The Use of Tranexamic Acid to Reduce Blood Loss in Acetabular Surgery
Phase: PHASE3
Conditions: Acetabular Fractures
Sponsor: Wake Forest University Health Sciences

 
 
 
The Use of Tranexamic Acid to Reduce Blood Loss in Acetabular Surgery 
 
 
 
 
 
 
 
Primary Investigator:  
Madhav Karunakar, MD 
 
 
Co-Investigator: 
William Lack, MD 
Michael Bosse, MD 
Stephen Sims, MD 
James Kellam, MD 
Rachel Seymour, PhD 
Matthew Wilson, MD 
Joseph Hsu, MD 
 
Protocol Version:3 
Protocol Date: 4/15/2013 

 
 
Background and Significance: 
 
 
Orthopaedic surgery carries with it a significant risk for blood loss.  Historically, 
this blood loss has been managed with allogenic blood transfusion when necessary.  
However, in recent years there has been a strong push to reduce the use of allogenic 
blood.[6, 9,24,34]  Even in developed countries, the demand for allogenic blood 
frequently exceeds the supply, and although multiple safety measures are in place to 
prevent “wrong blood” transfusions, the incidence of clerical errors is still unacceptably 
high, ranging from 1/15,000-1/20,000.[23]  Allogenic blood carries with it a risk for HIV 
and Hepatis C, as well as multiple adverse reactions.[23]  Furthermore, allogenic blood 
transfusion is known to have significant immunomodulatory effects, and the results of 
three extensive studies, involving more than 22,000 orthopaedic patients, showed that 
allogenic blood transfusion significantly increases the risk of postoperative infection.[5, 
7, 29]  Thus, significant effort has been expended toward reducing allogenic blood 
transfusion in orthopaedic surgery. 
Multiple anti-fibrinolytic agents have been used for this purpose, including 
tranexamic acid (TXA), aprotinin, and epsilon-aminocaproic acid (EACA).  Of these 
three, TXA has been the most widely used in recent orthopaedic studies.[21]  Reasons for 
this include the fact that aprotinin has a higher mortality rate than either TXA or 
EACA.[12]  Furthermore, TXA is the cheapest of the three and has excellent penetration 
of the major joints.[35]  Thus, we feel that TXA is the most appropriate anti-fibrinolytic 
for further study. 
 
  
 
Specific Research Questions: 
1. Do patients undergoing acetabular ORIF who receive tranexamic acid have a 
reduced risk of allogenic blood transfusion as compared to patients who receive 
placebo? 
2. Do patients undergoing acetabular ORIF who receive tranexamic acid have 
reduced peri-operative blood loss as compared to patients who receive placebo?  
3. Do patients undergoing acetabular ORIF who receive tranexamic acid have a 
higher risk for thromboembolic events than patients who receive placebo? 
4. Do patients undergoing acetabular ORIF who receive tranexamic acid have a 
reduced risk of wound complications (prolonged wound drainage, return to the 
OR within 30 days, infection)? 
5. Is the use of tranexamic acid cost effective relative to the use of allogenic blood 
transfusion as a blood loss management strategy in acetabular ORIF?     
 
 
 
 
 
 

1. Do patients undergoing acetabular ORIF who receive tranexamic acid have a 
reduced risk of allogenic blood transfusion as compared to patients who receive 
placebo? 
 
