NIHRDataInsights/HRCSData huggingface dataset:
Title: Lusutrombopag and avatrombopag for Thrombocytopenia (severe, chronic liver disease, surgery) [ID1520]
Funder: Department of Health and Social Care

Abstract: To systematically review the effectiveness and estimate the cost effectiveness of avatrombopag versus lusutrombopag versus established clinical management without avatrombopag and lusutrombopag (including, but not limited to platelet transfusion) for people with thrombocytopenia associated with chronic liver disease needing an elective procedure.

Lay abstract: Thrombocytopenia is characterised as a reduction in the number of circulating platelets within the blood. Platelets come from megakaryocytes in the bone marrow. They play a critical role in haemostasis, a process which causes bleeding to stop. Thrombocytopenia can generally be classified on the basis of the platelet count in the blood. It is usually defined as a platelet count of less than 150 x 109 per litre of blood. Thrombocytopenia is a common complication in people with chronic liver disease either as a direct result of the liver pathology or a consequence of interferon-based antiviral therapy. While mild to moderate thrombocytopenia rarely causes bleeding during procedures including liver biopsy or liver transplantation, severe thrombocytopenia increases the risk of excessive bleeding during and after surgery and can have a significant impact on the clinical management of chronic liver disease. It can delay or prevent the start of appropriate therapy leading to increased morbidity and mortality and a reduced quality of care. The prevalence of thrombocytopenia in people with chronic liver disease varies from 15% to 70% depending on the stage of liver disease and differences in platelet count cut-off used to define thrombocytopenia. Between 2016 and 2017, Hospital Episode Statistics showed 27,927 admissions with liver disease in England.(1) There are currently no licensed treatment options in the UK for treating thrombocytopenia in people with chronic liver disease requiring surgery. Therapies include stimulation of megakaryocyte maturation and platelet production. Treatment for severe thrombocytopenia can include platelet transfusion, splenic artery embolisation and surgical splenectomy. The purpose of this report is to systematically review the effectiveness and estimate the cost effectiveness of avatrombopag and lusutrombopag versus established clinical management without avatrombopag and lusutrombopag and compared with each other for people with thrombocytopenia associated with chronic liver disease needing an elective procedure. Reference: [1] NHS Digital. Hospital Episode Statistics admitted patient care England 2016-17 [Internet]. London: NHS Digital, 2017 [accessed 21.11.18] Available from: https://digital.nhs.uk/data-and-information/publications/statistical/hospital-admitted-patient-care-activity/2016-17

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: BLOOD
Title: A Device for the removal of circulating autophagic vesicles in patients with sickle cell disease
Funder: Wellcome Trust

Abstract: Sickle Cell Disease(SCD) is the commonest inherited genetic disorder in the UK with 14,000 patients and over 300 affected children born annually. There are three disease modifying treatments available, hydroxyurea, blood transfusion and stem cell transplant. Of these, transfusion is the mainstay of preventative treatment. However, there are frequent clinical situations where transfusion would be recommended but blood is not available in sufficient quantity on a regular basis or not available at all. Ninety percent of patients with SCD worldwide live in the developing world where there is no safe and freely available access to blood. Consequently, there is a need for a novel therapy that does not require donated red cells. Professor David Anstee proposes a novel technology to address this need. Recent work in his laboratory at NHS Blood and Transplant in Bristol has shown that a critical step in the formation of normal red blood cells involves the removal of membranous vesicles containing waste products from immature red cells when the cells pass through the spleen. Patients with SCD lose the function of their spleen very early in life and as a consequence vesicles cannot be removed and remain in their blood. The vesicles that are retained in the peripheral circulation likely contribute to the pathology of SCD. Professor Anstee and colleagues are developing a device to selectively remove these vesicles from the blood of patients with SCD and anticipate that patients undergoing this treatment will enjoy a dramatic improvement in their quality of life.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: BLOOD
Title: Two tier protection and metabolic genotoxicity during blood production
Funder: Medical Research Council

Abstract: We investigate how cells and organisms repair highly toxic DNA interstrand crosslinks. In the human inherited illness Fanconi’s anaemia the repair of DNA crosslinks fails, causing developmental defects, bone marrow failure, and marked cancer predisposition. Over the last 5 years our research has made important contributions in understanding how the FA genes promote crosslink repair; how the biochemical regulation of the FA repair pathway works; how the new genes identified function in this pathway; and the creation of mouse models which revealed that an in vivo role of the FA pathway working together with aldehyde dehydrogenases protects against endogenous genotoxic aldehydes (two-tier protection). In the future, our research plans will build on these foundations. We wish to define the molecular and genetic basis of the repair of DNA crosslinks caused by known mutagens and endogenous aldehydes. We want explain how aldehyde mediated DNA damage corrupts development and causes carcinogenesis. Finally, our discoveries have shown that the two-tier protection mechanism against endogenous aldehydes is crucial for stem cell maintenance. We want to better understand how this protection mechanism is regulated within stem cells, and the physiological consequences when it fails.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD
Title: Haematopoietic stem cell fitness mechanisms
Funder: Medical Research Council

