RE-BLEED: A Digital Platform for Identifying Bleeding Patients - a Feasibility Study
Conditions: Hemorrhage, Trauma, Gastro Intestinal Bleeding
Sponsor: University of Oxford

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RE-BLEED:  A digital platform for identifying bleeding patients – a feasibility 
study 
 
Internal Reference Number / Short title: RE-BLEED 
 
Version and Date: Version 5 – 15/08/2022 
Ethics Ref: 21/SC/0290 
CAG Ref: 21/CAG/0123 
IRAS Project ID: 292593 
Joint Research Office Ref: PID15451 
clinicaltrials.gov Ref: xx 
 
Chief Investigator: 
Professor Peter Watkinson, Associate Professor of Intensive Care 
Medicine, University of Oxford 
Haematology specialist: 
Professor Simon J Stanworth, Associate Professor of Haematology and 
Transfusion Medicine, University of Oxford 
Investigators:  
Dr Nicola Curry, Consultant Haematologist, Oxford University Hospital 
NHS Trust 
Dr Robert Hatch, Clinical Research Fellow, University of Oxford 
Professor James Davies, Professor of Software Engineering, University 
of Oxford 
Dr Oliver Redfern, Clinical Research Fellow, University of Oxford 
Professor Tim Coats, Professor of Emergency Medicine, University of 
Leicester 
Kinga Varnai, Senior Programme Manager, Oxford University Hospital 
NHS Trust 
Professor Ly-Mee Yu, Associate Professor, University of Oxford 
Sponsor:  
University of Oxford 
Funder: 
NIHR Biomedical Research Centre Oxford. 

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Chief Investigator Signature:  
 
 
Statistician Signature (Professor Ly-Mee Yu):  
 
 
 
Please declare any/no potential conflicts of interest: None declared 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, HRA, host organisation, and members of the Research Ethics Committee, 
unless authorised to do so

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TABLE OF CONTENTS 
 
1 
KEY CONTACTS ................................................................................................................................... 5 
2 
LAY SUMMARY................................................................................................................................... 5 
3 
SYNOPSIS ........................................................................................................................................... 6 
4 
ABBREVIATIONS ................................................................................................................................. 8 
5 
BACKGROUND AND RATIONALE ........................................................................................................ 9 
6 
OBJECTIVES AND OUTCOME MEASURES ......................................................................................... 10 
7 
STUDY DESIGN ................................................................................................................................. 11 
8 
PARTICIPANT IDENTIFICATION ........................................................................................................ 12 
8.1 
Study Participants .................................................................................................................... 12 
8.1.1 
Retrospective cohort ........................................................................................................... 12 
8.1.2 
Prospective cohort .............................................................................................................. 12 
9 
PROTOCOL PROCEDURES ................................................................................................................ 12 
9.1 
Algorithm development and validation................................................................................... 12 
9.2 
Consent patients identified by system for use of surplus routine blood samples in research 
analysis. 13 
9.3 
Blood sample handling /temporary storage and testing......................................................... 14 
9.4 
Consent & patient notification ................................................................................................ 15 
9.4.1 
Screening/enrolment........................................................................................................... 15 
9.4.2 
Dissent ................................................................................................................................. 15 
9.4.3 
Patients with capacity to consent ....................................................................................... 15 
9.4.4 
Patients without capacity to consent .................................................................................. 17 
9.5 
Description of study intervention(s), comparators, and study procedures (clinical) .............. 18 
9.6 
Patient Public Involvement (PPI) ............................................................................................. 18 
9.7 
Early Discontinuation/Withdrawal of Participants .................................................................. 19 
9.8 
Definition of End of Study ....................................................................................................... 19 
10 
SAFETY REPORTING ......................................................................................................................... 19 
11 
STATISTICS AND ANALYSIS ............................................................................................................... 19 
11.1 
Description of the Statistical Methods .................................................................................... 19 
11.1.1 
The plans for the statistical analysis of the study are outlined below. assessed using 
descriptive statistics. Variables ........................................................................................................... 19 
11.1.2 
Descriptive statistics ............................................................................................................ 20 
11.1.3 
Retrospective cohort ........................................................................................................... 20 
11.2 
Sample Size Determination ..................................................................................................... 20 

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11.2.1 
Retrospective data............................................................................................................... 20 
11.2.2 
Prospective data .................................................................................................................. 21 
11.3 
Analysis populations ................................................................................................................ 21 
11.4 
Decision points ........................................................................................................................ 21 
11.5 
Stopping rules .......................................................................................................................... 21 
11.6 
The Level of Statistical Significance ......................................................................................... 21 
11.7 
Procedure for Accounting for Missing, Unused, and Spurious Data. ...................................... 21 
11.8 
Procedures for Reporting any Deviation(s) from the Original Statistical Plan ........................ 22 
12 
DATA MANAGEMENT ...................................................................................................................... 22 
12.1 
Data sources ............................................................................................................................ 22 
12.2 
Data transfer and analysis ....................................................................................................... 22 
12.3 
Data recording and record keeping ......................................................................................... 22 
12.4 
Access to data .......................................................................................................................... 23 
13 
QUALITY ASSURANCE PROCEDURES ............................................................................................... 23 
13.1 
Risk assessment ....................................................................................................................... 23 
13.2 
Study monitoring ..................................................................................................................... 23 
13.3 
Study Committees ................................................................................................................... 23 
13.3.1 
Study Management Group .................................................................................................. 23 
13.3.2 
PPI Group ............................................................................................................................. 24 
14 
PROTOCOL DEVIATIONS .................................................................................................................. 24 
15 
SERIOUS BREACHES ......................................................................................................................... 24 
16 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................................... 24 
16.1 
Declaration of Helsinki............................................................................................................. 24 
16.2 
Guidelines for Good Clinical Practice ...................................................................................... 24 
16.3 
Approvals ................................................................................................................................. 24 
16.4 
Other Ethical Considerations ................................................................................................... 25 
16.5 
Reporting ................................................................................................................................. 25 
16.6 
Transparency in Research ........................................................................................................ 25 
16.7 
Participant Confidentiality ....................................................................................................... 25 
17 
FINANCE AND INSURANCE .............................................................................................................. 25 
17.1 
Funding .................................................................................................................................... 25 
17.2 
Insurance ................................................................................................................................. 25 
17.3 
Contractual arrangements ...................................................................................................... 25 
18 
PUBLICATION POLICY ....................................................................................................................... 25 

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19 
DEVELOPMENT OF A NEW PRODUCT/ PROCESS OR THE GENERATION OF INTELLECTUAL 
PROPERTY .................................................................................................................................................... 26 
20 
ARCHIVING....................................................................................................................................... 26 
21 
REFERENCES .................................................................................................................................... 26 
22 
APPENDIX A:  AMENDMENT HISTORY ............................................................................................. 27 
 
