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Introduction: Stroke, a devastating complication in children with Sickle Cell Anemia (SCA), consists of silent cerebral infarct (SCI) and large overt stroke. The current management relies on blood transfusion without the use of thrombolytic agents. However, a recent study showed that co-existent SCA does not impact the safety of tissue plasminogen activator (tPA) treatment. This finding calls for systemic analysis of the effects of thrombolysis in experimental stroke.Hypothesis: We hypothesize that sickle mice are highly vulnerable to hypoxia/ischemia-induced stroke, but respond to tPA-thrombolytic therapy.Methods: Townes sickle mice (knock-in/out mice that express the human α, γ, and sickle-β hemoglobin genes) were subjected to Doppler measurement of the carotid artery and evaluated for their responses to repetitive-mild hypoxia-ischemia (rmHI) and transient hypoxia-ischemia (tHI)-induced stroke at 3 and 6 months of age, respectively. The effects of tPA treatment after tHI in sickle mice were also examined.Results: First, 3-month-old sickle mice of SS genotype with a higher resistive index (RI) in common carotid artery were also prone to rmHI-induced cerebral infarct and mortality. Second, 6-month-old SS mice developed elevated flow velocity and greater RI without stenosis of the carotid artery akin to those previously implicated in large overt stroke in SCA. Finally, 6-month-old SS mice endured 20-min, but manifested enhanced leukocyte and platelet adherence to cerebral blood vessel, as well as, extensive vascular perfusion deficits and fibrin deposition at 4 h post-injury, followed by greatly increased mortality than AA and AS mice at 24 h recovery (p<0.0001, n>8 for each group). Importantly, intravenous tPA treatment at 0.5 h post-tHI markedly improved vascular reperfusion, mitigated fibrin deposition, and cut the mortality of SS mice by nearly 60%.Conclusions: Humanized sickle mice develop hyper-coagulation and hypersensitivity to HI-induced stroke without large-vessel obstructive vasculopathy at up to 6 months of age. Elevated RI may be an early ultrasonic marker for sickle cell vasculopathy and the risk of SCI in SCA. Future studies are warranted to confirm the therapeutic benefits of thrombolytic stroke therapy in SCA.