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Biomedical subjects

M D Etherington

Publications and source records attributed to M D Etherington.

At least 19 recordsLinked to original sources
PubMed2001

A comparison of von Willebrand Factor antigen with platelet activity in vitro in normal and venous occlusion blood.

Von Willebrand Factor (vWF) is essential for normal haemostasis involving platelet aggregation induced by high shear forces. In vitro a functional test of platelet aggregation using the filterometer is abnormal in von Willebrand's disease. However in normal people there is no significant correlation between the antigenic assay of vWF and the filter results. To study this discrepancy normal blood before and during venous occlusion, and blood before and after infusion of 1 deamino-(8-D-arginine) vasopressin was studied. During venous occlusion (VO) the increase in vWF due to the release of large multimers correlated precisely with the increase in the filterometer results. That this was due to the plasma vWF and not to any change induced in the platelets was shown as follows: The methodology was altered so that a small amount of the donor's platelet-poor plasma (PPP) was added to homologous normal substrate blood. The effect of the added donor's PPP was then shown to be closely correlated to the increase in the antigenic assay. Analysis of vWF multimer size showed during VO an increase in large multimers. We conclude that the effect of vWF on normal blood may be obscured by variation in platelet aggregability. In the filterometer system as elsewhere the large active multimers probably play a major part in causing platelet adhesion, aggregation and filter blocking. The filterometer test is influenced by the amount of vWF antigen, by the molecular size and activity of the vWF and by platelet sensitivity. Clinically this is a useful global test.

Adult↗
PubMed2000

Defective von willebrand factor activity detected by the filterometer in three clinical conditions.

When exposed to high levels of shear in a filterometer, platelets bind to von Willebrand factor (vWF) via receptors Ib and IIb/IIIa, forming aggregates that block the filteromer. In this study we used the filterometer to explore the mechanisms by which abnormal vWF-platelet interaction might occur. In the first phase of the study, the global vWF-platelet interaction in native blood was investigated. In the second phase, to eliminate the difference that platelets might contribute, samples of platelet-poor plasma from test individuals were added to normal control blood and the mixtures were investigated by the filterometer. The filterometer results were adjusted for the antigen concentrations to obtain vWF potency ratios. Sodium dodecyl sulphate (SDS) agarose gel electrophoresis and SDS-Polyacylamide gel electrophoresis (PAGE) were used to analyze multimeric size and proteolytic profiles of vWF. Pregnancy was associated with high platelet retention, high vWF antigen concentration, normal multimeric size distribution, but decreased vWF potency ratios. The plasma samples of pregnancy contained one 183-kDa fragment not detected in normal plasma. These results suggested that in pregnancy, platelets were highly active. However, presumably due to abnormal proteolytic cleavage, vWF potency was decreased. This decrease in vWF potency might minimize the risk of thrombosis in association with highly active platelets. Renal transplant patients had normal platelet retention but high vWF levels. The plasma vWF contained normal multimers. A decrease in vWF potency, presumably caused by toxic inhibitors in the plasma, was detected. Aortic valve stenosis patients had decreased platelet retention, normal or slightly increased vWF antigen concentration and a decrease in large multimers. As a result, the vWF potency was markedly decreased. However, the results obtained with the filterometer became normal when the studies were repeated 3 months postpartum, when renal function had improved after transplantation, and when the aortic valves were corrected by surgery. These results indicate that the filterometer is a useful tool for elucidating the mechanisms by which vWF-platelet interaction might be impaired in various clinical conditions.

Adult↗
PubMed1999

White cell retention compared with platelet retention in the filterometer: controls and abnormal states.