The ability of TXA to reduce the use of allogenic blood transfusion relative to placebo 
is unclear.  The largest ever study on the use of TXA was conducted in general trauma 
patients, and included 10,096 patients randomized to receive TXA, and 10,115 
randomized to receive placebo with an equivalent dose of normal saline.[33]  This study 
showed no significant difference in the incidence of blood transfusion between groups 
(relative risk of transfusion with TXA of 0.98, 95% CI 0.96-1.01).   
Multiple studies have attempted to answer this question specifically in joint 
arthroplasty patients and the results have been mixed.  Several studies in total joint 
arthroplasty found no benefit of TXA relative to a saline placebo.[4,13,14,27]  In 
contrast, at least 5 other prospective studies of joint arthroplasty patients have shown at 
least a mild reduction in the risk of transfusion with use of TXA in total joint 
arthroplasty.[2,8,11,18,26]  A metanalysis of these studies in total joint patients showed a 
transfusion benefit of TXA relative to placebo, with a risk difference of -.20 (-0.20, 95% 
CI -0.29 to -0.11).[35]  These results were consistent with two other meta-analyses, 
which included orthopaedic patients from all of the sub-specialties, and estimated that use 
of TXA reduced the incidence of blood transfusion by up to 50%.[21,39]  However, the 
authors noted that none of the prior studies in orthopaedics have ever included more than 
150 patients, and called for a large prospective randomized trial in order to clarify the 
differences in reported literature.[14,21,35,39]  
In this study, we plan to prospectively record the overall incidence of allogenic 
blood transfusions.  In addition, we will record the total number and volume of allogenic 
blood products required by each patient.  We do not plan to use erythropoietin in any of 
our patients.  This study will not have a specific “transfusion trigger.”  Previous studies 
have advocated for blood transfusions to be based on an overall assessment of the 
patient’s physiologic status, and not an arbitrary “transfusion trigger.”[6,9,34] We agree 
that you should treat the patient and not a number, and thus the decision to transfuse will 
be left up to the individual treating surgeon.  While the decision to transfuse will thus be 
subjective, and could possibly differ between surgeons, the fact that our study is double 
blinded and randomized should account for this potential source of bias.  Overall, we 
hypothesize that our study will demonstrate a reduction in the incidence of allogenic 
blood transfusion in patients that receive TXA, regardless of dosing, as compared to 
patients who receive a saline placebo.    
 
 
2. Do patients undergoing acetabular ORIF who receive tranexamic acid have 
reduced perioperative blood loss as compared to patients who receive placebo?  
 
There have been at least three meta-analyses of prospective randomized trials in 
orthopaedics which attempted to answer this question, and each meta-analysis has 
consistently shown reduced perioperative blood loss with the use of TXA relative to 
placebo.[21,35,39]  Specifically in total joint arthroplasty, patients who received TXA 
had a mean of 289 ml less peri-operative blood loss, as compared to patients who 

received a saline placebo.[35]  However, a separate meta-analysis isolated to total hip 
arthroplasty patients showed no benefit for TXA in terms of reduced blood loss.[14]  
Furthermore, the magnitude of reduction in peri-operative blood loss varied significantly 
between studies, and as reported above, the correlation between this result and with 
decreased risk of transfusion is not clear.  Two studies of this outcome in hip fracture 
patients found trends toward decreased transfusion risk.[32,40] 
In this study, we plan to report intra-operative blood loss based on the estimated 
blood loss (EBL) dictated into the procedure note at the time of surgery.  The EBL is an 
estimate based on the amount of blood remaining in sponges and drapes, as well as in 
suction containers at the end of the case.  Although this measurement has a subjective 
component, the fact that our study will be double blinded, and that patients will be 
randomized to the different treatment groups should reduce potential bias.   
In order to objectively quantify peri-operative blood loss, we will report total peri-
operative blood loss based on the formula derived by Gross,[16] where peri-operative 
blood loss = estimated blood volume × (haematocrit reduction/mean haematocrit), and 
blood volume is estimated with the formula: Blood volume (BV) (ml) = 70 × weight 
(kg).[25]  Since these calculations will be based on objective laboratory values, this 
should further help to control for any potential bias introduced by the subjective nature of 
the EBL measurement.  Overall, we hypothesize that TXA will be reduce peri-operative 
blood loss relative to placebo.      
 
 
 
3. Do patients undergoing acetabular ORIF who receive tranexamic acid have a 
higher risk for thromboembolic events than patients who receive placebo? 
 
