Study Population: All acute ischemic stroke patients treated with standard iv tPA therapy within 3 hours from stroke onset will be considered for study participation. Patient will be selected by criteria to minimize likelihood of toxicity and maximize likelihood of response. These criteria include age 18-85 years old acute ischemic stroke of moderate severity measured using the National Institutes of Health Stroke Scale Stroke Scale (NIHSS) less than 22 for left hemisphere strokes, less than 17 for others) and no other clinical, radiological or laboratory features associated with increased risk of hemorrhage of thrombolytic therapy. In the MRI arm of the trial, patients must have positive MRI evidence of hypoperfusion corresponding to the acute stroke symptoms and no MRI evidence of chronic micro-hemorrhages. Design: This is an open-label, dose escalation, safety and proof of principle clinical trial. All patients will receive iv tPA therapy plus 81 mg aspirin orally (or 150 mg rectally) and 80 anti Xa IU/kg tinzaparin subcutaneously and some patients will receive iv eptifibatide. Intravenous eptifibatide will be given in a dose-escalating manner. The five dosing groups for eptifibatide are 0, 45 micro g/kg bolus, 90 micro g/kg bolus, 90 micro g/kg bolus plus 0.25 micro g/kg/min infusion for 24 hours, and 90 mg/kg bolus plus 0.5 micro g/kg/min infusion for 24 hours. Investigational therapy is to begin as early as possible but no later than 6 hours after the onset of the patient's symptoms. Two arms - an MRI and a non-MRI arm - will receive identical drug regimes,and dose escalation will proceed independently in either arm. A maximum of 100 patients in each arm will be studied, a minimum of 15 patients treated at each dose level. The outcomes will be monitored by a Data and Safety Monitoring Board (DSMB). The DSMB will have the authority to stop or recommend modifications of the trial for safety concerns throughout the trial and after any occurrence of severe adverse events (SAE). Dose escalation from one dose level to the next will be contingent on DSMB approval. Outcome Measures: The primary safety endpoint for determination of toxicity will be any one of the following: symptomatic intracranial hemorrhage (ICH), major systemic hemorrhage, or other SAE related to study drug administration, within 72 hours from start of therapy. Adverse events will be monitored for 30 days. The primary efficacy endpoint for response in the MRI arm will be reperfusion as measured by perfusion weighted imaging (PWI) at both 2 hours and 24 hours after start of therapy and substantial clinical recovery at 24 hours for the non-MRI arm. Clinical outcome variables and imaging variables will be recorded and analyzed in secondary and exploratory analyses. If an acceptable dose of eptifibatide is identified, that dose of eptifibatide will be investigated in a subsequent randomized placebo-controlled trial. MRI and CT are used as radiological measures of brain hemorrhage. The NIH Stroke Scale (NIHSS) is used to measure neurological worsening or recovery. The NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of acute stroke on the levels of consciousness, language, neglect, visual-field loss, extra ocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patient's ability to answer questions and perform activities. Ratings for each of the 15 items are scored. Patients who have a score of 0 are considered to have "normal" examination. Patients with a score of 40 have the most severe stroke symptoms.
INCLUSION CRITERIA: 1. Diagnosis of acute ischemic stroke with planned start of intravenous tPA. Acute ischemic stroke is defined as a measurable neurological deficit of sudden onset, presumed secondary to focal cerebral ischemia. Stroke onset will be defined as the time the patient was last known to be without the new clinical deficit. If the stroke started during sleep, stroke onset will be recorded as the time the patient was last known to be at baseline. 2. Disabling neurological deficit attributable to acute ischemic stroke. 3. NIHSS less than or equal to 21 for left hemisphere strokes, NIHSS less than or equal to 16 for others. 4. Age 18-85 years, inclusive. 5. Body weight greater than 50 kg. For MRI Arm only: 6. Screening MRI diagnostic of focal cerebral ischemia corresponding to the clinical deficits. The MRI evaluation must involve echo planar diffusion weighted imaging, magnetic resonance angiography(MRA),and MRI perfusion. A normal appearing MRA with an appropriate perfusion deficit is eligible. An apparent stenosis or occlusion on MRA with normal appearing perfusion distally will not be eligible. Poor quality or uninterpretable MRA will not make patient ineligible. Patients who have a normal appearing diffusion weighted image (DWI) are eligible. 7. Evidence on perfusion weighted image (PWI) MRI or a perfusion defect corresponding to the acute stroke syndrome. The PWI will be assessed by relative mean transit time (MTT) images obtained prior to the start of tPA therapy. EXCLUSION CRITERIA: 1. Current participation in another study with an investigational drug or device within, prior participation in the present study, or planned participation in another therapeutic trial, prior to the final (day 30) assessment in this trial. 2. Symptoms suggestive of subarachnoid hemorrhage, even if CT or MRI scan is negative for hemorrhage. 3. Evidence of acute myocardial infarction defined as having at least two of the following three features: 1) Chest pain suggestive of cardiac ischemia; 2) EKG findings of ST elevation of more greater than 0.2 millivolts (mV) in 2 contiguous leads, new onset left bundle branch block, ST segment depression, or T-wave inversion; 3) Elevated troponin I. 4. Acute Pericarditis. 