Abstract: Multipotent self-renewing haematopoietic stem cells (HSCs) are essential for human health and the curative potential of HSC transplantation therapies. I joined the MRC Molecular Haematology Unit (MHU) in April 2021 to investigate mechanisms regulating HSC activity and to apply this knowledge to improve therapies for haematological diseases. The specific aim of my research programme is to define mechanisms regulating HSC fitness. High fitness HSCs display durable and balanced blood system reconstitution activity. By contrast, low fitness HSCs have weak or biased activity and are thought to contribute to various pathologies, particularly age-associated haematopoietic diseases and complications following HSC transplantation. However, our understanding of what determines HSC fitness is still incomplete. Additionally, despite increasing interest in the clinical applications of ex vivo cultured HSCs for cell and gene therapies, our knowledge of HSC fitness in the context of ex vivo expansion is still poorly developed. Within this programme, we plan to undertake: (1) A candidate-based approach to investigate epigenetic regulators of HSC fitness. We recently identified several epigenetic factors as novel regulators of HSC expansion potential and now aim to better understand how these novel epigenetic factors regulate HSC activity and fitness. With collaborators in the MHU, I will investigate the roles of these epigenetic regulators through molecular, cellular, and functional assays. These studies aim to improve our understanding of how HSC fitness is regulated at the epigenetic level. (2) A screening-based approach to identify novel mechanisms of HSC fitness. With HSC experts within the MHU, we will perform genetic and small molecule screening to identify key factors and pathways regulating HSC fitness and identify new strategies to improve ex vivo HSC expansion and manipulation. Together, this research programme aims to provide novel insights into HSC biology and to help develop next-generation HSC therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: MICA: Hydroxyurea - Pragmatic Reduction In Mortality and Economic burden (H-PRIME)
Funder: Medical Research Council

Abstract: H-PRIME will be a phase III 2x2x2 factorial randomised partially placebo-controlled trial. We aim to conduct a policy changing trial to address three key interventions that could make a substantial difference to the lives of children born with sickle cell anaemia (SCA) in low-income regions in sub-Saharan Africa. H-PRIME will answer all three questions efficiently in a single clinical trial. We will recruit 1800 children with confirmed SCA at three sites in Eastern Uganda who will be randomised to: (1) daily oral hydroxyurea vs placebo; (2) enhanced antimalarial prophylaxis with monthly dihydroartemisinin-piperaquine (DHA-PQP) vs standard of care (SOC) (monthly sulphadoxine-pyrimethamine, SP) (open-label) and (3) enhanced antimicrobial prophylaxis with daily co-trimoxazole (CTX) AND twice-daily penicillin V throughout childhood vs SOC (twice-daily penicillin V until the age of 5 years; open-label). A 3-month pre-treatment screening and observation period will allow diagnostic confirmation of SCA status and the collection of baseline data on clinical event rates, laboratory variables and potential confounders. The primary outcome the hydroxyurea randomization will be death from any cause. The primary outcome for the anti-malarial randomisation will be malaria-associated hospitalisation while for the antibiotic randomisation it will be hospital admission (all-cause, due to the challenges in diagnosing bacterial infections as above). Assuming recruitment over 2 years, a maximum 4 years of follow-up, 10% loss to follow-up at 4 years and mortality in the control arm of 2.6/100CY (i.e. 10% cumulative mortality at 4 years, H-PRIME will provide 90% power to detect a 50% relative reduction for hydroxyurea vs placebo. The study will provide 86% power to detect a 36% relative reduction from 4.7 to 3.0 malaria-associated hospitalisations/100CY respectively and 87% power to detect a 20% relative reduction from 20 to16 all-cause hospitalisations/100CY respectively.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: BLOOD
Title: Developing human model cellular systems for studying Red Blood Cell diseases and as screening platforms
Funder: Medical Research Council

