Does the Intraoperative Administration of Tranexamic Acid (TXA) Increase the Incidence of Deep Venous Thrombosis in Total Knee Arthroplasty?
Conditions: Venous Thrombosis
Sponsor: University of New Mexico

Does the intraoperative administration of tranexamic acid (TXA) increase the incidence 
of deep venous thrombosis in total knee arthroplasty?
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Version Date: January 26, 2017
PROTOCOL TITLE:
Does the intraoperative administration of tranexamic acid (TXA) increase the 
incidence of deep venous thrombosis in total knee arthroplasty?
Short title: Tranexamic acid and blood clots in knee surgery
PRINCIPAL INVESTIGATOR:
David Siegel, MD
Anesthesiology & Critical Care Medicine
VERSION NUMBER:
3.
DATE:
August 3, 2017.
REGULATORY FRAMEWORK:
Please indicate all that apply:
DOD (Department of Defense)
DOE (Department of Energy)
DOJ (Department of Justice)
ED (Department of Education)
EPA (Environmental Protection Agency)
FDA (Food and Drug Administration)
HHS (Department of Health and Human Services)
Other:      
Is this a clinical trial under ICH-GCP E6?   
 Yes   
 No
If yes, please confirm that the research team is familiar with and agrees to comply 
with the investigator requirements cited in ICH-GCP E6.  
 Yes   
 No 
ICH-GCP E6 can be accessed by copying and pasting this URL into your 
browser: http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf

Does the intraoperative administration of tranexamic acid (TXA) increase the incidence 
of deep venous thrombosis in total knee arthroplasty?
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Table of Contents
1.
Objectives.....................................................................................................................4
2.
Background ..................................................................................................................4
3.
Study Design ................................................................................................................4
4.
Inclusion and Exclusion Criteria ..................................................................................4
5.
Number of Subjects......................................................................................................4
6.
Study Timelines............................................................................................................5
7.
Study Endpoints ...........................................................................................................5
8.
Research Setting...........................................................................................................5
9.
Resources Available.....................................................................................................5
10.
Prior Approvals.........................................................................................................6
11.
Multi-Site Research ..................................................................................................6
12.
Study Procedures ......................................................................................................7
13.
Data Analysis............................................................................................................7
14.
Provisions to Monitor the Data to Ensure the Safety of Subjects.............................8
15.
Withdrawal of Subjects.............................................................................................8
16.
Data Management/Confidentiality............................................................................8
17.
Data and Specimen Banking...................................................................................10
18.
Risks to Subjects.....................................................................................................10
19.
Potential Benefits to Subjects .................................................................................11
20.
Recruitment Methods..............................................................................................11
21.
Provisions to Protect the Privacy Interests of Subjects ..........................................11
22.
Economic Burden to Subjects.................................................................................11
23.
Compensation .........................................................................................................12
24.
Compensation for Research-Related Injury............................................................12
25.
Consent Process......................................................................................................13
26.
Documentation of Consent .....................................................................................15
27.
Study Test Results/Incidental Findings ..................................................................16
28.
Sharing Study Progress or Results with Subjects...................................................17
29.
Inclusion of Vulnerable Populations ......................................................................17
30.
Community-Based Participatory Research.............................................................18
31.
Research Involving American Indian/Native Populations .....................................18
32.
Transnational Research...........................................................................................19
33.
Drugs or Devices ....................................................................................................19
Checklist Section ...............................................................................................................20

