EPSRC Healthcare Impact Partnership for new blood clotting diagnostics and management

Lead Research Organisation: Swansea University
Department Name: School of Engineering

Abstract

We propose to establish a Healthcare Impact Partnership for research which is stimulated by an unmet clinical need for improved monitoring and prediction of abnormal clotting responses to therapy or disease. Thromboembolic disease and associated blood clotting abnormalities cause significant morbidity and mortality in Western society, with stroke being the third-leading cause of death in the UK. Clotting abnormalities are responsible for thousands of preventable deaths annually inside UK hospitals and increasing numbers of NHS outpatients require monitoring of oral anticoagulant therapy (e.g. warfarin). But correlation of standard clotting tests to clinical outcome has been unsatisfactory, with uncertain healthcare benefits and limited clinical utility in terms of informing responses to ongoing treatment or disease progression.

We wish to overcome these shortcomings by exploiting our advances in nanotechnology and clot detection. They provide the basis of a new way of monitoring, assessing and predicting the key microstructural and mechanical properties of fully-formed clots, based on information acquired within a few minutes in near-patient tests on small samples of blood. The fully-formed clot's microstructure determines its mechanical strength (hence ability to prevent bleeding) and its resistance to breakdown and dispersal by the body. Abnormalities in these properties are linked to significant health risks.

Our discovery of the fractal microstructure of incipient ('infant') clots and its role in templating fully-formed ('mature') clots provides the basis of our proposal. We have established its feasibility through advanced imaging and analysis of model (fibrin-thrombin) clots. We now need to do this in therapeutically and pathologically modified blood. But our previous imaging techniques are not suitable for blood and we plan a new approach. Our work on nanoparticle fluorescence has established advanced identification/tracking techniques and we have implemented them to study biological cells. We plan to translate these approaches to analyse abnormal microstructure development in blood clots. The concept is based on interrogating nanoscale moving light displays (clusters of light), formed by fluorescent nanoparticles loaded into blood samples. An exciting aspect involves analysing clot deformation in response to stress. The light arrays provide a binary map of points delimiting clot structure and reporting deformation. We anticipate that this concept will provide a 'world-first' in yielding linked microstructural and mechanical properties of evolving clots, in the same measurement.

The improved monitoring, assessment and prediction capabilities arising from this work will underpin (i) improved monitoring of clotting responses to anticoagulant and/or antiplatelet (e.g. aspirin) therapies; (ii) improved predictions of clot breakdown in response to therapy; (iii) improved dose response assessments of these treatments, and (iv) a basis for abnormal clot screening in patients who, while taking warfarin, suffer recurrent deep vein thrombosis or pulmonary embolism while appearing adequately anticoagulated in terms of present tests (INR). Our Healthcare Impact Partnership will provide the framework for collaboration between (i) experts in nanotechnological aspects of devices, imaging and analysis of biosystems; (ii) industrial partners with expertise in medical devices and microfabrication; and (iii) the Haemostasis Biomedical Research Unit (HBRU) at ABMU NHS Trust Hospital Morriston Swansea. The HBRU, with its expert clinical scientists and NHS Consultant colleagues, provides the clinically-facing focus for our studies, and their translation. Our industrial partners bring expertise which we foresee will underpin the development of technologies for near-patient tests both inside and outside hospital care settings.

Planned Impact

The research involves the development of new techniques for improving the monitoring, assessment and prediction of abnormal blood clot formation in therapeutically and pathologically modified blood. The principal beneficiaries will therefore be patients (in the UK mainly NHS patients), particularly those suffering from diseases which involve abnormal clot formation. These include patients suffering from thromboembolic disease (which causes significant morbidity and mortality in Western society), with stroke being the third leading cause of death in the UK. In addition, the research will directly benefit over 1 million NHS outpatients who require monitoring of oral anticoagulant therapy (OAT). Correlation of present standard clotting tests (e.g. INR) to clinical outcome has been unsatisfactory, with uncertain healthcare benefits. In particular the research will benefit those patients receiving warfarin OAT as a result of venous thromboembolism (VTE) who suffer recurrence of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) despite appearing adequately anticoagulated in terms of their standard (INR) test results. Repeated instances of DVT and PE in such patients represent a serious healthcare issue and are a financially significant challenge to the NHS. VTE causes in excess of 25,000 potentially preventable deaths per annum within UK hospitals (five times the number from hospital-acquired infection).