1 
KEY CONTACTS 
 
Chief Investigator 
Professor Peter Watkinson 
Associate Professor of Intensive Care Medicine 
University of Oxford 
 
Kadoorie Centre 
John Radcliffe Hospital 
Oxford 
OX3 9DU 
Sponsor 
University of Oxford  
Research Governance, Ethics and Assurance (RGEA),  
Boundary Brook House,   
Oxford,  
OX3 7GB,  
United Kingdom 
Telephone: +44 1865 616480 
Email: ctrg@admin.ox.ac.uk  
Funder(s) 
Oxford Biomedical Research Centre 
Biomedical Research Centre Office Room 4503, Level 4, John Radcliffe 
Hospital Oxford 
Statistician 
Professor Ly-Mee Yu 
Deputy Director and Lead Trial Statistician 
Primary Care Clinical Trials Unit 
Nuffield Department of Primary Care Health Sciences 
University of Oxford 
ly-mee.yu@phc.ox.ac.uk 
01865 617199 
Committees 
• 
Study management group (Prof Simon Stanworth, 
simon.stanworth@msd.ox.ac.uk, 01865 387976) 
• 
PPI - Oxford Blood Group (Dr Catriona Gilmour Hamilton, 
Catriona.GilmourHamilton@ouh.nhs.uk, 01865 226499) 
2 
LAY SUMMARY  
Bleeding affects up to 40% of all trauma patients, up to 30% of all surgery patients and is one of the 
commonest causes of death for women giving birth. The presentation and features of bleeding are 

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different between patients – in some cases bleeding is very obvious to recognise, but in other cases 
bleeding is more “hidden”, for example in the stomach. Bleeding must be stopped promptly to prevent 
severe illness or death.   
Many studies have shown differences in how patients who bleed are treated. There is also variation in 
how individual patients respond to the same treatment, with some patients doing better than others. 
Understanding how variation in practice and patient characteristics affect outcomes will help us design 
and test improvements in care.seconda 
Patients in hospital have regular tests that measure levels of the different types of cells in their blood 
and its ability to clot. For example, a drop in red blood cells can indicate that patients have suffered 
bleeding. More advanced blood tests are available that can provide more detailed information on why 
patients are bleeding and what treatments might be most effective.  
This study aims to develop a real-time, hospital-wide digital system to identify patients in hospital who 
have suffered from bleeding and test whether this system could be used in the future to potentially 
identify patients to recruit into trials of new treatments or blood tests.  
To do this, we will: 
• 
Assemble a panel of experts to identify criteria (for example, specific blood test results and drug 
prescriptions) that could indicate a patient has suffered from bleeding 
• 
Use historical electronic patient records to test how well these criteria identify patients who 
have received treatments for bleeding (blood transfusion)  
• 
Develop and refine a web-based digital system where the most useful criteria can be applied in 
“real-time” to identify bleeding patients 
• 
Test how well the digital platform identifies bleeding patients  
• 
Test whether a significant number of patients identified by the digital platform are willing to 
allow their routine blood samples tested for blood clotting and endothelial factors. 
3 
SYNOPSIS 
Study Title 
RE-BLEED:  A digital platform for identifying bleeding patients: a feasibility study 
Internal ref. no. / short title 
RE-BLEED 
Study registration 
The study will be registered on clinicaltrials.gov 
Sponsor  
University of Oxford  
Funder  
Oxford BRC 
Study Design 
Study incorporating database analysis, cohort observation and laboratory study 
 
Study Participants 
Patients with actual or suspected acquired bleeding  
Sample Size 
Retrospective data 
Up to 1,750,000 patient admissions (up to 10 years of admissions) 
Prospective data 
Up to 87, 500 will be screened by the digital platform to identify those who may 
have bled during the six-month recruitment period. Research nurses will review 

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electronic records of patients with potential bleeding (identified by the digital 
platform), with the aim of gaining consent from at least 50 in the last three 
months of the study. 
Planned Study Period 
1/10/2021 to 31/8/2023 
Planned Recruitment period 
Retrospective data from the period: 
1/3/2011 to 31/8/2022 
Prospective study: 
1/10/2021 to 31/8/2023 
 
Objectives 
Outcome Measures 
Timepoint(s) 
Primary 
 
To test whether a digital 
platform can efficiently 
identify patients who 
have suffered a bleeding 
event and are willing to 
consent for the routine 
blood samples to be 
used in research. 
At least 200 patients 
correctly identified as 
having suffered bleeding, 
of which 40 (20%) 
provide consent  
End of study 
 
 
Secondary 
 
1. To conduct a 
Delphi process 
with an expert 
panel to identify 
criteria that 
could be applied 
in the electronic 
patient record to 
identify patients 
with acquired 
bleeding 
2. To use 10 years’ 
of retrospective 
data to map 
bleeding criteria 
to appropriate 
data fields within 
the electronic 
patient record 
data sources 
3. To encode 
bleeding criteria 
into a real-time 
“algorithm” and 
display results 
within a digital 
web-based 
platform 
4. To measure and 
refine the 
accuracy of the 
algorithm, by 
1. List of bleeding 
criteria 
2. Bleeding criteria 
mapped to 
appropriate data 
fields on the 
electronic patient 
record 
3. Digital platform 
capable of 
identifying bleeding 
patients in real-time 
4. Algorithm accuracy 
before/after 
refinement 
5. List of unique 
challenges faced by 
the laboratory team 
during blood sample 
retention and 
analysis 
6. Numbers of samples 
retained and 
additional blood 
clotting and 
endothelial factor 
results captured 
from the retained 
samples. 
 
 
 
End of study 
 
 
 
 
 
 
 

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manual review of 
free-text notes 
of patients 
identified as 
bleeding  
5. Assess the 
feasibility of 
sample 
sequestering by 
the lab  
6. Assess the 
feasibility of 
performing 
blood clotting 
and endothelial 
factor analysis 
on the 
sequestered 
samples. 
 
