Advertisement

Editorial Commentary: Tranexamic Acid: Okay, It Reduces the Bleeding, but Are We Sure Topical Use Is Not Harmful to the Cartilage?

      Abstract

      Numerous studies have estimated the role of hemarthrosis and intra-articular drains in anterior cruciate ligament (ACL) reconstructive procedures. Long-standing hemarthrosis and related pain can disrupt rehabilitation and lead to arthrofibrosis. A significant number of orthopaedic surgeons use intra-articular suction drains following arthroscopic ACL reconstruction. Hemarthrosis and pain have undesirable effects on the functional outcomes of ACL reconstruction in the early postoperative period.
      An increasing number of studies on use of tranexamic acid (TXA) for controlling bleeding in orthopaedic surgery have been published over the last decade. TXA has been shown to be effective in orthopaedic surgery, especially total knee and hip arthroplasty and spinal surgery, in minimizing perioperative bleeding. Even though worldwide agreement has not been reached on TXA administration, it is effective in reducing blood loss and the need for transfusion. By decreasing other costs, TXA is cost-effective in specific orthopaedic surgical procedures.
      • Karaaslan F.
      • Karaoglu S.
      • Mermerkaya M.U.
      • Baktir A.
      Reducing blood loss in simultaneous bilateral total knee arthroplasty: Combined intravenous-intra-articular tranexamic acid administration. A prospective randomized controlled trial.
      • Lin Z.X.
      • Woolf S.K.
      Safety, efficacy, and cost-effectiveness of tranexamic acid in orthopedic surgery.
      • Lu V.M.
      • Ho Y.T.
      • Nambiar M.
      • Mobbs R.J.
      • Phan K.
      The perioperative efficacy and safety of antifibrinolytics in adult spinal fusion surgery: A systematic review and meta-analysis.
      • Wang Z.
      • Zhang H.J.
      Comparative effectiveness and safety of tranexamic acid plus diluted epinephrine to control blood loss during total hip arthroplasty: A meta-analysis.
      • Xiong H.
      • Liu Y.
      • Zeng Y.
      • Wu Y.
      • Shen B.
      The efficacy and safety of combined administration of intravenous and topical tranexamic acid in primary total knee arthroplasty: A meta-analysis of randomized controlled trials.
      • Zhang P.
      • Bai J.
      • He J.
      • Liang Y.
      • Chen P.
      • Wang J.
      A systematic review of tranexamic acid usage in patients undergoing femoral fracture surgery.
      • Zhang Y.
      • Liu H.
      • He F.
      • Chen A.
      • Yang H.
      • Pi B.
      Does tranexamic acid improve bleeding, transfusion, and hemoglobin level in patients undergoing multi-level spine surgery? A systematic review and meta-analysis.
      • Zhao Z.
      • Ma J.
      • Ma X.
      Comparative efficacy and safety of different hemostatic methods in total hip arthroplasty: A network meta-analysis.
      The use of TXA to reduce operative and postoperative bleeding and the subsequent need for blood transfusion is well defined for certain orthopaedic procedures, yet it still raises some questions for arthroscopic surgeons.
      • 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.
      • Felli L.
      • Revello S.
      • Burastero G.
      • et al.
      Single intravenous administration of tranexamic acid in anterior cruciate ligament reconstruction to reduce postoperative hemarthrosis and increase functional outcomes in the early phase of postoperative rehabilitation: A randomized controlled trial.
      The subject of this commentary is the well-performed study in this issue on reducing hemarthrosis after anterior cruciate ligament reconstruction (ACLR) by Chiang, Chen, Wang, Ma, Chang, Liu, Chen
      • 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.
      titled “Intra-articular Injection of Tranexamic Acid Reduced Postoperative Hemarthrosis in Arthroscopic Anterior Cruciate Ligament Reconstruction: A Prospective Randomized Study.” It is well written, has an important clinical message, and should be of great interest to readers. The authors have considered both postoperative bleeding as well as pain scores. In addition, they studied postoperative clinical scores both with or without use of TXA. Patients were excluded for the following reasons: previous knee procedures on the same side, renal disorder or insufficiency, abnormal coagulation profile, and refusal to participate in the study. The same surgical team performed the same surgical procedure and used a standard postoperative regimen of physiotherapy for all patients. The TXA group patients underwent ACLRs and 10-mL intra-articular injection of TXA after the procedure. Results show that 24 hours after surgery a significant decrease in the amount of drainage in patients receiving the intra-articular injections was observed in the TXA group (56.1 ± 34.1 mL) versus the control group (80.1 ± 48 mL; P < .05). Also, at day 3 and week 4, significantly reduced pain scores were reported by the TXA group patients. However, at week 4, clinical function scores did not show significant differences between the 2 groups. The authors concluded that intra-articular injection of TXA could be considered as an effective and relatively safe solution to reduce postoperative bleeding and pain in ACLR.
