Shear stress changes the mechanism of prophylactic thrombolysis by incorporated RBC-PAs from multilateral lysis to formation of flow-directed patent channels. Z-projections of fibrin fiber (green) lysis by RBC-PAs (red) incorporated in clots before perfusion. (A-B) In the absence of flow, network pores (outlined) form multilaterally (panels A and B, 17.5 and 21 minutes, respectively). (C-I) Rate, extent, and mechanism of clot dissolution change with shear rate. (C) Percent clot lysis was determined by measuring the amount of network present at each time point and was plotted versus time. This plot combines results from 5 independent experiments, whereas the other panels in this figure provide representative examples. In the presence of venous shear (160 s⁻¹), network pores merge in the direction of flow (from bottom to top; 17.5 and 21 minutes, panels D and E, respectively). (F) A 3-dimensional rendering of the network near the end of the venous shear experiment (35 minutes) shows the presence of patent channels (areas without green fibrin) and the passage of bystander RBCs (blue). Flow-directed channel formation becomes even more evident and faster in the presence of higher arterial shear (900 s⁻¹, 17.5 and 21 minutes in panels G and H, respectively). (I) A 3-dimensional rendering shows that, under arterial shear, an increasing fraction of buffer-derived bystander RBCs traverse the clot via patent channels. Because so many bystander RBCs enter the clot at the higher shear rate, many of these RBCs get trapped inside the network pores (supplemental Data). Image acquisition information is available in supplemental Methods.