Minimizing blood loss in orthopaedic surgery: the role of Antifibrinolytics.
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)
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.
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.
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 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.
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.
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.
(1.) Bong MR, Patel V, Chang E, et al. Risks associated with blood transfusion after total knee arthroplasty. J Arthroplasty. 2004 Apr;19(3):281-7.
(2.) Yagi M, Hasegawa J, Nagoshi N, et al. Does the intraoperative tranexamic acid decrease operative blood loss during posterior spinal fusion for treatment of adolescent idiopathic scoliosis? Spine (Phila Pa 1976). 2012 Oct 1;37(21):E1336-42.
(3.) Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine. First of two parts--blood transfusion. N Engl J Med. 1999 Feb 11;340(6):438-47.
(4.) Sabiston DC, Townsend CM. Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice (18th ed). Philadelphia: Saunders/Elsevier, 2008.
(5.) Tice DA, Worth MH Jr, Clauss RH, Reed GH. The Inhibition of Trasylol of Fibrinolytic Activity Associated with Cardiovascular Operations. Surg Gynecol Obstet. 1964 Jul;119:71-4.
(6.) Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD001886.
(7.) 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 Jul 3;94(13):1153-9.
(8.) 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 Nov;90(11):2399-407.
(9.) Blanchette CM, Wang PF, Joshi AV, et al. Resource utilization and costs of blood management services associated with knee and hip surgeries in US hospitals. Adv Ther. 2006 JanFeb;23(1):54-67.
(10.) Ralley FE, Berta D, Binns V, et al. One intraoperative dose of tranexamic Acid for patients having primary hip or knee arthroplasty. Clin Orthop Relat Res. 2010 Jul;468(7):1905-11.
(11.) Bierbaum BE, Callaghan JJ, Galante JO, et al. An analysis of blood management in patients having a total hip or knee arthroplasty. J Bone Joint Surg Am. 1999 Jan;81(1):2-10.
(12.) CDC. Number, rate, and standard error of all-listed surgical and nonsurgical procedures for discharges from short-stay hospitals, by selected procedure categories: United States, 2010. http://www.cdc.gov/nchs/data/nhds/4procedures/2010pro4_numberrate.pdf. Accessed April 16, 2013.
(13.) Shaz BH, Stowell SR, Hillyer CD. Transfusion-related acute lung injury: from bedside to bench and back. Blood. 2011 Feb 3;117(5):1463-71.
(14.) Vamvakas EC, Blajchman MA. Transfusion-related immunomodulation (TRIM): an update. Blood Rev. 2007 Nov;21(6):327-48.
(15.) Innerhofer P, Klingler A, Klimmer C, et al. Risk for postoperative infection after transfusion of white blood cell-filtered allogeneic or autologous blood components in orthopedic patients undergoing primary arthroplasty. Transfusion. 2005 Jan;45(1):103-10.
(16.) Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine. Second of two parts--blood conservation. N Engl J Med. 1999 Feb 18;340(7):525-33.
(17.) Goodnough LT, Shander A. Current status of pharmacologic therapies in patient blood management. Anesth Analg. 2013 Jan;116(1):15-34.
(18.) Kagoma YK, Crowther MA, Douketis J, et al. Use of antifibrinolytic therapy to reduce transfusion in patients undergoing orthopedic surgery: a systematic review of randomized trials. Thromb Res. 2009 Mar;123(5):687-96.
(19.) Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008 Feb 27;299(8):91424.
(20.) Shermock KM, Horn E, Lipsett PA, et al. Number needed to treat and cost of recombinant human erythropoietin to avoid one transfusion-related adverse event in critically ill patients. Crit Care Med. 2005 Mar;33(3):497-503.
(21.) Ritter MA, Keating EM, Faris PM. Closed wound drainage in total hip or total knee replacement. A prospective, randomized study. J Bone Joint Surg Am. 1994 Jan;76(1):35-8.
(22.) Umlas J, Foster RR, Dalal SA, et al. Red cell loss following orthopedic surgery: the case against postoperative blood salvage. Transfusion. 1994 May;34(5):402-6.
(23.) Levy O, Martinowitz U, Oran A, et al. The use of fibrin tissue adhesive to reduce blood loss and the need for blood transfusion after total knee arthroplasty. A prospective, randomized, multicenter study. J Bone Joint Surg Am. 1999 Nov;81(11):1580-8.
(24.) Molloy DO, Archbold HA, Ogonda L, et al. 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 Mar;89(3):306-9.
(25.) Handin RI, Lux SE, Stossel TP. Blood: Principles and Practice of Hematology (2nd ed). Philadelphia: Lippincott Williams & Wilkins, 2003.
(26.) Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008 May 29;358(22):2319-31.
(27.) Murkin JM. Lessons learned in antifibrinolytic therapy: The BART trial. Semin Cardiothorac Vasc Anesth. 2009 Jun;13(2):127-31.
(28.) Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs. 1999 Jun;57(6): 1005-32.
(29.) Mannucci PM. Hemostatic drugs. N Engl J Med. 1998 Jul 23;339(4):245-53.