 
 
Intervention(s) 
Non-interventional study 
• 
No change to the normal clinical care or treatment of participants.  
Comparator 
None (n/a) 
4 
ABBREVIATIONS 
AVPU 
Alert, Verbal, Pain, Unconscious (description of 
consciousness level) 
APTT 
Activated Partial Thromboplastin Time 
BP 
Blood Pressure 
CAG 
Clinical Advisory Group 
CCRG 
Critical Care Research Group 
CDW 
Clinical Data Warehouse 
CI 
Chief Investigator 
CIS 
Clinical Information System 
CRF 
Case Report Form 
CTRG 
Clinical Trials & Research Governance, University 
of Oxford 
ED 
Emergency Department 
EDTA 
Ethylenediamine tetraacetic acid 
HER 
Electronic Health Records 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GP 
General Practitioner 
HALT-IT 
Haemorrhage ALleviation with Tranexamic acid – 
InTestinal system 
HAT 
Hospital Acquired Thrombosis 
HAVEN 
Hospital Alerting Via Electronic Noticeboard 
HRA 
Health Research Authority 
HTA 
Human Tissue Authority 

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ICD 
International Classification of Diseases 
ICF 
Informed Consent Form 
ICO 
Information Commissioner's Office  
ICU 
Intensive Care Unit 
IR 
Interventional Radiology 
IVC 
Inferior Vena Cava 
JLA 
James Lind Alliance 
MHP 
Major Haemorrhage Protocol 
MICE 
Multiple imputation by chained equations 
NHS 
National Health Service 
NHS API 
NHS Application Programming Interface 
ONS 
Office of National Statistics 
OUH 
Oxford University Hospitals NHS Trust 
PI 
Principal Investigator 
PIL 
Participant/ Patient Information Leaflet 
PPI 
Patient and Public Involvement 
PR 
Pulse Rate 
PT  
Prothrombin Time 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
TARN 
Trauma Audit Research Network 
TXA 
Tranexamic acid 
UKOSS 
United Kingdom Obstetric Surveillance Service 
VTE 
Venous Thromboembolism 
WHO 
World Health Organisation 
WIMM 
Weatherall Institute of Molecular Medicine 
5 
BACKGROUND AND RATIONALE 
What is the health care problem? 
Bleeding is a common cause of poor health as well as death (1).  A recent UK-wide audit showed that 
acquired bleeding is most commonly seen in patients admitted for trauma, obstetric, surgical, and 
gastro-intestinal conditions (2). Bleeding affects up to 40% of all trauma patients, up to 30% of all surgery 
patients and is one of the commonest causes of death for women giving birth (3). However, bleeding is a 
treatable and preventable cause of death (4). A recognised feature of deaths due to bleeding is that they 
often occur soon after bleeding begins, or the patient is admitted to hospital. This emphasises the need 
for timely interventions (5,6). 
Research into acquired bleeding has largely been restricted to clinical trials, focussed on single settings or 
specific groups of patients. For example, the HALT-IT Trial assessed whether treatment with tranexamic 
acid is safe and reduced mortality in patients with gastrointestinal bleeding (7). These studies tend to 
include one clearly defined type of patient with major bleeding and address a single research question. 
This does not permit a broader investigation of variations in treatment and response across different 
settings and different groups. 
Why is research needed?  

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The James Lind Alliance’s (JLA) research prioritising partnerships on blood transfusion, blood donation 
and bleeding rated the “management of major bleeding” as a high priority for future research (8). 
Previous observational studies have revealed considerable variation in treatment and diagnostic testing 
across different settings and causes of major bleeding. This variation may reflect altered physiological 
responses to bleeding, which in turn can be impacted by factors such as the patient’s age (9,10). There is 
also considerable variation in response to specific treatments across the patient population (11). Some of 
this variation will be easy to explain. For example, a young woman bleeding after giving birth will be 
treated differently from an older patient bleeding after surgery. However, patients with similar types of 
bleeding can also receive different treatments. To investigate variations in treatment and individual 
responses requires a detailed understanding of the patient’s condition, and of the timing and nature of 
treatments applied. Moreover, it is likely that some of this variation in practice is due to treatment 
delays and subsequent impact on patient outcomes, alongside inconsistent uptake of research findings 
(12).  
Complications following treatment for major bleeding include thrombotic events (e.g. pulmonary 
embolism), which can impact on the long-term health of patients. For example, it is well recognised that 
trauma and pregnancy are pro-thrombotic conditions, but the balance between bleeding and thrombotic 
risk remains unclear (13). New resuscitation therapies may be defined by different patterns of risk for 
thrombosis (14). Understanding natural variation in thromboprophylaxis treatment (e.g. anticoagulants) 
after major bleeding may help us determine the optimal timing of starting or reintroducing them, 
potentially giving rise to hypotheses to be tested in a clinical trial. 
Aim 
Understanding variation in patients’ response to treatments for bleeding requires large studies. This 
study aims to develop a real-time digital platform, whereby bleeding patients among the whole hospital 
population can be efficiently identified by an algorithm and approached for their consent to participate 
in research studies. The platform will also integrate multiple sources of patient data, from which study 
data sets can be automatically created.  In this feasibility study, we will assess the accuracy of the 
algorithm for identifying bleeding patients and whether a significant proportion (25%) of these patients 
are willing to consent for their data and routine blood samples to be used for research. Once developed, 
the digital platform could be deployed across multiple sites to facilitate efficient identification of 
potential participants for future clinical trials.  
6 
OBJECTIVES AND OUTCOME MEASURES 
 
Objectives 
Outcome Measures  
Timepoint(s) of evaluation 
of this outcome measure (if 
applicable) 
Primary 
To test whether a digital platform 
can efficiently identify patients who 
have suffered a bleeding event and 
At least 200 patients correctly identified 
as having suffered bleeding, of which 40 
(20%) provide consent  
End of study 
 
 

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are willing to consent for the 
routine blood samples to be used in 
research. 
Secondary 
1. To conduct a Delphi process 
with an expert panel to 
identify criteria that could 
be applied in the electronic 
patient record to identify 
patients with acquired 
bleeding 
2. To use 10 years’ of 
retrospective data to map 
bleeding criteria to 
appropriate data fields 
within the electronic 
patient record data sources 
3. To encode bleeding criteria 
into a real-time “algorithm” 
and display results within a 
digital web-based platform 
4. To measure and refine the 
accuracy of the algorithm, 
by manual review of free-
text notes of patients 
identified as bleeding  
5. Assess the feasibility of 
sample sequestering by the 
lab  
6. Assess the feasibility of 
performing blood clotting 
and endothelial factor 
analysis on the sequestered 
samples. 
 
1. List of bleeding criteria 
2. Bleeding criteria mapped to 
appropriate data fields on the 
electronic patient record 
3. Digital platform capable of identifying 
bleeding patients in real-time 
4. Algorithm accuracy before/after 
refinement 
5. List of unique challenges faced by the 
laboratory team during blood sample 
retention and analysis 
6. Numbers of samples retained and 
additional blood clotting and 
endothelial factor results captured 
from the retained samples. 
 
 
 
 
 
End of study 
 
 
 
 
 
 
 
 
7 
STUDY DESIGN 
This study will use both retrospective and prospectively collected data to develop and test an algorithm 
to identify patients in hospital with acquired bleeding.  