      • 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.
      However, intra-articular administering of TXA brings some concerns.
      Topical administration of TXA may avoid the danger of potentially increased systemic coagulating risk, mainly in patients defined as high risk. Nevertheless, the theory that systemic TXA levels could be reduced is related to TXA administered intravenously. Some studies suggest that topically used TXA in doses of 1.5 and 3 g can reach mean plasma values of 4.5 and 8.5 mg/L. Plasma concentrations 1 hour after administration of 10 mg/kg TXA have yielded mean levels of 18 mg/L. Although topically used TXA seems therefore to lead to lower plasma values, one should observe that values between 5 and 10 mg/L are regarded as pharmaceutically active. Thus, at least in theory, topical administration has systemic effects and, possibly, side effects.
      • Danninger T.
      • Memtsoudis S.G.
      Tranexamic acid and orthopedic surgery-the search for the holy grail of blood conservation.
      • Nilsson I.M.
      Clinical pharmacology of aminocaproic and tranexamic acids.
      • Dunn C.J.
      • Goa K.L.
      Tranexamic acid: A review of its use in surgery and other indications.
      The risk that a high local level of TXA, once it has been used topically, could cause increasing local complications at the operation site must be carefully considered. Topical use of TXA may offer advantages over intravenous administration with regard to reducing systemic plasma values, but well designed studies are needed to show safety. Meanwhile, the administration of TXA has risen in popularity because of its effectiveness and affordability. However, its risks and benefits need to be continuously evaluated as new data appear, particularly regarding adverse events.
      Further studies are required to discover more about the correlation of the effectiveness of TXA with alternative administration procedures, doses, exposure duration, and timing as well as the association of TXA use with functional outcomes. However, we still do not have enough data supporting its use in all joints. There are a few other studies that are concerning with regard to topical use.
      • Sukur E.
      • Kucukdurmaz F.
      Comparison of cytotoxic effects of intra-articular use of tranexamic acid versus epinephrine on rat cartilage.
      • Goderecci R.
      • Giusti I.
      • Necozione S.
      • et al.
      Short exposure to tranexamic acid does not affect, in vitro, the viability of human chondrocytes.
      • Cirakli A.
      • Gurgor P.N.
      • Uzun E.
      • Erdem H.
      • Cankaya S.
      • Bas O.
      Local application of tranexamic acid affects tendon healing negatively in the late period.
      • Busse P.
      • Vater C.
      • Stiehler M.
      • et al.
      Cytotoxicity of drugs injected into joints in orthopaedics.
      • Ambra L.F.
      • de Girolamo L.
      • Niu W.
      • Phan A.
      • Spector M.
      • Gomoll A.H.
      No effect of topical application of tranexamic acid on articular cartilage.
      The results reported by McLean et al.
      • McLean M.
      • McCall K.
      • Smith I.D.M.
      • et al.
      Tranexamic acid toxicity in human periarticular tissues.
      suggest that attention must be paid when thinking through exposing articular tissues to TXA at high levels or for exposure times even as short as 1 hour. The method of intra-articular injection or infusion, extended surgical soaking, or tissue saturation, especially in an enclosed joint space, needs to be examined in conjunction with the findings of this study and other studies that demonstrate increasing cell mortality.
      • McLean M.
      • McCall K.
      • Smith I.D.M.
      • et al.
      Tranexamic acid toxicity in human periarticular tissues.
      I believe it is necessary for studies to focus on determining the chondral and synovial toxic dose limit and exposure time in the joint space, as we well know that the use of TXA may decrease bleeding. I wonder if instead of injection into the joint, diluted TXA in the irrigation fluid may have the same effect with a reduced concern about probable toxic effects. Further studies should add a third group without drains to resolve the uncertainties about the necessity for drain use in ACLR. An analytical and recurrent reconsideration of accessible data is essential to confirm an evidence-based methodology on the suitable administration of TXA. TXA acid may reduce bleeding, but its effect on cartilage requires investigation.