(30.) Keyl C, Uhl R, Beyersdorf F, et al. High-dose tranexamic acid is related to increased risk of generalized seizures after aortic valve replacement. Eur J Cardiothorac Surg. 2011 May;39(5):e114-21.
(31.) Martin K, Knorr J, Breuer T, et al. Seizures after open heart surgery: comparison of epsilon-aminocaproic acid and tranexamic acid. J Cardiothorac Vasc Anesth. 2011 Feb;25(1):20-5.
(32.) Amar D, Grant FM, Zhang H, et al. Antifibrinolytic therapy and perioperative blood loss in cancer patients undergoing major orthopedic surgery. Anesthesiology. 2003 Feb;98(2):337-42.
(33.) Ray M, Hatcher S, Whitehouse SL, et al. Aprotinin and epsilon aminocaproic acid are effective in reducing blood loss after primary total hip arthroplasty--a prospective randomized double-blind placebo-controlled study. J Thromb Haemost. 2005 Jul;3(7):1421-7.
(34.) Sukeik M, Alshryda S, Haddad FS, Mason JM. Systematic review and meta-analysis of the use of tranexamic acid in total hip replacement. J Bone Joint Surg Br. 2011 Jan;93(1): 39-46.
(35.) Bennett-Guerrero E, Sorohan JG, Gurevich ML, et al. Cost-benefit and efficacy of aprotinin compared with epsilon-aminocaproic acid in patients having repeated cardiac operations: a randomized, blinded clinical trial. Anesthesiology. 1997 Dec;87(6):1373-80.
(36.) Shakur H, Roberts I, Bautista R, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010 Jul 3;376(9734):23-32.
(37.) Fahmy NR, Patel DG. Hemostatic changes and postoperative deep-vein thrombosis associated with use of a pneumatic tourniquet. J Bone Joint Surg Am. 1981 Mar;63(3):461-5.
(38.) Reikeras O, Clementsen T. Time course of thrombosis and fibrinolysis in total knee arthroplasty with tourniquet application. Local versus systemic activations. J Thromb Thrombolysis. 2009 Nov;28(4):425-8.
(39.) Johansson T, Pettersson LG, Lisander B. Tranexamic acid in total hip arthroplasty saves blood and money: a randomized, double-blind study in 100 patients. Acta Orthop. 2005 Jun;76(3):314-9.
(40.) Eubanks JD. Antifibrinolytics in major orthopaedic surgery. J Am Acad Orthop Surg. 2010 Mar;18(3):132-8.
(41.) Benoni G, Fredin H. Fibrinolytic inhibition with tranexamic acid reduces blood loss and blood transfusion after knee arthroplasty: a prospective, randomised, double-blind study of 86 patients. J Bone Joint Surg Br. 1996 May;78(3):434-40.
(42.) 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 Nov 3;92(15):2503-13.
(43.) Maniar RN, Kumar G, Singhi T, et al. Most effective regimen of tranexamic acid in knee arthroplasty: a prospective randomized controlled study in 240 patients. Clin Orthop Relat Res. 2012 Sep;470(9):2605-12.
(44.) Khurana A, Guha A, Saxena N, et al. Comparison of aprotinin and tranexamic acid in adult scoliosis correction surgery. Eur Spine J. 2012 Jun;21(6):1121-6.
(45.) Sethna NF, Zurakowski D, Brustowicz RM, et al. Tranexamic acid reduces intraoperative blood loss in pediatric patients undergoing scoliosis surgery. Anesthesiology. 2005 Apr;102(4):727-32.
(46.) Berenholtz SM, Pham JC, Garrett-Mayer E, et al. Effect of epsilon aminocaproic acid on red-cell transfusion requirements in major spinal surgery. Spine (Phila Pa 1976). 2009 Sep 1;34(19):2096-103.
(47.) Tsutsumimoto T, Shimogata M, Ohta H, et al. Tranexamic acid reduces perioperative blood loss in cervical laminoplasty: a prospective randomized study. Spine (Phila Pa 1976). 2011 Nov 1;36(23):1913-8.
(48.) Baldus CR, Bridwell KH, Lenke LG, Okubadejo GO. Can we safely reduce blood loss during lumbar pedicle subtraction osteotomy procedures using tranexamic acid or aprotinin? A comparative study with controls. Spine (Phila Pa 1976). 2010 Jan 15;35(2):235-9.
(49.) FDA. Cyklokapron product label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019281s030lbl.pdf. Accessed April 16, 2013.
(50.) FDA. Amicar product label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/015197s043,015230s035lbl.pdf. Accessed April 16, 2013.
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; firstname.lastname@example.org.
Please note: Illustration(s) are not available due to copyright restrictions.
|Printer friendly Cite/link Email Feedback|
|Author:||Lerman, Daniel M.; Rapp, Timothy B.|
|Publication:||Bulletin of the NYU Hospital for Joint Diseases|
|Date:||Apr 1, 2015|
|Previous Article:||Simultaneous versus staged total hip arthroplasty: a review.|
|Next Article:||Sports hernia and extra-articular causes of groin pain in the athlete.|