Characterisation of the United Kingdom thrombotic thrombocytopenic purpura (TTP) patient cohort

Lead Research Organisation: University College London
Department Name: Haematology

Abstract

Thrombotic thrombocytopenic purpura (TTP) is an acute, sudden onset, life threatening illness, affecting females: males 3:1, typically 30-40 years, but can present at any age between birth and 80 years. The true incidence is unknown, but values of 4-6/million of the population are quoted. Von Willebrand Factor (vWF) with platelets acts to prevent bleeding. VWF is broken down by ADAMTS 13. ADAMTS 13 is missing in TTP. This results in widespread, small vessel thrombosis, affecting all organs, but a variable clinical phenotype. The main treatment is plasma exchange, the removal on a special cell separator machine, of blood plasma and replacement with large volumes of donor plasma, which is a replenishing source of ADAMTS 13.

The South East (SE) England TTP group have identified TTP subgroups. Cases of congenital TTP, in adults and children require individually based treatment programmes depending on their clinical phenotype. The majority of cases are acquired idiopathic TTP, the majority ( 90%) have antibody, mainly IgG, against ADAMTS 13 and prevent its action. Patients with recurrent or unresponsive TTP episodes were treated with Rituximab, a monoclonal antibody against B-lymphocytes, important in antibody formation. With standard therapy (plasma exchange and steroids) patients have had excellent responses clinically, increases in ADAMTS 13 enzyme levels, decrease in IgG antibody levels and significantly reduced relapses. Approximately 15% of cases have defined precipitating causes, such as HIV, pregnancy or pancreatitis. Some pregnancy cases present as adult congenital TTP and HIV patients require antiretroviral therapy with plasma.
The aim of the grant is to organise a UK wide TTP registry, to determine the incidence, important epidemiological data regarding patient characteristics and mortality/morbidity in different areas. Baseline ADAMTS 13 assay, repeated in remission, to define if specific antibody levels are associated with related clinical characteristics. Further work on other antibody subtypes/groups within a larger cohort may highlight characteristics in patients not evident from clinical presentation, such as risk of relapse. DNA analysis, in all cases, to determine if mutations or polymorphisms in the ADAMTS 13 gene may be responsible for precipitating subtypes of TTP, or alter responsiveness to therapy. Ultimately, randomised clinical trials, to improve time to remission, by turning off the thrombotic process and improve mortality, using monoclonal antibody therapy. Genetically engineered ADAMTS 13 will be available for congenital TTP.

Technical Summary

Thrombotic thrombocytopenic purpura (TTP) is an acute life threatening disorder. It typically affects females between 30-40 years, but can present from birth to 80 years. TTP results from a deficiency of the enzyme ADAMTS 13, required for the cleavage (on secretion) of von Willebrand Factor (VWF) converting it from ultra large (ulVWF) molecular forms with excessive platelet reactivity, to normal forms. Lack of ADAMTS13 results in platelet clumping and multi-organ microvascular thrombosis, with resultant clinical sequelae. Identification and treatment is the key to survival; without therapy mortality is 90%; with plasma exchange mortality is 15-20%. Plasma is a source of the missing/dysfunctional enzyme, ADAMTS 13, and plasma exchange using cell separators allows large volumes to be given as well as assisting in removal of ulVWF and ADAMTS13 antibodies. The majority of cases are acquired idiopathic (antibody mediated), but congenital TTP (identified in childhood or adults) and TTP secondary to other conditions make up 20% of all cases. We have presented a local, non-funded, observational, South East England TTP registry, but want to extend this throughout the UK. The aim is to gather important epidemiological information about patient characteristics, mortality/morbidity and treatment availability in the UK. After a review of this data, we the aim to extend multicentre trials to all centres treating TTP. The availability of recombinant ADAMTS13 (rADAMTS13) will be assessed for congenital TTP cases, who would be more easily identified from a UK registry. The adaptation of therapy to individual phenotypes will not only serve to assess the efficacy of rADAMTS 13, but prevent long term sequelae of no treatment. Statistically powered, randomised, controlled trials can only be undertaken when an appropriate cohort of patients are available. It is imperative to attain remission as quickly as possible in acute episodes to prevent long term morbidity or mortality. As idiopathic autoimmune TTP accounts for the majority of the cases, this will be the other primary focus using monoclonal antibody therapy (directed against autoantibody production). Assessment of the baseline and remission ADAMTS13 levels via central analysis will provide more information on the importance of antibody titres and epitope specificity in relation to precipitation of disease. Involving all UK sites and cases will provide a large DNA bank for analysis of ADAMTS13 gene mutations/polymorphisms and allow their importance in the risk of TTP subtypes to be assessed. Ultimately, this will improve the scope of treatment for patients with this devastating disease.

