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Minimizing blood loss in orthopaedic surgery: the role of Antifibrinolytics.

Large volume perioperative blood loss has long been a concern for orthopaedic surgeons. Both arthroplasty and spine surgery are associated with significant total blood loss, often requiring postoperative allogenic blood transfusions (ABT). (1,2) While ABT allows the maintenance of a patient's hemoglobin, it is accompanied by a variety of potential risks ranging from allergic reactions to hemolysis and death. (3,4) Given the potential complications associated with ABT, many blood conservation strategies have been proposed.

Preoperative autologous blood donation, erythropoietin, cell salvage, hypotensive anesthesia, normovolemic hemodilution, and antifibrinolytics have all been tried with varying degrees of success. In comparison to the alternatives, antifibrinolytic therapy is inexpensive and simple to administer. First used in cardiac surgery, multiple surgical subspecialties have experimented with antifibrinolytics in a quest to decrease perioperative blood loss. (5,6) The orthopaedic literature contains an increasing number of studies with level-one evidence in arthroplasty and spine surgery demonstrating antifibrinolytics' ability to decrease total blood loss and subsequently reduce the need for ABT. (6-8)

Allogenic Blood Transfusion, Autogenous Blood Transfusion and Blood Conservation Strategies

While blood transfusions are readily available and effective in the management of postoperative anemia, their use comes with significant expense and risk of complications. Excluding the hidden costs associated with the maintenance and administration of ABT, a single unit costs an average of $400. (9,10) The incidence of ABT following primary unilateral total joint arthroplasty has been reported as high as 25% to 38%. (1,9,11) With roughly one million total joint arthroplasties performed in the USA in 2010, (12) postoperative ABT represents an additional cost of approximately $150 million to the USA healthcare system.

Multiple complications, some potentially fatal, are associated with ABT. Transfusion associated lung injury (TRALI) is the most common fatal transfusion reaction with an incidence of 1 in 5,000 units. TRALI is fatal in 5% to 30% of cases. (13) The symptoms are dyspnea, hypotension, fever, and bilateral pulmonary edema caused by donor antibodies attacking recipient leukocytes resulting in cytokine release and increased vascular permeability. Postoperative patients are more susceptible to TRALI, and only supportive treatment is available. (4)

Additional potentially fatal complications are severe acute hemolytic reaction, usually a result of ABO incompatibility, and the transfusion of bacteria-contaminated blood products. Other transfusion-transmitted infectious diseases are exceedingly rare, occurring at a rate of 1 in 1 million units for hepatitis C virus and an estimated 1 in 1 to 2 million units for HIV (4)

Non-fatal ABT complications are allergic non-hemolytic reaction and transfusion related immunomodulation (TRIM). Allergic non-hemolytic reaction causes fevers and chills shortly after transfusion initiation. Symptoms can progress to urticaria, anaphylaxis, and hemodynamic instability. TRIM is the proposed mechanism responsible for decreased rejection of allogenic renal transplants amongst ABT recipients. ABT may suppress the recipients' immune response, predisposing them to infection and virus reactivation. (14) An increased incidence of postoperative infection has been observed in total joint arthroplasty patients who have received ABT, compared to those who received autologous blood transfusions. (11,15)

In order to decrease the exposure to these potential complications, multiple blood conservation strategies have been utilized with varying degrees of success. To eliminate the risk of transfusion-transmitted infectious disease, preoperative autologous blood donation has been proposed for patients without active infection, anemia, or significant cardiac disease. Autologous donation effectively decreases postoperative ABT requirements but is not without risk. (1) Roughly 1 in 16,000 autologous donors develop a donation-related reaction that requires hospitalization. And while rare, autologous units are susceptible to the potentially fatal complications of bacterial contamination and ABO mismatch resulting in severe acute hemolytic reaction. (16) Preoperative autologous donation is an independent risk factor for postoperative transfusion and is associated with a significant waste of resources; up to 50% of donated units are ultimately discarded. (1,3,11)

Erythropoiesis-stimulating agents (ESA), such as recombinant erythropoietin, have been approved for use prophylactically prior to elective surgery and therapeutically for anemia due to chemotherapy and chronic kidney disease. Prospective RCTs of ESA has shown its ability to decrease the need for ABT in these patient populations. (17) Although no significant complications are associated with its use in arthroplasty patients, an increased incidence of DVT has been observed with ESA use in spine surgery. (18) More recently, ESA has been shown to increase the incidence of DVT and all-cause mortality in oncology patients. (19) A subsequent black box warning in addition to its significant cost has caused enthusiasm for ESA use to decline. (9,20)

