Toxicity of tranexamic acid (TXA) to intra-articular tissue in orthopaedic surgery: a scoping review

Abstract

Purpose Intra-articular administration of tranexamic acid (TXA) in orthopaedic arthroplasty and arthroscopic procedures has become increasingly common over the past decade. However, several recent reports have shown that TXA has the potential to be cytotoxic to cartilage, tendon and synovium. Our aim was to review the literature for evidence of toxic efects from TXA exposure to intra-articular tissue. Methods A scoping review methodology was used to search for studies assessing the toxic efects of TXA exposure to intra-articular tissues. MEDLINE, EMBASE, SCOPUS and The Cochrane Library were searched. Relevant information was extracted and synthesis of the retrieved data followed a basic content analytical approach. Results A total of 15 laboratory studies were retrieved. No clinical studies reporting a toxic efect of TXA on intra-articular tissue were identiied in our search. Studies were analysed according to species of origin, tissue of origin and study setting (in vitro, ex vivo, or in vivo). There was increasing cytotoxicity to chondrocytes, tenocytes, synoviocytes and periosteumderived cells with TXA concentrations beyond 20 mg/ml. Monolayer cell cultures appear more susceptible to TXA exposure, than three-dimensional and explant culture models. In vivo studies have not demonstrated a major toxic efect. Conclusions Current evidence suggests a dose-dependent toxic efect on cartilage, tendon, and synovial tissue. Concentrations of 20 mg/ml or less are expected to be safe. There is a signiicant body of evidence to suggest the need for caution with intraarticular administration of TXA. There is a need for further human clinical trials in order to clarify the long-term safety of TXA topical application. AbbreviationsTXA Tranexamic acid IV Intravenous PRISMA-ScR Preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews ECM Extracellular matrix 2D Two-dimensional 3D Three-dimensional LDH Lactate dehydrogenase

Cytotoxicity of tranexamic acid to tendon and bone in vitro: Is there a safe dosage?

“…There is a lack of understanding about how rapidly TXA diffuses out of the joint space following intra-articular administration or to what degree it is diluted by bleeding or synovial fluid. In addition, the dynamic environment of the joint space and the presence of other cells types (inflammatory cells and platelets) could have a role in the absorbance of TXA into surrounding tissues [ 6 ]. During arthroplasty, TXA has been shown to diffuse rapidly into synovial fluid after IV administration, equal to serum concentrations, and the half-life in synovial fluid is 3 h [ 2 ].…”

“…TXA (Trans-4-amino-methylcyclohexane-1-carboxylic acid) was obtained from Apollo Scientific (Stockport, UK). The cells in each experiment were exposed to TXA in ranges of concentrations to mimic the range that could be expected following intra-articular administration (0, 10, 20, 35, 50 or 100 mg/mL), with specific graduations of TXA chosen to better define the toxic threshold previously predicted to be 20 mg/ml [ 4 , 6 , 18 , 20 , 33 ].…”

“…This concentration can be achieved with an IV dose of 10 mg/kg that leads to concentrations of < 20 ug/ml 1 h after administration [ 21 , 28 ]. Several clinical studies have found reduced blood loss with relatively low concentrations (10–20 mg/ml) of intra-articularly administered TXA, implying that concentration up to 20 mg/ml can be effective and non-harmful [ 1 , 6 , 17 , 33 , 35 , 38 , 42 ].…”

Comparison of intra-articular administration of adenosine, lidocaine and magnesium solution and tranexamic acid for alleviating postoperative inflammation and joint fibrosis in an experimental model of knee arthroplasty

“…IA administration of TXA is increasingly cited as a preferred route, producing comparable postoperative systemic coagulation and fibrinolytic profiles to systemic administration [ 37 ]. However, there is controversial evidence of TXA chondrotoxicity following topical administration [ 17 , 18 , 36 , 38 ]. Given the ongoing controversies, we believe current guidelines should address the indiscriminate use of TXA and recommend against its widespread use in major surgery, like TKA, without first demonstrating the presence of hyperfibrinolysis.…”

Tranexamic Acid: When is It Indicated in Orthopaedic Surgery?

“…Intra-articular TXA has been used in some RCTs, but there remains a concern due to a potential cytotoxic effect of TXA on cartilage, tendons, and synovial tissue. A recent scoping review in-cluded 15 laboratory studies, as no clinical study reporting a toxic effect was found [47]. They conclude that the current evidence suggests a dose-dependent toxic effect on cartilage, tendons, and synovial tissue, but that concentrations of 20 mg/ml TXA or less are expected to be safe.…”