Plain English Summary
Background and study aims
This study aims to understand why certain patients bleed excessively. We look at the following groups of patients:
1. Patients with mild bleeding who have been seen by a blood specialist who feels their symptoms could be due to a problem in the platelets (clinically diagnosed platelet defects)
2. Patients who have unexpectedly heavy periods with no obvious cause
3. Patients with lifelong low platelet counts in the blood with no known cause
For these populations we suspect that there may be a problem in small cells in the blood, known as platelets, but we are not certain that this is the case. This study is using new and more specialist tests in an attempt to confirm that there is a problem in platelets in these groups and to use this information to help identify the gene or genes that cause this problem.
Who can participate?
Patients aged under 85 with a platelet disorder of unknown cause
What does the study involve?
Participants are asked questions about their medical history and complete a bleeding questionnaire. Participants are also asked to give a sample of blood (between 10–50 ml). The blood sample is usually be taken at a local Haematology Clinic, ideally early in the day so that the analyses can be carried out on the same day. Depending on the results of the tests, participants may be asked to give blood on up to three further occasions. This is to carry out different types of tests on the platelets and therefore find out more information on the problem. This can be taken either during a ‘regular’ visit to the Haematology Clinic/surgery or through a specific appointment. There is a minimum of one month between the dates that the blood is taken and no upper time limit on the gap between the donations. The blood samples are sent to research laboratories in Birmingham and/or Sheffield for analysis of the platelets. A frozen sample is also kept for a maximum of 10 years, which may be used to look for gene defects that could cause the platelet problem or changes in blood proteins that may increase your chance of bleeding. The sample is destroyed at this time, or earlier if requested. The sample may be kept for this length of time in the event that we are unable to find a problem with your genes in the first set of investigations. It is possible that, as we gain more knowledge, the sample is investigated at later times to find a gene defect that may be the cause of the bleeding problem.
What are the possible benefits and risks of participating?
The study will generate important information on possible defects in the platelets and may also identify the genes that are responsible for the defects. The identification of a defect in your platelets may influence clinical treatment. If a gene defect is found, it will be possible to investigate whether one or more members of the participant’s family have the same gene defect, should they wish.
Where is the study run from?
University of Birmingham (UK)
When is the study starting and how long is it expected to run for?
December 2010 to September 2020
Who is funding the study?
1. British Heart Foundation (UK)
2. Wellcome Trust (UK)
Who is the main contact?
Dr Neil Morgan
N.V.Morgan@bham.ac.uk
Trial website
Contact information
Type
Scientific
Primary contact
Dr Neil Morgan
ORCID ID
http://orcid.org/0000-0001-6433-5692
Contact details
Institute of Cardiovascular Sciences
College of Medical and Dental Sciences
University of Birmingham
Birmingham
B15 2TT
United Kingdom
+44 (0)121 414 6820
N.V.Morgan@bham.ac.uk
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
9858
Study information
Scientific title
Mild bleeding disorders caused by platelet defects: a non-randomised observational study
Acronym
Genotyping and platelet phenotyping (GAPP)
Study hypothesis
It is becoming increasingly recognised that platelet function disorders are heavily under diagnosed and therefore under researched. Several factors have contributed to this including:
1. The absence of a gold standard point-of-care assay of platelet function
2. The generally asymptomatic presentation of patients with mild defects in platelet function who only exhibit symptoms of excessive bleeding when subject to an appropriate challenge such as surgery or severe injury
3. The considerable redundancy in the pathways underlying platelet activation such that a single gene defect may not be sufficient to give rise to excessive bleeding (but may become clinically important under challenging conditions)
4. The limited amount of mRNA that can be recovered from the anucleate platelet which severely hampers many standard approaches in molecular biology including use of microarrays.
The Birmingham Platelet Group has an approach to gene mapping of platelet disorders based on initial evaluation of clinical and laboratory phenotypes of patients with clinically diagnosed bleeding disorders and subsequent targeted gene sequencing.
In this project, we intend to investigate populations of patients enriched for bleeding to test the hypothesis that a proportion of patients who present with excessive bleeding have a previously unrecognised impairment in platelet function which may explain their propensity to bleed in conditions which would not normally be associated with severe bleeding. The proposed research will use a combination of platelet phenotyping and targeted gene sequencing approach to identify candidate mutations underlying platelet dysfunction. The effect of a small number of missense mutations on protein function will be investigated through expression studies in immortalised cell lines.