Cell salvage is another effective blood conservation strategy. Intraoperative red blood cell (RBC) salvage is cost effective compared to ABT if at least two units can be generated and administrated. (4) Contraindications to cell salvage include the presence of malignancy or infection in order to prevent the intravenous administration of contaminated blood. Reinfusion of blood collected from surgical drains following orthopaedic surgery has been shown to be safe albeit ineffective. (15,21) Blood recovered from surgical drains is often dilute and partially hemolyzed, with an effective hematocrit of 20%. (22)

The topical application of fibrin sealants has been shown to decrease postoperative ABT requirements by 75% following TKA. (23) Meta-analysis has demonstrated their safety, failing to show an increased risk of infection, hematoma, or death associated with their usage. (17) A prospective RCT comparing topical fibrin spray and "low dose" intravenous tranexamic acid (TXA) in TKA demonstrated equivalent reductions in total blood loss and postoperative ABT requirements. The investigators favored TXA use, noting the significantly greater cost of fibrin spray (approximately $600) compared to TXA ($6.00) per patient. (24)

Anesthesia techniques, such as hypotensive anesthesia and normovolemic hemodilution, have both been shown to be effective in decreasing postoperative ABT requirements but can be challenging logistically. The latter entails the removal of two to three units of RBCs and their replacement by crystalloid following anesthesia induction. The withdrawn blood is anticoagulated, stored at room temperature, and is reinfused as needed during surgery. Although demanding, normovolemic hemodilution has been shown to be more cost effective than preoperative autologous donation. (4)

Hemostasis

Coagulation and fibrinolysis are in constant equilibrium to maintain hemostasis and vessel patency. While full elucidation of the coagulation cascade and fibrinolysis is beyond the scope of this review, pertinent elements of the system are highlighted in order to clarify antifibrinolytics' mechanism of action.

Upon vascular injury, newly exposed tissue factor and subendothelial collagen cause platelet activation and adhesion to the site of injury. Platelet activation promotes platelet aggregation and stimulates the coagulation cascade. The coagulation cascade is an illustrative model for the initiation and sequential activation of serine protease coagulation factors which culminates in the formation of thrombin (coagulation factor IIa). Thrombin then cleaves fibrinogen into its active form, fibrin. Initially, fibrin molecules are distributed abundantly and randomly among the newly aggregated platelets, reinforcing the initial platelet plug. Clot maturation, the process of fibrin molecule cross-linking and resorption, results in the formation of an organized, insoluble, stable clot. (4)

Fibrinolysis is the process of fibrin resorption; it occurs harmoniously with the coagulation system in order to control clot formation and prevent excessive clot propagation. (17) Plasminogen is the circulating precursor of fibrinolysis. It binds tissue plasminogen activator (tPA) and fibrin simultaneously, producing the active protease plasmin. Once activated, plasmin breaks down fibrin, resulting in the formation of D-dimer, a fibrin degradation product and a clinical marker of fibrinolysis.

Antifibrinolytics

By inhibiting fibrin breakdown, antifibrinolytics prevent clot resorption and decrease bleeding. (17) Used in cardiac surgery since the 1960s, aprotinin is a nonspecific serine protease inhibitor derived from bovine lung tissue. (5) It binds directly to the active site on plasmin, inhibiting its enzymatic function. (25) Aprotinin's ability to decrease blood loss and ABT in cardiac surgery patients promoted its regular use and utilization by other specialties, specifically thoracic, vascular, transplant, and orthopaedic surgery. (6) Though effective, aprotinin was removed from the USA market in 2007 in response to the BART study (Blood conservation using Antifibrinolytics: a Randomized Trial in high-risk cardiac surgery patients) when it was shown to increase all-cause mortality rates compared to another class of antifibrinolytics, the lysine analogues. (26,27) Aprotinin is included in this review for completeness and context, as it is included in many earlier studies.