This is a key question that has not been answered by prior studies of TXA in 
orthopaedics.  TXA is a lysine analogue that functions by inhibiting the conversion of 
plasminogen to its active form plasmin.  Since plasmin is responsible for the breakdown 
of fibrin in clots, TXA’s mechanism is presumably one of decreased clot breakdown.   
Theoretically, TXA could thus place the patient at increased risk for thromboembolic 
events.  However, previous studies have shown that TXA exerts its effects mostly in the 
wound bed,[3] and that it has no effect on fibrinolytic activity in the wall of the veins.[1]  
Therefore, the effect of TXA on thromboembolic events should be minimal.   
This presumption is borne out by the fact that none of the previous meta-analyses 
on this topic in orthopaedics has ever demonstrated a significantly increased risk of 
thromboembolism following the use of TXA.[14,21,35,39]  However, only two studies 
have been performed in orthopaedic trauma and these studied hip fracture patients. 
[32,40] Additionally, no prospective clinical trial of TXA in orthopaedics has ever 
included more than 150 patients, and the meta-analyses were markedly underpowered to 
detect clinically significant differences in the incidence of DVT.   
Patients will be treated in standard fashion with mechanical and anticoagulant 
prophylaxis against VTE as appropriate based on the clinical scenario. Symptomatic 
venous thromboembolism will be diagnosed by history, exam, and standard tests. We will 
not screen for asymptomatic DVT. The American Academy of Orthopaedic Surgeons 
guidelines on DVT prophylaxis recommend against screening asymptomatic patients 

with Doppler ultrasound and there are significant questions regarding the correlation 
between DVT and more significant outcomes such as PE. Although our study will not be 
specifically powered for other thromboembolic outcomes, we will also prospectively 
record the incidence symptomatic thromboembolic events such as pulmonary embolism, 
stroke, and myocardial infarction.  We hypothesize that there will be no increased risk of 
thromboembolic events in patients receiving TXA, regardless of dosing, as compared to 
patients receiving placebo. 
 
4. Do patients undergoing acetabular ORIF who receive tranexamic acid have a 
reduced risk of wound complications (prolonged wound drainage, return to the 
OR within 30 days, infection)? 
 
This is an important question as decreasing blood loss may reduce transfusion risk as well 
as risk of drainage and hematoma formation, with the potential to decrease risk of 
infection. This has not yet been shown to be true in orthopaedics, let alone orthopaedic 
trauma surgery. The incidence of infection with acetabular ORIF has been reported to be 
2 to 5% in general populations and up to 15% in morbidly obese patients and showing a 
decreased infection rate with tranexamic acid would be a very important finding. 
Infection and associated outcomes including wound drainage and return to the OR for 
drainage and hematoma evacuation can be recorded to study the affects of tranexamic 
acid on wound healing.  
 
 
5. Is the use of tranexamic acid cost effective relative to the use of allogenic blood 
transfusion as a blood loss management strategy in acetabular ORIF?     
 
A few small previous studies have shown TXA to be cost effective relative to a 
placebo in orthopaedic patients.[20,26,28]  However, the majority of trials have not 
reported on cost-effectiveness, and meta-analyses on this topic have not been able to 
draw definitive conclusions on this issue.[8,13,15,19,21,27,35,39]  Neither of the two 
studies in orthopaedic trauma, specifically hip fracture patients, reported on this. [32,40] 
In this study, we will calculate the cost of tranexamic acid administration in each 
treatment group, and compare this to the total cost of allogenic blood transfusion in each 
treatment group.  Since TXA is an inexpensive drug, we hypothesize that TXA will be a 
cost effective blood loss management strategy with acetabular ORIF.  
 
We plan to enroll 50 patients (N=25 treatment, N=25 controls) in a pilot study to test 
procedures and collect preliminary data.  While this pilot study will likely not have 
sufficient power to definitively address the specific aims and hypotheses, the preliminary 
data collected will provide information to plan future work.  
 
 
Study Design:  
 
Eligibility: 
 

Inclusion Criteria: All patients aged 18 or above undergoing acetabular ORIF.   
 