More widely, and longer term, the beneficiaries will include patients in whom abnormal blood clot formation requires improved monitoring of responses to anticoagulant/antiplatelet therapies (including aspirin); and those patients who require improved predictions of clot lysis in response to drug treatments; and patients who require improved dose assessments of these treatments. Clinicians will also be beneficiaries of the research in terms of being equipped with new tools/techniques for assessing and predicting abnormal clot formation. Such techniques are urgently needed e.g. NICE guidelines (2010) require all 1.3M annual UK hospital admissions to be screened for clotting abnormalities but standard coagulation tests have failed to relate hypercoagulability to abnormal clots in thromboembolic disease due to insensitivity and poor reproducibility.

Companies in the medical device technologies sector will also benefit from the research. Significant commercial opportunities exist for the production of commercially available forms of new tests for clotting abnormalities, both within hospital (near patient) settings and more widely as the basis for point of care testing in GP surgeries, clinics or, eventually, within the homes of outpatients. The opportunities are substantial: the global market for monitoring and screening anticoagulated patients is estimated at over $2.25billion, growing at 5% annually (STFC). The opportunities are global due to demographic change and the increasing incidence of disease related clotting abnormalities linked to the acquisition of westernised diets.

In addition to the obvious ways in which patients would benefit from improved tests and treatments, a principal benefit would be to their clinicians who would enjoy more reliable, timely information regarding responses to ongoing treatment or disease progression (better information, better care). An ability to screen patients who are non-responsive to warfarin and who develop abnormal clots would benefit the NHS by alerting clinicians to warfarinised VTE patient non-responsiveness, thereby allowing alternative treatments to be sought; and by reducing the financial costs of hospital admissions associated with recurrence of DVT/PE. Companies providing new tests to target such patients would benefit from a recurrent source of income based on the sale of test consumables. Ultimately, by making such tests compatible with operation in non-hospital settings (GP surgeries or homes), patients would benefit in terms of improved quality of life.

Publications

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Burke L (2017) In-situ synthesis of magnetic iron-oxide nanoparticle-nanofibre composites using electrospinning. in Materials science & engineering. C, Materials for biological applications

 
Description THE NEW FINDINGS ARISING FROM THE AWARD HAVE POTENTIALLY SIGNIFICANT COMMERCIAL IMPACT. THIS POTENTIAL LED TO THE AWARD (TO PROFESSOR PR WILLIAMS) OF A ROYAL ACADEMY OF ENGINEERING 'ENTERPRISE FELLOWSHIP' 2012-2013. THIS ENABLED PROFESSOR WILLIAMS TO EXPLORE FURTHER ASPECTS OF THE COMMERCIAL POTENTIAL OF THE RESEARCH FINDINGS. BASED ON THIS, THE ESTABLISHMENT OF NEW INTELLECTUAL PROPERTY, AND ITS EXPLOITATION, IS BEING EXPLORED WITH SEVERAL POTENTIAL COMMERCIAL PARTNERS IN THE HEALTHCARE AND PHARMA SECTORS. NEW INTELLECTUAL PROPERTY FILINGS ARE EXPECTED IN 2019/20.
First Year Of Impact 2012
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal

 
Description EPSRC PLATFORM GRANT
Amount £999,726 (GBP)
Funding ID EP/N013506/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 01/2016 
End 12/2020
 
Title A NEW TECHNIQUE FOR ASSESSING AND MONITORING BLOOD CLOT BREAKDOWN IN RESPONSE TO THERAPEUTIC INTERVENTION 
Description A NEW HAEMORHEOLOGICAL TECHNIQUE HAS BEEN DEVELOPED WHICH, FOR THE FIRST TIME, PROVIDES A RELIABLE AND RIGOROUSLY DEFINED ASSESSMENT OF BLOOD CLOT BREAKDOWN IN RESPONSE TO THERAPUTIC INTERVENTION. 
Type Of Material Technology assay or reagent 
Year Produced 2016 
Provided To Others? Yes  
Impact THIS DEVELOPMENT WORK IS ONGOING IN PARTNERSHIP WITH THE NHS AT THE TIME OF REPORT. 
 
