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The Dangers and Concerns of Intra-articular Tranexamic Acid

      I read with interest the article from Chiang et al.
      • Chiang E.R.
      • Chen K.H.
      • Wang S.T.
      • et al.
      Intra-articular injection of tranexamic acid reduced postoperative hemarthrosis in arthroscopic anterior cruciate ligament reconstruction: A prospective randomized study.
      entitled “Intra-articular Injection of Tranexamic Acid Reduced Postoperative Hemarthrosis in Arthroscopic Anterior Cruciate Ligament Reconstruction: A Prospective Randomized Study.” The authors have done an excellent job of reporting their results and findings. After completion of the study, they concluded that “intra-articular injection of TXA [tranexamic acid] could be considered an effective and relatively safe solution to reduce postoperative bleeding.” This conclusion is based on measurements of postoperative drainage and a 4-week follow-up evaluation of pain. The methodology describes the concentration of TXA as a 10% solution.
      Readers of Arthroscopy are typically clinically active surgeons looking for advances in techniques that will improve recovery. The article of Chiang et al.
      • Chiang E.R.
      • Chen K.H.
      • Wang S.T.
      • et al.
      Intra-articular injection of tranexamic acid reduced postoperative hemarthrosis in arthroscopic anterior cruciate ligament reconstruction: A prospective randomized study.
      appears to provide an easily accepted treatment that decreases bleeding and pain. Unfortunately, this may not be the case. I was disturbed by the fact that the authors made a statement of safety that is neither proved nor referenced. The safety of TXA in terms of the articular cartilage is an area of ongoing research. There are numerous publications showing the effect of topical TXA on articular chondrocytes. Tuttle et al.
      • Tuttle J.R.
      • Feltman P.R.
      • Ritterman S.A.
      • Ehrlich M.G.
      Effects of tranexamic acid cytotoxicity on in vitro chondrocytes.
      showed that bovine and murine chondrocytes had no viability at 48 hours when exposed to a 10% solution. They concluded that the safest concentration for chondrocyte viability was 2.5%.
      Parker et al.
      • Parker J.D.
      • Lim K.S.
      • Kieser D.C.
      • Woodfield T.B.F.
      • Hooper G.J.
      Is tranexamic acid toxic to articular cartilage when administered topically? What is the safe dose?.
      performed an in vitro study involving cellular morphology, adhesion, metabolic activity, and viability of human chondrocytes in which increases in the concentration of TXA (from 0 to 40 mg/mL) and length of exposure to TXA (from 0 to 12 hours) were analyzed in a 2-dimensional model. This analysis was then repeated, excluding cellular adhesion, in a 3-dimensional model and confirmed in viable samples of articular cartilage. Parker et al. concluded that any concentration of TXA above 2% resulted in increased chondrocyte death. At 12 hours, the viability of chondrocytes using a 4% solution was less than 3%. The authors found a 97% loss of viability at a concentration that was less than half that used by Chiang et al.
      • Chiang E.R.
      • Chen K.H.
      • Wang S.T.
      • et al.
      Intra-articular injection of tranexamic acid reduced postoperative hemarthrosis in arthroscopic anterior cruciate ligament reconstruction: A prospective randomized study.
      Regarding topical TXA and the surrounding tissues, McLean et al.,
      • McLean M.
      • McCall K.
      • Smith I.D.M.
      • et al.
      Tranexamic acid toxicity in human periarticular tissues.
      similarly to Chiang et al.,
      • Chiang E.R.
      • Chen K.H.
      • Wang S.T.
      • et al.
      Intra-articular injection of tranexamic acid reduced postoperative hemarthrosis in arthroscopic anterior cruciate ligament reconstruction: A prospective randomized study.
      used a 10% solution. They performed an in vitro study on the periarticular tissues and found that at an exposure of 10% for 16 hours, tendon showed 96% cellular death, cartilage showed 65% cellular death, and synovium showed 66% cellular death. At 1 hour, a 10% solution resulted in a 50% death rate of chondrocyte cells. With chondrocyte death or damage, the onset of symptoms may not be apparent or noted in the first 4 weeks. Evaluating the onset of symptoms in the shoulder after exposure to bupivacaine, a review by Gulihar et al.
      • Gulihar A.
      • Robati S.
      • Twaij H.
      • Salih A.
      • Taylor G.J.S.
      Articular cartilage and local anaesthetic: A systematic review of the current literature.
      found that an average of 14 months elapsed before symptomatic chondrolysis occurred.
      Even if one ignores the evidence of the chondrotoxic effects of 10% TXA, one must consider the cost versus benefit of this product. Chiang et al.
      • Chiang E.R.
      • Chen K.H.
      • Wang S.T.
      • et al.
      Intra-articular injection of tranexamic acid reduced postoperative hemarthrosis in arthroscopic anterior cruciate ligament reconstruction: A prospective randomized study.
      reported a decrease in drainage of 36 mL. This is approximately 2.5 tablespoons of blood. The patient cost for this product in the American health care system is approximately $1,000.
      • DiBlasi J.F.
      • Smith R.P.
      • Garavaglia J.
      • Quedado J.
      • Frye B.M.
      • Dietz M.J.
      Comparing cost, efficacy, and safety of intravenous and topical tranexamic acid in total hip and knee arthroplasty.
      What this published study has encouraged is the use of a proven chondrotoxic drug (when used at the concentrations reported by Chiang et al.
      • Chiang E.R.
      • Chen K.H.
      • Wang S.T.
      • et al.
      Intra-articular injection of tranexamic acid reduced postoperative hemarthrosis in arthroscopic anterior cruciate ligament reconstruction: A prospective randomized study.
      ), at high cost, for a decrease in blood loss of 2.5 tablespoons. If there is a need for the use of TXA, one would hope and encourage that oral or intravenous TXA would be used. This has been shown to be equally effective in reducing blood loss in hip replacement arthroplasty.
      • Cao G.
      • Huang Z.
      • Xie J.
      • et al.
      The effect of oral versus intravenous tranexamic acid in reducing blood loss after primary total hip arthroplasty: A randomized clinical trial.
      Considering the potential damage to the joint, the limited benefit, and the cost of the product, it is hard to understand why this approach would be used or allowed without further ongoing research and long-term studies. One would hope that the use of 10% TXA intra-articularly in the knee joint is tempered by these concerns and delayed until long-term safety has been proved.