Exclusion Criteria:  
 
• 
All patients aged below 18 undergoing acetabulum surgery 
• 
Patients with color-blindness (color vision changes used to assess toxicity) 
• 
Patients with subarachnoid hemorrhage.  
• 
Patients with active intravascular coagualation.  
• 
Patients with a previous history of venous thromboembolism or with a history of 
hypercoaguable conditions (i.e. Factor V Leiden, antiphospholipid antibody).  
• 
Prisoners 
• 
Pregnant women 
 
Patient Consent:   
 
Orthopaedic surgery attendings and residents will identify potential study candidates 
during the initial consultation based on the presence of an acetabular fracture.  If the 
patient meets the inclusion and exclusion criteria (noted above), a member of the 
treatment team will discuss the study with eligible patients.  If the patient expresses 
interest in the study, the physician will notify the research staff.  Orthopaedic Clinical 
Research staff will describe study procedures in detail and go through the informed 
consent process to enroll the patient in the study.   The number of eligible patients, and 
the eventual number enrolled will be specifically reported. 
 
Dosing:   
 
Multiple different treatment regimens with TXA have been proposed, with doses ranging 
from as little as 10mg/kg in a single dose, up to a total of 2g given as an infusion 
throughout the peri-operative period.[21,33,35]  No prospective study has ever directly 
compared the efficacy of different dosing regimens.  Two previous meta-analyses showed 
a trend towards decreased peri-operative blood loss with increasing doses of TXA in 
orthopaedic patients.[35,39]  However, both of these studies, in spite of being meta-
analyses, were underpowered to demonstrate a significant treatment effect of the higher 
dose regimens.  Furthermore, neither meta-analysis reported on differences in the 
incidence of complications with higher dose regimens.  Thus, the safety and efficacy of 
different dosing regimens of TXA remains poorly defined.  Since TXA is potentially a 
prothrombotic agent, a clear understanding of the thrombotic potential of a high dose 
regimen would be critical prior to making definitive treatment recommendations. In this 
study, we plan to administer a 10mg/kg dose within 30 minutes of surgery followed by a 
10mg/kg infusion over a 4hr period to the treatment group (for patients weighting over 
100kg, a weight of 100kg will be used for the dose calculation). The control group will 
receive equal volumes of and rates of normal saline.  
 
Stratification: 
 

Stratification by known prognostic factors prior to randomization is a commonly 
employed technique to optimize balance of known prognostic factors between study 
groups.[17] Preoperative hemoglobin values have been shown to be the strongest 
predictor of transfusion following major orthopaedic surgery.[31] Enrolled patients will 
be stratified based on their preoperative hemoglobin value prior to randomization.  The 
three groups they will be stratified into will be based on previous researching 
categorizing the risk of transfusion by preoperative hemoglobin into three groups (< 13 
g/dL, 13 to 15 g/dL, and > 15g/dL).[31] 
 
Randomization: 
 
Study participants will be stratified as described above and then block randomized and 
assigned by sequentially numbered sealed opaque envelopes to one of the two treatment 
groups based on computerized selection.         
 
Blinding:   
 
The study coordinator completing the randomization and the statisticians analyzing the 
data will not be involved in the treatment of the patient.  The Investigational Pharmacy 
will provide treatment packs that are identical in appearance and differ only by their 
random number, it will not be possible for either the treating physician, or the patient to 
know the treatment regimen received.   
 
Unblinding:   
 
In general, it should not be necessary for unblinding to occur.  If a contraindication to the 
treatment regimen develops after randomization (i.e. suspicion of allergic reaction to the 
treatment), the treating physician will contact the study coordinator immediately to 
explain the reasons behind the request for unblinding. A thromboembolic event will not 
be considered a reason for unblinding, as this is a primary outcome measure. However, 
the rate of thromboembolic events will be monitored and if this rate is noted to be higher 
than the baseline rate in patients undergoing acetabular ORIF, this will trigger a safety 
evaluation. Patients whose treatment is unblinded in this manner will be excluded from 
the final data analysis.  The numbers of patients unblinded, and the reasons for the 
decisions will be specifically reported. 
 
