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Biomedical subjects

Gordon D O Lowe

Publications and source records attributed to Gordon D O Lowe.

At least 55 records · Page 3Linked to original sources
PubMed2004

Plasma fibrinogen.

Fibrinogen is the major plasma protein coagulation factor. Low plasma fibrinogen concentrations are therefore associated with an increased risk of bleeding due to impaired primary and secondary haemostasis. Fibrinogen is a classical positive acute-phase reactant protein and is an independent predictor of coronary heart disease events. This review considers available methods for measurement of fibrinogen and makes recommendations as to their appropriate use. Total clottable fibrinogen assays are the definitive and reference method for plasma fibrinogen measurement. However, they are time-consuming and are rarely required in clinical practice. Clotting rate assays remain the routine method of choice for investigation, monitoring and treatment of bleeding disorders associated with low plasma fibrinogen concentrations. They are appropriately sited in haematology or haemostasis laboratories, with facilities for further relevant investigations, and expert advice from consultant haematologists on appropriate management. They have also been used in the majority of studies investigating increasing fibrinogen concentrations as a cardiovascular risk factor. Prothrombin-time derived assays are widely used, because they are less expensive and come at no extra cost with prothrombin time assays. However, their results vary widely with analysers and reagents, show discrepancies with clotting rate assays for both low and normal plasma fibrinogen samples, and at present they are not recommended by routine clinical use. Immunoassays (radial immunodiffusion, enzyme-linked immunosorbent assay or nephelometric) are useful in (a) differentiating hypofibrinogenaemia from dysfibrinogenaemia, and (b) assessing cardiovascular risk and acute-phase reactions. Unlike clottable fibrinogen assays, immunoassays can be performed in dipotassium edetate anticoagulated samples.

Biomarkers↗
PubMed2003

Relationship of the platelet glycoprotein PlA and fibrinogen T/G+1689 polymorphisms with peripheral arterial disease and ischaemic heart disease.

INTRODUCTION: Genetic variation in plasma fibrinogen and the platelet receptor GP IIIa locus has been independently associated with increased risks of ischaemic heart disease, but there have been few reports on the relationship with peripheral arterial disease. This study determined the risk of peripheral arterial disease and ischaemic heart disease associated with polymorphisms of fibrinogen T/G(+1689) and platelet glycoprotein Pl(A) genes and the effects of cigarette smoking and fibrinogen. MATERIALS AND METHODS: In the 5-year follow-up phase of the Edinburgh Artery Study, 939 subjects (60-79 years) had DNA extracted from a venous blood sample. One hundred sixteen subjects were identified as having angina, 87 a myocardial infarction, 104 had intermittent claudication and 663 subjects comprised a healthy group. RESULTS: Distribution of the fibrinogen genotype was similar across the disease and healthy groups. Logistic regression analyses found no significant association between fibrinogen genotype and ischaemic heart disease and peripheral arterial disease. A lower percentage of claudicants had the Pl(A2) allele (8.3% vs. 15.2%, p=0.025). After adjustment for age and sex, the risk of IC associated with the Pl(A2) was half that of the homozygous Pl(A1) genotype (OR 0.49, 95% CI 0.25, 0.88; p<==0.05). Adjustment for lifetime smoking and fibrinogen levels increased the odds slightly to nonsignificance. CONCLUSIONS: The Pl(A2) genotype was associated with a decreased risk of developing IC. There was no significant relationship between fibrinogen T/G(+1689) genotype and ischaemic and peripheral heart disease in this older population.

Aged↗
PubMed2003

C-reactive protein: associations with haematological variables, cardiovascular risk factors and prevalent cardiovascular disease.

C-reactive protein (CRP) has been proposed as a risk factor for cardiovascular disease; however, this association is confounded by mutual relationships with both classical and haematological cardiovascular risk factors. We, therefore, measured CRP with a high-sensitivity assay in stored plasma samples from 414 men and 515 women in the north Glasgow MONICA (MONItoring trends in CArdiovascular diseases) survey, to study its correlation with haematological variables, classical risk factors and prevalent cardiovascular disease. CRP correlated with age, oral contraceptive use, menopause and most classical cardiovascular risk factors (except blood pressure). CRP also correlated with plasma levels of the pro-inflammatory cytokine interleukin 6, and haematocrit, viscosity, red cell aggregation, white cell count, and coagulation factors [fibrinogen, factor (F) VII in women, FVIII, FIX] and inhibitors (antithrombin and protein C in women; protein S) but not coagulation activation markers. CRP was significantly associated with prevalent cardiovascular disease in both men (P = 0.03) and women (P = 0.009), however, the association became non-significant after adjustment for firstly classical risk factors, then fibrinogen. We conclude that correlations with classical and haematological risk factors account for a substantial component of the association of CRP with prevalent cardiovascular disease, but there is evidence of a residual, independent effect among women.

Adult↗
PubMed2003

Does sticky blood predict a sticky end? Associations of blood viscosity, haematocrit and fibrinogen with mortality in the West of Scotland.

There is increasing evidence that blood viscosity and its major determinants (haematocrit, plasma viscosity and fibrinogen) are associated with an increased risk of incident cardiovascular events; however, their associations with mortality are not established. We therefore studied the associations of these variables with cardiovascular events and total mortality in 1238 men and women aged 25-64 years, followed for 13 years in the first North Glasgow MONICA (MONItoring CArdiovascular disease) survey and West of Scotland centres in the Scottish Heart Health Study. After adjustment for age and sex, increasing whole blood viscosity, plasma viscosity, haematocrit and fibrinogen (analysed by both von Clauss and heat precipitation assays) were significantly associated with mortality. Only the association for fibrinogen (von Clauss assay) remained significant after adjustment for major cardiovascular risk factors. We conclude that clottable fibrinogen may be independently associated with mortality. However, the significance of this association, and the extent to which viscosity is associated with mortality, remain to be established in larger studies and meta-analyses.

