Retinal vascular dynamics: A window for observing an irregular heartbeat. A case report.

OBJECTIVE: We aimed to characterize several aspects of retinal vascular dynamics in a patient with arrythmia in order to elicit additional diagnostic information on microvascular dysfunction. METHODS: A 68-year-old male patient with arrythmia and an age- and gender-matched control subject underwent ocular examination including dynamic retinal vessel assessment with flicker light provocation. Retinal vessel diameters were measured continuously following a standard protocol (IMEDOS Systems, Jena, Germany). The data were evaluated using methods of signal analysis. RESULTS: Retinal vessel response following flicker provocation as well as local structural and functional behavior of retinal vessels were comparable between both individuals. The arrhythmia case demonstrated irregular arterial and venous heart rate (HR) pulsation with an average frequency of 1 Hz. Moreover, the case showed a higher magnitude and larger periods of low-frequency retinal vessel oscillations as well as lower periodicity of both HR pulsations and low-frequency vasomotions. CONCLUSIONS: Besides numerical examination of irregular HR pulsations in case of arrhythmia, from the direct noninvasive assessment of retinal vessel dynamics one can derive more detailed information on microvascular function including the whole spectrum of retinal arterial and venous pulsations and vasomotions. This may have implications for health screening not limited to atrial fibrillation.

Analysis of laboratory blood parameter results for patients diagnosed with COVID-19, from all ethnic group populations: A single centre study.

INTRODUCTION: Although factors such as age, sex, diabetes, obesity and changes in certain laboratory investigations are important prognostic factors in COVID-19 infection, these may not apply to all ethnic/racial groups. We hypothesized differences in routine biochemistry and haematology indices in Caucasian and a combined group of Black, Asian and Minority Ethnic (BAME) patients who tested positive for COVID-19 who died, compared to survivors. METHODS: We tested our hypothesis in 445 patients (229 Caucasian, 216 BAME) admitted to secondary care with proven COVID-19 infection, in whom standard routine laboratory indices were collected on admission. RESULTS: After 28 weeks, 190 (42.7%) had died within 28 days of COVID diagnosis (97 Caucasians [42.4%], 93 BAMEs [43.1%], P = .923). A general linear model analysis found the ethnicity interaction with mortality to be significant for fibrinogen, ferritin and HbA1 c (after controlling for age). In a multivariate analysis, a neutrophil/lymphocyte ratio > 7.4 and a urea/albumin ratio > 0.28 increased the odds of death for both the Caucasian and the BAME group. Additional factors increasing the odds ratio in the BAME group included age >60 years and being diabetic. CONCLUSION: Neutrophil/lymphocyte ratio and urea/albumin ratio are simple metrics that predict death to aid clinicians in determining the prognosis of COVID-19 and help provide early intensive intervention to reduce mortality. In the BAME groups, intensive monitoring even at younger age and those with diabetes may also help reduce COVID-19 associated mortality.

Von Willebrand factor antigen levels predict major adverse cardiovascular events in patients with carotid stenosis of the ICARAS study.

BACKGROUND AND AIMS: Von Willebrand factor (VWF) plays an important role in thrombogenesis and mediates platelet adhesion particularly under high shear stress. Such conditions are generally found in stenotic arteries and can eventually cause myocardial infarction or stroke. We aimed to study whether levels of VWF antigen (VWF:Ag) predict future major adverse cardiovascular events (MACE) in patients suffering from carotid artery stenosis. METHODS: Patients with atherosclerotic carotid artery disease defined by the presence of nonstenotic plaques or any degree of carotid stenosis were prospectively enrolled. Concentrations of VWF were measured by enzyme immunoassay. RESULTS: VWF:Ag levels were more stable after 4 freeze-thaw cycles, when compared to VWF activity, and we showed similar concentrations of VWF in citrated plasma and serum (±4%). Levels of VWF:Ag predicted future cardiovascular events in 811 patients with carotid stenosis independent of known cardiovascular risk factors. Patients with VWF:Ag concentrations in the 4th quartile had a 44% event rate after an average 3-year follow up and a hazard ratio of 2.15 (95% confidence interval 1.46-3.16; p < 0.001). CONCLUSIONS: High concentrations of VWF:Ag predict major cardiovascular events in patients with carotid stenosis, and given their high event rate may be useful for risk stratification of such patients.