Publications

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Alakbarzade V (2018) Utility of current thrombophilia screening in young patients with stroke and TIA. in Stroke and vascular neurology

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Blombery P (2014) Management of thrombotic thrombocytopenic purpura: current perspectives. in Journal of blood medicine

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Brown JH (2012) Postpartum aHUS secondary to a genetic abnormality in factor H acquired through liver transplantation. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

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Crowley MP (2018) More on Ofatumumab for TTP. in The New England journal of medicine

 
Description BCSH guidelines on TTP na dthrombotic microangiopathies
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact Improved understanding of TTP and TMAs has increased the diagnosis of these disorders
 
Description NHS England specialist commissioning
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact The policy is aimed at ensuring equity of standards in England, associated with reduced mortality and reduced relapse rates. Aim to go live 2019
 
Description Octaplas data
Geographic Reach North America 
Policy Influence Type Participation in advisory committee
Impact Use of a safer plasma product to Canada for TTP patients
 
Description Presenting Octaplas data
Geographic Reach North America 
Policy Influence Type Participation in advisory committee
Impact use of double viral inactivated plasma, which is safer, to the USA for TTP
 
Description SPECIALIST CENTRES IN TTP
Geographic Reach National 
Policy Influence Type Citation in systematic reviews
Impact confirmed reduction in morbidity and a reduction in mortality from 40%-<10% in 12 months
 
Description aHUS action
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact raised awarenedss of aHUS and leading to presentation of complement inhibitors as therapy
 
Description british society of haematology-obstetric group
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact presentation x 2 (2012 and 2010 ) of data on congenital TTP-late onset-in pregnancy, management and frequency
 
Description educational talks
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact up to date management of conditions, influencing diagnosis and treatment
 
Description highly specialist national commissioning for ttp
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact development of regional centres with equality of care, based on UCLHs model, aiming to improve patient outcomes re morbidity and mortality and prevent relapse
 
Description local and national talks to increase awaremess of TTP
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Improved awareness in TTP, such that it is now recognised as an acute emergency that needs to be excluded, not only in haematology, but also in other specialities eg medicine, renal and intensive care. The output is the increased number of acute cases, real or suspected which the registry is capturing
 
Description national commissioning of ttp
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact implementation of our local model to england and ultimately the UK to provide regional specialist centres, with improvement in mortality, relapse rates and ensure availability of 24/7 care
 
Description ADAMTS 13 assays
Amount £40,000 (GBP)
Organisation Alexion Pharmaceuticals 
Sector Private
Country United States
Start 06/2013 
End 05/2014
 
Description Project grant
Amount £141,800 (GBP)
Organisation TTP Foundation 
Sector Charity/Non Profit
Country Canada
Start 09/2016 
End 08/2019
 
Description Unrestricted educational grant
Amount £20,000 (GBP)
Organisation Alexion Pharmaceuticals 
Sector Private
Country United States
Start 04/2012 
End 04/2013
 
Description Unrestricted educational grant
Amount £25,000 (GBP)
Organisation Octapharma 
Sector Private
Country Switzerland
Start 09/2012 
End 08/2013
 
Description clinical research training fellowship
Amount £204,778 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2010 
End 03/2013
 
