EPSRC Healthcare Impact Partnership for new blood clotting diagnostics and management

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.

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.