Peri-articular tranexamic acid injection in total knee arthroplasty: a randomized controlled trial
© The Author(s). 2016
Received: 11 February 2016
Accepted: 20 July 2016
Published: 26 July 2016
Intravenous tranexamic acid (IV TXA) is one of the most effective agents in use for reducing blood loss following total knee arthroplasty (TKA) but its safety regarding venous thromboembolic events (VTEs) remains in question. The direct, local application of TXA may reduce systemic toxicity whilst maintaining good or better bleeding control compared to IV TXA. The topical application of TXA via Hemovac drains has been reported previously with good results. However, there are no data on peri-articular TXA injections during TKA.
We conducted an open randomized, pilot study of peri-articular vs. IV TXA in 60 patients undergoing TKA. 30 patients received either: (i) 750 mg peri-articular TXA into the medial, lateral capsules and the quadriceps tendon prior to capsular closure and tourniquet deflation (group1), or (ii) 750 mg of IV TXA just before tourniquet deflation. Blood loss in the hemovac drain and hemoglobin (Hb) concentrations were measured at 24 and 48 h (h), and the number of blood transfusions and leg circumference measurements were recorded.
At 48 h, the total blood loss in the hemovac drain was 445 mL in group 1 vs. 520 mL in group 2 (p = 0.081) and the corresponding declines in Hb were 1.85 g/dL vs. 1.87 g/dL (p = 0.84). 16 patients received blood transfusions: 9 vs. 7 in groups 1 and 2, respectively (p = 0.928). There were no differences in thigh and lower leg circumferences, pain scores, knee flexion at discharge date and lengths of hospital stay. There were no clinically detected venous thromboembolic events.
This pilot study has shown promising results for peri-articular TXA during TKA. Additional, larger studies are needed to confirm our results and be powered to show differences in efficacy and safety of peri-articular vs. IV TXA.
ClinicalTrials.gov Identifier NCT02829346. Retrospectively registered: 07/11/2016.
KeywordsTranexamic acid Peri-articular injection Total knee arthroplasty Blood loss
Postoperative bleeding in total knee arthroplasty (TKA), which can result in hypovolemic shock and the need for allogenic blood transfusions, is a major concern for orthopedic surgeons. Several strategies are used to reduce postoperative blood loss, including preoperative autologous blood transfusions, hemoglobin raising agents, intraoperative tourniquets, cell savers, intravenous (IV), and topical tranexamic acid (TXA) [1–7]. TXA is an antifibrinolytic agent that inhibits the conversion of plasminogen to plasmin and also acts as a plasmin inhibitor. This results in inhibition of the breaking down of fibrin blood clots (fibrinolysis)  and fibrin clot stabilization rather than the promotion of clot aggregation [9, 10]. Plasmin activation due to tissue trauma increases after release of the surgical tourniquet and increased fibrinolysis [8, 11, 12].
IV TXA is commonly used intravenously for reducing blood loss and blood transfusions following TKA. Blood loss reduction varies from 10 % to 70 % compared to control groups not receiving TXA [13–15]. However, there are reports of thrombus formation associated with IV TXA [16, 17]. Topical TXA applications have been reported as another method to reduce blood loss and are associated with fewer systemic side effects compared to IV TXA [6, 7, 18–21]. Topical TXA is usually applied by soaking TXA in the operating field and washed after period of time or left to drain out following wound closure and drain insertion. Topical TXA is only has superficial contact with the bleeding surface and for a limited period of time. We do not know the effect of topical TXA on polyethylene and this needs the further study.
Another approach could be peri-articular TXA injections which would act directly on the injured tissue and for a longer duration compared to topical and IV TXA. This may result in better reduced blood loss comparable or better than topical or IV TXA but without the potential systemic toxicity of IV TXA [22, 23].
Given the lack of data on peri-articular TXA, we evaluated the benefits and toxicity of peri-articular TXA compared to standard IV TXA and report the results, herein.
This prospective, randomized trial was conducted from October 2012 to October 2013, and approved by the Ethics Committee, Institutional Review Board of Thammasat University (Registry #MTU-EC-OT-0-096/54). All patients had been provided with written, informed consent prior to their participation in the study.
The study inclusion criteria were adult patients with osteoarthritis in need of a TKA.
The exclusion criteria were the patients with inflammatory arthritis, post-traumatic arthritis, a history of or current venous thromboembolic disease, any underlying disease of haemostasis, cirrhosis, chronic renal failure, patients on anticoagulants or strong antiplatelet drugs (e.g. warfarin, clopidogrel), know allergy to TXA, defective color vision, and a preoperative hemoglobin <10 g/dL or a platelet count < 140,000 /uL3.