Does the intraoperative administration of tranexamic acid (TXA) increase the incidence 
of deep venous thrombosis in total knee arthroplasty?
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1. Objectives
1.1. The purpose of this study is to estimate the incidence of diagnosable 
deep-vein thrombosis (DVT) in total knee arthroplasty (TKA) patients 
after administration of tranexamic acid (TXA).
1.2. The hypothesis is that intraoperative administration of TXA will increase the 
incidence of DVT as detected by lower-extremity ultrasound on postoperative 
day 1 in TKA patients when compared to the historic incidence of this 
complication in patients not administered TXA.
2. Background
2.1. The administration of the anti-fibrinolytic agent tranexamic acid (TXA) to 
prevent bleeding and transfusion has become commonplace in a variety of 
clinical settings following the publication of many studies documenting its 
efficacy (1-4). However, questions remain regarding the safety of this agent in 
known thrombogenic settings such as total joint arthroplasty.   Because TXA 
directly inhibits the activation of plasmin, an increase in risk of pathologic 
thrombosis is possible.    Safety claims to date for TXA are based upon 
secondary outcomes of clinically apparent deep venous thrombosis/pulmonary 
embolus (DVT/PE) between treated and control groups in studies designed 
primarily to assess blood loss (5,6).   None have prospectively examined the risk 
of DVT as a primary outcome in patients treated with TXA in total joint 
arthroplasty.  Furthermore, most studies have only used the presence of clinically 
apparent DVT to define the complication, which is known to significantly 
underestimate the true incidence (13).   This lack of safety data has been noted by 
the author of a recent meta-analysis of TXA, who concluded:  “The effect of 
tranexamic acid on thromboembolic events remains uncertain”(1).  Conversely, a 
recent retrospective study of total hip arthroplasty patients using screening lower 
extremity ultrasound did show a significant increase in DVT in the TXA treated 
patients (8).  Case reports of DVT, myocardial infarction and PE temporally 
associated with TXA administration continue to accumulate (9-11).  Clearly, the 
safety of routine TXA administration remains a topic of concern.
2.2. The investigators have not obtained any preliminary data.
3. Study Design
3.1. This is a prospective observational study.  
3.2. This is an open-label study.  
4. Inclusion and Exclusion Criteria
4.1. Participants will be recruited from among those presenting for total knee 
arthroplasty (joint replacement) at UNM Sandoval Regional Medical Center.
4.2. Inclusion criteria include: 
Age >18 years

Does the intraoperative administration of tranexamic acid (TXA) increase the incidence 
of deep venous thrombosis in total knee arthroplasty?
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Scheduled for total knee arthroplasty at SRMC with administered 
tranexamic acid, according to UNM Orthopedic Surgery protocol
Exclusion criteria:

Previous deep vein thrombosis or pulmonary embolism episode

Known coronary artery disease or peripheral vascular disease

Previously diagnosed hypercoagulable states (e.g. Leiden factor V, 
antiphospholipid antibody, protein C or S deficiency)

Pregnancy

Creatinine clearance less than 30 ml/min

Non-fluency in English
4.3. This study will not include participants from the special populations of: adults 
unable to consent, individuals who are not yet adults, pregnant women, or 
prisoners.
4.4. The investigators will not enroll participants who are not fluent in English.  
Funding for this study is limited, and thus its study size is small.  If the 
investigators were to obtain translation for the consent/HIPAA documentation, 
the cost of that service would have a substantial adverse effect on the available 
sample size and thus on study power, likely rendering its findings 
uninterpretable.  Also, there is not a substantial a priori reason to suspect that 
language skills themselves have any effect on postoperative thrombotic risk, so 
the investigators believe that this exclusion will not adversely affect the rights of 
Spanish-speaking people to enjoy the benefits of clinical research.  Because this 
exclusion will not present an injustice, but will serve to preserve study validity, 
the investigators plan to exclude non-English speakers.
5. Number of Subjects
5.1. We currently plan to complete data collection for 30 patients for this study, but 
may extend it to 100.  With traditional thresholds of 80% power and α=0.05, 30 
patients should be sufficient to detect a statistically-significant increase in DVT 
rate from the historic 12% to approximately 32%.  The investigators are seeking 
additional funding to further refine the actual incidence of post-TKR DVT, and if 
this funding is obtained may extend the study to 100 patients.  Due to dropouts 
and exclusions, we may enroll up to 50 patients in order to complete data 
collection on the planned initial sample of 30.
6. Study Timelines
6.1.

Individual subjects will be involved in the research on two consecutive days: 
they will provide consent on the day of surgery, and receive an ultrasound 
scan for deep vein thrombosis on postoperative day 2.

The investigators estimate that approximately 10 participants per month will 
choose to enroll in this study; hence enrollment is estimated to take 
approximately 3 months.