British Journal of Biomedical Science in 2017: What have we learned?

In 2017 the British Journal of Biomedical Science published 35 articles in the various disciplines that comprise biomedical science. These were 6 reviews, 22 original articles, 6 'In Brief' short reports and one guideline. Of these, the majority were in clinical chemistry (one review, six data papers), microbiology (one review, four data papers), cellular pathology (four data papers) and virology (one review, two data papers). There were two data papers in transfusion science, whilst haematology, cytopathology and immunology were each represented by one review and one data paper. Reflecting the increasing complexity of the laboratory, five data papers crossed barriers between traditional disciplines, and so may be described as multidisciplinary. The present report will summarise key aspects of these publications.

British Journal of Biomedical Science in 2016. What have we learned?

In 2016, the British Journal of Biomedical Science published 36 reports outlining specific advances in each of the various disciplines within biomedical science. These were one review, 25 original articles, 9 'In Brief' reports and one letter to the Editor. Of these, the majority were in blood science (5 in biochemistry, 7 in haematology and 2 in immunology) and infection science (8 in microbiology, 2 in virology) with a smaller number in cellular sciences (6 in cellular pathology and 2 in cytopathology). Three reports considered both biochemistry and immunology, while another reported an advance in the identification of chromosomal abnormalities. The present report will summarise key aspects of these publications that are of greatest relevance to laboratory scientists.

Relationship between renal function and circulating microparticles, soluble P-selectin and E-selectin levels in atrial fibrillation.

Atrial fibrillation (AF) and chronic kidney disease are closely related, and any associated risk of stroke and thromboembolism due to AF is increased by concurrent renal dysfunction. The mechanism(s) for this include abnormalities in platelets and endothelial cells. We hypothesized relationships between levels of circulating platelet microparticles (PMPs, defined by CD42b), soluble P selectin (both reflecting platelet activation), soluble E-selectin (reflecting endothelial activation) and endothelial/platelet microparticles (EPMPs, defined by CD31) with progressive renal dysfunction. Blood samples were obtained from 160 anticoagulated AF patients. Microparticles were measured by flow cytometry, soluble E and P selectin levels by ELISA. Renal function was determined by estimated glomerular filtration rate (eGFR). EPMP levels demonstrated a linear increased trend across quartiles of eGFR (p = 0.034) and CKD stage (p < 0.001), and correlated with eGFR and serum creatinine (p < 0.01). PMPs, P-selectin and E-selectin levels were not significantly different across groupings of renal dysfunction, and no significant correlations with eGFR were evident (p = 0.186, p = 0.561, p = 0.746 respectively). Stepwise multivariable regression analysis demonstrated that worsening renal function was an independent predictor of EPMP levels (p < 0.001). In well-anticoagulated AF patients, there is potential relationship between endothelial function (as judged by elevated EPMP levels, with no change in PMPs) and renal function. Other markers of prothombotic state or cellular activation (PMP, P-selectin and E-selectin levels) were not significantly different across the various degree of renal dysfunction. Renal function must be addressed when measuring EPMP levels.

Modelling projections for the uptake of edoxaban in an European population to 2050: effects on stroke, thromboembolism, and health economics perspectives.