The lysine analogues, TXA and e-aminocaproic acid (EACA), are a synthetic class of antifibrinolytics. They bind reversibly to lysine binding sites on plasminogen, preventing the plasminogen/plasmin molecule from binding to fibrin (Fig. 1).28 In the presence of the lysine analogues, plasminogen can still be activated to plasmin, but it is inhibited from binding and degrading fibrin. In vitro studies demonstrate that TXA has a 6 to 10 times greater affinity for plasminogen/plasmin than EACA, and this difference is reflected in their clinical dosing. Typical "low dose" TXA is 10 to 20 mg/kg compared to EACA dosages which range from 75 to 150 mg/kg. (6) Both medications are renally cleared, and dosing needs to be adjusted in cases of renal insufficiency. Though typically well tolerated, the most common adverse reactions are gastrointestinal--nausea or diarrhea. (29) Intravenously administered TXA transfuses easily into synovial fluid and through the blood brain barrier. Once in the central nervous system, "high dose" TXA (100 mg/ kg, 5 g to 10 g) inhibits GABA receptors, resulting in an increased incidence of seizure activity. (30,31) Although TXA and EACA prevent the breakdown of fibrin, demonstrated by decreased D-dimer levels, (32,33) they do not appear to be thrombogenic as their use is not associated with an increase in venous thromboembolism (VTE). (6-8,18,34)

Comparison studies between aprotinin and the lysine analogues demonstrate that aprotinin is more effective at decreasing the need for ABT but at a greater expense and risk of side effects. (6,35) Due to their benign side effect profile and high therapeutic index, TXA and EACA have attracted interest from multiple areas of medicine.

Research in cardiac surgery laid the foundation of our knowledge about antifibrinolytics. A recent Cochrane Collaboration by Henry and coworkers identified over 170 randomized control trials (RCT) involving antifibrinolytics in cardiac surgery. The majority of these studies examined the effectiveness of a single medication compared to placebo (84 RCTs for aprotinin, 34 RCTs for TXA, and 11 RCTs for EACA). The review demonstrated that all three medications decreased postoperative ABT: 32% for aprotinin and TXA and 30% for EACA. And, compared to controls, all three medications showed no significant increase in all-cause mortality, deep venous thrombosis (DVT), pulmonary embolism (PE), cerebral vascular accident (CVA), or myocardial infarction (MI). (6) In an attempt to compare these three drugs, the multicenter BART study enrolled 2,331 high-risk cardiac surgery patients and found a roughly equivalent effect on bleeding prevention, although as previously mentioned, the aprotinin group's mortality rate was significantly greater than in the TXA or EACA groups: 6.0% versus 3.9% and 4.0%, respectively. (6)

The efficacy of antifibrinolytic therapy was further demonstrated when the effect of TXA versus placebo was examined in trauma patients with, and at risk of, significant bleeding. The multinational CRASH-2 trial contained 20,211 adult trauma patients and produced level-one data demonstrating that TXA decreased all-cause mortality to 14.5% from 16.0% with placebo. No significant difference was identified in death from hemorrhage, transfusion requirements, or vascular occlusion, including DVT, PE, CVA, and MI. (36) The study concluded that TXA should be included in the treatment protocol for trauma patients with a significant risk of bleeding.

Arthroplasty

The total blood loss associated with total joint arthroplasty can be 1,500 ml to 2,000 ml, with up to 40% of patients requiring postoperative ABT. (1,11,18) Tourniquet usage in total knee arthroplasty (TKA) alters the normal relationship between coagulation and fibrinolysis. The fibrinolytic system is activated in the operative extremity during surgery and increased systemically following tourniquet deflation. (37,38) Antifibrinolytics were initially introduced in TKA in an attempt to combat this tourniquet-induced derangement of the fibrinolytic system. Due to their efficacy, antifibrinolytics' application has extended to total hip arthroplasty (THA) in an attempt to decrease postoperative transfusion Requirements. (7,39)

While orthopaedic research of antifibrinolytics dates back only 20 years, their efficacy in arthroplasty has been consistently demonstrated. (40) Ray and colleagues performed a small prospective, blinded RCT comparing aprotinin, EACA, and placebo in 45 patients undergoing THA. They reported a significant decrease in intraoperative blood loss in the aprotinin group only, though both the aprotinin and EACA groups had significant decreases in postoperative blood loss compared to placebo, a 60% and 53% reduction, respectively. There was no difference in postoperative transfusion requirements or VTE on surveillance lower extremity dopplers. (33) Another prospective, blinded RCT in THA compared a 15 mg/kg dose of TXA to placebo and noted a 27% reduction in total blood loss and a 50% decrease in postoperative ABT compared to the control group. (39) A meta-analysis by Sukiek and associates examined the efficacy of TXA in the reduction of blood loss and postoperative transfusions in primary THA. Eleven RCTs were reviewed which demonstrated an average reduction in total blood loss of 289 ml and a 20% reduction in the risk of ABT for patients receiving TXA compared to placebo. (34) Additionally, they noted that there was no difference in the incidence of DVT, PE, or surgical site infections between the two groups.