      Supplementary Data

      References

        • Chiang E.R.
        • Chen K.H.
        • Wang S.T.
        • et al.
        Intra-articular injection of tranexamic acid reduced postoperative hemarthrosis in arthroscopic anterior cruciate ligament reconstruction: A prospective randomized study.
        Arthroscopy. 2019; 35: 2127-2132
        • Tuttle J.R.
        • Feltman P.R.
        • Ritterman S.A.
        • Ehrlich M.G.
        Effects of tranexamic acid cytotoxicity on in vitro chondrocytes.
        Am J Orthop (Belle Mead NJ). 2015; 44: E497-E502
        • Parker J.D.
        • Lim K.S.
        • Kieser D.C.
        • Woodfield T.B.F.
        • Hooper G.J.
        Is tranexamic acid toxic to articular cartilage when administered topically? What is the safe dose?.
        Bone Joint J. 2018; 100-B: 404-412
        • McLean M.
        • McCall K.
        • Smith I.D.M.
        • et al.
        Tranexamic acid toxicity in human periarticular tissues.
        Bone Joint Res. 2019; 8: 11-18
        • Gulihar A.
        • Robati S.
        • Twaij H.
        • Salih A.
        • Taylor G.J.S.
        Articular cartilage and local anaesthetic: A systematic review of the current literature.
        J Orthop. 2015; 12: S200-S210
        • DiBlasi J.F.
        • Smith R.P.
        • Garavaglia J.
        • Quedado J.
        • Frye B.M.
        • Dietz M.J.
        Comparing cost, efficacy, and safety of intravenous and topical tranexamic acid in total hip and knee arthroplasty.
        Am J Orthop (Belle Mead NJ). 2016; 45: E439-E443
        • Cao G.
        • Huang Z.
        • Xie J.
        • et al.
        The effect of oral versus intravenous tranexamic acid in reducing blood loss after primary total hip arthroplasty: A randomized clinical trial.
        Thromb Res. 2018; 164: 48-53

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