers and slightly thicker fibers than gammaA/gammaA 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 gamma'/gamma' and gammaA/gammaA 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, gamma' fibrin was found to be 3-times stiffer than gammaA 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 gamma A/gamma' fibrinogen in the clot is related primarily to an increase of fibrin cross-linking with only slight modifications of the clot architecture.