Platelets and white cells contribute to thrombus formation. In the filterometer, platelet retention in normal citrated blood increases from 47.5% at 0-5 s to 81.5% at 20-40 s. White cell retention is normally closely related to platelet retention at 0-5 s but less so at 20-40 s. However at 20-40 s the number of white blood cells (WBC) retained has decreased relative to 0-5 s. This apparent paradox is now further explored using antibodies to glycoprotein (GP) Ib, to von willebrand factor (vWf) and to GPIIb-IIIa together with observations on a number of clinical conditions with abnormal platelet retention. In citrated blood, platelet retention of 0-5 s was significantly decreased relative to normal in von Willebrand's disease, in aortic valve stenosis and with the addition of anti-vWf-GPIb and minimally with anti-GPIIb-IIIa antibodies. WBC retention of 0-5 s in these groups was always 41 2%. However when platelet retention 0-5 s was raised (pregnancy and venous occlusion), white cell retention was also raised. At 20-40 s in all the nine conditions studied, the white cell and platelet retention were closely related, but the percentage WBC retained decreased relative to the platelet retention. Granulocyte retention was higher than lymphocyte retention, but both cell types were similarly affected. We conclude that the platelets are retained as previously described. The white cells (all types) initially bind at least in part in an independent unexplained way (0-5 s). Thereafter the degree of platelet activity (retention %) largely determines the degree of WBC retention. This is probably due to a proportional amount of P-selectin liberated by the activated platelets.

Journal Article↗
PubMed1998

The relative power of heat-precipitation nephelometric and clottable (Clauss) fibrinogen in the prediction of ischaemic heart disease: the Caerphilly and Speedwell studies.

The Caerphilly and Speedwell studies have previously reported the predictive power of heat-precipitation, nephelometric, fibrinogen for 10-year incidence of ischaemic heart disease. A Clauss, clotting time, fibrinogen was also measured at baseline, but has not previously been reported. The predictive power of the two assays is compared. Both methods were employed on fasting blood samples from a total of 4391 men aged 45-63 years. Over the following 10 years 533 (12%) developed major ischaemic heart disease. Nephelometric fibrinogen was higher by 0.33 g/l among the men who developed disease; clottable fibrinogen was higher by 0.20 g/l. This difference is statistically significant (P=0.01). Relative odds of developing heart disease increased steadily to 3.53 (P<0.0001) in the 20% of men with the highest nephelometric fibrinogen; for clottable fibrinogen the corresponding relative odds increased to 2.24 (P<0.0001). When both measures of fibrinogen were included in logistic regression models together with age and smoking habit, the trend for incidence to increase with increasing nephelometric fibrinogen remained highly significant (P<0.0001), whereas for the Clauss fibrinogen the trend almost entirely disappeared (P = 0.37). We conclude that functional assays of clottable fibrinogen may not reflect all of the mechanisms which mediate the association between fibrinogen and cardiovascular disease and that assays of both 'heat precipitable' and 'clottable' fibrinogen should be included in all future prospective studies.

Aged↗
PubMed1998

Anti-glycoprotein Ib causes platelet aggregation: different effects of blocking glycoprotein Ib and glycoprotein IIb/IIIa in the high shear filterometer.

In 1987 we reported that when blood was forced through a fine filter under pressure in the filterometer the platelets aggregated and blocked the filter. von Willebrand factor (vWF) and glycoprotein (Gp) IIb/IIIa and calcium were involved. Results with anti-GpIb were equivocal. We now report that all the anti-GpIb antibodies studied, glycocalicin, as well as some concentrations of aurin tricarboxylic acid caused platelet aggregation in the pre-filter blood and therefore could not be used in the filterometer. Using two different molecules that prevent vWF binding to GpIb and two anti-GpIIb/IIIa antibodies at two pressures it has now been shown that GpIb, vWf and high shear are primarily responsible for platelet retention at 0-5 s. Progressive platelet retention studied between 20 and 40 s required high shear and GpIIb/IIIa after the calcium influx mediated by GpIb/vWF binding. When GpIb was inhibited, GpIIb/Ila could not function normally, so GpIb inhibition resulted in decreased aggregation both at 0-5 s and at 20-40 s. Anti-GpIIlb/IIIa caused a minimal decrease in retention at 0-5 s and marked inhibition at 20-40 s. These findings fit and amplify concepts derived from other high shear methodologies. A diagram is presented of the events leading up to the final 'passivation' of the 'thrombus' in the filter when the surface of the aggregated platelets becomes unattractive.