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The algorithm will be developed using retrospective data from patients admitted to one hospital over a 
ten year period. The algorithm will be refined using prospective data collected over a three month period 
and its accuracy tested prospectively in the final 3 months of the study. 
In this latter period, we will also assess the feasibility of consenting patients for the sequestering and 
subsequent analysis of their left-over blood samples, for additional tests of blood clotting. 
8 
PARTICIPANT IDENTIFICATION 
8.1 
Study Participants 
In both the retrospective and prospective cohorts, we will screen all adult patients admitted to Oxford 
University Hospitals NHS Foundation Trust for signs of bleeding.  
8.1.1 
Retrospective cohort 
Inclusion Criteria 
• 
Adults aged between 16 and 110  
• 
Admitted to hospital (OUH) or attended the emergency department between 1/3/2011 to 
31/8/2022 
Exclusion Criteria 
• 
Patients who inform us directly that they do not wish their records used in this research study 
• 
Patients who have completed the NHS Opt-out.  
8.1.2 
Prospective cohort 
Inclusion Criteria 
• 
Adults aged between 16 and 110  
• 
Admitted to hospital (OUHFT) or attended the emergency department between 1/10/2021 to 
31/8/2022 
Exclusion Criteria 
• 
Patients who inform us directly that they do not wish their records used in this research study 
• 
Patients who have completed the NHS Opt-out.  
9 
PROTOCOL PROCEDURES  
9.1 
Algorithm development and validation 

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• 
Conduct a modified Delphi process using a panel of clinical experts to identify a set of starting 
criteria (algorithm) e.g. transfusion request or absolute/drop in Hb. In the first instance, we will 
aim to agree broad criteria that maximise the sensitivity of the algorithm. 
• 
The Clinical Data Warehouse (CDW) is a digital resource within the Oxford University Hospitals 
NHS Trust (OUH) that will provide up to 10 years of retrospective anonymised patient data to the 
study. This dataset will comprise demographics and diagnostic/therapeutic codes, hospital 
locations, admission/discharge timings as well as laboratory results, radiology reports, blood 
product usage and operative management and outcomes.  All data will be time-stamped. 
• 
Using this retrospective patient data, we will develop an algorithm by mapping criteria identified 
by the Delphi process to routinely-collected data sources. We will combine these mapped 
criteria into a single algorithm to identify bleeding patients. We will assess its sensitivity to 
identify patients who have received treatments/investigations for bleeding (e.g. urgent 
endoscopy, prescription of tranexamic acid, blood transfusions). We will calculate basic 
demographics (e.g. age, mortality rates) for the patient cohort and compare these to previously 
published data e.g. from the Trauma Audit Network (TARN) audit.  We will also look at how 
individual criteria overlap to see whether we can identify any redundancy in the list of data 
sources. 
• 
Sources of patient data required by the algorithm will be integrated into a “real-time” digital 
platform by processing HL-7 messaging from individual hospital IT systems. This will expand on a 
pre-existing software platform (developed for the HAVEN Study, 
https://ora.ox.ac.uk/objects/uuid:322561c7-866e-4c1e-bcc1-65da4da477fb) which listens to 
hospital wide computer systems, integrating relevant data into a real-time research database. 
• 
Using the real-time database, we will implement the algorithm on a lightweight web interface (R 
Shiny). The interface will include the ability for users to input additional data from the notes 
review (details below). 
• 
Research nurses will use the interface to identify (up to 200) patients who are potentially 
bleeding and review their free-text notes in the electronic patient record, notifying attending 
clinicians when there is no documentation of bleeding. Using the additional clinical information 
in patients’ notes, the nurses will record whether they agree with the output of the algorithm. 
Where the algorithm has incorrectly identified patients as having bled, the nurses will record the 
reasons for bleeding based on the clinical information in the notes.     
• 
The expert panel will review the results of the notes review and refine the algorithm to increase 
its specificity. 
• 
The expert panel will not have any access to confidential patient information. 
9.2 
Consent patients identified by system 
for use of surplus routine blood 
samples in research analysis. 
In the final three months of the study, we will prospectively test the accuracy of the algorithm and the 
feasibility of using the real-time platform for consenting patients to use their data and routine blood 
samples for future research.  
When the algorithm identifies that a patient has met the criteria for bleeding, the platform will: 
• 
Allocate the patient a RE-BLEED study ID. 

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• 
Electronic Hospital Record (EHR) data for this entire encounter will be retained in the study 
database and when the encounter ends the record will be pseudo-anonymised. 
• 
A notification will be sent to the main hospital laboratory requesting that their (left-over) blood 
samples, once all clinical testing has been completed as part of routine clinical care, be retained 
for use in the study, pending patient consent. Where consent is not given, the samples will be 
destroyed as per local protocols. 
 
In order to be able to screen all patients in the hospital, the system must collect data for all adult 
patients from their admission to their discharge. The records of adult patients admitted to the hospital 
who do not meet the eligibility at any point during their admission will be destroyed at the point they are 
discharged from hospital. 
9.3 
Blood sample handling /temporary 
storage and testing 
Following notification by the electronic identification process, left-over EDTA and citrate blood samples 
from potentially eligible patients (which were taken as part of normal clinical care) will be transferred to 
a dedicated `holding area` in the MRC Weatherall Institute of Molecular Medicine (WIMM).  
Prior to consent being sought, all sequestered left-over samples will undergo processing to extend their 
viability for later analysis.  This will occur in the holding area.  The processing will consist of: 
• 
Citrate samples will be spun down and the plasma and buffy coat will be aliquoted off into 
separate tubes  
• 
Any remaining serum from a sample will also be aliquoted off 
Samples will be processed, frozen and retained by the WIMM (The MRC Weatherall Institute of 
Molecular Medicine) laboratory in a dedicated area allocated to only this study. The samples will be 
labelled with the study ID number. Samples will be held (without consent) for a total of 28 days from the 
time they were taken, to maximise the time and opportunity for the study team to formally consent 
patients for use of these samples in the study.  
Members of the study team will liaise with the clinical care team who will approach the patient and if 
appropriate introduce the trained study team member. The study team member will then explain the 
purpose of the study and seek the patient’s consent. If consent is obtained, the laboratory will be 
notified that the sample can retained until the end of the study. If the patient does not consent, the 
laboratory will be notified to destroy the sample in line with local policies. 
If written consent has not been obtained after 28 days from the bleeding episode all samples will be 
destroyed in line with local policies. 
Where consent is provided, plasma samples will be analysed for haemostatic potential using: 
• 
Standard clotting analysis: Prothrombin time (PT) and activated partial thromboplastin time 
(APTT) (if not already performed as part of the clinical care), clot lysis, thrombin generation, 
clotting factor levels and the contributing role of platelet factors. 
• 
Fibrinogen concentration  

