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Antifibrinolytics in Total Knee Arthroplasty

Introduction

In a number of clinical trials, antifibrinolytic drugs used perioperatively have been shown to reduce blood loss and transfusion rates in a variety of surgical subspecialties. (5-18).

Background

Antifibrinolytic drugs can decrease the need for blood transfusions following surgical procedures. Two such drugs are epsilon aminocaproic acid (EACA) and tranexamic acid (TA). Tranexamic acid has been studied more thoroughly in the orthopaedic literature and appears to be effective at decreasing blood loss and blood transfusion rates. There has been some hesitancy in utilizing these drugs due to fear of adverse effects, primarily thromboembolic disease.  Concerns for the potential systemic ramifications of the use of antithrombolytics have increased interest in their local use. Topical TA and EACA has been effectively and safely utilized in cardiac, ophthalmic, oral, and orthopaedic surgery, resulting in low systemic concentrations of the drug.(26, 27, 28, 29, 30, 31)

Mechanism and Pharmacokinetics

TA and EACA are water soluble analogs of lysine, which block the lysine binding site of plasminogen and free plasmin (3,4). This effectively displaces plasminogen from the fibrin surface, leading to inhibition of fibrinolysis (3,4).

Following intravenous (I.V.) administration, maximum plasma levels of TA and EACA are reached in 5 to 15 minutes and diffuse rapidly in synovial fluid and membranes; the half-life of these drugs in plasma is 1 to 3 hours (3). They are excreted by glomerular filtration, non-metabolized in their form. Thus, excretion is prolonged in patients with renal impairment (4). Animal studies have shown that a serum concentration of 1,000 mcg/mL reduces fibrinolytic activity by 98%; 250 mcg/mL, by 90%; and a 100 mcg/mL, by 80% (4). EACA collects in soft tissues causing a continued inhibitory effect approximately 3 hours after its presence in the serum (4). TA and EACA are compared in Table 1.

Table 1. Pharmacokinetics of TA and EACA

 

TA

EACA

Half-life in plasma

1-3 hours

1-3 hours

24-hour urine recovery rate after single IV bolus

91%

71%

Plasma concentration yielding 80% fibrinolytic activity

10 mcg/mL

100 mcg/mL

Continued inhibition after I.V. dosing

8-12 hours

3 hours

TA = tranexamic acid; EACA = Epsilon aminocaproic acid


To decrease the systemic effects, a 5-minute intraoperative bath of TA in total knee arthroplasty (TKA) has resulted in plasma concentrations of 4.5 to 8.5 mg/L; 1 hour after a single I.V. injection of 10mg/kg of TA, the plasma concentration has been shown to reach 18 mg/L. (29) 

Dosing and Efficacy

The amount and frequency of dosing is variable in the literature. TA dosing ranges most frequently from 10 to 20 mg/kg. However, dosing as high as 150 mg/kg has been reported. There does not yet appear to be a clear correlation between the dosage amount and clinical efficacy (5-18). The frequency of the dose given is even more variable, with some investigators giving a single I.V. injection preoperatively, others administering pre- and postoperative doses, and still others giving a bolus followed by a slow infusion.

Timing of the antifibrinolytic dose was investigated by Tanaka et al in a prospective randomized study. They used a 20-mg/kg TA dose in 99 patients undergoing a primary TKA, dividing the patients into three TA groups, based on when the TA dose was given:

  • Preoperatively
  • Just prior to deflation of the tourniquet
  • Half preoperatively and half just prior to touniquet deflation (20)

A control group receiving no TA was also utilized. The study showed that a split does was the most beneficial with respect to measured intraoperative blood loss; however, there was no difference in blood transfusion rates when compared with the onetime preoperative does. Investigators showed a 40% improvement in blood loss with administration of TA, with no difference in deep vein thrombosis (DVT) as measured by venogram (20).

In another study on administration of TA, Alvarez et al utilized a 10-mg/kg dose given 30 minutes before deflation of the tourniquet followed by 1 mg/kg/hour over the first 6 postoperative hours. Patients who received TA showed a 25.4% decrease in postoperative drain output (5). Of the 95 patients in the study, 4% who received TA and 73% of those in the saline control group received an autologous blood transfusion. (5)

A recent prospective randomized study compared 1.5 g and 3 g of TA in 100 mL of normal saline solution with a normal saline placebo applied topically in an intraoperative, 5-minute bath during TKA. The bath was performed after cementation. The tourniquet was not released until postoperative dressings were in place. Randomizing 124 patients, of whom 24 were removed, revealed a statistically significant reduction in blood loss, from 20% to 25% with a 16-17% increase in postoperative hemoglobin. There was also a trend towards a reduction in blood transfusion in patients who received TA; however, this was not statistically significant. (29)

Not every study demonstrates a reduction in blood loss with use of antifibrinolytics. Good et al showed no decrease in hidden blood loss in patients who received TA. However, the study did identify a significant decrease in blood transfusion rates when compared with a saline placebo group (22).