AIMS: In the coming decades, the number of Europeans with atrial fibrillation (AF) is set to rise as the population ages, and so with it will the number of strokes. The risk of thromboembolism (principally stroke and systemic embolism) and death can be reduced by the use of the vitamin K antagonists (VKA, e.g. warfarin) and more so by non-VKA oral anticoagulants (NOACs) such as edoxaban. METHODS AND RESULTS: We modelled the effect of the increasing use of edoxaban in preference to warfarin in a European AF population from both clinical and economic perspectives. We estimate that the introduction of NOACs in 2010 eliminated over 88 000 thromboembolisms and deaths annually, of which over 17 000 were ischaemic strokes. At a 1-year cost of €30k per ischaemic stroke, this strategy saved €510 million annually. Should the use of edoxaban increase from 11% in 2013 to 75% by 2030, we expect that rate of thromboembolism and death will fall from 5.67 to 5.42 total events per million patients per year, which will further eliminate over 12 000 of these events annually. At an inflation-adjusted 1-year cost of approximately €35k per ischaemic stroke, this will save €44.5 million each year. At a conservative rate of increase in the AF population of 2.2-fold from 2005, in 2050 there will be around 180 000 AF-related ischaemic strokes that, at an inflation-adjusted cost of around €62k per stroke, sums to €11 116 million. Should the rate of AF rise 2.6-fold from 2005, then in 2050 there will be 214 500 ischaemic strokes that will cost around €13 300 million. CONCLUSION: Our data point to a substantial increase in the human and economic cost burden of AF and so emphasize the need to reduce this burden. This may be achieved by the increased use of oral anticoagulants, particularly with the NOACs such as edoxaban.

Atrial Fibrillation and Thromboembolism in Patients With Chronic Kidney Disease.

A bidirectional relationship exists between atrial fibrillation (AF) and chronic renal disease. Patients with AF have a higher incidence of renal dysfunction, and the latter predisposes to incident AF. The coexistence of both conditions results in a higher risk for thromboembolic-related adverse events but a paradoxical increased hemorrhagic risk. Oral anticoagulants (both vitamin K antagonists [VKAs] and non-VKA oral anticoagulants [NOACs]) have been demonstrated to be effective in mild to moderate renal dysfunction. Patients with severe renal impairment were excluded from the non-VKA oral anticoagulant trials, so limited data are available. In end-stage renal failure, the net clinical benefit of VKAs in dialysis-dependent patients remains uncertain, although some evidence suggests that such patients may do well with high-quality anticoagulation control. Risk stratification and careful follow-up of such patients are necessary to ensure a net clinical benefit from thromboprophylaxis.

Effects of non-vitamin K antagonist oral anticoagulants on fibrin clot and whole blood clot formation, integrity and thrombolysis in patients with atrial fibrillation.

Non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin and heparins in several clinical situations. With varying modes of action, the effects of NOACs on thrombus formation, integrity, and lysis is unknown. To determine whether two techniques of thrombelastography (TEG) and a micro-plate assay (MPA) provide novel data on thrombus formation, integrity and lysis in those taking a NOACs compared to warfarin and a control group taking aspirin. We assessed thrombogenesis, clot integrity and fibrinolysis in blood (TEG) and plasma (MPA) from 182 atrial fibrillation patients-50 on aspirin, 50 on warfarin, and 82 on a NOAC (17 apixaban, 19 dabigatran and 46 rivaroxaban). Eleven of 16 TEG indices and 4 of 5 MPA indices differed (p ≤ 0.01) between those on aspirin, warfarin or a NOAC. Three TEG indices and 4 MPA indices differed (p < 0.01) between the NOACs. Time to initiation of clot formation was most rapid on apixaban, then rivaroxaban and slowest on dabigatran. The rate of clot formation was most rapid on dabigatran, then apixaban, and slowest on rivaroxaban. Clot density was greatest on rivaroxaban, then apixaban, but weakest on dabigatran. The rate of clot dissolution was most rapid in apixaban, then dabigatran, and slowest on rivaroxaban. The TEG and MPA identify major differences in thrombogenesis and fibrinolysis in different NOACs. These techniques may have value in investigating the effects of these drugs on haemostasis in a clinical setting, and in identifying those in need of targeted therapy.

The rolling evolution of biomedical science as an essential tool in modern clinical practice.