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• 
Endothelial cell markers: Thrombomodulin & syndecan-1  
Where possible the tests will be performed on the EDTA and citrate samples to maximise the yield (e.g. 
endothelial markers).  Tests such as those that assess the contributing role of platelet factors, can only 
be performed on the buffy coat aliquots.   
Samples will be destroyed in keeping with standard laboratory practice at the end of the study period 
(unless the patient has provided specific written consent for their samples to be used in future ethically 
approved research).   The results of these tests will be added to the digital study record.  An anonymous 
version of this data maybe used by future studies and this mentioned specifically on the consent form. 
We do not expect the results to be relevant to current or future treatment. However, if an unexpected 
finding is reported, such as an abnormally low level of a clotting factor, the research team will invite the 
participant for review by a senior clinician within the Oxford Haemophilia and Thrombosis Centre. 
9.4 
Consent & patient notification  
This applies to the prospective part of the study. 
9.4.1 
Screening/enrolment 
Permission to screen all patients in the hospital by digitally accessing their confidential health records 
and will be sought from the Confidentiality Advisory Group (CAG).  The justification for requiring access 
to health records without explicit consent is that patients must be identified very rapidly, and at a 
hospital wide scale, making this not practicable to obtain informed consent. 
9.4.2 
Dissent 
Screening for eligibility will occur digitally and the NHS Opt out will be used as a marker of prior patient 
dissent.  Patients who have completed the NHS Opt out will be removed from the screening process and 
all associated data will be destroyed. 
Contact details for study specific dissent / withdrawal will present on the study website, patient 
information sheet and patient facing materials such as posters etc.  Contact details for the study team / 
office will be present on these documents and anyone contacting the study team will be able to request 
for their records to be removed from the study without any effects on their care. 
9.4.3 
Patients with capacity to consent 
Formal written consent will be sought from a subset of patients to analyse surplus clinical blood samples. 
This will be conducted by group of experienced research nurses.   
Patients with the physical and mental capacity to give informed consent will be approached in person 
during the first 28 days following their episode of bleeding and it will be explained to the patient that 
they have already had blood samples sent for storage. It will be made clear that these samples have not 
yet been analysed and that these samples will be destroyed if they do not agree to the samples being 
used.   

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For any patient where a sample was retained with the intent to be used in the study but the patient did 
not regain capacity within 28 days, information will be provided to either a personal or a professional 
consultee for advice about the research use of the sample (see next section).  
After this period has past, if consent has not been obtained, all samples will be destroyed.   
 
Patients or their personal or professional consultee will be provided with: 
• 
RE-BLEED patient information leaflet 
• 
RE-BLEED consent form  
The RE-BLEED study documentation will detail no less than: the nature of the study; what it will involve 
for the participant; the implications and constraints of the protocol; the known side effects and any risks 
involved in taking part. It will be clearly stated that the participant is free to withdraw from the study at 
any time for any reason without prejudice to future care, without affecting their legal rights, and with no 
obligation to give the reason for withdrawal. 
The participant or consultee will personally sign and date the latest approved version of the Informed 
Consent form or Consultee Declaration.  
The participant, or their consultee, will be allowed a maximum of 28 days to consider the information, 
and the opportunity to question the Investigator, their GP, or other independent parties to decide 
whether they will participate in the study.  
Written Informed Consent will then be obtained by means of participant-dated signature (or consultee 
dated signature) and dated signature of the person who presented and obtained the Informed 
Consent/Consultee Declaration. The person who obtained the consent will be suitably trained and will 
have been authorised to do so by the Chief Investigator.  A copy of the signed Informed 
Consent/Consultee declaration will be given to the participant. A copy will be added to the medical 
notes.  The original signed form will be retained at the study site.  

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Figure 1 - Consent flow chart 
9.4.4 
Patients without capacity to consent 
Patients who experience an episode of bleeding may transiently experience a lack of capacity to consent, 
either due to the bleeding itself or the resulting treatment.  Bleeding also occurs in those who already 
lack capacity or in patients who may lose capacity as a result of the event (i.e. trauma with brain injury).   
This is a feasibility study trialling a consent model designed to be used in a subsequent interventional 
trial, of patients during a bleeding episode.  A future trial would include randomisation to an 
intervention, as well as sequestering all available blood samples.  Our consent model must be able to 
include those who lack capacity at the time of bleeding in order to be able to offer an effective future 
intervention.  It is essential that any future study does not exclude those who either had a temporary or 
permanent lack of capacity, as this would both introduce bias into the study but also deprive the most 
vulnerable and severely affected from a chance to participate in a study. 
Capacity to consent to this study, will be assessed by the clinical team looking after the patient and 
confirmed by members of the study team.  For patients lacking capacity, a personal or professional 
consultee will be approached.   
If a personal consultee is not available, a professional consultee will be consulted. For the purpose of this 
study, a professional consultee is defined as a clinician (qualified doctor or registered nurse) with 

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appropriate training (according to local Trust policies) to take on the role of professional consultee. 
Professional consultees must not be directly involved in the patient’s care and cannot be a member of 
the core study team at site.  
If a consultee declines to give consent/advice for the samples and any associated sample data to be 
retained in the study at any stage, his/her wishes will be respected. A consultee is free to withdraw their 
support for continuation in the study at any time.   
Participants where a consultee has been sought will be visited regularly during their admission, including 
just prior to discharge.  If capacity is regained at any point, then informed consent will be sought.  If the 
patient chooses not to provide consent data and samples will be destroyed.  If capacity is not regained, 
then the samples and data will be included in the planned analysis. 
9.5 
Description of study intervention(s), 
comparators, and study procedures 
(clinical) 
This is a non-interventional study. The algorithm within the Digital Platform will identify potential 
patients with acquired bleeding, of any severity. Once the cohort has been identified, they will be 
approached to consent for research use of their surplus clinical sample. 
9.6 
Patient Public Involvement (PPI) 
PPI engagement remains integral to this project. The main ethical issue arising from this study is the use 
of patient information from Oxford University NHS Foundation Trust without consent.  
A virtual PPI meeting was held on 14th December 2020, between the study team and the PPI group 
which included patients who have suffered significant bleeding, their carers, and members of the public.  
The meeting focused on two specific issues relating to consent: a) we explored the acceptability of using 
patient identifiable data in this study without consent and b) the use of personal and nominated 
consultees for advice about  blood samples being stored  and later analysed.  
 
