Indwelling Pleural Catheters (IPC) are increasingly being used for management of recurrent pleural effusions (RPEs). Use of IPC for management of both malignant and non-malignant recurrent pleural effusions has been associated with complications such as dysfunctional or nonfunctioning IPCs. Alteplase, a tissue plasminogen activator (tPA) is often used to restore flow of non-draining IPC in symptomatic patients. We present a case of a sixty-eight-year old patient with life-threatening pleural hemorrhage following intrapleural catheter instillation of tPA that was managed successfully by thoracotomy. Our case describe the importance of individualizing the fibrinolytic dose, frequency and the indwelling time in high risk patients. We have reviewed the current literature and recommendations for use of fibrinolytic therapy for IPC in high risk patients on anticoagulation.