Adult↗
PubMed1996

High shear-induced platelet activation and inactivation: the importance of methodology.

High shear platelet activation may be conveniently studied by forcing blood through a fine filter in the filterometer. To achieve haemostasis in vivo platelets are activated. When haemostasis is achieved, inactivation must follow. In the filterometer, activation occurs with filter blocking (first phase) and after 100s inactivation ('rebleeding') may occur (second phase). We report the effect of different pressures, temperatures, incubation times, anticoagulants and aspirin in this system. Most 'rebleeding' occurred in citrate, followed by native blood, r-hirudin and low-molecular-weight heparin. Unfractionated heparin inhibited 'rebleeding' whereas aspirin potentiated it. These and other findings are technically and clinically relevant and contribute to an understanding of the mechanisms involved in 'rebleeding' and hence perhaps in thrombogenesis.

Adenosine Diphosphate↗
PubMed1995

Decreased platelet function in aortic valve stenosis: high shear platelet activation then inactivation.

OBJECTIVE: To elucidate the mechanism of the bleeding tendency observed in patients with aortic valve stenosis. DESIGN: A prospective study of high and low shear platelet function tests in vitro in normal controls compared with that in patients with severe aortic valve stenosis with a mean (SD) systolic gradient by Doppler of 75 (18) mm Hg before and at least 4 months after aortic valve replacement. SETTING: District general hospital. RESULTS: The patients showed reduced retention in the high shear platelet function tests. (a) Platelet retention in the filter test was 53.6 (12.6)% in patients with aortic valve stenosis and 84.8 (9.6)% in the controls (P < 0.001). (b) Retention in the glass bead column test was 49.8 (19.2) in the patients and 87.4 (8.7) in the controls (P < 0.001). (c) The standard bleeding time was longer in the patients (P < 0.06). Results of the high shear tests (a, b, and c) after aortic valve replacement were within the normal range. The platelet count was low but within the normal range before surgery and increased postoperatively (P < 0.01). There were no differences in the results of standard clotting tests, plasma and intraplatelet von Willebrand's factor, or in 15 platelet aggregation tests using five agonists between patients with aortic valve stenosis and controls. CONCLUSIONS: The high shear haemodynamics of aortic valve stenosis modify platelet function in vivo predisposing to a bleeding tendency. This abnormality of platelet function is detectable only in vitro using high shear tests. The abnormal function is reversed by aortic valve replacement. High shear forces in vitro activate and then inactivate platelets. By the same mechanisms aortic valve stenosis seems to lead to high shear damage in vivo, resulting in a clinically important bleeding tendency in some patients.

Aged↗
PubMed1993

Gender and employment grade differences in blood cholesterol, apolipoproteins and haemostatic factors in the Whitehall II study.

In the first Whitehall study, plasma cholesterol was a strong predictor of coronary heart disease (CHD) but it showed a positive association with grade of employment: the higher the grade the higher the level. Because it could not explain the higher rate of CHD in lower employment grades, further investigation of biochemical CHD risk factors has been conducted with data from the baseline examination of the Whitehall II cohort in 1985-88. These data also allow investigation of gender differences and the effect of menopause. Serum cholesterol (6860 men and 3374 women) and apolipoproteins A-I and B (apo AI and apo B) were measured in those aged 35-55 working in the London offices of twenty Civil Service departments. Plasma fibrinogen and factor VII were determined in 45-55 year olds. The apo B/apo AI ratio (95% confidence interval) after age adjustment is lowest in premenopausal women: 0.557 (0.549-0.565), intermediate in postmenopausal women: 0.601 (0.589-0.613) and highest in men: 0.703 (0.698-0.709). After age adjustment fibrinogen is higher in postmenopausal (2.90 (2.85-2.95) g/l) than in premenopausal women (2.78 (2.71-2.84) g/l), who have higher levels than men (2.64 (2.62-2.67) g/l). A positive association with employment grade is seen for apo AI and a negative association is seen for fibrinogen, apo B (women only) and the apo B/apo AI ratio, after age adjustment. These patterns are consistent with the higher rates of CHD in lower grades. Cholesterol and factor VII show no gradient with our sensitive measure of social position. After adjusting for the effects of smoking rates, alcohol consumption, exercise and dietary pattern, as well as age, ethnicity, body mass index and report of symptoms, the regression coefficient for apo AI on employment grade is reduced by 43% in men and 70% in women. Corresponding reductions for fibrinogen are 53% and 65%. These attenuations suggest that a considerable part of the social gradients in apo AI and fibrinogen are explained by variations in health related behaviours. The remaining gradients may represent effects independent of these behaviours.

