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Author Reply to “The Dangers and Concerns of Intra-articular Tranexamic Acid” and “Regarding ‘Intra-articular Injection of Tranexamic Acid Reduced Postoperative Hemarthrosis in Arthroscopic Anterior Cruciate Ligament Reconstruction: A Prospective Randomized Study’”

      It has been our privilege to receive feedback on our study from researchers from around the world. Thus, we have the opportunity to discuss the topic in more depth.
      In Dr. Siegel's letter, he raised concerns about the effect of tranexamic acid (TXA) on articular cartilage in terms of safety. Indeed, a number of studies have shown that a higher concentration of TXA might have a detrimental effect on animal
      • Tuttle J.R.
      • Feltman P.R.
      • Ritterman S.A.
      • et al.
      Effects of tranexamic acid cytotoxicity on in vitro chondrocytes.
      or human
      • Parker J.D.
      • Lim K.S.
      • Kieser D.C.
      • et al.
      Is tranexamic acid toxic to articular cartilage when administered topically? What is the safe dose?.
      chondrocytes. However, as we know, there is always a gap between in vitro studies and the real clinical scenario. First, the cell culture conditions in these studies might not truly reflect the surrounding cartilage tissue in a postoperative knee joint, such as the complete absence of any drug clearance and tissue distribution in these in vitro or ex vivo experimental models. Second, a post-arthroscopic knee may be filled with some irrigation fluid and hemarthrosis, which might further lower the true concentration of TXA. Parker et al.
      • Parker J.D.
      • Lim K.S.
      • Kieser D.C.
      • et al.
      Is tranexamic acid toxic to articular cartilage when administered topically? What is the safe dose?.
      showed that TXA had no effect on the glycosaminoglycan content of human articular chondrocyte–laden hydrogels after 6 hours of exposure (with concentrations up to 40 mg/mL). Siegel also mentioned the study by McLean et al.,
      • McLean M.
      • McCall K.
      • Smith I.D.M.
      • et al.
      Tranexamic acid toxicity in human periarticular tissues.
      who found that after exposure to 10% TXA for 16 hours, there was a 96% rate of cellular death of tendon and 66% rate of cellular death of synovium. However, these negative clinical effects have never been reported in patients receiving arthroplasty or spine surgery. Therefore, the conditions in these experiments might far exceed any protocols realistically encountered in clinical applications. We believed that the optimal dosage of topical TXA still needed to be clarified. In addition, the long-term effect of TXA on human articular cartilage remained unknown.
      Another issue is the cost of TXA. The cost of 10 mL of TXA (100 mg/mL) is approximately $30 to $40 in Taiwan. Therefore, we believed that the cost/performance of TXA was acceptable in this clinical application.
      In their letter, Gobbi et al. raised concerns about using drain output as the method chosen to evaluate blood loss. They pointed out that a 24-mL output reduction, although statistically significant, might not appear to be clinically significant. In previous literature, TXA was shown to exert its beneficial effects not only by reducing blood loss but also through its anti-inflammatory effects, which might improve analgesia, promoting early rehabilitation in total knee arthroplasty patients.
      • Wang D.
      • Luo Z.Y.
      • Yu Z.P.
      • et al.
      The antifibrinolytic and anti-inflammatory effects of multiple doses of oral tranexamic acid in total knee arthroplasty patients: A randomized controlled trial.
      This might explain the significantly lowered visual analog scale score in our patients. In our study, patients without the use of TXA might have had an average 80 mL of drain output on the first day.
      • 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.
      In the study by Karaaslan et al.,
      • Karaaslan F.
      • Karaoglu S.
      • Yurdakul E.
      Reducing intra-articular hemarthrosis after arthroscopic anterior cruciate ligament reconstruction by the administration of intravenous tranexamic acid: A prospective, randomized controlled trial.
      patients might have had 150 mL of hemarthrosis after anterior cruciate ligament reconstruction if TXA was not used. We believed that this amount of hemarthrosis might cause, in some patients, discomfort and functional disability. Therefore, we still routinely use intra-articular drainage on the first postoperative day. Besides, patients are always admitted for anterior cruciate ligament reconstruction procedures in Taiwan because of the national insurance policy. Therefore, during the admission, recording drain output in the early postoperative period is relatively simple and convenient.
      Another question mentioned by Gobbi et al. relates to potential tamponade and clot formation in the drain. Our control-group patients also had the drain clamped for 2 hours; therefore, the tamponade effect was the same in both groups. In our patients, we did not find the drains plugged by clots. Hence, clot formation might not be as evident as expected.

      Supplementary Data

      References

        • Tuttle J.R.
        • Feltman P.R.
        • Ritterman S.A.
        • et al.
        Effects of tranexamic acid cytotoxicity on in vitro chondrocytes.
        Am J Orthop. 2015; 44: E497-E502
        • Parker J.D.
        • Lim K.S.
        • Kieser D.C.
        • et al.
        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
        • Wang D.
        • Luo Z.Y.
        • Yu Z.P.
        • et al.
        The antifibrinolytic and anti-inflammatory effects of multiple doses of oral tranexamic acid in total knee arthroplasty patients: A randomized controlled trial.
        J Thromb Haemost. 2018; 16: 2442-2453
        • 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
        • Karaaslan F.
        • Karaoglu S.
        • Yurdakul E.
        Reducing intra-articular hemarthrosis after arthroscopic anterior cruciate ligament reconstruction by the administration of intravenous tranexamic acid: A prospective, randomized controlled trial.
        Am J Sports Med. 2015; 43: 2720-2726

      Linked Article

      • The Dangers and Concerns of Intra-articular Tranexamic Acid
        ArthroscopyVol. 35Issue 11
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          I read with interest the article from Chiang et al.1 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.
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      • Regarding “Intra-articular Injection of Tranexamic Acid Reduced Postoperative Hemarthrosis in Arthroscopic Anterior Cruciate Ligament Reconstruction: A Prospective Randomized Study”
        ArthroscopyVol. 35Issue 11
        • Preview
          We read with great interest the recently published article by Chiang et al.1 on the use of tranexamic acid (TXA) in arthroscopic anterior cruciate ligament (ACL) reconstruction. Previously, the drug had been successfully used to control bleeding and reduce total blood loss in non-orthopaedic procedures2,3; more recently, several high-quality studies have addressed the use of TXA in joint replacement, and its efficacy in this setting is now widely recognized.4-6 The benefits of TXA should be studied for other orthopaedic procedures that may take advantage of reduced bleeding, such as closed-joint surgery, in which hemarthrosis is a cause of pain, functional limitation, and difficulty in rehabilitation.
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