Combined fibrinolytic and anticoagulant therapy causes sudden recanalization and paradoxical cerebral hypoperfusion. Treatment cohorts described in Figure 4C were further analyzed for cerebral perfusion (A, LDF, left hemisphere [LHS]; LSCI, right hemisphere [RHS]), mortality (A, [skull and crossbones], expressed as %) and infarct volume (B). For mice treated with the combination of rtPA/argatroban (n = 14), outcomes were further differentiated into mice that successfully recanalized (Recan) vs those that remained occluded (No Recan). (B) Cerebral infarct was assessed with TTC staining of excised brain sections from the mouse cohorts presented in Figure 4C. Animals that died before the 24-hour point were not included in the infarct assessment. Infarct assessment was performed on experiments conducted at Site 2. In panels A and B, open circles represent animals in which embolization was observed on the flow trace, as characterized by a sudden and sustained recanalization event; half circles represent recanalization without embolization; and closed circles represent sustained occlusion. (C) Based on blood flow (LDF), the incidence of sudden and sustained recanalization events in rtPA vs rtPA/argatroban cohorts was expressed as percentage of the total number of animals in each treatment group (as indicated). (D) Examples of real-time flow traces from the iCAT procedure (i) or electrolytic injury alone (ii), and the corresponding LDF (ii) shows the sudden recanalization events, in which an abrupt return of blood flow (↑, i,ii) was observed concomitant with a reduction in LDF (ii), and sustained deficient in cerebral perfusion (LSCI heat map images, i, ii), despite full carotid recanalization. LSCI images depict CBF at baseline (pre-injury) and 90 minutes’ post-carotid occlusion . ns, not significant; RBCs, red blood cells.