Description non surgical
Amount £230,000 (GBP)
Organisation Baxter 
Sector Private
Country United States
Start 08/2014 
End 08/2015
 
Description project grant
Amount £398,931 (GBP)
Organisation Baxalta Inc 
Sector Private
Country United States
Start 12/2017 
End 11/2020
 
Description project grant
Amount £196,924 (GBP)
Funding ID PG/15/103/31900 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2016 
End 03/2019
 
Title ADAMTS 13 antigen assay 
Description elisa based assay, previously difficult to develop, in collaboration with belgian colleagues, using a protype assay. Methodology published in blood journal, and its benefit is towards understanding pathophysiology and prognostic significance 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? Yes  
Impact as above 
 
Title Anti-ADAMTS13 Ab domain specificity 
Description Developed novel assays to determine domain specificity of anti A13 antibodies 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Ability to determine which regions of ADAMTS13 are targeted by antibodies and potential to correlate with outcome 
 
Title FLOW CHAMBER BASED ASSAY FOR DEGREE OF THROMBUS FORMATION IN CONGENITAL TTP + TREATMENTS 
Description DESCRIBES SUBACUTE THROMBOSIS DESPITE NORMAL PLATELET COUNTS PLUS THE EFFECT OF TREATMENT. A POTENTIAL FOR USE AS A BIOMARKER 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2018 
Provided To Others? No  
Impact BIOMARKER 
 
Title FRETS assay 
Description FRETS technlogy has resulted in assays within 2 hours rather than 3 days. Fully validated and comparable to previous assays 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact quicker assay times 
 
Title GWAS 
Description GWAS and bioinformatics in immune TTP 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2018 
Provided To Others? No  
Impact IDENTIFICATION OF A NEW PROTEIN INVOLVED IN THE PATHOGENESIS OF TTP 
 
Title UK TTP Registry and DNA bank 
Description Identification of a number of late onset congenital cases related to pregnancy 
Type Of Material Biological samples 
Provided To Others? No  
Impact treatment protocols in subsequent pregnancies have been identified/developed on the basis of all the cases submitted via the registry-largest cohort internationally 
 
Title complement assays 
Description using samples from the registry and other research groups, reviewing the role of complement and cytokines in TTP , other TMAs and allied medical disorders 
Type Of Material Technology assay or reagent 
Year Produced 2011 
Provided To Others? Yes  
Impact understanding of role of complement in specific disease states 
 
Title congenital TTP cases 
Description cases with TTP, identified as congenital 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2011 
Provided To Others? Yes  
Impact awaiting start of phase I trial of recombinant ADAMTS 13 in congenital TTP 
 
Title factor H assay 
Description In house development-only commercial kits available 
Type Of Material Technology assay or reagent 
Year Produced 2011 
Provided To Others? Yes  
Impact useful for aHUS cases-previously only sent to Newcastle 
 
Title non TTP cases 
Description data and samples 
Type Of Material Biological samples 
Year Produced 2011 
Provided To Others? Yes  
Impact review of non TTP cases had not initally been a significant part of the registry, although data was being captured. With new medications for aHUS, this has become more relevant and may highlight cases not previously diagnosed 
 
Title use of rituximab in TTP 
Description Data from registry cases (and previous non registry cases) 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact presentation in a peer reviewed journal and oral presentation at EHA 
 
Title UK TTP registry 
Description web based NHS compliant database incorporating the CRF nationally 
Type Of Material Database/Collection of data 
Year Produced 2010 
Provided To Others? Yes  
Impact this is the largest international database for this disorder 
 
Title uk ttp registry 
Description change from mdsas to red cap, over the last 2 years, to allow an improved method of providing reports from data 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact improved data capture, in line with other international academicunits and far better outputs. Web based 
 
Description ADAMTS 13 assays 
Organisation Sheffield Teaching Hospitals NHS Foundation Trust
Department Haematology
Country United Kingdom 
Sector Academic/University 
PI Contribution to undertake UK wide analysis of ADAMTS 13
Collaborator Contribution RUN 50/50 WITH SHEFFIELD
Impact not completed
Start Year 2013
 
