Efficacy of Tranexamic Acid in Preventing Post Operative Blood Loss and Associated Complications in Bone Sarcoma Patients Treated With Limb Salvage Surgery: A Randomized Controlled Trial
Phase: EARLY_PHASE1
Conditions: Blood Loss, Surgical
Sponsor: Shaukat Khanum Memorial Cancer Hospital & Research Centre

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy of Tranexamic Acid in preventing post operative 
blood loss and associated complications in bone 
sarcoma patients treated with limb salvage surgery: A 
randomized controlled trial. 
 
 
 
 
IRB# IRB-22-07 
DATE OF DOCUMENT: 06-04-2022 

 
 
 
 
 
STUDY PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Efficacy of Tranexamic Acid in preventing post operative blood loss and associated 
complications in bone sarcoma patients treated with limb salvage surgery: A randomized 
controlled trial. 
 
Introduction: 
 
Limb salvage surgery for malignant bone tumors results in extensive bone and soft tissue resection which 
leads to massive bleeding and requiring a large number of transfusions [1] [2]. Blood transfusions have 
their own complications like hemolytic reaction, graft versus host disease, the spread of infection and 
sometime can lead to mortality [3]. Blood loss and related complications may lead to high risk of 
reoperation, an increased hospital stay, and increases burden over the health resources especially among 
anemic cancer patients [4]. 
Tranexamic acid (TXA) is a synthetic analog of lysine that prevents fibrinolysis by blocking the lysine 
binding sites on plasminogen and it has been extensively used over the past decade in orthopedic 
surgeries to decrease perioperative blood loss and the transfusion rate [5][6]. Perioperative use of TXA 
has been shown to reduce intraoperative and postoperative blood loss and to decrease transfusion rates 
in both total knee arthroplasty and total hip arthroplasty [7][8]. Furthermore, it results in higher 
postoperative hemoglobin, decreased postoperative pain, swelling, length of hospital stays, and higher 
patient satisfaction [9][10]. 
Although there is a long-standing concern about TXA-induced hypercoagulability that may increase the 
risk for postoperative venous thromboembolism (VTE), there are multiple studies even in high-risk 
patients supporting its safe use [3][11]. In a review of more than 1,000 patients, 240 of which had multiple 
risk factors for embolic disease including known prothrombotic conditions, those who received TXA had 
no additional thrombotic events [12]. In addition, two studies have documented an overall reduction in 
healthcare costs due to fewer transfusions.[11][13]. 
Despite ample research documenting the safety and efficacy of perioperative TXA in patients undergoing 
arthroplasty, there is no known clinical trial focusing on TXA's use in musculoskeletal oncology patients 
undergoing endoprosthesis reconstruction. Nonetheless, TXA is used within the musculoskeletal oncology 
community, with its use varying from surgeon to surgeon. Surgeons who use TXA do so with the intent of 
limiting perioperative blood loss and transfusion rates in these high blood-loss procedures. However, 
without clinical trial to support its use in this cohort, these patients, who tend to have an increased 
number of comorbidities, could be inheriting an increased risk of perioperative complication without the 
benefits documented. Conversely, patients within this cohort that do not receive TXA could be missing 
out on the clinical benefits of TXA seen in patients undergoing arthroplasty. This randomized clinical trial 
will determine the efficacy of tranexamic acid in musculoskeletal oncology population who underwent 
wide local excision and reconstruction with endoprosthesis and will result in the formation of a guideline 
about its efficacy in reducing blood loss and adverse events that can be resulted by the use of tranexamic 
acid in the musculoskeletal oncology population. 
 
 
 
 
 
 
 
 
Objectives:

To determine the efficacy of tranexamic acid in musculoskeletal tumor who underwent wide local 
excision and reconstruction with endoprosthesis and determine adverse events that can be resulted by 
the use of tranexamic acid. 
Primary outcome measures: 
Blood loss in a surgical patient can be monitored by: 
• 
Drop-in hemoglobin in 72 hours 
• 
The number of transfused PRBC unit 
• 
72-hour total blood loss as calculated by hemoglobin balance method 
Hemoglobin balance method: 
The Hemoglobin - balance method is based on the balance of Hemoglobin during the perioperative 
period of surgery. It is regarded as an important method with intuitive expressiveness and high accuracy 
and often addresses contemporary clinical issues [14] 
 
 
 
 
Secondary outcome measures: 
• 
Thromboembolic events: to be observed over six weeks from the date of surgery 
• 
Hospital stay 
• 
drain output till 72 hours 
Methodology 
 
Study Design: A Randomized control trial (RCT) 
 
Setting: Department of surgical oncology, Shaukat Khanum Memorial Cancer Hospital and Research 
Center, Lahore. 

