Coupling PAs to carrier RBC may convert risky fibrinolytic therapy into safe transient thromboprophylaxis. (A) PAs are used in the emergency setting for reperfusion. High doses are needed to compensate for rapid inactivation by PAI-1 and clearance by the liver and other organs. PAs diffuse into hemostatic mural clots, as well as occlusive pathological clots, increasing the risk of bleeding, and into tissues, such as the CNS, where they cause toxicity. Therapeutic doses can deplete fibrinogen and plasminogen increasing the risk of bleeding while reducing fibrinolytic potential. Only a small proportion of the residual circulating PA reaches and penetrates the interior of clots. (B) RBC-coupled PAs avoid rapid clearance, circulating for many hours to days without damaging carrier RBCs. The large size and hemodynamic factors prevent access to preexisting hemostatic clots, limit extravasation into tissues, and block interaction with cellular receptors such as uPAR (CD87) and integrins that may initiate deleterious intravascular signaling cascades. RBC-coupled PAs are incorporated within nascent intravascular clots formed after treatment, which they lyse from within, rapidly restoring flow and preventing ischemia at doses that are orders of magnitude less than free fibrinolytics.