Description Alexion UK 
Organisation Alexion Pharmaceuticals
Country United States 
Sector Private 
PI Contribution Use of UK TTP registry to identify the non TTP/Renal causes ?aHUS
Collaborator Contribution Use of registry data
Impact Audit of cases, for subsequent presentation of frequency
Start Year 2012
 
Description Baxter healthcare 
Organisation Baxter
Department Baxter Healthcare
Country United Kingdom 
Sector Private 
PI Contribution make samples available to progress assay development preceeding phase 1 trials
Collaborator Contribution none yet-but important to position the UK for the trials
Impact as above
Start Year 2012
 
Description GWAS 
Organisation Royal Free Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution expertise in all 3 areas to progress GWAS study
Collaborator Contribution expertise in genomics and bioanalysis
Impact awaiting final results
Start Year 2012
 
Description GWAS 
Organisation Royal Free Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution presentation of initial internal data and supply of further samples froom UK TTP registry
Collaborator Contribution expertise in GWAS and bioanalysis
Impact this is a multidisciplinary approach and the outcomes are yet to be identified, but could present very novel proteins associated as a genetic link to aquired disease
Start Year 2012
 
Description GWAS 
Organisation University College London
Department UCL Genomics
Country United Kingdom 
Sector Academic/University 
PI Contribution presentation of initial internal data and supply of further samples froom UK TTP registry
Collaborator Contribution expertise in GWAS and bioanalysis
Impact this is a multidisciplinary approach and the outcomes are yet to be identified, but could present very novel proteins associated as a genetic link to aquired disease
Start Year 2012
 
Description GWAS 
Organisation University College London
Department UCL Genomics
Country United Kingdom 
Sector Academic/University 
PI Contribution expertise in all 3 areas to progress GWAS study
Collaborator Contribution expertise in genomics and bioanalysis
Impact awaiting final results
Start Year 2012
 
Description Octapharma 
Organisation Octapharma
Country Switzerland 
Sector Private 
PI Contribution relationship over many years, to review new plasma and data on previous plasma use
Collaborator Contribution funding support for trial coordinator
Impact outputs are: data on Octaplas use since 1.1.2006 2. review safety for 6 months use of Octaplas LG when introduced
Start Year 2012
 
Description Role of BAFF in the immune response 
Organisation University College London
Department Centre for Rheumatology and Bloomsbury Rheumatology Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution samples from acute and follow up TTP cases re the role of BAFF and markers looking at predicting relapse compared to rheumatoid cases
Collaborator Contribution samples and data from TTP cases
Impact european and international poster. Peer reviewed paper
Start Year 2011
 
Description UK TTP forum 
Organisation University College London Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration with the UK physicans to develop policy and research
Collaborator Contribution delivery of 24/7 apheresis service throughout the UK
Impact Discussed with NHSBT to create SLAs with specialist centres and 24/7 cover
Start Year 2013
 
Description aHUS action 
Organisation Newcastle upon Tyne Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Academic/University 
PI Contribution collaboration to ensure diagnosis and treatment availability for aHUS patients
Collaborator Contribution NHS england have agreed to fund new patients/those failing PEX while going through NICE
Impact NHS england have agreed to fund new patients/those failing PEX while going through NICE
Start Year 2013
 
Description collaboration with Imperial hospital scientists 
Organisation Imperial College Healthcare NHS Trust
Department Department of Clinical Haematology
Country United Kingdom 
Sector Hospitals 
PI Contribution Dr Mari Thomas' grant, funded by the BHF, is a dual project between UCL and Imperial, clinical and basic science haemostasis research groups
Collaborator Contribution Dr Thomas has excellent access and mentorship with the basic science group
Impact Good working relationships between the 2 groups, with the project impossible without both involved. provides a very experienced scientific group for Dr Thomas' PhD and clinical samples and expertise from UCL
Start Year 2010
 
