Poloxamer-188 is a synthetic, organic compound that acts by binding hydrophobic pockets on damaged lipid bilayers in the circulation. P-188 reduces blood viscosity and confers anti-inflammatory and cytoprotective effects. Vepoloxamer (Mast Therapeutics, San Diego, Calif) is a purified version of this compound that has limited side effects. The aim of this study was to investigate drug interactions between vepoloxamer and heparin and tissue plasminogen activator (tPA). An experimental rat tail transection model was used to study vepoloxamer's interaction with heparin. Sprague-Dawley rats were divided into saline (1 mL/kg; group 1) or vepoloxamer (25 mg/kg; group 2) treatment groups. The rats were then subjected to saline (n = 6), low-dose heparin (125 μg/kg; n = 6), or high-dose heparin (250 μg/kg; n = 6). After 5 minutes, the distal 2 mm of the tail was transected, and time to clot formation was measured as bleeding time. A rat internal jugular vein thrombosis model was used to assess vepoloxamer's interaction with tPA. Sprague-Dawley rats were divided into saline (1 mL/kg; group 1) or vepoloxamer (25 mg/kg; group 2) treatment groups. After internal jugular vein thrombosis, rats were treated with saline (n = 6), systemic low-dose tPA (0.5 mg/kg; n = 6), or systemic high-dose tPA (1.0 mg/kg; n = 6). Clot lysis was assessed using an ultrasound Doppler probe to detect blood flow. No flow up to 15 minutes was recorded as no lysis. Interaction with heparin: Vepoloxamer by itself, without any heparin, increased tail bleeding time (10.3 vs 7.1 minutes; P = .001). Effects of heparin on tail bleeding time were enhanced by vepoloxamer at low dose (14.2 vs 6.2 minutes; P < .001). At high-dose heparin, vepoloxamer did not prolong bleeding time (17.8 vs 17.0 minutes). Interaction with tPA: No rat exhibited spontaneous clot lysis with either saline or vepoloxamer. The effect of tPA was facilitated by vepoloxamer at low dose, as more rats showed clot lysis (4/6 [66%]) compared with tPA alone, which showed no clot lysis (0/6), although statistical significance was not reached (P = .06). At high-dose tPA, vepoloxamer had no additional effects on clot lysis (5/6 [83% ] vs 4/6 [66%]). Vepoloxamer alone modestly increased bleeding time. Vepoloxamer also increased bleeding time in rats treated with low-dose heparin but not with high-dose heparin. Vepoloxamer potentiated clot lysis in the setting of low-dose tPA. Copyright © 2016. Published by Elsevier Inc.