Patient Safety Monitoring 
A data safety monitor will be appointed for this study.  This person will otherwise be 
uninvolved in the planning or execution of this trial but will have the ability to unblind 
the collected data to analyze and determine if subjects experiencing an unacceptably high 
level of adverse events.  There had not been adverse effects of tranexamic acid reported.  
For this reason, only adverse events outside of what would reasonably be expected for a 
typical post-operative trauma patient will be considered.   These adverse events will be 
assessed by the treating physicians at every follow-up appointment (2 weeks, 6 weeks, 3 
months, and 6 months), who will notify the data safety monitor within 24 hours.  If 
deemed necessary, the data safety monitor will unblind the collected data and determine 

if the study group is experiencing adverse events at a significantly higher rate or with 
greater severity than the control group.   If the risk to patients is deemed unacceptably 
high by the data safety monitor, the study will be terminated and the results will be 
published. 
 
 
Sample Size and Feasibility: 
 
Pilot Study: 
 
We plan to enroll 50 patients to test the study procedures and collect preliminary data. 
These patients will be randomized to 25 patients receiving the intervention and 25 
receiving placebo. Results from the pilot study will be used to determine the need for 
expansion to a fully powered study and to aid in seeking funding for this further 
investigation.  
 
Future Investigation:  
 
We conducted a power analysis to determine the sample size necessary to demonstrate a 
treatment effect transfusion risk. Average perioperative blood loss with acetabular ORIF 
has been reported to be approximately 1300cc as reported in the literature by one of the 
study investigators. [22] The combined rate of intraoperative and postoperative 
allogeneic transfusion has been reported to be 58% in a study performed at the study 
institution (Carolinas Medical Center).[32] We plan to power our study to detect a 30% 
difference in intraoperative and postoperative allogeneic transfusion. Assuming an alpha 
value of 0.05 and a power of 0.8 this requires a study population of 212 patients.  
 
Assuming a transfusion rate of 58% we would need 106 patients in each treatment group 
to detect a 30% decrease in transfusion rate with a power of 0.8 and an alpha of 0.05, for 
a total study population of 212 patients.  
 
Given the incidence of infection with acetabular ORIF has been reported to be 2 to 5% in 
general populations and up to 15% in morbidly obese patients, our study will likely be 
underpowered to detect changes in this outcome. [22,36] Secondary outcome measures 
including wound drainage and return to the OR for drainage and hematoma evacuation 
will also be used to study affects on wound healing.  
 
Data Collection: 
 
The data points listed below will be prospectively collected for each patient.  The 
randomization number of each patient will be included in this report, and our study 
coordinator will use this to divide the aggregate data into the three treatment groups.  
This aggregate data will then be given to our statisticians in order to complete the data 
analysis.   
 
1.  Patient Demographic Data (Age, BMI, Gender, Race, Type of Insurance).  

2.  Patient Medical Comorbidities, including Diabetes, HTN, CAD, Smoking History, 
Alcohol Use, Cardiac, Gastro-Intestinal, Genito-Urinary, Pulmonary, or Renal Disease.  
3.  Type of anesthesia used (Spinal or General). 
4.  Type of implant used in the surgery. 
5.  Operative Time.  
6.  Preoperative PT/INR and platelet count 
7.  Intraoperative EBL, as recorded in the operative note. 
8.  Number of units of PRBC transfused per patient (separately record preoperative and 
postoperative transfusions). 
9.  Hemoglobin/hematocrit laboratory values, obtained pre-operatively, pre-transfusion 
(when transfusion required) and last hemoglobin prior to discharge 
10.  Length of Hospital Stay 
11. Readmission 
12.  Incidence of sympotomatic postoperative DVT, PE, MI, and Stroke. 
13. Wound infection (superficial vs deep) 
14. Wound dehiscence 
15. Return to the OR for hematoma evacuation / wound irrigation and debridement 
16. All bacterial infection (wound, UTI, respiratory) 
 
References: 
 
1. 
Astedt B, Liedholm P, Wingerup L. The effect of tranexamic acid on the 
fibrinolytic activity of vein walls. Annales chirurgiae et gynaecologiae. 
1978;67:203-205. 
 
2. 
Benoni G, Fredin H, Knebel R, Nilsson P. Blood conservation with tranexamic 
acid in total hip arthroplasty: a randomized, double-blind study in 40 primary 
operations. Acta orthopaedica Scandinavica. 2001;72:442-448. 
 
3. 
Benoni G, Lethagen S, Fredin H. The effect of tranexamic acid on local and 
plasma fibrinolysis during total knee arthroplasty. Thrombosis research. 
1997;85:195-206. 
 