Adult↗
PubMed1987

Effects of a fish oil supplement on serum lipids, blood pressure, bleeding time, haemostatic and rheological variables. A double blind randomised controlled trial in healthy volunteers.

Sixty male volunteers were randomised to take 10-16 ml of a fish oil supplement (MaxEPA) or 10-16 ml of olive oil for a period of 3-6 weeks. A fall in serum triglyceride of 54% (P less than 0.01) and a fall in diastolic blood pressure of 7% (P less than 0.05) was attributable to taking fish oil supplements. The bleeding time was prolonged by 12%, but this did not reach conventional levels of statistical significance. A global test of heparin-neutralising activity, the heparin thrombin clotting time, increased by 14% (P = 0.05) but there was no demonstrable effect on thrombin time, fibrinogen or (intraplatelet) platelet factor 4. A fall in red cell pore transit time of 23% was attributable to fish oil, but was not statistically significant. There was no convincing evidence of an effect of fish oil supplementation on total serum cholesterol, HDL-cholesterol, blood counts or platelet aggregation. A beneficial effect of fish oil on the cardiovascular risk profile was confirmed in this study. However, with this regime changes in total cholesterol, HDL-cholesterol and platelet aggregation are of unlikely clinical importance.

Adult↗
PubMed1987

Some long term effects of smoking on the haemostatic system: a report from the Caerphilly and Speedwell Collaborative Surveys.

Data from two community studies on men from South Wales and the west of England suggest that the effects of smoking on the haemostatic system remain for many years after giving up. Long term correlations between several variables, including plasma fibrinogen and white cell count, and the length of time after giving up were seen in ex-smokers. Dose response relations were apparent in current smokers in terms of the white cell count and two haematological variables, the packed and mean cell volumes. These long term correlations probably reflect the toxicity of other agents in tobacco smoke besides nicotine and carbon monoxide, which act only in the short term. Identification of these agents may further our understanding of the mechanism by which cigarette smoking is associated with atherosclerotic disease.

Blood Viscosity↗
PubMed1985

The heparin-mobilisable pool of platelet factor 4: a comparison of intravenous and subcutaneous heparin and Kabi heparin fragment 2165.

Some clinical advantages are claimed for low molecular weight heparin so the mobilisation of platelet factor 4 (PF 4) from the endothelial pool by the heparins may be relevant. Unfractionated (UF) heparin has been compared with Kabi heparin fragment 2165. A single intravenous (i.v.) injection of 60 iu/kg heparin was compared with 5000 anti-Xa units of Kabi-2165. Less PF 4 was mobilised by Kabi-2165 and some apparently remained in the pool and was released when the pool was subsequently challenged by giving i.v. heparin. Subcutaneous (s.c.) injections of 5000 iu heparin twice daily were compared with 5000 anti-Xa units of Kabi-2165 once daily, each given for a week. The plasma PF 4 was never raised yet when finally challenged with i.v. heparin the pool was "empty" or refractory after the s.c. heparin but some PF 4 remained after the s.c. Kabi-2165. The two glycosaminoglycans (GAGs) had widely differing half-lives but the t/2 of the PF 4 mobilised by the two GAGs was similar even though the PF 4 is apparently bound to the GAG.

Adult↗