5. Women known to be pregnant, lactating or having a positive or indeterminate pregnancy test. 6. Patients who would refuse blood transfusions if medically indicated. 7. Neurological deficit that has led to stupor or coma (NIHSS level of consciousness [item I a] score greater than or equal to 2). 8. High clinical suspicion of septic embolus. 9. Minor stroke with non-disabling deficit or rapidly improving neurological symptoms. 10. Baseline NIHSS greater than 21 for left hemisphere stroke or greater than 16 for others. 11. Evidence of acute or chronic ICH by head CT or MRI. 12. CT or MRI evidence of non-vascular cause for the neurological symptoms. 13. Signs of mass effect causing shift of midline structures on CT or MRI. 14. Persistent hypertension with systolic BP greater than 185 mmHg or diastolic BP greater than 110 mmHg (mean of 3 consecutive arm cuff readings over 20-30 minutes), not controlled by antihypertensive therapy or requiring nitroprusside for control. 15. Anticipated need for major surgery within 72 hours after start of study drugs, such as a carotid endarterectomy or hip fracture repair. 16. Any intracranial surgery, intraspinal surgery, or serious head trauma (any head injury that required hospitalization) within the past 3 months. 17. Stroke within the past 3 months. 18. History of ICH at any time in the past. 19. Major trauma at the time of stroke, such as a hip fracture. 20. Blood glucose greater than 200 milligrams per diluent (mg/dl). 21. Presence or history of intracranial neoplasm (except small meningiomas) or arteriovenous malformation. 22. Intracranial aneurysm, unless surgically or endovascularly treated more than 3 months before. 23. Seizure at the onset of stroke. 24. Active internal bleeding. 25. Major hemorrhage (requiring transfusion, surgery or hospitalization) in the past 21 days. 26. Major surgery, serious trauma, lumbar puncture, arterial puncture at a non-compressible site, or biopsy of a parenchymal organ in last 14 days. Major surgical procedures include but are not limited to the following: major thoracic or abdominopelvic surgery, neurosurgery, major limb surgery, carotid endarterectomy or other vascular surgery, and organ transplantation. For non-listed procedures, the operating surgeon should be consulted to assess the risk. 27. Presumed or documented history of vasculitis. 28. Known systemic bleeding or platelet disorder, e.g., von Willebrand's disease, hemophilia, idiopathic thrombocytopenia purpura (ITP),thrombotic thrombocytopenic purpura (TTP), others. 29. History of heparin induced thrombocytopenia. 30. Platelet count less than 100,000 cells/microliter. 31. Congenital or acquired coagulopathy (e.g. , secondary to anticoagulants) causing either of the following: 1. Activated partial thromboplastin time (aPTT) prolongation greater than 2 seconds above the upper limit of normal for local laboratory, except if due to isolated factor twelve (XII) deficiency. 2. International normalized ratio (INR) greater than or equal to 1.4. Patients receiving warfarin prior to entry are eligible provided INR is less than 1.4 and warfarin can be safely discontinued for at least 48 hours. 32. Life expectancy less than 3 months. 33. Other serious illness, e.g., severe hepatic, cardiac, or renal failure; acute myocardial infarction; or complex disease that may confound treatment assessment. 34. Severe renal failure: Serum creatinine greater than 4.0 mg/dL or dependency on renal dialysis. 35. Aspartate aminotransferase (AST) or Alanine transaminase(ALT) greater than 3 times the upper limit of normal for the local laboratory. 36. Treatment of the qualifying stroke with any thrombolytic, anti-thrombotic or glycoprotein inhibitor(GPIIbIIIa)outside of this protocol. 37. Any administration of a thrombolytic drug in the prior 7 days. 38. Treatment of the qualifying stroke with intravenous heparin unless aPTT prolongation is no greater than 2 seconds above the upper limit of normal for local laboratory prior to study drug initiation. 39. Treatment of the qualifying stroke with a low molecular weight heparin or heparinoid. 40. Known hypersensitivity to alteplase, aspirin, tinzaparin, eptifibatide, heparin, sulfites, benzyl alcohol, or pork products. 41. Anticoagulation (evidenced by abnormal INR, aPTT, or platelet count) caused by herbal therapy. 42. Known history of alcohol or illicit drug use (e.g. prior to study drug administration) FOR non-MRI arm only (items 43-44): 43. Ischemic changes on screening CT of greater than approximately one third of the territory of the middle cerebral artery territory by qualitative assessment. 44. Patients who were excluded by screening MRI, except for exclusions item 45 (contraindication to MRI) and item 46 (PWI was not obtained or is uninterpretable) and item 51 (MRI not obtainable because it would have put the patient out of the 3 hour time window for tPA). FOR MRI arm only (items 45-51): 45. Contraindication to MRI scan. 46. PWI not obtained or uninterpretable. 47. No MTT defect corresponding to acute stroke deficit. 48. Satellite DWI hyperintensity with corresponding hyperintensity on T2 weighted image or FLAIR in a vascular territory different than the index stroke 49. DWI abnormality larger than approximately one third of the territory of the middle cerebral artery territory by qualitative assessment. 50. Evidence of multiple microbleeds on gradient echo MRI (GRE). 51. Patient has a contraindication to gadolinium contrast agent: prior adverse reaction to gadolinium or estimated glomerular filtration rate(GFR) less than 60 milliliters per minute (mL/min).