Prolonged low-dose tPA ameliorates coagulopathy and organ injury in an LPS-induced rat DIC model

Currently, no established treatments for disseminated intravascular coagulation (DIC) specifically target fibrinolysis. We previously demonstrated that prophylactic administration of tissue plasminogen activator (tPA) to a lipopolysaccharide (LPS)-induced rat DIC model improved DIC pathophysiology. However, the optimal duration of tPA administration and its effectiveness when administered therapeutically remain unclear. In the present study, we investigated whether tPA remains effective when administered at the same dosage over different durations, and whether therapeutic administration is also effective. We found that both prophylactic and therapeutic administration of tPA increased D-dimer levels, reduced serum creatinine and the renal glomerular fibrin deposition rate, suppressed the formation of thrombin-antithrombin complex and interleukin-6, and attenuated decreases in platelet count. Furthermore, with both prophylactic and therapeutic administration of tPA, most markers of DIC pathophysiology demonstrated greater improvements with longer administration of tPA, from 15 min to 8 h. No bleeding tendency was observed based on urinary hemoglobin levels. These results suggest that a lower tPA dose rate and longer duration of administration may enhance efficacy and safety in the LPS-induced rat DIC model. A reduced dosage and extended duration of tPA administration could represent a new treatment option for clinical DIC and warrants further investigation.