The members of the PPI group recognised that patients who are suffering from acute blood loss are likely 
to require rapid and emergent care. Further, the majority, if not all of the participants we would like to 
enrol in this study will be incapacitated at the time of presentation and routine blood sample collection, 
due to several factors - including in some cases acute circulatory failure or the need for urgent care and 
intubation.  The PPI group unanimously agreed that data collection for this patient group was acceptable 
without consent. They were keen to know that patients would not be identifiable by the data that were 
collected. 
A second question of retaining surplus clinical blood samples for research analysis was also explored. 
Within this study the researchers would like the samples to be retained for them, pending consent from 
the patients. We would then follow a strict consenting protocol (as set out above and which was 
explained to the PPI group) which would involve approaching the patient once they had regained 
competence to provide informed consent, or if this were to not happen to approach a personal 
consultee. Again, there was unanimous agreement within the PPI group that this route of consenting was 
acceptable. We discussed approaching relatives for agreement if a patient died and they were 

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comfortable in general with this, although recognised that a professional consultee could also be used. 
They were accepting of the option of gaining agreement from an independent professional consultee, 
although were clear that this route should be ‘the last resort'.  
The Oxford University Hospitals NHS Foundation Trust patient facing website and privacy notice state 
that "Information may be used for approved research projects. In most instances the information will be 
made anonymous so that you cannot be identified. If this is not possible, we will ask your permission or 
request approval from the Health Research Authority’s Confidentiality Advisory Group. If you are not 
happy with information about you being used in research projects, please speak to your clinical team”. 
We commit to ongoing PPI/PPIE involvement throughout the lifecycle of the study. 
9.7 
Early Discontinuation/Withdrawal of 
Participants 
During the course of the study a participant may choose to withdraw at any point. 
The patient information sheet and study website will all carry contact details for the study team.  
According to the design of the study, participants may have the following two options for withdrawal: 
• 
Withdrawal from screening: Data will be destroyed from the study database 
• 
Withdrawal of consent obtained in prospective recruitment:  Data will be destroyed from the 
study database and the samples destroyed (if applicable). 
 
9.8 
Definition of End of Study 
The end of study is the point at which all the study data has been entered and queries resolved. 
10 SAFETY REPORTING 
This is a non-interventional study and at no point will clinical care be modified or affected by the study. 
11 STATISTICS AND ANALYSIS 
The statistical aspects of the study are summarised below. A statistical analysis plan (SAP) that will be 
available from the time that the last participant is recruited. The SAP will be finalised before any analysis 
takes place. 
11.1 Description of the Statistical Methods  
11.1.1 The plans for the statistical analysis of the study are outlined below. assessed using descriptive 
statistics. Variables 
The following variables will be extracted for each patient admission in the retrospective and prospective 
cohorts: 

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• 
Laboratory data 
o Biochemistry/haematology/transfusion/coagulation data 
• 
Demographics 
o Age, sex, type/site of bleeding 
• 
Prescriptions on admission and through hospital stay 
o Anti-platelets, anti-coagulants etc. 
• 
Vital signs 
o Blood pressure, heart rate, temperature, respiratory rate, level of consciousness 
(AVPU/GCS), oxygen therapy, sedation (if applicable) 
• 
Procedures as treatments for bleeding: 
o Surgery/Interventional radiology/need for massive transfusion/haemostatic 
agents/tranexamic acid/uterotonics if obstetric 
o Treatments for VTE 
• 
Prevention (to include IVC filter) 
• 
Treatments 
o If treated pre-hospital, any features of monitoring (e.g. blood pressure) and time from 
injury to arrival in hospital and interventions (such as tranexamic acid or fluid infusion or 
blood transfusion). 
• 
Blood sample data / laboratory feedback 
o Number of blood samples successfully retained 
o Number of additional clotting data points obtained via testing the retained samples 
o Challenges faced by the laboratory team during sample retention 
11.1.2 Descriptive statistics 
We will calculate summary statistics (e.g. demographics,  treatments, mortality,) for both the 
retrospective and prospective cohorts identified by the algorithm.  
For continuous variables we will use the median/interquartile range; for binary or categorical variables 
we will use the proportion. Confidence intervals for proportions were calculated using the Pearson-
Klopper method. We will be able to make compare event rates with previously published data (UK, USA, 
Europe). 
11.1.3 Retrospective cohort 
As part of algorithm development we will perform additional analyses on the retrospective cohort. These 
will include exploring specific subgroups (obstetric, gastro-intestinal, emergency surgery, trauma) and 
examining treatment rates (e.g. rates of tranexamic acid use in post-partum haemorrhage). Results of 
these more detailed analyses will be compared with previously published data and current clinical 
guidelines. 
11.2 Sample Size Determination  
11.2.1 Retrospective data 

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The retrospective database will contain up to 1,750,000 patient admissions over ten years (based on an 
estimate of 175,000 admissions to Oxford University Hospitals NHS Foundation Trust each year). 
11.2.2 Prospective data 
Up to 87,500 records will be screened by the digital platform to identify those who may have bled over 2 
three-month periods.  
In the first three-month period, research nurses will review electronic records of patients with bleeding 
(identified by the algorithm), we estimate around 250 will experience a bleeding event. Assuming the 
algorithm has a sensitivity of 80%, we plan to review 200 electronic records. 
In the second three-month prospective period, research nurses will approach patients for consent. Based 
on the assumption that 200 patients will also be identified by the algorithm in this period, we will aim for 
at least 40 (20%) of patients to consent to their participation. 
We will assess the efficacy of the sample retention process being used by the study.  This will include the 
number of samples successfully retained, the number of additional clotting laboratory resulted gained 
from these samples and any feedback from the laboratory staff regarding challenges they faced. 
11.3 Analysis populations 
Analysis population will be based on all the evaluable data collected as far as possible.  Any subgroups 
that will not be included in the analysis will be prespecified in the statistical analysis plan with 
justification. 
11.4 Decision points 
There are no decision points in this feasibility study.  
11.5 Stopping rules 
Formal stopping rules are not considered appropriate for this observational study.  A main consideration 
for terminating the study would be an inability of the iteratively refined algorithm to correctly identify 
patients with bleeding. All results would be reviewed by the study management team, who would make 
the ultimate decisions to stop the study.  
11.6 The Level of Statistical Significance 
 The level of statistical significance will be at 5% (2-sided). 
11.7 Procedure for Accounting for Missing, 
Unused, and Spurious Data. 
We will use multiple imputation to impute missing covariates (e.g.  using the Multivariate Imputation by 
Chained Equations (MICE) algorithm). 