4. 
Benoni G, Lethagen S, Nilsson P, Fredin H. Tranexamic acid, given at the end of 
the operation, does not reduce postoperative blood loss in hip arthroplasty. Acta 
orthopaedica Scandinavica. 2000;71:250-254. 
 
5. 
Bierbaum BE, Callaghan JJ, Galante JO, Rubash HE, Tooms RE, Welch RB. An 
analysis of blood management in patients having a total hip or knee arthroplasty. 
The Journal of bone and joint surgery. American volume. 1999;81:2-10. 
 
6. 
Callaghan JJ, Spitzer AI. Blood management and patient specific transfusion 
options in total joint replacement surgery. The Iowa orthopaedic journal. 
2000;20:36-45. 
 

7. 
Carson JL, Altman DG, Duff A, Noveck H, Weinstein MP, Sonnenberg FA, 
Hudson JI, Provenzano G. Risk of bacterial infection associated with allogeneic 
blood transfusion among patients undergoing hip fracture repair. Transfusion. 
1999;39:694-700. 
 
8. 
Claeys MA, Vermeersch N, Haentjens P. Reduction of blood loss with tranexamic 
acid in primary total hip replacement surgery. Acta chirurgica Belgica. 
2007;107:397-401. 
 
9. 
Clark CR. Perioperative blood management in total hip arthroplasty. Instructional 
course lectures. 2009;58:167-172. 
 
10. 
Eikelboom JW, Karthikeyan G, Fagel N, Hirsh J. American Association of 
Orthopedic Surgeons and American College of Chest Physicians guidelines for 
venous thromboembolism prevention in hip and knee arthroplasty differ: what are 
the implications for clinicians and patients? Chest. 2009;135:513-520. 
 
11. 
Ekback G, Axelsson K, Ryttberg L, Edlund B, Kjellberg J, Weckstrom J, Carlsson 
O, Schott U. Tranexamic acid reduces blood loss in total hip replacement surgery. 
Anesthesia and analgesia. 2000;91:1124-1130. 
 
12. 
Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, 
Teoh K, Duke PC, Arellano R, Blajchman MA, Bussieres JS, Cote D, Karski J, 
Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R. A 
comparison of aprotinin and lysine analogues in high-risk cardiac surgery. The 
New England journal of medicine. 2008;358:2319-2331. 
 
13. 
Garneti N, Field J. Bone bleeding during total hip arthroplasty after 
administration of tranexamic acid. The Journal of arthroplasty. 2004;19:488-492. 
 
14. 
Gill JB, Rosenstein A. The use of antifibrinolytic agents in total hip arthroplasty: 
a meta-analysis. The Journal of arthroplasty. 2006;21:869-873. 
 
15. 
Good L, Peterson E, Lisander B. Tranexamic acid decreases external blood loss 
but not hidden blood loss in total knee replacement. British journal of anaesthesia. 
2003;90:596-599. 
 
16. 
Gross JB. Estimating allowable blood loss: corrected for dilution. Anesthesiology. 
1983;58:277-280. 
 
17. 
Haynes RB, et al. Clinical Epidemiology: How to Do Clinical Practice Research. 
3rd ed. Lippincott Williams and Wilkins, 2006.  
 
18. 
Husted H, Blond L, Sonne-Holm S, Holm G, Jacobsen TW, Gebuhr P. 
Tranexamic acid reduces blood loss and blood transfusions in primary total hip 

arthroplasty: a prospective randomized double-blind study in 40 patients. Acta 
orthopaedica Scandinavica. 2003;74:665-669. 
 
19. 
Ido K, Neo M, Asada Y, Kondo K, Morita T, Sakamoto T, Hayashi R, Kuriyama 
S. Reduction of blood loss using tranexamic acid in total knee and hip 
arthroplasties. Archives of orthopaedic and trauma surgery. 2000;120:518-520. 
 
20. 
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 
orthopaedica. 2005;76:314-319. 
 
21. 
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. Thrombosis research. 
2009;123:687-696. 
 
