Title: Study of brain Magnetic Resonance Imaging (MRI) scans to assess bleeding risk in children with immune thrombocytopenia (ITP-low platelet count)
Funder: Department of Health and Social Care

Abstract: Research Question: Do children with immune thrombocytopenia (ITP) have cerebral micro-bleeds (CMBs)? Can they be predicted and do they affect cognitive function or health-related quality of life (HRQoL)? Background: Children with ITP have low platelets due to autoimmune destruction and reduced production. ITP increases bleeding risk, with potentially devastating consequences if intracranial. However, most children have mild disease that resolves spontaneously1. For this reason UK guidelines recommend observing children with ITP unless bleeding overtly3. This has resulted in fewer patients exposed to treatment, but there is little data evaluating the safety and impact of this approach. Patients with ITP often have petechiae associated with thrombocytopenia and we hypothesised that these may be occurring in the brain parenchyma. Using advanced susceptibility weighted MRI (SW-MRI) methods we identified occult CMBs in 43% of thrombocytopenic adults with ITP14. Studies in other disorders have associated CMBs with impaired cognitive function13. This has not been evaluated in thrombocytopenic children. Aim/Objectives: We propose performing SW-MRI brain scan to establish whether CMBs are seen in children with ITP and, if present, whether they impact on cognitive function and HRQoL. We will assess whether biomarkers can predict CMBs and stratify these patients for intervention. Methods: 100 children with ITP will undergo a non-sedated SW-MRI scan. Images will be analysed using a semi-automated programme to detect CMBs and overseen by a Neuroradiologist. Number, size and location of CMBs will be correlated with potential risk factors e.g. platelet count/disease duration, to stratify a severe phenotype. We will perform validated cognitive testing and compare to age/education-matched normative data in patients with and without CMBs. In addition, we will assess HRQoL and fatigue scores to assess other impacts of CMBs. Patients with CMBs will be offered Thrombogenomic testing (commercial platform sequencing genes for variants in bleeding/platelet disorders) to assess other correlates to CMBs and bleeding.Timelines: In the first 18months I will recruit patients and oversee SW-MRI scans alongside performing cognitive testing, bleeding scores, HRQoL and fatigue questionnaires. I will have training on genomic medicine and arrange Thrombogenomics in patients with CMBs and analyse results.Interim analysis will be performed after 20 patients. This will ensure we are appropriately targeting patients to study. During the second 18 months, I will collate and analyse the biological/clinical biomarkers with scan results and present findings. Anticipated Impact/Dissemination: I anticipate this research will change patient management strategies. If no CMBs are identified, this will ratify the current treatment strategy. We will disseminate this to countries with higher treatment rates. If it identifies CMBs, it will allow stratification of patients with severe phenotypes who would benefit from treatment. It will also provide valuable information regarding cognition and HRQoL which have not been extensively investigated in these patients. If SW-MRI allows patient stratification and CMBs have a clinically important effect on brain function we plan to set-up a UK-wide prospective study to incorporate SW-MRI into treatment pathways for childhood ITP. We will disseminate our results in high impact factor journals, the UK ITP Forum and ITP Support Association.

Lay abstract: Aims: The aim of this study is to establish whether children with immune thrombocytopenia (ITP) have small bleeds in the brain. If small bleeds are identified, we will see whether these can be predicted, and whether they are affecting the patient's health. Background: ITP is a disease where the immune system mistakenly destroys the patient's platelets. Platelets are essential for blood clotting, so having reduced numbers leads to increased risk of bleeding. Bleeding can have devastating consequences, especially in the brain. When ITP is diagnosed in childhood, it often resolves spontaneously, but this can take many months1. Current guidelines in the UK recommend conservative management, and only those with obvious signs of bleeding are treated3. While this approach leads to reduced toxicity from treatment, it also means some children with milder bleeding are untreated with unknown effects on health in addition to more frequent appointments and tests for monitoring. There is also potential for heightened anxiety about bleeding risks, leading to avoidance of physical activities. Patients with ITP often have tiny bleeds in the skin called petechiae (like small red dots). We propose investigating whether there is a similar phenomenon in the brain. In our study in adults with ITP we found that 43% of patients have small bleeds in the brain14. We wish to investigate if this is also occurring in children, and whether this affects their life. Design and Methods: 100 children aged 8-18yrs old with ITP will undergo a brain scan using special magnetic resonance imaging (MRI) to see if there are small bleeds that would not be detected on a normal scan. They will not require any sedation. Furthermore MRI is extremely safe and involves no radiation. We will compare the presence of any bleeds with other results to see whether we can predict which patients are most likely to bleed and which would benefit from more active treatment. Patients will also complete cognitive (brain performance) testing e.g. memory skills, to see if these bleeds affect the way the brain functions and we will assess health-related quality of life using a questionnaire designed for children with ITP. We believe patients will be helped by this research because it will inform more specific decision-making around management, ensuring appropriate treatment and also avoiding unnecessary treatment. If our study shows bleeds, we will use this special MRI scan in UK-wide treatment pathways. If no bleeding is seen, patients and parents can be reassured that monitoring whilst awaiting spontaneous resolution is a proven safe approach for the majority of patients. Patient and Public Involvement: We discussed the project with a cohort of children and their parents. For the majority of families, the most difficult aspect of ITP is worrying about whether the child is going to bleed and anxiety over taking treatment. They were enthusiastic about this study and have helped with the development of our protocol, including advising DVDs to watch during the scan. They reviewed age-appropriate participant information sheets and consent/assent forms, and recommended alterations in wording. We are holding a patient involvement day in February 2019 to inform children and parents about the progress of the study and discuss any issues which may have arisen. We have formed a trial steering group to help as the trial progresses. Dissemination: We will circulate our results with publications in important scientific journals, newsletters of the ITP Support Association and the UK ITP forum and at our annual patient involvement day. The ITP Support Association has an Instagram account with ~1000 followers and we can utilise this for communicating our results and future studies.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: BLOOD;INFLAMMATORY AND IMMUNE SYSTEM