Publications relevant to the study:
1. 2009 results in: http://www.ncbi.nlm.nih.gov/pubmed/19237732
2. 2010 results in: http://www.ncbi.nlm.nih.gov/pubmed/19828703
3. 2010 review in: http://www.ncbi.nlm.nih.gov/pubmed/20162250
Ethics approval
West Midlands Research Ethics Committee, original approval date 10/08/2006, substantial amendment AM 2/1 approved on 06/12/2010
Study design
Non-randomised observational study
Primary study design
Observational
Secondary study design
Non randomised controlled trial
Trial setting
Other
Trial type
Diagnostic
Patient information sheet
Not available in web format, please use contact details to request a patient information sheet
Condition
Non-malignant haematology
Intervention
Assessment of bleeding history
1. By medical questionnaire
2. Assessment: Laboratory testing for defect, extended aggregometry, flow cytometry, protein expression studies and DNA sequencing for platelet genes
Intervention type
Other
Phase
Not Applicable
Drug names
Primary outcome measure
Identification of defects: End of project 2016, aim to identify on a molecular basis platelet defects which cause bleeding
Secondary outcome measures
No secondary outcome measures
Overall trial start date
31/12/2010
Overall trial end date
30/09/2020
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Patients, aged 0 - 85 years, either sex
2. Diagnosed with a platelet disorder of unknown cause
3. Willing to participate and able to provide informed consent
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 800; UK Sample Size: 800
Participant exclusion criteria
1. Patients taking drugs that are known to influence platelet function, including nonsteroidal anti-inflammatory drugs (NSAIDs) including COX-2 selective anti-inflammatory drugs), aspirin, clopidogrel, dipyridamole, warfarin or acenocoumarol within 7 days of enrolment
2. Patients having undergone a major surgical procedure within 1 month of enrolment
3. Patients with chronic renal failure requiring dialysis
4. Patients with a platelet count outside the 100 000 to 450 000/µL range
5. Patients with severe anaemia (haemoglobin < 8g/dl)
Recruitment start date
31/12/2010
Recruitment end date
30/09/2020
Locations
Countries of recruitment
United Kingdom
Trial participating centre
University of Birmingham
Birmingham
B15 2TT
United Kingdom
Trial participating centre
25+ referring centres
-
United Kingdom
Funders
Funder type
Charity
Funder name
British Heart Foundation
Alternative name(s)
BHF
Funding Body Type
private sector organisation
Funding Body Subtype
Trusts, charities, foundations (both publically funded and privately funded)
Location
United Kingdom
Funder name
Wellcome Trust
Alternative name(s)
Wellcome
Funding Body Type
private sector organisation
Funding Body Subtype
international
Location
United Kingdom
Results and Publications
Publication and dissemination plan
To be confirmed at a later date
Intention to publish date
30/09/2021
Participant level data
Not expected to be available
Basic results (scientific)
Publication list
2013 results in: http://www.ncbi.nlm.nih.gov/pubmed/23809206
2014 results in: http://www.ncbi.nlm.nih.gov/pubmed/24408324
2014 results in: http://www.ncbi.nlm.nih.gov/pubmed/24618131
2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/26280575
2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/25556537
2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/25567036
2017 results in: http://www.ncbi.nlm.nih.gov/pubmed/28762630
Publication citations
-
Results
Lowe GC, Lordkipanidzé M, Watson SP, , Utility of the ISTH bleeding assessment tool in predicting platelet defects in participants with suspected inherited platelet function disorders., J. Thromb. Haemost., 2013, 11, 9, 1663-1668, doi: 10.1111/jth.12332.
-
Results
Lordkipanidzé M, Lowe GC, Kirkby NS, Chan MV, Lundberg MH, Morgan NV, Bem D, Nisar SP, Leo VC, Jones ML, Mundell SJ, Daly ME, Mumford AD, Warner TD, Watson SP, , Characterization of multiple platelet activation pathways in patients with bleeding as a high-throughput screening option: use of 96-well Optimul assay., Blood, 2014, 123, 8, e11-22, doi: 10.1182/blood-2013-08-520387.
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Results
Dovlatova N, Lordkipanidzé M, Lowe GC, Dawood B, May J, Heptinstall S, Watson SP, Fox SC, , Evaluation of a whole blood remote platelet function test for the diagnosis of mild bleeding disorders., J. Thromb. Haemost., 2014, 12, 5, 660-665, doi: 10.1111/jth.12555.
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Results
Fletcher SJ, Johnson B, Lowe GC, Bem D, Drake S, Lordkipanidzé M, Guiú IS, Dawood B, Rivera J, Simpson MA, Daly ME, Motwani J, Collins PW, Watson SP, Morgan NV; UK Genotyping and Phenotyping of Platelets study group, SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects, J Clin Invest, 2015, 125, 9, 3600-3605, doi: 10.1172/JCI80347.
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Results
Leo VC, Morgan NV, Bem D, Jones ML, Lowe GC, Lordkipanidzé M, Drake S, Simpson MA, Gissen P, Mumford A, Watson SP, Daly ME; UK GAPP Study Group, Use of next-generation sequencing and candidate gene analysis to identify underlying defects in patients with inherited platelet function disorders, J Thromb Haemost, 2015 , 13, 4, 643-650, doi: 10.1111/jth.12836.
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Results
Jones ML, Norman JE, Morgan NV, Mundell SJ, Lordkipanidzé M, Lowe GC, Daly ME, Simpson MA, Drake S, Watson SP, Mumford AD1; UK GAPP study group, Diversity and impact of rare variants in genes encoding the platelet G protein-coupled receptors, Thromb Haemost, 2015, 113, 4, 826-837, doi: 10.1160/TH14-08-0679.