Our team applies statistical and computational methods to discover new genes and molecular mechanisms that control platelet life and function in health and disease. We translate this knowledge into the clinic by developing comprehensive and cost effective DNA tests to improve the diagnosis of inherited bleeding and platelet disorders. Finally, we integrate our findings from the gene discovery efforts and from various genome annotation assays to define the networks of protein-protein interactions and of gene regulation that underpin the lineage commitment and maturation of blood progenitors along the platelet lineage.
The INTERVAL study is a randomised controlled trial (RCT) in up to 50,000 NHS Blood and Transplant whole-blood donors recruited at the 25 donation centres across England (http://www.blood.co.uk/). Over a period of two years, participants will be randomised to give blood either at their usual donation intervals or more frequently. Current practice is to invite men and women to give whole blood every 12 and 16 weeks, respectively. During INTERVAL men will be randomised to donate every 12, 10 or 8 weeks and women every 16, 14 or 12 weeks. At the end of the study, we will compare the amount of blood donated and assessments of well-being between the different study groups.
The study’s main objectives are to determine:
- the optimum interval between donations, for men and women, that maximizes blood supply without unacceptably increasing iron deficiency/anaemia and its potential complications;
- if blood donation intervals can be tailored to donors on the basis of demographic, haematological, genetic and lifestyle factors.
During the course of the study, additional blood samples will be taken for a full blood count and storage of plasma, serum and DNA. These will be used to measure biomarkers as well as genetic factors. Online questionnaires regarding health, lifestyle and cognitive function will also be collected. A subset of participants will take part in a study of the impact of donation interval on physical activity levels.
ThromboGenomics (TG) is a working group of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH). The TG project currently includes 59 members from various countries with different areas of expertise.
The TG project has the following key activities:
- To develop and validate a next-generation sequencing (NGS) platform for the DNA-based diagnosis of rare inherited bleeding and platelet disorders (BPD).
- To identify and annotate pertinent BPD genes and variation in these genes to clinical standards.
- To develop and maintain a database to provide a stable and sustainable frame of reference for sequence variation information.
- To develop and apply Human Phenotype Ontology (HPO) terms to patients with BPDs.
According to the United Kingdom National Database for inherited BPDs (UKHCDO), more than 20% of patients affected by bleeding disorders do not have a definitive diagnosis. These cases include platelet function defects and unclassified bleeding disorders, for which the current laboratory tests are not sufficient to establish the genetic causes. There are no accurate data on the prevalence of inherited disorders of the count, volume and morphology of platelets, where there is no bleeding. The TG project aims to overcome this problem of undiagnosed cases using NGS technologies. A NGS platform has been developed and validated to screen in parallel about 69 genes known to be causative of BPDs. The DNA-based test will be affordable and is therefore expected to become a part of the routine diagnostic algorithms for BPDs. To this purpose, the TG working group is in the process of depositing information about all known BPD genes in a single publicly accessible reference database of DNA sequence thereby complementing the existing single gene databases.
Key people: Dr Ilenia Simeoni, Professor Willem Ouwehand.
Key people: Dr Roger James