Abstract: Thalassemia syndromes and sickle cell disease (SCD) represent a significant global health problem and financial burden to health services. Studying these diseases is severely impeded by paucity of suitable and adequate quantities of material from patients, and lack of suitable cell lines. Mouse models of the diseases are therefore routinely used for biological studies and drug evaluation, but fundamental differences exist between mouse and human erythropoiesis. New approaches and human systems for these disorders are therefore essential. We have recently created 1) the first immortalised adult human erythroid cell line (BEL-A) that recapitulates normal erythropoiesis, expresses normal levels of adult globin, terminally differentiates and enucleates to generate mature reticulocytes, providing a sustainable supply of cells we have extensively characterised 2) a platform for CRISPR genome editing of BEL-A cells, creating sublines with single or multiple gene edits. We now have opportunity to exploit these tools and technologies to create lines as human model cellular systems of RBC diseases, providing a sustainable and reproducible supply of cells for study. Disease mutations will be introduced into BEL-A cells via CRISPR. We aim to create a range of beta and alpha thalassemia lines with mutations associated with different disease severity, and a SCD line. Such a compendium of lines for a disease will also help determine variability in disease mechanisms, as well as evaluation of drugs etc across spectra of phenotypes. Importantly all lines will have a constant genetic background, and the same as the founder line, negating the many experimental variables between patient samples Lines will undergo extensive characterisation using a wide range of approaches both to validate disease phenotype and to provide a data resource to facilitate application of the lines by ourselves and others, including comparative proteomics to also identify novel dysregulated proteins.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD
Title: Control of blood cell emergence by YAP and environmental cues
Funder: Medical Research Council

Abstract: The haematopoietic system is maintained throughout adult life by haematopoietic stem cells that produce a constant supply of all blood cells. In the clinic, these stem cells are the cells which upon transplantation successfully restore the blood system in a range of disease. One major limitation to the use of blood stem cell transplantation in the clinic is the restricted availability of compatible donor for graft recipients. The possibility to generate these blood stem cells in vitro for clinical purposes would significantly advance the use of this curative treatment. Pluripotent stem cells can be efficiently differentiated in vitro to form all blood progenitors but researchers are still struggling to generate blood stem cells. Here we propose to investigate how the mechanotransducer YAP might regulate the emergence of blood cells from hemogenic endothelium during embryonic development. Through gain and loss of function, we will determine how changes in YAP activity impact the generation of blood progenitors upon the in vitro differentiation of embryonic stem cells. Additionally, we will determine whether cellular responses to change in environmental cues, such as adhesiveness, are controlled by YAP. Flow cytometry, time lapse imaging and clonogenic assays will be used to determine the outcome of the culture upon changes in the microenvironment and YAP activity level. This knowledge will allow us ultimately to more precisely control and manipulate biophysical properties for the design of artificial niches to generate blood stem cells usable in the clinic.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD
Title: Switching mammalian genes on and off during development, lineage specification, and differentiation, and its impact on human genetic disease
Funder: Medical Research Council

Abstract: This programme addresses a key question in biomedical research: how are genes switched on and off during development, lineage commitment, differentiation and maturation? To date we know that this involves the three fundamental regulatory elements of the genome: enhancers, promoters and boundary elements. Here we investigate how these elements interact to regulate gene expression in three-dimensional space and time. To address this, we study how the human and mouse alpha-globin multi-gene clusters are switched on and off as haematopoietic stem cells differentiate into mature erythroid cells. Past lessons from studying globin gene expression have elucidated many of the general principles underpinning our understanding of mammalian gene regulation. Using newly developed synthetic biology, and proteomics approaches, together with new experimental models, the unanswered questions we address here are: how do promoters and enhancers come into close physical contact; how do enhancers interact specifically with their cognate promoters; what specifically does the enhancer bring to the promoter and how does this alter the transcription cycle; what is the role of CTCF binding sites in this process? While elucidating the normal process of gene regulation we will also examine how this process is perturbed in human genetic diseases. Studying globin gene disorders has elucidated many general principles underlying human genetic disease. While some single gene disorders are known to result from mutations in promoters and enhancers, it seems likely that variations in gene expression underlying complex diseases and variable human traits mainly affect the regulatory landscape. Our programme will address in detail, how changes in intergenic DNA may influence gene expression. Finally, we are using this information to develop new approaches to regulating gene expression via genome editing in pre-clinical and eventually clinical studies by manipulating haematopoietic stem cells


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD
Title: Counteracting hematopoietic ageing by pharmacological inhibition of TGFbeta and IL-6 signaling
Funder: Medical Research Council

