Thrombin flux and wall shear rate regulate fibrin fiber deposition state during polymerization under flow

Thrombin is released as a soluble enzyme from the platelet surface to trigger fibrin polymerization during thrombosis under flow conditions. While isotropic fibrin polymerization under static conditions involves protofibril extension and lateral aggregation leading to a gel, factors regulating fiber diameter and orientation 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/$\mu$ m$^2$ s) and the wall shear rate (10 to 100 s$^{-1}$) of a flowing fibrinogen solution. At the thrombin flux of 10$^{-12}$ nmol/$\mu$ m$^2$ 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 phase diagram to predict fibrin morphology. For Da$<$10,we only observed thin films at all Pe. For 10$<$Da$<$100, we observed either mats of surface fibers or gels depending on the Pe. For Da$>$900 and Pe$<$100, we observed three-dimensional gels. These results indicate that increase wall shear rate first quenches lateral aggregation and then protofibril extension.