The primary outcomes were: the volume of postoperative blood loss in the drain, changes in hemoglobin concentrations, and the necessity for a blood transfusion. As for secondary outcomes, we measured knee diameter for swelling, local soft tissue complications, skin necrosis, and clinically confirmed VTEs, and pain, using a Visual Analogue Scales (VAS, 0 = no pain, 10 = the worst imaginable pain), knee flexion at discharge and the length of hospital stay.
Knee swelling was measured circumferentially at the thigh (taken at 10 cm above the upper pole of the patella) and the lower leg (taken at 10 cm below the lower pole of the patella), and calculated as the differences in the circumferences pre- and 48-h post-operation.
The sample size was calculated based on the measured postoperative blood loss. We assumed an alpha error of 0.05 and applied an allocation ratio of 1. A sample size of 30 participants, which allowed with a dropout rate of 10 % (3 participants), was calculated to provide a 80 % power in detecting a difference of 150 mL or reducing postoperative blood loss by 30 % in favour of the peri-articular TXA injection (from 10 patients of our earlier pilot study); we considered these parameters to be clinically relevant . All statistical analyses were performed using SPSS software version 17.0 (SPSS Inc, Chicago, IL, USA). Differences in categorical variables were analyzed by chi squared or Fisher’s exact test, as necessary, and the unpaired ‘t’ test was used for normally distributed, continuous variables.
Patient characteristics at baseline
(n = 30)
(n = 30)
67.63 (+/− 7.96)
69.97 (+/− 7.55)
66.88 (+/− 11.29)
65.14 (+/− 9.32)
155.73 (+/− 6.59)
156.77 (+/− 6.39)
27.96 (+/− 4.99)
26.52 (+/− 3.71)
12.01 (+/− 1.27)
12.27 (+/− 1.30)
36.58 (+/− 3.63)
37.58 (+/− 3.49)
Blood loss and blood transfusions
Group 1: Peri-articular group (n = 30)
Group 2: Intravenous group (n = 30)
Blood in Hemovac drain(ml)
300 (+/− 128)
334 (+/− 124)
145 (+/− 92)
186 (+/− 106)
445 (+/− 158)
520 (+/− 175)
36.4 (+/− 3.6)
37.6 (+/− 3.5)
29.7 (+/− 3.4)
30.4 (+/− 4.0)
31.0 (+/− 2.7)
31.8 (+/− 3.4)
Total Hct change (%) (pre op – 48 hr)
−5.4 (+/− 3.1)
−5.8 (+/− 4.4)
12.01 (+/− 1.27)
12.27 (+/− 1.30)
9.69 (+/− 1.19)
10.09 (+/− 1.50)
10.16 (+/− 0.98)
10.40 (+/− 1.28)
Total Hb change (g/dL) (pre op – 48 hr)
−1.85 (+/− 0.95)
−1.87 (+/− 1.37)
Total blood transfusion (PRC in unit)
Number of patients with blood transfusion
Thigh and leg circumferences (centimeters)
(n = 30)
(n = 30)
44.25 (+/− 6.61)
43.63 (+/− 4.24)
46.30 (+/− 7.03)
45.10 (+/− 4.21)
2.05 (+/− 1.47)
1.47 (+/− 1.19)
35.20 (+/− 3.88)
33.57 (+/− 2.97)
36.57 (+/− 3.96)
34.70 (+/− 3.37)
1.39 (+/− 1.27)
1.16 (+/− 1.08)
Visual Analogue score (VAS) for pain, knee flexion at discharge, and length of hospital stay
(n = 30)
(n = 30)
3.8 (+/− 2.48)
3.70 (+/− 2.44)
3.56 (+/− 1.89)
3.43 (+/− 1.67)
Knee flexion at discharge
97° (+/− 10.87°)
90° (+/− 17.41°)
5.7 (+/− 1.46)
5.3 (+/− 0.84)
No patients had clinical evidence of tense hemarthroses, subcutaneous hematomas, peroneal nerve palsies, surgical wound infections, skin necrosis or symptomatic VTEs up to 14 days following the surgery.
TXA has been shown to be an effective antifibrinolytic agent for reducing blood loss following TKA [8, 10]. However, IV TXA is a systemic therapy and requires systemic distribution to exert its antibleeding effects. Peri-articular TXA injection could, theoretically, be more effective and cause less systemic toxicity like thrombosis and systemic hypersensitivity reactions . Given the lack of data, a randomized trial was needed comparing peri-articular with the current standard treatment of IV TXA.
Our study has demonstrated that the 750 mg of peri-articular TXA injection group had less blood loss in the drain and lower decreases in hemoglobin concentration but a slight increase in the number of blood transfusion rates which would be from lower initial hemoglobin level in the peri-articular TXA injection group. Although none of these differences were statistically significant, the data hint that the antibleeding effects may have been roughly similar. This was a pilot study using a “best guess” dose. No dose ranging studies have been conducted to determine the optimal peri-articular dose and this is an area of future research.
