Modernising the diagnosis of mucocutaneous bleeding disorders: next generation sequencing of novel loci associated with platelet dysfunction.

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Mild and moderate bleeding disorders are relatively common and much more prevalent than severe bleeding disorders such as haemophilia. Because the symptoms are usually of mucocutaneous bleeding such as nosebleeds and menorrhagia, they are frequently attributed to defects of primary haemostasis: in particular abnormalities of platelet function. This is often supported by abnormalities of platelet function in laboratory tests. However, although platelet function testing is complicated and laborious, it has a limited ability to identify or to exclude, specific defects in platelet function. In addition this approach to testing will not identify alternative or additional causative factors in the vascular wall or other blood components. As a consequence many of these patients may receive inappropriate or unnecessary treatment, usually platelet transfusions, which are a scarce resource.An alternative approach to detecting and diagnosing defects in platelets and other vessel or blood components that may be defective is to detect the defects at the genetic level. Hitherto this would have been a prohibitively difficult and expensive undertaking. Technological advances over the last few years have made it possible to rapidly and cheaply sequence the entirety of an individual's expressed genes in days. This therefore provides a very comprehensive analysis of the individual genes. It is important to note that this approach does not require any understanding or assumptions about platelet physiology or their interaction with other tissues. In this study we propose to identify patients with mild bleeding disorders who are attending clinics at the Hammersmith Hospital and subject them to genetic analysis. This analysis will be performed at the Wellcome Trust Sanger Institute near Cambridge. Sequencing of all expressed segments of the human genome will generate an enormous amount of information. Careful analysis will be required to identify those changes that are likely to be of significance in determining the clinical problems from which the patients suffer. These analyses will be carried out in conjunction with computer experts who have already analysed the results of the genetic analysis of thousands of healthy individuals that can be used for the purpose of comparison. Finally, when candidate genetic changes have been identified it will be necessary to prove that they are capable of producing the clinical phenotype of interest. The last part of this training fellowship will therefore entail reproducing the candidate genetic changes in experimentally produced platelets or other systems and examining cultured platelet producing cells, which have been derived from patients with bleeding disorders, to determine whether any critical aspects of platelet function or production can be reproduced. I therefore expect to become proficient in three different but complementary areas: clinical and laboratory assessment of patients with bleeding disorders, performance and analysis of high throughput genetic analysis and in vitro manipulation and analysis of platelet production and function. The skills and competencies gained during the fellowship will allow me to become one of the future experts in the application of modern DNA-based tests in the NHS and beyond. I also foresee that new insights gained from the proposed study will eventually lead to new treatments for patients with bleeding disorders, which are better tailored on basis of the genetic cause of their disorder or for patients with heart attacks or strokes. The latter seems counter-intuitive that by investigating patients with bleeding disorders better and safer drugs for the treatment of the Number 1 killer diseases in our society may be developed. However platelet-driven clot formation is in part the cause of heart attacks and strokes.