Safety

While most studies have not shown an increased incidence in symptomatic DVT or pulmonary embolus (PE) with the use of antifibrinolytics (1,7,10,23,24), a few studies have shown a non-statistically significant increased risk of DVT or PE (19,26). A meta-analysis of 27 studies reporting on venous thromboembolic complications revealed no absolute change in risk between patients receiving antifibrinolytics and those receiving placebo. The relative risk for patients receiving antifibrinolytics was 0.95 with a CI of 0.80 to 1.10. However, the authors cautioned that the strength of these conclusions is limited due to the lack of systematic investigation and small numbers of events.

Most studies excluded patients with a recent heart attack or stroke and patients with a history of venous thrombosis (VTE) disease or genetic predisposition to clotting disease.

Recommendations

Perioperative use of TA in TKA seems to be safe and effective at reducing blood loss and decreasing transfusion rates. A single 20-mg/kg I.V. dose just prior to incision or two split doses of 10 mg/kg dose, one given prior to incision and the other given 4 hours later, appear to be reasonable until further research on optimal dosing is performed. Alternatively, 1.5-3 g of local TA in 100 mL of saline of may be utilized in a 5-minute intraoperative bath after cementation and before release of the tourniquet. Exclusion criteria may include patients with a recent heart attack or stroke, history of VTE disease, or genetic predisposition to clotting disease. More data on the use of EACA in TKA is needed before its efficacy can be determined.

References

1. Harley BJ, Beaupre LA, Jones CA, Cinats JG, Guenther CR. The effect of epsilon aminocaproic acid on blood loss in patients who undergo primary total hip replacement: a pilot study.  Can J Surg 2002:45(3) 185-190.

2. Walzman M, Bonnar J. Effects of tranexamic acid on the coagulation and fibrinolytic systems in pregnancy complicated by placental bleeding. Arch Toxicol Suppl 1982;5:214-20.

3. Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs 1985;29:236-61.

4.  Andersson L, Nilsson IM, Colleen S, Granstrand B, Melander B. Role of urokinase and tissue activator in sustaining bleeding and the management thereof with EACA and AMCA. Ann NY Acad Sci 1968;146:642-58.

5.  Alvarez JC, Santiveri FX, Ramos I, Vela E, Puig L, Escolano F. Tranexamic acid reduces blood transfusion in total knee

arthroplasty even when a blood conservation program is applied.  Transfusion. 2008;48:519--525.

6. Camarasa MA, Olle´ G, Serra-Prat M, Mart?´n A, Sa´nchez M, Rico´s P, Pe´rez A, Opisso L. Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: a randomized clinical trial. Br J Anaesth. 2006;96:576--582.

7. Cid J, Lozano M. Tranexamic acid reduces allogeneic red cell transfusions in patients undergoing total knee arthroplasty: results of a meta-analysis of randomized controlled trials. Transfusion. 2005;45:1302--1307.

8. Claeys MA, Vermeersch N, Haentjens P. Reduction of blood loss with tranexamic acid in primary total hip replacement surgery.Acta Chir Belg. 2007;107:397--401.

9. Gill JB, Rosenstein A. The use of antifibrinolytic agents in total hip arthroplasty: a meta-analysis. J Arthroplasty. 2006;21:869--873.

10. Ho KM, Ismail H. Use of intravenous tranexamic acid to reduce allogeneic blood transfusion in total hip and knee arthroplasty: a meta-analysis. Anaesth Intensive Care. 2003;31:529--537.

11. Johansson T, Pettersson LG, Lisander B. Tranexamic acid in total hip arthroplasty saves blood and money: a randomized, doubleblind study in 100 patients. Acta Orthop. 2005;76:314--319.

12. 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--696.

13. Lozano M, Basora M, Peidro L, Merino I, Segur JM, Pereira A, Salazar F, Cid J, Lozano L, Mazzara R, Macule F. Effectiveness and safety of tranexamic acid administration during total knee arthroplasty. Vox Sang. 2008;95:39--44.

14. Molloy DO, Archbold HA, Ogonda L, McConway J, Wilson RK, Beverland DE. Comparison of topical fibrin spray and tranexamic acid on blood loss after total knee replacement: a prospective, randomised controlled trial. J Bone Joint Surg Br. 2007;89:306--309.

15. Niskanen RO, Korkala OL. Tranexamic acid reduces blood loss in cemented hip arthroplasty: a randomized, double-blind study of 39 patients with osteoarthritis. Acta Orthop. 2005;76:829--832.

16. Orpen NM, Little C, Walker G, Crawfurd EJ. Tranexamic acid reduces early post-operative blood loss after total knee

arthroplasty: a prospective randomised controlled trial of 29 patients. Knee. 2006;13:106--110.

17. Rajesparan K, Biant LC, Ahmad M, Field RE. The effect of an intravenous bolus of tranexamic acid on blood loss in total hip replacement. J Bone Joint Surg Br. 2009;91:776--783.

18. Zufferey P, Merquiol F, Laporte S, Decousus H, Mismetti P, Auboyer C, Samama CM, Molliex S. Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery? Anesthesiology.

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