Plasminogen supplementation enhances alteplase fibrinolysis efficacy in a systemic embolization rat model

Enhancing the fibrinolysis efficacy of recombinant tissue plasminogen activators (r-tPA) may be achieved by increasing the blood plasminogen levels. This study evaluated the effect of plasminogen (PLG) addition to a clinically relevant alteplase (r-tPA) dose on fibrinolysis. Sixty nine Wistar albino rats were divided into 7 groups; control (n = 10), r-tPA 0.9 mg/kg (0.9r-tPA) (n = 10), r-tPA 0.9 mg/kg + PLG 8 IU/kg (0.9r-tPA+8PLG) (n = 10), r-tPA 0.9 mg/kg + PLG 16 IU/kg (0.9r-tPA+16PLG) (n = 10), r-tPA 0.6 mg/kg + PLG 8 IU/kg (0.6r-tPA+8PLG) (n = 10), r-tPA 0.6 mg/kg + PLG 16 IU/kg (0.6r-tPA+16PLG) (n = 10), and r-tPA 0.9 mg/kg + PLG 8 IU/kg (0.9r-tPA+8PLG60) (n = 9) with the PLG administered 60 min before the r-tPA administration. In all groups, systemic embolism was induced by application of three barium sulfate-labeled artificial clots in abdominal aorta. Artificial clots were visualized under micro-fluoroscopy, and radiographs were captured every 5 min during fibrinolytic/saline infusion. The measurement of clot area was used to calculate fibrinolysis rate (%/min) and the area under the curve (AUC; %*min). Results show that all PLG combinations enhanced fibrinolysis relative to untreated controls (p < 0.001). At the clinical 0.9 mg/kg dose, PLG supplementation significantly increased the fibrinolysis rate compared with r-tPA alone (r-tPA: 0.8 ± 0.5%/min; 8 IU/kg, p = 0.025; 16 IU/kg, p < 0.001), and this benefit was retained when PLG was administered 60 min in advance (p = 0.024). Differences between PLG doses were not statistically significant. Systemic plasminogen supplementation therefore enhances r-tPA-mediated fibrinolysis in vivo at a clinically relevant dose and regimen, without requiring catheter-directed delivery.