Safety and Feasibility of Argatroban, Tissue Plasminogen Activator and Intra-arterial Therapy in Stroke

Inclusion Criteria: * Disabling Ischemic stroke symptoms with onset \< 3 hours treated with IV rt-PA by local standards\*. * or \</= 4.5 hours according to local standard of care. Symptoms must be distinguished from another ischemic event such as syncope, seizure, migraine, subarachnoid hemorrhage and hypoglycemia. If the patient reports awakening with the event, the time of onset should be considered as the last time the patient (or a witness to the patient's condition) considered herself/himself normal. * Patients should meet local, institutional criteria to undergo emergent Endovascular Therapy (Intra-Arterial) to include: 1. IAT must be able to begin before 6-hours of stroke onset or last seen well. 2. CT-Angiogram confirmation of intra-arterial occlusion in any of the following locations: terminal ICA, MCA (M1 or M2 territories), PCA, distal vertebral or basilar artery. 3. ASPECTS score on non-contrast head CT must be \>/= 6. 4. IAT must be able to begin within 90 minutes of qualifying CT scan. * Age \>/= 18. * Females of childbearing potential must have a negative pregnancy test prior to the administration of trial medication. * Signed (written) informed consent by the patient or the patient's legal representative and/or guardian. Exclusion Criteria: * Evidence of intracranial hemorrhage (ICH) on baseline CT scan or diagnosis of a non-vascular cause of neurologic deficit. * NIHSS Level of Consciousness score (1a) \>/= 2. * Pre-existing disability with mRS \> 2. * Any evidence of clinically significant bleeding, or known coagulopathy. * INR \>1.5. * Patients with an elevated aPTT greater than the upper limit of normal (test can be repeated if investigator suspects a falsely elevated value such as when the collection tube is not completely filled). * Patients currently, or within the previous 24 hours, on an oral direct thrombin inhibitor (i.e., dabigatran), a factor 10a inhibitor (i.e., rivaroxaban, apixaban), or any other long-acting anticoagulant. * Heparin flush required for an IV line. Line flushes with saline only. * Any history of intra-cranial hemorrhage, known ateriovenous-malformation or unsecured cerebral aneurysms. * Significant bleeding episode \[e.g. gastrointestinal (GI) or urinary tract\] within the 3 weeks before study enrollment. * Major surgery or serious trauma in last 2 weeks. - Patients who have had an arterial puncture at a non-compressible site, biopsy of parenchymal organ, or lumbar puncture within the last 2 weeks. * Previous stroke, myocardial infarction (MI), post myocardial infarction pericarditis, intracranial surgery, or significant head trauma within 3 months. * Uncontrolled hypertension (SBP \> 185 mmHg or DBP \>110 mmHg) that does not respond to intravenous anti-hypertensive agents. * Surgical intervention (any reason) anticipated within the next 48 hours. * Known history of clinically significant hepatic dysfunction or liver disease - including a current history of alcohol abuse. * Abnormal blood glucose \<50 mg/dL (2.7 mmol/L). * History of primary or metastatic brain tumor. * Current platelet count \< 100,000/mm3. * Life expectancy \< 3 months. * Patients who, in the judgment of the investigator, needs to be on concomitant (i.e., during the Argatroban infusion) anticoagulants other than Argatroban, including any form of heparin, UFH, LMWH, defibrinogenating agent, dextran, other direct thrombin inhibitors or thrombolytic agents, GPIIb/IIIa inhibitor or warfarin. \[\*Caveat: However, if in the judgment of the investigator a patient needs to be anticoagulated, but this can be deferred for 48 hours, then they could be included.\] * Currently participating or has participated in any investigational drug or device study within 30 days before the first dose of study medication. * Known hypersensitivity to Argatroban or its agents. * Additional exclusion criteria if patient presents between 3-4.5 hours: 1. Age \>80 2. Currently taking oral anticoagulants (regardless of INR) 3. A history of stroke and diabetes. 4. NIHSS \> 25.