Thrombin Flux and Wall Shear Rate Regulate Fibrin Fiber Deposition State during Polymerization under Flow

AbstractThrombin is released as a soluble enzyme from the surface of platelets and tissue-factor-bearing cells to trigger fibrin polymerization during thrombosis under flow conditions. Although isotropic fibrin polymerization under static conditions involves protofibril extension and lateral aggregation leading to a gel, factors regulating fiber growth are poorly quantified under hemodynamic flow due to the difficulty of setting thrombin fluxes. A membrane microfluidic device allowed combined control of both thrombin wall flux (10−13 to 10−11 nmol/μm2 s) and the wall shear rate (10–100 s−1) of a flowing fibrinogen solution. At a thrombin flux of 10−12 nmol/μm2 s, both fibrin deposition and fiber thickness decreased as the wall shear rate increased from 10 to 100 s−1. Direct measurement and transport-reaction simulations at 12 different thrombin flux-wall shear rate conditions demonstrated that two dimensionless numbers, the Peclet number (Pe) and the Damkohler number (Da), defined a state diagram to predict fibrin morphology. For Da < 10, we only observed thin films at all Pe. For 10 < Da < 900, we observed either mat fibers or gels, depending on the Pe. For Da > 900 and Pe < 100, we observed three-dimensional gels. These results indicate that increases in wall shear rate quench first lateral aggregation and then protofibril extension