      Supplementary Data

      References

        • Karaaslan F.
        • Karaoglu S.
        • Mermerkaya M.U.
        • Baktir A.
        Reducing blood loss in simultaneous bilateral total knee arthroplasty: Combined intravenous-intra-articular tranexamic acid administration. A prospective randomized controlled trial.
        Knee. 2015; 22: 131-135
        • Lin Z.X.
        • Woolf S.K.
        Safety, efficacy, and cost-effectiveness of tranexamic acid in orthopedic surgery.
        Orthopedics. 2016; 39: 119-130
        • Lu V.M.
        • Ho Y.T.
        • Nambiar M.
        • Mobbs R.J.
        • Phan K.
        The perioperative efficacy and safety of antifibrinolytics in adult spinal fusion surgery: A systematic review and meta-analysis.
        Spine. 2018; 43: e949-e958
        • Wang Z.
        • Zhang H.J.
        Comparative effectiveness and safety of tranexamic acid plus diluted epinephrine to control blood loss during total hip arthroplasty: A meta-analysis.
        J Orthop Surg Res. 2018; 13: 242
        • Xiong H.
        • Liu Y.
        • Zeng Y.
        • Wu Y.
        • Shen B.
        The efficacy and safety of combined administration of intravenous and topical tranexamic acid in primary total knee arthroplasty: A meta-analysis of randomized controlled trials.
        BMC Musculoskel Disord. 2018; 19: 321
        • Zhang P.
        • Bai J.
        • He J.
        • Liang Y.
        • Chen P.
        • Wang J.
        A systematic review of tranexamic acid usage in patients undergoing femoral fracture surgery.
        Clin Interv Aging. 2018; 13: 1579-1591
        • Zhang Y.
        • Liu H.
        • He F.
        • Chen A.
        • Yang H.
        • Pi B.
        Does tranexamic acid improve bleeding, transfusion, and hemoglobin level in patients undergoing multi-level spine surgery? A systematic review and meta-analysis.
        World Neurosurg. 2019; 127: 289-301
        • Zhao Z.
        • Ma J.
        • Ma X.
        Comparative efficacy and safety of different hemostatic methods in total hip arthroplasty: A network meta-analysis.
        J Orthop Surg Res. 2019; 14: 3
        • 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
        • Felli L.
        • Revello S.
        • Burastero G.
        • et al.
        Single intravenous administration of tranexamic acid in anterior cruciate ligament reconstruction to reduce postoperative hemarthrosis and increase functional outcomes in the early phase of postoperative rehabilitation: A randomized controlled trial.
        Arthroscopy. 2019; 35: 149-157
        • 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
        • Danninger T.
        • Memtsoudis S.G.
        Tranexamic acid and orthopedic surgery-the search for the holy grail of blood conservation.
        Ann Transl Med. 2015; 3: 77
        • Nilsson I.M.
        Clinical pharmacology of aminocaproic and tranexamic acids.
        J Clin Pathol. 1980; 14: 41-47
        • Dunn C.J.
        • Goa K.L.
        Tranexamic acid: A review of its use in surgery and other indications.
        Drugs. 1999; 57: 1005-1032
        • Sukur E.
        • Kucukdurmaz F.
        Comparison of cytotoxic effects of intra-articular use of tranexamic acid versus epinephrine on rat cartilage.
        Med Sci Monitor. 2018; 24: 1166-1170
        • Goderecci R.
        • Giusti I.
        • Necozione S.
        • et al.
        Short exposure to tranexamic acid does not affect, in vitro, the viability of human chondrocytes.
        Eur J Med Res. 2019; 24: 15
        • Cirakli A.
        • Gurgor P.N.
        • Uzun E.
        • Erdem H.
        • Cankaya S.
        • Bas O.
        Local application of tranexamic acid affects tendon healing negatively in the late period.
        Eklem Hastalik Cerrahisi. 2018; 29: 20-26
        • Busse P.
        • Vater C.
        • Stiehler M.
        • et al.
        Cytotoxicity of drugs injected into joints in orthopaedics.
        Bone Joint Res. 2019; 8: 41-48
        • Ambra L.F.
        • de Girolamo L.
        • Niu W.
        • Phan A.
        • Spector M.
        • Gomoll A.H.
        No effect of topical application of tranexamic acid on articular cartilage.
        Knee Surg Sports Traumatol Arthrosc. 2019; 27: 931-935
        • McLean M.
        • McCall K.
        • Smith I.D.M.
        • et al.
        Tranexamic acid toxicity in human periarticular tissues.
        Bone Joint Res. 2019; 8: 11-18

      Linked Article