Does the intraoperative administration of tranexamic acid (TXA) increase the incidence 
of deep venous thrombosis in total knee arthroplasty?
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
Upon completion of enrollment and data collection, analysis and manuscript 
preparation are estimated to take one year.
7. Study Endpoints
7.1. The primary study outcome is the incidence of deep vein thrombosis observed by 
lower-extremity ultrasound on postoperative day 2.  The investigators have not 
identified secondary outcomes.
7.2. The investigators have not identified safety outcomes.  The only modification to 
routine practice that is entailed in this study is the administration of an ultrasound 
scan for lower-extremity preclinical DVT.
8. Research Setting
8.1. All study activities will occur in the context of normal medical treatment at UNM 
SRMC, including recruitment/consent, medical treatment, and ultrasonography.  
8.2. Potential subjects will be identified from among investigators’ routine patients.  
Recruitment will occur in the preoperative holding areas at SRMC, where the 
preoperative anesthesia consultation already occurs.  
8.3. The ultrasound scan for thrombosis will occur in the patient’s room on 
postoperative day 2.  The scan will be read by appropriate Radiology personnel 
in their offices soon thereafter.  
9. Resources Available
9.1. Investigators Drs. David Siegel and Neal Gerstein are faculty members in the 
Department of Anesthesiology with substantial research experience.  Investigator 
Dr. Brad Cushnyr is a faculty member in the Department of Radiology and the 
Chief of Radiology at SRMC.  Investigator Tim Petersen PhD is a member of the 
Anesthesiology department and routinely advises that department’s researchers.  
9.2. All medical decisions will be made by licensed providers in accordance with 
their routine job duties.  This is an observational trial and does not involve any 
manipulation of patient treatment for research purposes.  
9.3. Other resources:

Approximately 250 one-sided knee replacement surgeries are performed 
annually at SRMC.  The investigators estimate that approximately 10 per 
month would consent to participate.  

Investigators will conduct this study and associated activities as part of their 
routine job duties.  
10.Prior Approvals
10.1. The Departmental Review Form is included with this application.
10.2. The Drug Attachment is included with this application.
11.Multi-Site Research
11.1. This is not multi-site research.  

Does the intraoperative administration of tranexamic acid (TXA) increase the incidence 
of deep venous thrombosis in total knee arthroplasty?
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12.Study Procedures 
12.1.

Subjects included in the study will have ultrasonic (US) examination of their 
lower extremity veins performed on postoperative day #2 by an authorized 
ultrasound technician.  The US examination will be interpreted by one of the 
investigators (Dr. Cushynr) for the presence or absence of deep and superficial 
venous thrombosis.  No other investigations are planned.

Each patient will have been scheduled for elective total knee replacement, 
which by protocol at our institution includes the administration of tranexamic 
acid (TXA).  Some surgeons administer it intravenously, and others use intra-
articular administration during surgery.  The use of this medication is not 
modified by the existence of this research study.  Other than the study 
intervention (bilateral lower extremity US examination) described above, no 
alteration in the patient’s perioperative care will occur as a result of the study.  
The use of TXA for this purpose is widespread in orthopedic surgery but is 
technically off-label. 

The main data source will be the stored ultrasound images and the associated 
radiologic interpretations, provided in a routine radiology report. 

Patients undergoing total knee arthroplasty who develop clinical evidence of 
deep venous thrombosis (pain, swelling, redness in the lower extremity) or 
evidence of pulmonary embolus would be referred for ultrasound of the lower 
extremity regardless of study participation.  Conversely, each study patient 
who is found to have an asymptomatic DVT on US on postoperative day 2 
will be referred to their orthopedic surgeon for appropriate management.  This 
management may include medical or intravascular therapy, as appropriate in 
the clinical judgment of the physicians involved.
13.Data Analysis
13.1. The primary outcome (rate of development of DVT) will be analyzed with a 
binomial test of proportion.  The null hypothesis is that the one-sided 95% 
confidence interval around the observed rate of DVT will include the historic 
rate of 12%.  The alternate hypothesis is that this 95% confidence interval will 
be higher than and exclude 12%.   
13.2.
With traditional thresholds of 80% power and α=0.05, 30 patients should 
be sufficient to detect an increase in DVT rate from the historic 12% to 
approximately 32% with statistical significance.
14.Provisions to Monitor the Data to Ensure the Safety of Subjects
This section is required when research involves more than Minimal Risk to subjects. 
Describe:
14.1. This is an observational trial, so participation in this study does not increase 
patient risk.  This study does not modify patients’ surgical experience, drugs 
administered, route of administration, or any other component of surgery.  The 
only change from routine practice is the addition of a screening exam.