The British Journal of Biomedical Science is committed to publishing high-quality original research that represents a clear advance in the practice of biomedical science, and reviews that summarise recent advances in the field of biomedical science. The overall aim of the Journal is to provide a platform for the dissemination of new and innovative information on the diagnosis and management of disease that is valuable to the practicing laboratory scientist. The Editorial that follows describes the Journal and provides a perspective of its aims and objectives.

British Journal of Biomedical Science in 2015: what have we learned?

In 2015, the British Journal of Biomedical Science published 47 reports on topics relating to the various disciplines within biomedical science. Of these, the majority were in infection science (15 in microbiology and two in virology) and blood science (seven in biochemistry, four in haematology, three in immunology and one in transplantation), with a smaller number in cellular sciences (four reports) and with one review across disciplines. The present report will summarise key aspects of these publications that are of greatest relevance to laboratory scientists.

Effect of renal function on whole blood and fibrin clot formation in atrial fibrillation patients on warfarin.

OBJECTIVE: Atrial fibrillation (AF) brings a risk of thrombosis, requiring oral coagulation, and is associated with renal impairment. The two processes may be linked, as altered fibrin clot structure is present in end-stage renal failure. We hypothesised that progressively deteriorating renal function is linked to altered whole blood and fibrin clot properties and fibrinolysis. METHODS: Thrombogenesis and fibrinolysis in 200 warfarinised AF patients was assessed by thromboelastography (TEG), a micro-plate assay (MPA) and the international normalized ratio (INR). Renal function was determined by creatinine clearance and two versions of the estimated glomerular filtration rate (eGFR). RESULTS: Two TEG indices independently reflecting thrombogenesis were linked to creatinine clearance (p < 0.01), whilst a third, reflecting clot strength, was linked to the eGFR (p < 0.001). MPA indices of thrombogenesis and clot density (p < 0.001), and an index of fibrinolysis (p < 0.001) were linked to the eGFR. The time for 50% of the fibrin clot to lyse was linked to creatinine clearance (p = 0.001). The INR was unrelated to any renal function index, and the CHA2DS2VASc score was unrelated to any index. CONCLUSION: In warfarinised AF patients, renal function is linked to whole blood clot and fibrin clot formation, structure and dissolution, but has no effect on the INR. Key messages Despite oral anticoagulation, patients with atrial fibrillation (AF) still suffer from stroke and venous thromboembolism. The effect of renal function in warfarinised patients with AF is unknown and may account for excess thrombosis and/or haemorrhage. Using two different laboratory methods, our data point to an effect of renal function on clot structure and function that is independent of an effect of warfarin.

Non-Vitamin K Oral Anticoagulants (NOACs) A Review of Clinical Management and Laboratory Issues.

The non-vitamin K oral anticoagulants (NOACs) are set to replace vitamin K antagonists (principally warfarin), unfractionated heparin and low molecular weight heparin as the leading antithrombotic prophylaxis in several medical and surgical settings. As a group, NOACs have a better safety profile and at least an equivalent (and sometimes superior) efficacy profile than their comparator. The objective of this review is to provide the practitioner with a comprehensive, balanced and contemporary view of these drugs and their applications. More specifically, it focuses on the evidence base for their licences, use in clinical practice (such as in renal dysfunction, orthopaedic surgery, atrial fibrillation, and venous thromboembolism, and the effects of co-medications), responses to actual or perceived haemorrhage, and the role of the laboratory.

Net Clinical Benefit of Edoxaban for Stroke, Mortality, and Bleeding Risk: Modeling Projections for a European Population.