Sample size: 
 
Sample size was calculated on the basis of previous study published by Haase, Douglas R.in 2020. Mean 
post-operative blood loss in TXA group and non TXA were 981±290 mL and 1542±394mL, respectively. 
[02] At 80% power, 95% confidence interval, assuming 10% drop out rate, a total of 36 patients included 
in this study divided into two groups (18 in each group, TXA versus non TXA) would be required in this 
study. 
 
Sample selection: 
Inclusion criteria: 
Patients with primary or metastatic bone tumors who underwent a resection and an endo-prosthetic 
reconstruction of the proximal femur, distal femur, proximal tibia and proximal humerus. All patients 
will be tested for liver function using PT (INR), renal function by serum creatinine and Marrow function 
by CBC 
 
 
Exclusion Criteria: 
• 
Patient with a congenital or acquired coagulopathy 
• 
Severe renal or liver insufficiency 
• 
Previous thromboembolic condition 
• 
A patient who received perioperative plasma product 
• 
Pelvic tumor 
• 
Patient who is taking anti-coagulant before surgery 
• 
Patient allergic to tranexamic acid 
 
 
Enrollment duration: Being a dedicated cancer center, a large number( 30-40 per year) of Limb salvage 
surgeries are performed at Shaukat Khanum Memorial Cancer Hospital. The above-given sample size can 
therefore be achieved in 10 months. 
Dose of tranexamic Acid: A single dose of tranexamic acid will be given intravenously at time of 
induction according to body weight i.e., 15 mg/kg 
Anti-coagulation Protocol: All limb salvage patients started on anticoagulant Injection Enoxaprin 
subcutaneously after 24 hours of surgery according to body weight i.e. 1.5 mg/kg. Enoxaprin converted 
to oral tablet Aspirin 75 mg on discharge for 4 weeks. 
Study Duration: 12 months after the start of enrollment. 

In house admission: Limb salvage surgery patients remain admitted on the floor for an average of 5 days 
Follow up Schedule: Physical follow up in clinic 2 weeks after surgery (as per institutional guidelines) 
and a second follow up at 4 weeks after surgery 
Randomization: Intraoperative randomization, patients would be allocated to either of the groups by 
selecting names from sealed envelopes. 
Type of randomization: Computerized block randomization. This will ensure a similar number of patients 
in both groups. Patients will have their names written on an envelope with contents of the envelope 
indicating whether tranexamic acid should be given or not. Only one member of research team will be 
aware of the contents of the envelope, who will not be present in Operation Theater at the time of 
surgery and will not take part in data collection. Patient in control group will be given 10 cc of normal 
saline as as placebo. 
Blinding: It will be a triple-blind trial since the patients will be unaware of the group to which they have 
been randomized. The statistician carrying out data analysis and examiners/interviewers carrying out 
clinical examinations/interviewing patients will also be unaware of the status of tranexamic acid. 
Minimizing Bias: It is not possible to eliminate bias altogether. However, the performance bias of the 
operating surgeon will be limited by not revealing the contents of the sealed envelope. The interviewer's 
bias will be limited by ensuring that the interviewer is not aware of tranexamic acid status at the time of 
the interview and by ensuring a standardized interaction between the patient and interviewer. 
Intervention: Surgeon who will carry out Limb salvage surgeries, will be a consultant with > 5-year 
experience in Limb salvage. A single standardized technique will be used in all of the patients. 
There is a difference of opinion about the use of tranexamic acid in surgeons at SKMH and both surgical 
options are practiced. The trial will therefore pose no additional risks to the patients. 
 
 
 
 
References 
 
 
• 
Sabatini L, Atzori F, Revello S, Scotti L, Debiasi F, Massè A: Intravenous use of tranexamic acid 
reduces postoperative blood loss in total knee arthroplasty. Arch Orthop Trauma Surg 
2014;134:1609-1614. 
• 
Haase, D.; Templeton, K.; Rosenthal, H.; Sweeney, K. Tranexamic acid in patients with cancer 
undergoing endoprosthetic reconstruction. J. Am. Acad. Orthop. Surg. 2020, 28, 248–255. 
• 
Wei W, Wei B: Comparison of topical and intravenous tranexamic acid on blood loss and 
transfusion rates in total hip arthroplasty. J Arthroplasty 2014;29:2113-2116 
• 
Vera-Llonch, M.; Hagiwara, M.; Oster, G. Clinical and economic consequences of bleeding 
following major orthopedic surgery. Thromb. Res. 2006, 117, 569–577 

