66 patients were randomized to receive topical tranexamic acid (TXA) or intravenous (IV) TXA for the reduction of blood loss in total knee arthroplasty (TKA). The primary outcome of interest was the systemic and wound levels of plasma-anti-plasmin (PAP). Additional outcomes of interest included systemic and wound levels of prothrombin fragment 1.2 (PF1.2), interleukin (IL)-6 and TXA, total blood loss, drainage volume, time to discharge from physical therapy, length of stay, hemoglobin levels and hematocrit levels. Results revealed significantly lower levels of systemic PAP at 4 hours post-tourniquet release, higher systemic and wound TXA levels, and shorter length of stay in the intravenous group compared to the topical group. Hemoglobin levels on post-operative day 1 and 2 as well as hematocrit levels on post-operative day 2 were significantly higher in the intravenous group compared to the topical group.