Studies of antifibrinolytics in TKA yielded similar results. Benoni and coworkers were among the first to examine the effect of a two-dose regimen of TXA (10 mg/kg given prior to tourniquet lease and three hours later) in primary TKA. In their prospective, blinded RCT of 86 patients, they observed a roughly 50% decrease in total blood loss and a 66% decrease in both the number of patients who received ABT and the total number of units required. Although too small of a study population to demonstrate significance in VTE, no difference was seen between the two studied groups. (41)

Topical application of TXA has also been shown to be effective. Wong and colleagues applied two different doses of TXA (1.5 g and 3 g) versus placebo intra-articularly after TKA component cementation and irrigation. The study's medication solutions were applied and kept in place for 5 minutes, after which time excess solution was removed, and the arthrotomy was closed without further irrigation. They reported an average total blood loss of 1,208 ml and 1,295 ml for the 1.5 g and 3 g dosages compared to 1,610 ml for the placebo group, a reduction of 20% to 25%.42 The difference in total blood loss between the TXA dosages was not statistically significant. No differences occurred in the incidence of ABT or VTE, though the study was not powered sufficiently for those endpoints. A meta-analysis by Yang and associates reviewed 15 RCTs of TXA use in primary TKA. On average, the TXA groups had 500 ml less total blood loss when compared to placebo. The odds ratio for patients requiring transfusion was 0.16 for TXA compared to placebo, and the ABT units transfused per patient decreased by 1. (43) units. And again, no difference was identified in the rate of DVT or PE between the two groups. (2) In this study, as in all the meta-analyses, the TXA dosage and timing of administration was variable among the reviewed studies.

In order to determine the optimal TXA dosing regimens, Maniar and coworkers compared five different dosing protocols in primary TKA: 1. one intraoperative dose (prior to tourniquet deflation); 2. intraoperative and preoperative doses; 3. intraoperative and postoperative doses; 4. preoperative, intraoperative, and postoperative doses; and 5. topical application. A dose was defined as TXA 10 mg/kg. Only groups 2 and 4 demonstrated a decrease in postoperative drainage and total blood loss. The three-dose regimen had the most significant effect, limiting drainage to 303 ml and total blood loss to 688 ml, though its benefit was not statistically significant compared to the preoperative and intraoperative two-dose protocol.43 Of note, topical application decreased total blood loss but did not decrease postoperative drain output; the significance of which is unclear. This study produced level-one evidence defining the effect dose of TXA in TKA, which helps guide clinical practice and interpretation of the literature.

Spine Surgery

Spine surgery encompasses a heterogeneous group of procedures for a wide range of pathology. In addition to this diversity, variability in the number of vertebral levels involved further complicates comparison study groups. Khurana and coworkers in a retrospective study of aprotinin and TXA in adult scoliosis surgery calculated intraoperative blood loss per vertebral level and found a significant reduction compared to controls, 57.7 ml and 62.0 ml compared to 137 ml per level, respectively. Among their controls, the average intraoperative blood loss was 972 ml, which was reduced 27% with aprotinin and 24% with TXA. (44)

One of the earliest prospective RCTs was performed by Sethna and colleagues investigating the effect of "high dose" TXA on blood loss in pediatric scoliosis surgery. A 100 mg/kg bolus was given, followed by an infusion of 10 mg/kg per hr. Forty-four patients were included, and they demonstrated a 41% reduction in intraoperative blood loss (1,230 ml versus 2,085 ml) though there was no difference in transfusion requirements. (45)

In another prospective RCT, Berenholtz and associates evaluated the efficacy of EACA in maj or spine surgery. They noted that the EACA group required less ABT (2.0 units versus 2.8 units) and spent less time in the ICU postoperatively (1.8 days versus 2.8 days) compared to placebo. No differences in postoperative complications were observed--specifically VTE, infection, and death. (46) A heterogeneous group of diagnoses and procedures were included in this study, making its clinical implications ambiguous. Alternatively, Tsutsumimoto and coworkers investigated the role of TXA in cervical laminoplasties and demonstrated a 25% reduction in total blood loss with one preoperative dose of TXA 15 kg/ mg. (47) As in other studies, the bleeding reduction imparted by TXA all occurred in the immediate postoperative period, intraoperative, and late (> 16 hours) postoperative blood loss was equal to placebo.