Does the intraoperative administration of tranexamic acid (TXA) increase the incidence 
of deep venous thrombosis in total knee arthroplasty?
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15.Withdrawal of Subjects
15.1. The investigators have not identified any likely circumstances in which subjects 
may be withdrawn from the study without their consent.  They may do so, 
however, if in their opinion this action would be best for participants or for the 
study.  An exhaustive listing of these unlikely situations is not possible, but one 
example would be a disruptive patient. 
15.2. As it does not involve treatment, this study does not include a plan for orderly 
termination/safe withdrawal.  
15.3. This study involves a single ultrasound scan after routine surgery.  Partial 
withdrawal is not practical.  
15.4. If a subject withdraws, existing data will be maintained but with a note 
indicating that withdrawal.  
16.Data Management/Confidentiality
16.1. Investigators include physicians who treat prospective subjects as part of their 
routine job duties.  
16.2. The research requires the use of direct identifiers in order to accurately match 
scans to patients.  The scans and the surgical information constitute Protected 
Health Information.
16.3. The data do not include information that is usually considered “sensitive.” 
16.4. The investigators do not plan to obtain a Certificate of Confidentiality. 
16.5. Data will be maintained in locked files in secure areas.  All electronic data will 
be maintained on UNM HSC secure password-protected servers.  All 
investigators are HIPAA-certified and have completed CITI training.  
16.6. Data will not be collected or transmitted via the internet.
16.7.
The data do not include audio or video recordings, or photographs. 
17.Data and Specimen Banking
17.1. Deidentified data may be stored indefinitely to serve as underlying data to 
inform future studies, such as for sample size estimation.  
18.Risks to Subjects
18.1. Ultrasound scans do not involve substantial risk.  It is possible that some 
patients’ scans may indicate underlying health conditions that are not known at 
the time of the scan.  All scans involve the lower extremity, so this probability 
is low.  
18.2. The investigators have minimized risk by selecting an observational strategy 
and by using ultrasound for the DVT scans.  
19.Potential Benefits to Subjects

Does the intraoperative administration of tranexamic acid (TXA) increase the incidence 
of deep venous thrombosis in total knee arthroplasty?
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19.1. The scans may indicate pre-clinical thrombosis and allow the patient to obtain 
antithrombotic treatment earlier than would otherwise be available.  
20.Recruitment Methods
20.1. Patients will be recruited in the preoperative holding areas at SRMC, during the 
preoperative anesthesia consultation.  
20.2. Potential subjects will be identified from among investigators’ regularly 
scheduled patients.   
20.3. Other than the consent/HIPAA materials, there will not be any recruitment 
materials.  
21.Provisions to Protect the Privacy Interests of Subjects
21.1. Recruitment and consent discussions will occur in the context of the 
preoperative anesthesia consultation, which is already handled in a 
private/confidential manner.  Investigators will first ask whether potential 
subjects are interested in participating in a study, and if so, the details will be 
discussed and the consent material introduced.
22.Economic Burden to Subjects
22.1.
Responsible Party
Research Procedures
Number of 
Samples/Procedures
Study
3rd Party Payer 
or Participant
Ultrasonographic scan of lower extremity
All
Radiology services (read scan)
All
     
     
Responsible Party
Standard of Care Procedures
Number of 
Samples/Procedures
Study
3rd Party Payer 
or Participant
Surgery, hospitalization, medications
All
     
     
     
     
22.2. Patients or 3rd-party payers will be responsible for any costs related to adverse 
events.
23.Compensation
23.1. Participants will not be compensated.
24.Compensation for Research-Related Injury
24.1. This is a minimal-risk study.
25.Consent Process
25.1. The investigators will obtain consent prior to research-related activity.