There are the case reports of VTEs associated with IV TXA administration which is concern to the surgeon [16, 17]. Two recent meta-analyses of IV TXA in TKA was unable to conclude definitively on its safety because the studies were underpowered [26, 27]. Our study found no VTE in either group but our patient numbers were very small. The peri-articular TXA injection group did not show signs of drug toxicity as evidenced by the lack of local physical signs, like excess bleeding, swelling, and wound infections. This is a promising finding but more studies are needed, including dose ranging studies to ascertain if toxicity is dose related. Trying to detect if there might be differences in risk of VTEs between peri-articular and IV TXA would require very large sample sizes and is best left to pharmacovigilance if peri-articular TXA becomes an established practice. We acknowledge our study’s limitations. The sample size was small and so we were underpowered to detect uncommon events like VTEs. Moreover, we were guided by symptoms and signs of VTEs and did not actively seek asymptomatic VTEs. A lack of resources precluded the monitoring of serum TXA concentrations which could have suggested under or over exposure of IV TXA. We did not establish placebo group in the study, since the administration of IV TXA is a standard protocol for our patients and possible problem with ethical issues. The previous prospective randomized controlled trial study comparing IV TXA with placebo in the patients undergone TKA found significantly lower blood loss in IV TXA group .
Our small pilot study has shown promising initial results regarding peri-articular TXA injection. This, in primary TKA, peri-articular TXA injection could be an alternative route of TXA administration. More research is needed to determine the optimal TXA dose and define better the risks and benefits.
BMI, body mass index; TKA, total knee arthroplasty; VAS, visual analogue scales for pain; VTE, venous thromboembolic event
We thank Thananit Sangkomkamhang, MD, for help with the statistical analysis and Dr. Bob Taylor for reviewing the manuscript. We also thank all study participants.
The study has not received any external funding.
Availability of data and materials
Data will not be shared due to participants did not consent to public release of their data.
PP participated in the design, performed the surgeries, analysis and interpretation of the data and manuscript writing. SR participated in the design, gathered data of patients, analysis and interpretation of the data and manuscript writing. SC participated in the analysis and interpretation of the data and manuscript writing or revising it critically for important intellectual content. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
Ethical approval was granted by Institutional Review Board of Thammasat University (Registry #MTU-EC-OT-0-096/54). A written informed consent was obtained from all the participants in this study. The study was retrospectively registered on ClinicalTrials.gov (Identifier NCT02829346) on July 11st 2016.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Sinclair KC, Clarke HD, Noble BN. Blood management in total knee arthroplasty: a comparison of techniques. Orthopedics. 2009;32:19.View ArticlePubMedGoogle Scholar
- Gonzalez-Porras JR, Colado E, Conde MP, Lopez T, Nieto MJ, Corral M. An individualized pre-operative blood saving protocol can increase pre-operative haemoglobin levels and reduce the need for transfusion in elective total hip or knee arthroplasty. Transfus Med. 2009;19:35–42.View ArticlePubMedGoogle Scholar
- Parvizi J, Diaz-Ledezma C. Total knee replacement with the use of a tourniquet: more pros than cons. Bone Joint J. 2013;95-B(Supple A):133–4.View ArticlePubMedGoogle Scholar
- Sabatini L, Trecci A, Imarisio D, Uslenghi MD, Bianco G, Scagnelli R. Fibrin tissue adhesive reduces postoperative blood loss in total knee arthroplasty. J Orthop Traumatol. 2012;13:145–51.View ArticlePubMedPubMed CentralGoogle Scholar
- Pitta M, Zawadsky M, Verstraete R, Rubinstein A. Intravenous administration of tranexamic acid effectively reduces blood loss in primary total knee arthroplasty in a 610-patient consecutive case series. Transfusion. 2016;56(2):466–71.View ArticlePubMedGoogle Scholar
- Wong J, Abrishami A, El Beheiry H, Mahomed NN, Roderick Davey J, Gandhi R, et al. Topical application of tranexamic acid reduces postoperative blood loss in total knee arthroplasty: a randomized, controlled trial. J Bone Joint Surg Am. 2010;92:2503–13.View ArticlePubMedGoogle Scholar