Description RESEARCH COLLABORATION 
Organisation Swansea NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution PROVISION OF HEMORHEOLOGY AND ASSOCIATED TECHNIQUES
Collaborator Contribution PROVISION OF HBRU CLINCIAL HEMORHEOLOGY LABORATORY AND ASSOCIATED TECHNIQUES
Impact 15+ JOURNAL PUBLICATIONS INVOLVING MULIT-DISCIPLINARY AUTHORSHIP (ENGINEERING, CLINICAL, SCIENCE)
 
Description RESEARCH COLLABORATION UNDER HEALTHCARE IMPACT PARTNERSHIP 
Organisation Haemair Ltd
Country United Kingdom 
Sector Private 
PI Contribution SPECIALIST EXPERTISE AND APPARATUS IN BLOOD CLOTTING TECHNOLOGIES
Collaborator Contribution PARTNER BRINGS SPECIALIST EXPERTISE AND APPARATUS IN BLOOD FLOW TECHNOLOGIES
Impact COLLABORATION IS MULTI-DISCIPLINARY (ENGINEERING, SCIENCE (PHYSICS), INSTRUMENTATION, CLINICAL)
Start Year 2014
 
Description RESEARCH COLLABORATION UNDER HEALTHCARE IMPACT PARTNERSHIP 
Organisation Haemometrics Ltd
Country United Kingdom 
Sector Private 
PI Contribution RESEARCH TEAM UTILISES SPECIALIST KNOWLEDGE PROVIDED BY PARTNER AND DEDICATED RHEOMETRIC APPARATUS.
Collaborator Contribution PROVISION OF DEDICATED RHEOMETRIC APPARATUS AND BACKGROUND IPR.
Impact COLLABORATION IS MULTI-DISCIPLINARY (CLINICAL, ENGINEERING , PHYSICS)
Start Year 2014
 
Description RESEARCH COLLABORATION UNDER HEALTHCARE IMPACT PARTNERSHIP 
Organisation Massachusetts Institute of Technology
Country United States 
Sector Academic/University 
PI Contribution Development of new rheometric techniques based on controlled stress parallel superposition and optimal Fourier rheometry. These techniques are being further developed with MIT under a current EPSRC Healthcare Impact Partnership award.
Collaborator Contribution Development of underlying theory and analysis and rheometric implementation of advanced techniques and their further application to gel systems of interest, including critical-gels.
Impact Application of new optimal fourier technique to casein gels (paper in preparation).
Start Year 2014
 
Description RESEARCH COLLABORATION UNDER HEALTHCARE IMPACT PARTNERSHIP 
Organisation University of Pennsylvania
Country United States 
Sector Academic/University 
PI Contribution Rheological investigation of gel systems relevant to blood clotting studies are made at Philadelphia by the Swansea team in joint imaging - rheometry studies (Prof. John Weisel's group at Philadelphia provide expertise in high speed imaging of clot dynamics and microstructure).
Collaborator Contribution Prof. John Weisel's group at Philadelphia provide expertise in high speed imaging of clot dynamics and microstructure and host Swansea researchers during collaborative visits.
Impact 2 JOURNAL PAPERS WITH INTERNATIONAL (U.S.A.) CO-AUTHORS 1. Effects of unidirectional flow shear stresses on the formation, fractal microstructure and rigidity of incipient whole blood clots and fibrin gels. N Badiei, A Sowedan, DJ Curtis, MR Brown, PA Evans, JW Weisel, I Chernysh, C Nagaswami, PR Williams, K Hawkins. Clinical Hemorheology & Microcirculation 60(4), 451-464 (2015) 2. A new biomarker quantifies differences in clot microstructure in patients with venous thromboembolism. M Lawrence, A Sabra, W Abdullah, K Hawkins, SJ Davidson, L D'Silva, DJ Curtis, JW Weisel, PR Williams, PA Evans. British Journal of Haematol. 168(4) 571-575 (2014)
Start Year 2010
 
Description WORLD THROMBOSIS DAY GUINESS WORLD RECORD ATTEMPT ("CLOT BUSTERS") 
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 AS PART OF WORLD THROMBOSIS DAY ( A GLOBAL SET OF ACTIVITIES DESIGNED TO RAISE AWARENESS OF THE RISKS FROM VENOUS THROMBOEMBOLISM) A TEAM OF RESEARCHERS FROM SWANSEA UNIVERSITY ATTEMPTED TO SET A NEW GUINESS WORLD RECORD FOR THE NUMBER OF WATER-FILLED BALLOONS BURST ON A VOLUNTEER IN 12O SECONDS (EACH BALLON REPRESENTED A BLOOD CLOT - OUR EPSRC RESEARCH TARGETS NEW TECHNIQUES TO 'BUST' PERNICIOUS CLOTS).
Year(s) Of Engagement Activity 2016