Megakarocyte and Platelet Biology and Genomics

"Platelets are the smallest cell in the blood and are important in stopping bleeding. One hundred billion platelets are made daily from stem cells in the bone marrow (BM). The process of platelet production is highly controlled by our genes so that total platelet count, as well as the volume and the clotting function of each platelet are constant over time in each individual. All three parameters however are variable in the population at large. Platelet count and volume can be measured with an automated machine, but the measurement of their function is complex. The proposed programme of research has three main objectives. 1. To discover genes that control the count, volume, and function of platelets and to develop a simpler method to measure the latter: This is relevant for the care of two particular groups of NHS patients. The first group concerns cancer patients with a low number of platelets and who require the transfusion of donor platelets. We wonder whether platelets obtained from donors with hyper-active platelets are a poorer treatment. We will test this in a clinical study in cancer patients. The second group concerns patients who have undergone an operation to unblock an artery of the heart to reduce their risk of a heart attack. For a year following the operation patients take tablets that inhibit the function of their platelets. Each year about 2,000 of the 70,000 patients, who undergo this operation, experience a major bleed because their platelets are inhibited too much. We hope that the new genetic and function tests can be used to better predict who will be at risk of a bleed and the number of tablets can then be modified. 2. Producing platelets in the laboratory: Patients with a shortage of platelets are treated with transfusions of platelets to reduce the risk of bleeding. These platelets are isolated from the blood of donors and every day about 1000 donors visit a NHSBT clinic to donate their platelets. We would like to replace donor platelets with platelets derived from adult stem cells. Researchers in Cambridge have succeeded in generating clones of stem cells and even have mastered the tricks to generate cells for a specific tissue, i.e. cells for the liver. We now wish to determine the conditions that are needed in the laboratory to produce platelets from stem cells. 3. Inherited platelet disorders: In some families platelets may not function well, or their number and volume may not be correctly regulated. This may cause severe bleeding in some, but not all patients. It is highly likely that these platelet disorders are caused by a rare difference in the DNA code that is rather unique to every family. A new technique to read the DNA code faster than was previously possible has been developed by Cambridge researchers. We will apply this technique to discover the differences in the DNA code that are responsible for the platelet disorders. This knowledge can then be used in the NHS to improve the diagnosis of platelet disorders using a simple DNA-based test."