22. 
Karunakar MA, Shah SN, Jerabek S. Body mass index as a predictor of 
complications after operative treatment of acetabular fractures. J Bone Joint Surg 
Am. 2005;87-A:1498-1502. 
 
23. 
Klein HG, Spahn DR, Carson JL. Red blood cell transfusion in clinical practice. 
Lancet. 2007;370:415-426. 
 
24. 
Munoz M, Garcia-Erce JA, Villar I, Thomas D. Blood conservation strategies in 
major orthopaedic surgery: efficacy, safety and European regulations. Vox 
sanguinis. 2009;96:1-13. 
 
25. 
Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human 
adults. Surgery. 1962;51:224-232. 
 
26. 
Niskanen RO, Korkala OL. Tranexamic acid reduces blood loss in cemented hip 
arthroplasty: a randomized, double-blind study of 39 patients with osteoarthritis. 
Acta orthopaedica. 2005;76:829-832. 
 
27. 
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. The Knee. 2006;13:106-110. 
 
28. 
Rajesparan K, Biant LC, Ahmad M, Field RE. The effect of an intravenous bolus 
of tranexamic acid on blood loss in total hip replacement. The Journal of bone and 
joint surgery. British volume. 2009;91:776-783. 
 
29. 
Rosencher N, Kerkkamp HE, Macheras G, Munuera LM, Menichella G, Barton 
DM, Cremers S, Abraham IL. Orthopedic Surgery Transfusion Hemoglobin 
European Overview (OSTHEO) study: blood management in elective knee and 
hip arthroplasty in Europe. Transfusion. 2003;43:459-469. 

 
30. 
Sadeghi M, Mehr-Aein A. Does a single bolus dose of tranexamic acid reduce 
blood loss and transfusion requirements during hip fracture surgery? A 
prospective randomized double blind study in 67 patients. Acta Medica Iranica 
2007; 45: 437–42.  
 
31. 
Salido JA, et al. Preoperative hemoglobin levels and the need for transfusion after 
prosthetic hip and knee surgery. Analysis of Predictive Factors. The Journal of 
Bone and Joint Surgery (American) 84:216-220 (2002) 
 
32.  
Scannell, et al. Efficacy of intraoperative red blood cell salvage and 
autotransfusion in the treatment of acetabular fractures. J Orthop Trauma 
2009;23:340–345) 
 
33. 
Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, 
Gogichaishvili T, Gupta S, Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, 
Komolafe E, Marrero MA, Mejia-Mantilla J, Miranda J, Morales C, Olaomi O, 
Olldashi F, Perel P, Peto R, Ramana PV, Ravi RR, Yutthakasemsunt S. 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;376:23-32. 
 
34. 
Stulberg BN, Zadzilka JD. Blood management issues using blood management 
strategies. The Journal of Arthroplasty. 2007;22:95-98. 
 
35. 
Sukeik M, Alshryda S, Haddad FS, Mason JM. Systematic review and meta-
analysis of the use of tranexamic acid in total hip replacement. The Journal of 
bone and joint surgery. British volume. 2011;93:39-46. 
 
36. 
Tornetta, P. Displaced Acetabular Fractures: Indications for Operative and 
Nonoperative Management. J Am Acad Orthop Surg January/February 2001 vol. 
9 no. 1 18-28.  
 
37. 
Westrich GH, Bottner F, Windsor RE, Laskin RS, Haas SB, Sculco TP. 
VenaFlow plus Lovenox vs VenaFlow plus aspirin for thromboembolic disease 
prophylaxis in total knee arthroplasty. The Journal of arthroplasty. 2006;21:139-
143. 
 
38. 
Westrich GH, Sculco TP. Prophylaxis against deep venous thrombosis after total 
knee arthroplasty. Pneumatic plantar compression and aspirin compared with 
aspirin alone. The Journal of bone and joint surgery. American volume. 
1996;78:826-834. 
 
39. 
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. 2006;105:1034-1046. 

 
40.  
Zufferey P, et al. Tranexamic acid in hip fracture surgery: a randomized 
controlled trial. British Journal of Anaesthesia 104 (1): 23–30 (2010).