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11.8 Procedures for Reporting any 
Deviation(s) from the Original 
Statistical Plan 
Any deviations from the analysis plan with justification will be reported in the statistical report. 
12 DATA MANAGEMENT 
This study requires access to large numbers of confidential health care records in order to identify the 
cohort of interest. 
12.1 Data sources 
Source documents are where data are first recorded, and from which participants’ CRF data are 
obtained. These include, but are not limited to, hospital records (from which medical history and 
previous and concurrent medication may be summarised into the CRF), clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence. 
CRF entries will be considered source data if the CRF is the site of the original recording (e.g. there is no 
other written or electronic record of data).  All documents will be stored safely in confidential conditions. 
On all study-specific documents, other than the signed consent, the participant will be referred to by the 
study participant number/code, not by name. 
12.2 Data transfer and analysis 
All study data will be encrypted using AES-256 and transferred using either the secure file download 
service of the OUH or the OUH Citrix environment. Whilst stripped of all direct identifiers, it will still be 
considered controlled official sensitive data. This is because it will still contain multiple indirect 
identifiers such as date/time stamps. These are required for the correct analysis of the data (see data 
dictionary for justification). The data will be transferred on encrypted media chaperoned by a member of 
the study team from the participating site to the Critical Care Research Group based in Oxford. Here the 
data will be loaded onto specialist secure hardware held and maintained by the group. This system is 
referred to as a Data Safe Haven and is a secure computing environment which is designed to store and 
analyse complex datasets in a manner that is safe and secure. It conforms to NHS Digital Security Toolkit 
and Cyber Essentials Plus accreditation. The environment is designed so that patient level data never 
leaves the environment. 
12.3 Data recording and record keeping  
All study records apart from consent form/consultee declaration will be electronic, and their generation 
is detailed above.  
The participants will be identified by a unique study specific number in any database.  The name and any 
other identifying detail will NOT be included in any study data electronic file. 
The ledger(s) that link the source Clinical Information System (CIS) data and the unique study specific 
number will be held by the Oxford University Hospital NHS Trust and destroyed at the end of the study 
period.  Written CRFs will be kept for those patients that provide consent.  CRFs will be generated for 

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those who are not approached to give consent (and only contribute anonymised data into the study).  
These written CRFs will be stored in a dedicated storage facility and retained for a minimum of 5 years 
after the end of the study in keeping with current MRC guidance.  Personal data such as contact details 
that could identify a participant will be destroyed as soon as it is practical to do so and no later than 12 
months after the end of the study. 
12.4 Access to data 
Direct access will be granted to authorised representatives from the Sponsor and host institution for 
monitoring and/or audit of the study to ensure compliance with regulations.   
13 QUALITY ASSURANCE PROCEDURES  
The study may be monitored, or audited in accordance with the current approved protocol, GCP, 
relevant regulations and standard operating procedures.  
13.1 Risk assessment   
This study is an observational study that does not interact with patients or influence their care. No 
formal risk assessment will be performed.  This study requires access to a large number of confidential 
patient records.  
To mitigate the risk of identification of individual patients in the database and the risk of data loss we will 
undertake the following precautions:  
• 
All records will be accessed and pseudo-anonymised at the participating site, using a dedicated 
computer that will conform to NHS information security standards.   
• 
Only pseudonymous patient data will be transferred via secure/encrypted method to the 
coordinating centre (e.g. Critical Care Research Group (CCRG), Nuffield Department of Clinical 
Neurosciences, Oxford University).  
• 
Data will be held inside the groups `Data Safe Haven` which will conform to the same NHS 
standards of information security and cyber security.  
• 
Only pseudonymous data will be held by the CCRG.  
13.2 Study monitoring   
All study team members will be fully trained in Information Governance, data protection and 
confidentiality. The study may be monitored, or audited in accordance with the current approved 
protocol, GCP, relevant regulations and standard operating procedures.  
13.3 Study Committees  
13.3.1 Study Management Group 
Comprising of all the researchers and representative from the PPI group, chaired by Prof Simon 
Stanworth (CI). 

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13.3.2 PPI Group 
The Oxford Blood Group is Chaired by Dr Catriona Gilmour Hamilton, Haematology Quality Manager: 
Patient Experience and Engagement, PPI Co-ordinator, (Churchill Hospital, Old Road, Headington. Oxford 
OX3 7LE) 
14 PROTOCOL DEVIATIONS  
A study related deviation is a departure from the ethically approved study protocol or other study 
document or process (e.g. consent process or administration of study intervention) or from Good Clinical 
Practice (GCP) or any applicable regulatory requirements. Any deviations from the protocol will be 
documented in a protocol deviation form and filed in the study master file. 
15 SERIOUS BREACHES 
A “serious breach” is a breach of the protocol or of the conditions or principles of Good Clinical Practice 
which is likely to affect to a significant degree – 
 (a) the safety or physical or mental integrity of the trial subjects; or 
(b) the scientific value of the research. 
In the event that a serious breach is suspected the Sponsor must be contacted within 1 working day. In 
collaboration with the C.I., the serious breach will be reviewed by the Sponsor and, if appropriate, the 
Sponsor will report it to the approving REC committee and the relevant NHS host organisation within 
seven calendar days.  
16 ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki.  
16.2 Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant regulations and with 
Good Clinical Practice. 
16.3 Approvals 
Following Sponsor approval, the protocol, informed consent form, participant information sheet and any 
proposed advertising material will be submitted to an appropriate Research Ethics Committee (REC), 
Confidentiality Advisory Group (CAG) and HRA, and host institutions for written approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 

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16.4 Other Ethical Considerations 
If an unexpected finding is reported from the laboratory sample analysis, the participant will be invited 
to attend a clinic appointment at the Oxford Haemophilia and Thrombosis centre to discuss the finding 
further.  
16.5 Reporting 
The CI shall submit once a year throughout the study, or on request, an Annual Progress report to the 
REC Committee, HRA (where required) host organisation, Sponsor, and funder (where required). In 
addition, an End of Study notification and final report will be submitted to the same parties.  
16.6 Transparency in Research  
This type of study does not lend itself to registration, but the study team will aim to provide information 
through a publicly accessible protocol paper describing the aims and methods.  
16.7 Participant Confidentiality 
The study will comply with the UK-General Data Protection Regulation (UK-GDPR) and Data Protection 
Act 2018, which require data to be anonymised as soon as it is practical to do so. The processing of the 
personal data of participants will be minimised by making use of a unique participant study number only 
on all study documents and any electronic database(s) and the case report form (CRF).  The consent form 
will hold study number, name and participant initials.     All documents will be stored securely and only 
accessible by study staff and authorised personnel. The study staff will at times safeguard the notice of 
participants’ personal data. 
17 FINANCE AND INSURANCE 
17.1 Funding 
This study is funded by the NIHR Biomedical Research Centre for “A data science platform and biobank to 
rationalise the investigation and treatment of major bleeding” (Application number: BRCRCF20-08) 
17.2 Insurance 
The University has a specialist insurance policy in place which would operate in the event of any 
participant suffering harm as a result of their involvement in the research (Newline Underwriting 
Management Ltd, at Lloyd’s of London).  NHS indemnity operates in respect of the clinical treatment that 
is provided. 
17.3 Contractual arrangements  
Appropriate contractual arrangements will be put in place with all third parties.  
18 PUBLICATION POLICY 