Abstract: Ageing of the hematopoietic system is associated with declining erythropoiesis and lymphopoiesis, leading to decreased adaptive immunity and frequent anemia, together contributing to multiple age-related morbidities, including cognitive decline, decreased muscle strength, cardiovascular problems and susceptibility to infection. Using an unbiased approach to the identification of changes to the aged bone marrow microenvironment we identified the IL-6 and TGFbeta signalling pathways as up-regulated. We found that TGFbeta signaling plays a key role in sustaining increased HSC platelet priming in aged mice, as pharmacological inhibition of TGFbetaR1 lead to decreased HSC numbers and strong depletion of HSC platelet priming. Importantly, this was accompanied both by increased lymphoid priming of MPPs and rebalancing of HSC output in competitive repopulation assays, indicating that TGFbetaR1 inhibition provides a means to improve lymphopoiesis in aged hematopoiesis. In the present proposal we will measure the stability of the rebalancing of HSC lineage output after TGFbetaR1 inhibitor withdrawal, as well as the ability of TGFbetaR1 inhibition to improve the output of naïve, antigen-responsive lymphocytes. In addition, we observed that both IL-6 and TGFbeta signalling contributed to the age-dependent decrease in erythropoiesis: inhibition of IL-6 using a neutralising antibody reversed the age-dependent decline in erythroid progenitor function, whereas TGFbetaR1 inhibition improved erythroid progenitor output. We will therefore now test the ability of combined IL-6 and TGFbetaR1 inhibition to improve erythropoiesis, and in particular to restore peripheral blood hemoglobin levels, as this is the key parameter correlated to age-related multimorbidity. These studies will determine if TGFbetaR1 and IL-6 inhibition has therapeutic potential in aged hematopoiesis, and since drugs targeting these pathways are available, the potential for clinical application.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD
Title: The role of the endothelium in traumatic coagulopathy.
Funder: Medical Research Council

Abstract: As a clinician specialising in bleeding disorders, and as the Chair of the Major Haemorrhage Committee, I have seen how important it is to develop effective treatments for trauma-related-haemorrhage. Mortality associated with major bleeding is high and the lack of understanding of how coagulopathy develops in patients with uncontrolled bleeding underpins the lack of effective treatments. Aim: to understand the pathophysiology of acute traumatic coagulopathy, with a focus on the endothelial/coagulation interface. Objective 1: To critically evaluate the effects of thrombomodulin (TM) in vitro on key clotting factors in trauma coagulopathy using two dynamic haemostasis assays. Objective 2: To develop an endothelial model of trauma coagulopathy using blood outgrowth endothelial cells (BOECs). Objective 3: To investigate the effects of thrombomodulin on thrombus formation using the BOEC trauma model under flow conditions. I will set up a study to collect blood and plasma samples from 20 healthy volunteers and from 2 members of a family with a known THBD variant. I set up the ACIT-2 study in Oxford in 2010 and with my ongoing oversight it continues to recruit patients. Detailed clinical data and linked plasma samples have been collected according to the REC approved study protocol. All studies will comply and follow the Codes of Practice issued by the Human Tissue Authority. The dynamic real time haemostasis assays, and the ELISA tests will be conducted at the Oxford Haemophilia and Thrombosis Centre using existing resources. The BOEC work, in both static and flow conditions, will be completed within Professor Choudhury's laboratory within the Division of Cardiovascular Medicine, Oxford University using existing resources. Outcomes: My goal is to develop a robust 'trauma endothelial' model which will form the basis for future work exploring the key endothelial drivers of trauma coagulopathy and which will lead on to the testing of potential therapeutic targets.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD
Title: Improving cardiovascular outcomes in polycythaemia by risk stratification and targeted therapy.
Funder: Medical Research Council

Abstract: Thrombosis remains the major cause of morbidity and early mortality in JAK2 positive polycythaemia (PV). Preventative strategies are based on two RCTs which showed benefit of low-dose aspirin and venesection to maintain haematocrit <0.45. Patients considered at higher thrombosis risk are given additional cytoreductive therapy (hydroxyurea or interferon) with recognised side-effects, and with limited evidence of benefit for thrombotic risk. This collaboration brings together a national clinical expert in thrombosis, with a strong interest and background in laboratory haemostasis research, with internationally recognised scientific and clinical leaders in PV. A sub-study will be added to a large RCT of ruxolitinib against standard cytoreduction for treatment of high risk PV to prospectively measure state of the art biomarkers of platelet, endothelial and coagulation activation (baseline and after 6 months of treatment). The pattern of biomarkers will be analysed and correlated with clinical events. Additional work will be undertaken on a smaller number of samples (both before and after treatment) to study the mechanisms of thrombotic risk; testing the hypothesis of the central role of NETosis, triggered by activated platelets, in driving thrombosis. Planned techniques: ELISAs for biomarkers, flow cytometry for markers of platelet and neutrophil activation and platelet-neutrophil interactions; NETosis to various stimuli by MPO/DNA ELISA, and by immunofluorescence and microscopy techniques. This proposal will establish a set of biomarkers to improve thrombotic risk stratification, and improve mechanistic understanding, leading to personalised, targeted therapy to reduce thrombosis risk in PV. It will also be highly relevant for other conditions in which NETs have been implicated in thrombosis, including cancer and inflammatory/autoimmune conditions.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: BLOOD