• 
Aguilera, X.; Martinez-Zapata, M.J.; Bosch, A.; Urruita, G.; González, J.C.; Jordan, M.; Gich, I.; 
Maymó, R.M.; Martínez, N.; Monllau, J.C.; et al. Efficacy and safety of fibrin glue and tranexamic 
acid to prevent postoperative blood loss in total knee arthroplasty: A randomized controlled 
clinical trial. J. Bone Jt. Surg. Am. 2013, 95, 2001–2007. 
• 
Bidolegui, F.; Arce, G.; Lugones, A.; Pereira, S.; Vindver, G. Tranexamic acid reduces blood loss 
and transfusion in patients undergoing total knee arthroplasty without Tourniquet: A 
prospective randomized controlled trial. Open Orthop. J. 2014, 8, 250–254 
• 
Bidolegui F, Arce G, Lugones A, Pereira S, Vindver G: Tranexamic acid reduces blood loss and 
transfusion in patients undergoing total knee arthroplasty without Tourniquet: A prospective 
randomized controlled trial. Open Orthop J 2014;8:250-254. 
• 
Chang CH, Chang Y, Chen DW, Ueng SW, Lee MS: Topical tranexamic acid reduces blood loss and 
transfusion rates associated with primary total hip arthroplasty. Clin Orthop Relat Res 
2014;472:1552-1557 
• 
Goyal N, Chen DB, Harris IA, Rowden N, Kirsch G, MacDessi SJ: Clinical and financial benefits of 
intra-articular tranexamic acid in total knee arthroplasty. J Orthop Surg Hong Kong 2016;24:3-6. 
• 
 Huang Z, Ma J, Shen B, Pei F: Combination of intravenous and topical application of tranexamic 
acid in primary total knee arthroplasty: A prospective randomized controlled trial. J Arthroplasty 
2014;29: 2342-2346. 
• 
Chimento GF, Huff T, Ochsner JL Jr, Meyer M, Brandner L, Babin S: An evaluation of the use of 
topical tranexamic acid in total knee arthroplasty. J Arthroplasty 2013;28:74-77. 
• 
Whiting DR, Gillette BP, Duncan C, Smith H, Pagnano MW, Sierra RJ: Preliminary results suggest 
tranexamic acid is safe and effective in arthroplasty patients with severe comorbidities. Clin 
Orthop Relat Res 2014; 472:66-72. 
• 
Karam JA, Bloomfield MR, DiIorio TM, Irizarry AM, Sharkey PF: Evaluation of the efficacy and 
safety of tranexamic acid for reducing blood loss in bilateral total knee arthroplasty. J 
Arthroplasty 2014;29: 501-503. 
• 
Smith GH, Tsang J, Molyneux SG, White TO. The hidden blood loss after hip 
fracture. Injury. 2011;42:133–5 
 
 
 
 
 
 
 
 
 
 
PROFORMA 

 
 
 
Full Name:   
 
 
MR Number:   
 
 
Date of Surgery:   
 
 
 
Age 
Years 
 
Sex: 
• Male 
• Female 
 
Co-Morbid: 
• HTN 
• DM 
• CVA 
• IHD 
• Others 
 
Type of Malignant Bone Tumor: 
• Ewing Sarcoma 
• Osteosarcoma 
• PNET 
• Other 
 
Site of Primary Tumor: 
• Humerus   
 
• Femur  
 
• Tibia   
 
• Other 
Group: 
• Tranexamic Acid Given 
• Tranexamic Acid Not Given 
Length of Bone Resected 
Cm 

Wound Healing: (Satisfactory / Unsatisfactory) 
Preoperative Hemoglobin 
gms 
Preoperative INR  
 
Intraoperative Blood Loss: 
mls 
Postoperative Hemoglobin after 24 Hours 
gms 
Postoperative Hemoglobin after 72 Hours  
  
Number of PRBC Transfused Within 72 Hours of Surgery  
  
Blood Loss Calculated By Direct Hemoglobin Method  
 
Drain Output in 72 Hours: 
mls 
Any Thromboembolic Event:   
 
Status of Ambulation: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

             
       STATISTICAL ANALYSIS PLAN:  
 
Statistician independently pooled data from each case then conducted statistical analysis using 
SPSS Descriptive data are presented as mean ± standard deviation (SD). Odds ratio (OR) with 
95% confidence intervals (CI) or mean differences (MD) with 95% CI were calculated for 
dichotomous and continuous outcomes, respectively. Numerical and measured data were 
compared using a t-test and χ2-test, respectively. An appropriate power and sample size calculator 
was used to calculate statistical power. The following parameters were used in the calculations: α, 
probability of a type I error for a two-sided test; P0, probability of exposure in controls; N, number 
of patients; m: ratio of control to experimental subjects; and Ψ, odds ratio of exposure in 
experimental subjects relative to controls. P < 0.05 was considered significant.