Perioperative bleeding is a major concern in orthopaedics and is associated with additional risks and costs to the procedure. In addition, the rapid discharge of patients after surgery has increased the emphasis on blood conservation to enhance patient outcomes.

Antifibrinolytics have been used to reduce perioperative bleeding in other areas such as cardiac surgery. They have recently been introduced in spine and arthroplasty procedures. This article highlights important aspects of their use with respect to perioperative blood loss in orthopaedic surgery of the spine, hip, and knee.

Common antifibrinolytics
The three most common antifibrinolytics used in orthopaedic surgery are aprotinin, tranexamic acid (TXA), and epsilon-aminocaproic acid (EACA). These agents are classified as antifibrinolytics because they inhibit degradation of fibrin clots.

EACA and TXA reversibly bind lysine-binding sites of plasminogen, thus preventing plasminogen from binding to fibrin and thereby neutralizing the “clot-buster” effect. The exact mechanism of aprotinin is still unknown, but one theory is that it interacts with platelet glycoprotein Ib receptors, improving their function. Aprotinin may also have an antikallikrein effect, which prevents activation of plasminogen to plasmin.

Early studies reporting the use of antifibrinolytics in orthopaedic surgery were underpowered, and solid conclusions about overall efficacy were not available. Findings from a large meta-analysis performed in 2006 suggested that aprotinin and TXA were associated with fewer postoperative transfusions and identified a dose-dependent effect of TXA. A recent retrospective study of more than 2,000 primary arthroplasty patients reported no increase in the rate of sympto-matic thrombotic events when TXA was used in patients receiving chemoprophylaxis for deep venous thrombosis (DVT).

EACA has not been found to be as efficacious in reducing postoperative blood loss in orthopaedic surgery as it has in cardiac surgery. The use of aprotonin, which was once marketed and studied under the trade name “Trasylol,” was discontinued as a result of higher mortality rates in cardiac surgery compared to lysine analogs. However, the European Medicines Agency recommended lifting the ban on aprotinin in February 2012.

Use in orthopaedic surgery
The effect of these three major antifibrinolytics on transfusion rates in the setting of spine surgery was evaluated in a meta-analysis published in 2008. This analysis suggested that all three reduced blood transfusions and blood loss in spine surgery patients. Furthermore, the authors proposed that the drugs would have a greater effect in more complex surgical cases.

The analysis was unable to attribute any changes in complications such as DVT or pulmonary embolus (PE) due to these antifibrinolytics. Importantly, none of the studies included in the meta-analysis demonstrated sufficient power to clarify these complication rates when compared to a placebo control.

TXA has been used extensively in total knee arthroplasty (TKA), both topically and intravenously, and has demonstrated important reductions on blood loss and possibly transfusion rates. A randomized, placebo-controlled trial of a topical intra-articular application of 1.5 g TXA, 3g TXA, or placebo in cemented TKA demonstrated lower postoperative blood loss and higher hemoglobin levels with TXA. In this study, final irrigation, manipulation, and drains were not routinely used. Furthermore, the tourniquet was released after dressings were applied.

With respect to transfusion, the study results pointed to reduced transfusion rates with higher doses of TXA (3g), but a larger study will probably be needed to establish a major and significant reduction in transfusion rates compared to placebo. Although the study was extremely well designed and executed, its applicability to individual practice may require some technical modifications with respect to wound closure, irrigation, and drain use.

Intravenous administration of TXA (10 mg/kg) may also play an important role in reducing blood loss, and multidose regimens may be more effective than a single dose. A recent meta-analysis of randomized controlled trials of intravenous TXA in TKA concluded that TXA reduced blood loss and the number of transfusions per patient compared to placebo.

In the setting of cementless total hip arthroplasty (THA), one study showed that intravenous TXA (1,000 mg) resulted in decreased perioperative blood loss based on both laboratory analysis and perioperative bleeding. However, none of the patients in that study received a transfusion, whether they received TXA or not. Preoperative and multidose regimens may impart additional benefit to patients in terms of perioperative blood loss and postoperative hemoglobin levels, but further studies are required.

Conclusion
The interest and importance of antifibrinolytic therapy in arthroplasty and spinal surgery have increased. Although mortality associated with aprotinin was an early concern, thrombotic complications associated with EACA and TXA have not emerged. Future studies on definitive reductions in transfusions, costs, and longer-term mortality data will be useful in designing the optimal administration regimen for perioperative antifibrinolytic therapy. Both topical and intravenous administration appear to be efficacious, but the optimal route, timing, and dosages have not been defined.

Glenn D. Wera, MD is chief of orthopaedic surgery at the Cleveland Veterans Affairs Medical Center, director of the adult reconstruction fellowship, and assistant professor of orthopaedic surgery at Case Western Reserve University/University Hospitals Case Medical Center; Ryan M. Garcia, MD, is an orthopaedic surgeon and plastic surgery resident at Duke University; and Victor M. Goldberg, MD, is a professor of orthopaedic surgery at Case Western Reserve University.

Disclosure information: Drs. Wera and Garcia—no conflicts; Dr. Goldberg—Osteotech; Astrazenica; TissueLink; National Institutes of Health; Sultzer/Zimmer; Elsevair; Journal of Bone and Joint Surgery–American; Journal of Orthopaedic Research; Clinical Orthopaedics and Related Research; Osteoarthritis and Cartilage; AAOS Now; OASRI; Bioinnovations Institute

Bottom Line

• The importance of antifibrinolytics in orthopaedic surgery is growing.
• Antifibrinolytics decrease perioperative bleeding and may decrease transfusion rates after orthopaedic surgery.
• Clinical risks have been associated with aprotinin. However, TXA and EACA seem to be widely used and studied with encouraging initial results.

References

1. Eubanks JD: Antifibrinolytics in major orthopaedic surgery. J Am Acad Orthop Surg 2010;18(3):132-138.
2. Zufferey P, Merquiol F, Laporte S, et al: Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery? Anesthesiology 2006;105(5):1034-1046.
3. Vander Salm TJ, Kaur S, Lancey RA, et al: Reduction of bleeding after heart operations through the prophylactic use of epsilon-aminocaproic acid. J Thorac Cardiovasc Surg 1996;112(4):1098-1107.
4. Fergusson DA, Hébert PC, Mazer CD, et al: A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358(22):2319-2331.
5. Gillette BP, Desimone LJ, Trousdale RT, Pagnano MW, Sierra RJ: Low risk of thromboembolic complications With tranexamic acid after primary total hip and knee arthroplasty. Clin Orthop Relat Res 2013;471(1):150-154.
6. Gill JB, Chin Y, Levin A, Feng D: The use of antifibrinolytic agents in spine surgery: A meta-analysis. J Bone Joint Surg Am 2008;90(11):2399-2407.
7. Wong J, Abrishami A, El Beheiry H, 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(15):2503-2513.
8. 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(9):2605-2612.
9. Yang ZG, Chen WP, Wu LD. Effectiveness and safety of tranexamic acid in reducing blood loss in total knee arthroplasty: A meta-analysis. J Bone Joint Surg Am 2012;94(13):1153-1159.
10. Yamasaki S, Masuhara K, Fuji T: Tranexamic acid reduces postoperative blood loss in cementless total hip arthroplasty. J Bone Joint Surg Am 2005;87(4):766-770.
11. Imai N, Dohmae Y, Suda K, Miyasaka D, Ito T, Endo N: Tranexamic acid for reduction of blood loss during total hip arthroplasty. J Arthroplasty 2012;27(10):1838-1843.