OBJECTIVES: The purpose of this study was to determine, in a model based on Europeans at risk of stroke by virtue of atrial fibrillation (AF), the net clinical benefit of edoxaban in the reduction of the risk of stroke, mortality, and of hemorrhage. BACKGROUND: Vitamin K antagonists (e.g., warfarin) are commonly underused because of such factors as fear of hemorrhage in patients with high-risk AF. The non-vitamin K antagonist oral anticoagulants are similarly or more effective than warfarin and have lower rates of serious hemorrhage. Although outcomes of the ENGAGE AF-TIMI 48 trial that compared the non-vitamin K antagonist oral anticoagulant edoxaban with warfarin and indicated similar efficacy and better safety compared with warfarin for stroke prevention in AF, the application of trial data to the general population is unknown. METHODS: This study modelled a treatment effect of edoxaban on the risks of thromboembolism, major bleeding, and death in a real-world population of patients with AF drawn from the Euro Heart Survey, and extrapolated this to the general European population. RESULTS: In those at high risk of stroke (CHA2DS2VASc ≥2), edoxaban would need to be taken by 319 patients to prevent 1 thromboembolism, major bleeding event, or death compared with warfarin, and by 41 patients to prevent 1 thromboembolism or death compared with no treatment. These translate to demonstrating a net clinical benefit of 8.9 events saved per 1,000 patients with edoxaban 60 mg. Modeling these data to the population of Europe of 508 million, use of edoxaban 30 mg and 60 mg instead of warfarin would, respectively, prevent approximately 19,400 and 30,300 thromboembolic events, major bleeds, and deaths annually. CONCLUSIONS: Our modeling exercise suggests that the use of edoxaban for thromboprophylaxis in AF based on current guidelines could provide a profound benefit on rates of stroke, major bleeds, and deaths in European patients with AF.

Net clinical benefit of edoxaban versus no treatment in a 'real world' atrial fibrillation population: A modelling analysis based on a nationwide cohort study.

BACKGROUND: In non-valvular atrial fibrillation (AF), oral anticoagulation reduces the risk of thromboembolism such as stroke and systemic embolism (SSE), but increases the risk of major bleeding such as intracranial haemorrhage (ICH). The risk-benefit balance between SSE versus ICH can be expressed as the net clinical benefit (NCB); however, the risk of SSE and ICH varies according to clinical factors that can be assessed using CHADS2, CHA2DS2-VASc (both quantifying risk of stroke) and HAS-BLED (quantifying risk of major bleeding) scores, respectively. METHODS: Using established modelling based on event rates for thromboembolism and haemorrhage in the Danish nationwide cohort study, we tested the hypothesis that edoxaban has a superior NCB compared with warfarin. RESULTS: In our overall model, compared to no treatment, warfarin had a NCB of 0.26 (95% CI 0.24,0.28) events prevented per 100 patient years, edoxaban 60 mg daily a NCB of 0.71 [0.69,0.76], and edoxaban 30 mg daily a NCB of 0.71 [0.0.68,0.73]. When compared to no treatment, both doses of edoxaban have superior NCB values than those of warfarin at all CHADS2 and CHA2DS2-VASc scores. At CHADS2 ≥2 and CHA2DS2-VASc ≥2, edoxaban 60 mg dose had a better NCB than the 30 mg dose or warfarin, when compared to no treatment. With HAS-BLED score ≥3, both doses of edoxaban had a positive NCB compared to warfarin, at CHADS2 or CHA2DS2-VASc ≥2. CONCLUSION: Our modelling study suggests that both 30 mg and 60 mg doses of edoxaban have a favourable NCB compared to warfarin, and the degree of benefit differs according to CHADS2, CHA2DS2-VASc and HAS-BLED scores. At CHA2DS2-VASc score ≥2, both edoxaban doses were superior to warfarin, but compared to no treatment, the 60 mg dose had a better NCB than the 30 mg dose or warfarin.

An update on vitamin D deficiency and at risk groups.

Vitamin D is required for healthy bones. We need sunlight and good renal and liver function for the synthesis of vitamin D, although it can also be taken in diet. Severe deficiency causes the bone diseases rickets and osteomalacia. Supplementation with vitamin D can help prevent low birth weight and non-vertebral fractures. Roles for vitamin D in other aspects of health are controversial.