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The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and 
any other publications arising from the study.  Authors will acknowledge that the study was funded by 
NIHR Biomedical Research Centre. Authorship will be determined in accordance with the ICMJE 
guidelines and other contributors will be acknowledged. 
19 DEVELOPMENT OF A NEW PRODUCT/ PROCESS OR THE GENERATION OF INTELLECTUAL 
PROPERTY  
Ownership of IP generated by employees of the University vests in the University.  The University will 
ensure appropriate arrangements are in place as regards any new IP arising from the trial.  
20 ARCHIVING 
At the end of the study, electronic files containing the anonymised retrospective and prospective study 
datasets will be stored and retained in the CCRG, (University of Oxford) on secure severs (referred to as 
the Data Safe Haven).  This environment stores data in a manner that it can be securely analysed without 
removing or copying the data from its systems.  The data will remain here for at least 5 years in keeping 
with the MRC Research Framework.  After the archiving period has ended, the paper documents and 
electronic files will be confidentially and securely destroyed in line with University of Oxford guidelines. 
21 REFERENCES 
1.  
World Health Organization. World Health Statistics. Monitoring health. 2019;  
2.  
National Comparative Audit of Blood Transfusion. Audit of the Management of Major 
Haemorrhage. 2018.  
3.  
Say L, Chou D, Gemmill A, Tunçalp Ö, Moller A-B, Daniels J, et al. Global causes of maternal death: 
a {WHO} systematic analysis. Lancet Glob Heal [Internet]. 2014 Jun;2(6):e323--e333. Available 
from: https://doi.org/10.1016%2Fs2214-109x%2814%2970227-x 
4.  
Roshanov PS, Eikelboom JW, Sessler DI, Kearon C, Guyatt GH, Crowther M, et al. Bleeding 
Independently associated with Mortality after noncardiac Surgery ({BIMS}): an international 
prospective cohort study establishing diagnostic criteria and prognostic importance. Br J Anaesth 
[Internet]. 2021 Jan;126(1):163–71. Available from: https://doi.org/10.1016%2Fj.bja.2020.06.051 
5.  
Stanworth SJ, Davenport R, Curry N, Seeney F, Eaglestone S, Edwards A, et al. Mortality from 
trauma haemorrhage and opportunities for improvement in transfusion practice. Br J Surg 
[Internet]. 2016 Feb;103(4):357–65. Available from: https://doi.org/10.1002%2Fbjs.10052 
6.  
Gayet-Ageron A, Prieto-Merino D, Ker K, Shakur H, Ageron F-X, Roberts I, et al. Effect of treatment 
delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-
analysis of individual patient-level data from 40{\hphantom{,}}138 bleeding patients. Lancet 
[Internet]. 2018 Jan;391(10116):125–32. Available from: https://doi.org/10.1016%2Fs0140-
6736%2817%2932455-8 
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Roberts I, Shakur-Still H, Afolabi A, Akere A, Arribas M, Brenner A, et al. Effects of a high-dose 24-
h infusion of tranexamic acid on death and thromboembolic events in patients with acute 
gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-
controlled trial. Lancet [Internet]. 2020 Jun;395(10241):1927–36. Available from: 
https://linkinghub.elsevier.com/retrieve/pii/S0140673620308485 

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8.  
Shapiro S, Stephensen D, Camp C, Carroll L, Collins P, Elston D, et al. The top 10 research priorities 
in bleeding disorders: a James Lind Alliance Priority Setting Partnership. Br J Haematol [Internet]. 
2019 Apr;186(4). Available from: https://doi.org/10.1111%2Fbjh.15928 
9.  
Heffernan DS, Thakkar RK, Monaghan SF, Ravindran R, Adams CA, Kozloff MS, et al. Normal 
Presenting Vital Signs Are Unreliable in Geriatric Blunt Trauma Victims. J Trauma Inj Infect Crit 
Care [Internet]. 2010 Oct;69(4):813–20. Available from: 
https://doi.org/10.1097%2Fta.0b013e3181f41af8 
10.  
Brown JB, Gestring ML, Forsythe RM, Stassen NA, Billiar TR, Peitzman AB, et al. Systolic blood 
pressure criteria in the National Trauma Triage Protocol for geriatric trauma. J Trauma Acute Care 
Surg [Internet]. 2015 Feb;78(2):352–9. Available from: 
https://doi.org/10.1097%2Fta.0000000000000523 
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https://doi.org/10.1093%2Fbja%2Faex100 
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we compare and how might the {NHS} improve? BMJ [Internet]. 2018 Jul;k3036. Available from: 
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Bellomy ML, Engoren MC, Martin BJ, Shi Y, Shotwell MS, Hughes CG, et al. The Attributable 
Mortality of Postoperative Bleeding Exceeds the Attributable Mortality of Postoperative Venous 
Thromboembolism. Anesth Analg [Internet]. 2021 Jan 14;132(1):82–8. Available from: 
https://doi.org/10.1213%2Fane.0000000000004989 
14.  
Makhoul T, Kelly G, Kersten B, Nadler M, Zammit CG, Jones CMC, et al. Incidence of 
thromboembolic events following administration of four-factor prothrombin complex 
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Oct;194:158–64. Available from: https://doi.org/10.1016%2Fj.thromres.2020.06.028 
 
22 APPENDIX A:  AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
Version 
No. 
Date issued Author(s) of changes 
Details of Changes made 
N/A 
2 
6/10/21 
Robert Hatch and study 
team 
• 
Added a dissent 
section 
• 
Added further 
justification for 
consultee consent 
Non 
Substantial 
Amendment 1 
3 
22/11/2021 Robert Hatch 
• 
Added study specific 
sentence to dissent 
section 
Substantial 
Amendment 1 
4 
11/01/2022 Robert Hatch 
• 
Extended study 
timeframe 

RE-BLEED Protocol – Version 5 – 15/08/2022 
 
Clinical Research Protocol Template 
Form SP-01-i V15.0, 13 Aug 2019  
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2019  
Page 28 of 28 
Substantial 
Amendment 2 
5 
15/08/2022 Robert Hatch 
• 
Extending study 
timeframe