Does the intraoperative administration of tranexamic acid (TXA) increase the incidence 
of deep venous thrombosis in total knee arthroplasty?
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25.1.1. An investigator will obtain consent. All investigators are HIPAA-certified 
and have completed CITI training.
25.1.2. The consent process will occur in the preoperative holding areas of 
SRMC.
25.1.3. Prospective participants will be assured that participation is voluntary.
25.1.4. As this is an observational study, prospective participants should not need 
much time to consider participation.  Those who cannot decide in the 
available time will be excused from participation.
25.1.5. Consent will be assumed to be ongoing for the purpose of the scan on 
postoperative day 2 unless the subject objects to the scan.
25.1.6. The consenting investigator will ask subjects to describe the study in their 
own words, and will correct any misunderstandings.
Subjects not fluent in English
25.1.7. This is a low-enrollment study; the investigators do not plan to enroll non-
English speakers.  
Cognitively Impaired Adults/Adults Unable to Consent/Use of a Legally 
Authorized Representative
25.1.8. This study does not involve cognitively impaired adults or those unable to 
consent.  
Subjects who are not yet adults (infants, children, teenagers)
25.1.9. The study does not involve subjects who are not yet adults.
Waiver or Alteration of Consent Process (consent will not be obtained, required 
element of consent will not be included, or one or more required elements of 
consent will be altered) 

We are not requesting waiver or alteration of the consent process.
26.Documentation of Consent
26.1. A consent/HIPAA form is included with this application.  Only consenting 
patients will be enrolled.
27.Study Test Results/Incidental Findings
27.1. Individual Results: Individual results will be shared with participants inasmuch 
as they will be kept apprised of their condition by relevant medical personnel; a 
DVT is a medical condition that would be brought to the attention of the patient.  
As noted in section 12 above, this treatment may involve medical or 
intravascular treatment as appropriate, depending on the clinical judgment of the 
physicians involved.
27.2. Incidental Findings: The radiologist who reads the ultrasound scan will report 
any incidental findings to an investigator or the patient’s surgeon for followup.  
The exact nature of this followup depends on the nature of the incidental 

Does the intraoperative administration of tranexamic acid (TXA) increase the incidence 
of deep venous thrombosis in total knee arthroplasty?
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finding.  It is left to the clinical judgment of the physicians involved, and 
discussed with the patient as appropriate.  
28.Sharing Study Progress or Results with Subjects
28.1. The investigators do not plan to share partial study results with subjects.  
Similarly, the investigators do not plan to keep patient identifiers or contact 
information beyond completion of data collection, so it will not be possible to 
contact subjects with final study results.  In any event, the outcome of interest 
will have either occurred or not occurred for each subject, so the experiences of 
others will not be useful information to the subjects.
29.Inclusion of Vulnerable Populations
29.1. The study does not include vulnerable populations.  Some subjects may be 
students or employees of UNM or UNM HSC, but these are not specifically 
targeted or excluded.
30.Community-Based Participatory Research
30.1. This study does not involve community-based participatory research.
31.Research Involving American Indian/Native Populations
31.1. American Indian/Native persons may be incidentally enrolled in this study, but 
they are not specifically targeted or excluded.    
32.Transnational Research
32.1. This study does not involve transnational research.   
33.Drugs or Devices
33.1. Tranexamic acid is approved by the FDA, but is off-label for the usage 
described above.  This study does not modify its usage in any way.  The 
investigators have not sought an IND.

Does the intraoperative administration of tranexamic acid (TXA) increase the incidence of deep 
venous thrombosis in total knee arthroplasty?
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Checklist Section
This section contains checklists to provide information on a variety of topics that require special 
determinations by the IRB.  Please complete all checklists relevant to your research.
I.
Waivers or Alterations of Consent, Assent, and HIPAA Authorization
NA; we are not seeking this waiver or alteration.
II. Vulnerable Populations
NA; this study does not involve these populations.
III.Medical Devices
NA; this is not a device study.