Description congenital TTP assays 
Organisation University of Milan
Department Haematology
Country Italy 
Sector Academic/University 
PI Contribution access to UK TTP congenital samples for the project
Collaborator Contribution international collaboration led by a post doc in Milan
Impact Paper in Blood journal
Start Year 2011
 
Description european collaboration 
Organisation European Commission
Country European Union (EU) 
Sector Public 
PI Contribution providing patient samples for investigation
Collaborator Contribution providing patients samples for collaboration
Impact just being initiated
Start Year 2016
 
Title BAX930 
Description Phase I first in human study of recombinant ADAMTS 13 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Pure protein to replace the missing enzyme in congenital TTP 
 
Title ablynx trial 
Description nanobody in acute TTP-International trial phase 2 completed-phase 3 in development 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
Impact novel therapy in a rare disease 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-019375-30
 
Title hercules study 
Description new technology-nanobody.Results from phase III presented by myself as a late breaking abstract at ASHGoing through NICE approval and regulatory license with EMA 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2017
Development Status Actively seeking support
Clinical Trial? Yes
Impact As above 
 
Title recombinant ADAMTS 13 
Description RECOMBINANT THERAPY IN CONGENITAL TTP 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2011
Development Status Under active development/distribution
Impact FIRST IN HUMAN THERAPY 
 
Description EHA-SWG 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact developing an international consensus document

international collaboration of lead haemaatologists, renal physicans and academics
Year(s) Of Engagement Activity 2013
 
Description PATIENT UK MEETING 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact UK TTP MEETING FOR PATIENTS AND RELATIVES
Year(s) Of Engagement Activity 2018
 
Description SCHOOL VISIT 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact PRESENTING TO GCSE/A LEVEL STUDENTS ABOUT MEDICINE AND RESEARCH
Year(s) Of Engagement Activity 2019
 
Description TTP Patient day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact UK TTP patient day, with 80 patients and family from around the UK. All the TTP team presented their recent work including all the staff funded from the MRC grant

Feedback evaluation forms-appears very successfula dn informative. Many wanted a repeat day in the near future
Year(s) Of Engagement Activity 2010
 
Description TTP patient day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A TTP patient day to update on research and clinical activity, available nationally and internationally to patients and their relatives

support for future clinical trials, development of a new updated patients forum
Year(s) Of Engagement Activity 2014
 
Description UK TTP forum 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact 25 attendees. Primary aim: to ensure 24/7 apheresis for all sites in the UK. Attendance increased year upon year. specialist service specification and discussion with national commissioners. Update on clinical trials and centre participation

Discussions with NHSBT following the meeting. Discussion with commissioners
Year(s) Of Engagement Activity 2012,2013,2014
 
Description educational film 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact medscape educational film for TTP with 2 international colleagues, with questions and CPD
Year(s) Of Engagement Activity 2017
 
Description invited lectures-national meetings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I have been invited to give lectures at national meetings in the UK and in europe, including spain, portugal, norway, denmark and germany. Overall the presentations have amounted to hundreds of people and the feedback has always been very positive, with emails from attendees after the meetings , usually about clinical cases or research collaborations
Year(s) Of Engagement Activity 2014,2015,2016,2017
 
Description invited talks 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talks at international society of haemostasis and thrombosis and american society of haematology
Year(s) Of Engagement Activity 2015,2016,2017
 
Description meeting in parliment 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact pressure on government to support specialist services

awaiting parliments response
Year(s) Of Engagement Activity 2011
 
Description patient workshops 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact I have attended a number of patient group national meetings including ITP and HUS, but also organised the UK ttp meetings, every 2-3 years
Year(s) Of Engagement Activity 2010,2014,2015,2016,2017
 
Description specialist appraisal group of NICE 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Initiation of a specialist appraisal group for rare diseases, specifically ecluzimab in aHUS

Experts in the firld of TMAs in the UK to advise re benefit of ecluzimab in aHUS following AGNESS report
Year(s) Of Engagement Activity 2013
 
Description uk ttp forum 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact uk ttp forum discusses policy, research, treatment and trials
Year(s) Of Engagement Activity 2019