In a retrospective review, "low dose" TXA was compared to "high dose" aprotinin in patients undergoing pedical subtraction osteotomies. Baldus and colleagues demonstrated significantly less intraoperative and total blood loss with aprotinin (1,114 ml) compared to TXA (2,102 ml) and controls (2,260 ml). The "low dose" TXA regimen of 10 mg/ kg bolus

followed by 0.5 mg/kg per hour infusion failed to reduce bleeding compared to controls.48 Elwatidy and associates utilized a higher TXA dose in adult (2 g bolus, 100mg/ hr infusion) and pediatric (30 mg/kg bolus, 1 mg/kg per hour infusion) patients undergoing major spinal surgery. In this prospective RCT, a 49% reduction in total blood loss and 80% reduction in postoperative transfusions was observed. A meta-analysis of 18 prospective studies containing over 900 patients showed that aprotinin, TXA, and EACA were all effective in reducing total blood loss and decreasing the incidence of ABT in spinal surgery. The three medications had equivalent efficacy and no effect on the incidence of VTE. (8)

Major spinal surgery is an attractive cohort for the investigation of antifibrinolytics. While diverse, many procedures are associated with total blood loss greater than 1,000 ml, which represents a population in which the effect of antifibrinolytics is more significant. (2,40,48) Appropriately dosed antifibrinolytics consistently reduce total blood loss and postoperative ABT requirements. Even among a patient population who rarely receives DVT chemoprophylaxis, these medications have failed to show an increase in thromboembolic events.

Summary

Large volume blood loss occurs regularly in arthroplasty and spine surgery. The risks associate with ABT and the limitations of alternative blood conservation strategies have continued to drive interest in antifibrinolytics. With over 50 years of clinical experience, aprotinin consistently demonstrated the ability to decrease total blood loss and the need for postoperative transfusion. Safety concerns regarding its use in high-risk cardiac surgery patients and a well-documented risk of anaphylaxis prompted its removal from market. The synthetic lysine analogues, TXA, and EACA have a benign side effect profile and large therapeutic index.

The literature contains level-one evidence demonstrating that TXA and EACA use can decrease total blood loss by 25% to 50% and reduce the need for postoperative ABT by as much as one-third. (7,41,45,47) There is a trend indicating a greater effect imparted by TXA than EACA; however, variations in dosage and the timing of administration introduce ambiguity regarding their relative efficacy.

The studies contained in this review largely excluded patients with a history of VTE and coagulopathies; therefore, antifibrinolytic use in this high-risk patient population can not be recommended. At this time, TXA is FDA approved to decrease hemorrhage associated with tooth extraction in hemophiliacs, and the indications discussed in this review are off-label. (49) The FDA label for EACA is more general, stating the medication is approved to enhance "hemostasis when fibrinolysis contributes to bleeding." (50)

The lysine analogue antifibrinolytics have a well-elucidated mechanism of action and a large therapeutic index. They are inexpensive, safe, and decrease postoperative transfusion requirements. Therefore, it is our belief that antifibrinolytics are a cost-effective addition to blood conservation programs for patients undergoing total joint arthroplasty and spine surgery.

Disclosure Statement

None of the authors has a financial or proprietary interest in the subject matter or materials discussed in the manuscript, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony.

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Caption: Figure 1 Mechanism of action of tranexemic acid. To view this figure in color, see www.hjdbulletin.org. (Reprinted with permission: Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs. 1999 Jun;57(6):1005-32.)

Daniel M. Lerman, M.D., a Fellow, Sarcoma Services, Primary Children's Hospital & Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. Timothy B. Rapp, M.D., Associate Professor of Orthopaedic Surgery, Chief of the Division of Orthopaedic Oncology, NYU Hospital for Joint Diseases, New York, New York. Correspondence: Timothy B. Rapp, M.D., 160 East 34th Street, New York, New York 10016; timothy.rapp@nyumc.org.

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Author:Lerman, Daniel M.; Rapp, Timothy B.
Publication:Bulletin of the NYU Hospital for Joint Diseases
Article Type:Report
Geographic Code:1USA
Date:Apr 1, 2015
Words:5203
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