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Background: Infection is a major complication of ischemic stroke and contributes to the morbidity and mortality of stroke patients. Although growing evidence highlights the close relationship between inflammation and coagulation/fibrinolysis cascades, little has been reported regarding the influence of tPA on human immune system. Here, we explore changes in white blood cell (WBC) counts pre/post IV tPA and their association with tPA-related hemorrhagic transformation (HT).Method: 308 tPA-treated ischemic stroke patients were recruited with IRB approval, of which 16 developed HT within 24 hr post tPA. Routine WBC was analyzed at 1 month pre stroke, during stroke onset and during the first 48 hr post tPA.Result: We found that WBC was significantly increased within 12 hr post IV tPA and gradually reduced after 24 hr (Figure 1A). However, compared with patients without HT, HT patients had much higher levels of WBC throughout tPA treatment, and their WBC remained above normal even after 48 hr (Figure 1B). More importantly, we also found that HT patients had already developed elevated WBC as early as 1 month before their stroke onset (Figure 1B), which was predictive of tPA-related HT (Figure 1C, ROC AUC = 0.889, p = 0.001). Furthermore, the early elevation in WBC post-tPA was not associated with clinical evidence of infection.Conclusion: Our results provide early clinical evidence that in addition to activating fibrinolytic pathway, tPA may also modulate immune system during stroke treatment. In addition, elevated WBC pre-stroke maybe a predictive marker of tPA-related hemorrhage. While elevated WBC early in ischemic stroke was reported to correlate with poorer clinical outcome, the transient peak in WBC post tPA in this patient cohort ultimately had better clinical outcome, and is of interest. Further studies are needed and ongoing to evaluate differential WBC, stroke severity and long term clinical outcome, and to understand the molecular basis of tPA in immune cell modulation.