- Aggarwal AK, Singh N, Sudesh P. Topical vs Intravenous Tranexamic Acid in Reducing Blood Loss After Bilateral Total Knee Arthroplasty: A Prospective Study. J Arthroplasty. 2015 Dec 21. doi:https://doi.org/10.1016/j.arth.2015.12.033. [Epub ahead of print]
- Benoni G, Lethagen S, Fredin H. The effect of tranexamic acid on local and plasma fibrinolysis during total knee arthroplasty. Thromb Res. 1997;85:195–206.View ArticlePubMedGoogle Scholar
- Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs. 1999;57:1005–32.View ArticlePubMedGoogle Scholar
- Eubanks JD. Antifibrinolytics in major orthopaedic surgery. J Am Acad Orthop Surg. 2010;18:132–8.View ArticlePubMedGoogle Scholar
- Kluft C, Verheijen JH, Jie AF, Rijken DC, Preston FE, Sue-Ling HM, et al. The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma. Scand J Clin Lab Invest. 1985;45:605–10.View ArticlePubMedGoogle Scholar
- Murphy WG, Davies MJ, Eduardo A. The haemostatic response to surgery and trauma. Br J Anaesth. 1993;70:205–13.View ArticlePubMedGoogle Scholar
- Charoencholvanich K, Siriwattanasakul P. Tranexamic acid reduces blood loss and blood transfusion after TKA: a prospective randomized controlled trial. Clin Orthop Relat Res. 2011;469:2874–80.View ArticlePubMedPubMed CentralGoogle Scholar
- Orpen NM, Little C, Walker G, Crawford EJ. Tranexamic acid reduces early postoperative blood loss after total knee arthroplasty; a prospective randomized controlled trial of 29 patients. Knee. 2006;13:106–10.View ArticlePubMedGoogle Scholar
- Ortega-Andreu M, Pérez-Chrzanowska H, Figueredo R, Gómez-Barrena E. Blood loss control with two doses of tranexamic Acid in a multimodal protocol for total knee arthroplasty. Open Orthop J. 2011;5:44–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Mannucci PM. Hemostatic drugs. N Engl J Med. 1998;339:245–53.View ArticlePubMedGoogle Scholar
- Mannucci PM. Prevention and treatment of major blood loss. N Engl J Med. 2007;356:2301–11.View ArticlePubMedGoogle Scholar
- Ishida K, Tsumura N, Kitagawa A, Hamamura S, Fukuda K, Dogaki Y, et al. Intra-articular injection of tranexamic acid reduces not only blood loss but also knee joint swelling after total knee arthroplasty. Int Orthop. 2011;35:1639–45.View ArticlePubMedPubMed CentralGoogle Scholar
- Maniar RN, Kumar G, Singhi T, Nayak RM, Maniar PR. Most effective regimen of tranexamic acid in knee arthroplasty: a prospective randomized controlled study in 240 patients. Clin Orthop Relat Res. 2012;470:2605–12.View ArticlePubMedPubMed CentralGoogle Scholar
- Roy SP, Tanki UF, Dutta A, Jain SK, Nagi ON. Efficacy of intra-articular tranexamic acid in blood loss reduction following primary unilateral total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc. 2012;20:2494–501.View ArticlePubMedGoogle Scholar
- Wang H, Shen B, Zeng Y. Blood Loss and Transfusion After Topical Tranexamic Acid Administration in Primary Total Knee Arthroplasty. Orthopedics. 2015;38(11):e1007–16. doi:https://doi.org/10.3928/01477447-20151020-10.View ArticlePubMedGoogle Scholar
- Spreng UJ, Dahl V, Hjall A, Fagerland MW, Ræder J. High-volume local infiltration analgesia combined with intravenous or local ketorolac + morphine compared with epidural analgesia after total knee arthroplasty. Br J Anaesth. 2010;105:675–82.View ArticlePubMedGoogle Scholar
- Manor D, Sadeh M. Muscle fiber necrosis induced by intramuscular injection of drugs. Br J Exp Pathol. 1989;70:457–62.PubMedPubMed CentralGoogle Scholar
- Pinsornsak P, Chumchuen S. Can a modified Robert Jones bandage after knee arthroplasty reduce blood loss? A prospective randomized controlled trial. Clin Orthop Relat Res. 2013;471(5):1677–81.View ArticlePubMedPubMed CentralGoogle Scholar
- Kagoma YK, Crowther MA, Douketis J, Bhandari M, Eikelboom J, Lim W. Use of antifibrinolytic therapy to reduce transfusion in patients undergoing orthopedic surgery: a systematic review of randomized trials. Thromb Res. 2009;123:687–96.View ArticlePubMedGoogle Scholar
- Alshryda S, Sarda P, Sukeik M, Nargol A, Blenkinsopp J, Mason JM. Tranexamic acid in total knee replacement: a systematic review and meta-analysis. J Bone Joint Surg (Br). 2011;93:1577–85.View ArticleGoogle Scholar
- Gandhi R, Evans HM, Mahomed SR, Mahomed NN. Tranexamic acid and the reduction of blood loss in total knee and hip arthroplasty: a meta-analysis. BMC Res Notes. 2013;6:184.View ArticlePubMedPubMed CentralGoogle Scholar