For decades, tranexamic acid (TXA) has been used off-label to reduce perioperative blood loss in various surgical procedures, including orthopedic surgery, neurosurgery, urologic surgery, obstetrics and gynecology, and trauma surgery.1 TXA, a synthetic derivative of the amino acid lysine, produces antifibrinolytic activity by competitively inhibiting lysine-binding sites on plasminogen molecules—inhibiting the activation of plasmin and thus preserving the function of fibrin in clot formation. It is believed that, through this method, TXA retains blood clots more effectively, thereby reducing bleeding. Although intravenous delivery of TXA is generally accepted as safe, some studies have indicated that it may contribute to postoperative seizure activity as well as increased thromboembolic events.2,3 For these and other reasons, interest in topical (intra-articular) administration of TXA has increased.
Use of topical TXA in surgery has been expanding over the past several years, with reports of significant reductions in perioperative blood loss and transfusion requirements.4 Orthopedic surgeons specifically have explored the topical use of TXA, especially in total joint arthroplasty (TJA).5 The benefits are increased concentration at the operative site with reduced systemic exposure; cost reduction; and surgeon control.6,7 Several recent studies have yielded significant reductions in perioperative blood loss and transfusions with use of topical TXA.8-10 In the literature, effective dosing for topical TXA in TJA ranges from 250 mg to 3 g.11 The concentration of topical TXA is not consistently described but appears to fall between 15 and 100 mg/mL.12,13 Our institutions14 and several investigators15,16 have used topical TXA in TJA at a concentration of 100 mg/mL, so this was the initial TXA concentration we decided to study. We selected certain time points to allow for relatively early detection of cartilage damage and then followed it to 48 hours of exposure. In cases in which TXA is injected after capsular closure, it is unclear how rapidly the TXA diffuses out of the joint or to what degree it becomes diluted by bleeding or synovial fluid. Certainly, this varies from patient to patient. Clearly, TXA generally passes through the body unmodified when injected intravenously1 and therefore is unlikely to be chemically modified while in the joint.
Very little has been published on use of topical TXA in other orthopedic surgeries, such as intra-articular fracture fixation, ligament reconstruction, hemiarthroplasty, and unicompartmental arthroplasty. Unlike TJA, which removes all native cartilage, these procedures retain and depend on the viability of the native cartilage. Sitek and colleagues17 noted the effect of TXA on chondrocytes within the context of creating an extracellular fibrin matrix for chondrocyte transplant. There was no decrease in chondrocyte viability with TXA 10 mg/mL or 20 mg/mL. Use of fresh bovine cartilage explants as a model for the in vitro study of cartilage damage is well established, including chondrocyte viability and glycosaminoglycan (GAG) release as outcome measures.18,19 Human cartilage has also been studied in vitro using this model.20
In the present study, the primary goal was to test the hypothesis that TXA could be safely used in the presence of native cartilage. The secondary goal was to identify a safe concentration for intra-articular use if toxic characteristics were noted.
Materials and Methods
Young bovine stifle joints were obtained within 3 hours of slaughter at a local abattoir. The joint was disarticulated under sterile conditions, and the distal femoral articular surface was evaluated for any signs of damage or arthritis. All specimens contained healthy, undamaged articular surfaces. Full-thickness cartilage explants (excluding subchondral bone) were then immediately harvested—with use of a scalpel blade and a dermatologic biopsy punch 4 mm in diameter—from the distal, weight-bearing femur. The explants were placed in 24-well tissue-culture plates (USA Scientific), incubated in culture media (high-glucose Dulbecco’s Modified Eagle Medium, 10% fetal bovine serum, 1% penicillin/streptomycin, 1% fungizone; Life Technologies), and kept at 37°C and 5% CO2. Explants were allowed to rest in culture media for a minimum of 24 hours after harvest. The pH of the medium was not altered by the addition of TXA.
Bovine explants were randomly assigned to either TXA-exposure or control groups at several time points in replicates of 6. Culture medium was aspirated, and each explant was washed twice with sterile phosphate-buffered saline (PBS). Explants were then incubated at 37°C in culture medium as previously described, or in the same culture medium containing dissolved TXA at a concentration of 100 mg/mL. The explants were incubated at 37°C until harvest at 8, 24, or 48 hours after media addition. For harvest, the media were aspirated and stored at –20°C for GAG content analysis, and the explants were then harvested for LIVE/DEAD assay (Life Technologies) and GAG content analysis.