Adult↗
PubMed2003

Endothelial dysfunction and inflammation in asymptomatic proteinuria.

BACKGROUND: Proteinuria is associated with vascular risk and a systemic increase in vascular permeability. Endothelial dysfunction occurs early in atherosclerosis and modulates vascular permeability. Vascular risk and chronic inflammation are associated. This study investigates whether the increased vascular permeability in proteinuria reflects systemic endothelial dysfunction and chronic inflammation. METHODS: Twenty-one patients with asymptomatic proteinuria (1.29 g/24 h; range 0.18 to 3.17) and 21 matched controls were studied. Microvascular endothelial function was assessed using acetylcholine iontophoresis. Maximum microvascular hyperemia (MMH) was assessed by flux response to local skin heating. Macrovascular endothelial function was assessed by flow-associated dilation (FAD) in the brachial artery using ultrasound. von Willebrand factor (vWF) was measured as a marker of endothelial activation. Low-grade inflammation was assessed by measurement of circulating C-reactive protein (CRP) values using a high sensitivity assay. RESULTS: FAD was impaired in proteinuric subjects (AP) compared to controls [1.8 (0.2 to 5.3) AP vs. 3.8 (1.5 to 6.2) C %; P = 0.014]. There was no significant difference between groups in MMH or in the response to acetylcholine iontophoresis. The AP group had a higher CRP [4.0 (0.5 to 39.0) AP vs. 0.2 (0.1 to 21.3) C mg/L; P < 0.001] and tendency to higher vWF [101.5 (67.0 to 197.0) AP vs. 77.5 (45.0 to 185.0) C IU/dL; P = 0.046] compared to controls. In the AP, but not control, group there was an inverse correlation between CRP and microvascular function as determined by acetylcholine iontophoresis (r = -0.509; P = 0.018). CONCLUSIONS: In AP subjects there is evidence of macrovascular endothelial dysfunction remote from the kidney and of low-grade inflammation that is associated with microvascular endothelial dysfunction.

Adult↗
PubMed2003

The effects of different alcoholic drinks on lipids, insulin and haemostatic and inflammatory markers in older men.

Light to moderate drinking is associated with lower risk of coronary heart (CHD) than non-drinkers. We have examined the relationships between total alcohol intake and type of alcoholic beverage and several potential biological mechanisms. We carried out the study in 3158 men aged 60-79 years drawn from general practices in 24 British towns with no history of myocardial infarction, stroke or diabetes and who were not on warfarin. Total alcohol consumption showed a significant positive dose-response relationship with high density lipoprotein cholesterol (HDL-C), coagulation factor IX, haematocrit, blood viscosity, and tissue plasminogen (t-PA) antigen, and an inverse dose-response relationship with insulin, fibrinogen, von Willebrand factor (vWF) and triglycerides after adjustment for possible confounders. Total alcohol consumption showed weak associations with plasma viscosity and fibrin D-dimer, and no association with factors VII, VIII, or C-reactive protein (CRP). Wine was specifically associated with lower CRP, plasma viscosity, factor VIII and triglycerides. The findings are consistent with the suggestion that HDL-C in particular but also insulin and haemostatic factors may contribute to the beneficial effect of light to moderate drinking on risk of CHD. Wine has effects that may confer greater protection than other alcoholic beverages.

Adult↗
PubMed2003

Prolonged elevations in haemostatic and rheological responses following psychological stress in low socioeconomic status men and women.

Low socioeconomic status (SES) and psychological stress are associated with increased risk of coronary heart disease, and both may influence haemostatic responses. Von Willebrand factor (vWF), Factor VIII, plasma viscosity, haematocrit, blood viscosity, tissue plasminogen activator (t-PA) and fibrin D-dimer were measured at rest and following stressful tasks in 238 middle-aged British civil servants. SES was defined by grade of employment. Lower SES was associated with higher resting vWF, Factor VIII and plasma viscosity. Psychological stress stimulated increases in haemostatic and rheological factors. Initial stress responses did not vary with SES, but Factor VIII, plasma viscosity and blood viscosity remained more elevated 45 minutes post-stress in lower SES participants. High blood pressure stress reactivity was also associated with greater haemostatic responses. We conclude that lower SES is characterised by more prolonged elevations in procoagulant responses following psychological stress, and that these processes might contribute to increased cardiac risk.

Blood Viscosity↗
PubMed2002

Physical activity and hemostatic and inflammatory variables in elderly men.

BACKGROUND: Physical activity is associated with lower risk of cardiovascular disease, but the mechanisms are uncertain. Hemostatic and inflammatory markers have been linked with risk of cardiovascular disease. We therefore examined the relationship between physical activity and hemostatic and inflammatory variables. METHODS AND RESULTS: In 1998 to 2000, 20 years after the initial screening of 7735 men 40 to 59 years old from general practices in 24 British towns, 4252 subjects (77% of available survivors, now 60 to 79 old) attended for reexamination. A fasting blood sample was available in 4088 men. All men on warfarin (n=134) and men with incomplete data on physical activity (n=144) were excluded, leaving 3810 men for analysis. Physical activity showed a significant and inverse dose-response relationship with fibrinogen, plasma and blood viscosity, platelet count, coagulation factors VIII and IX, von Willebrand factor, fibrin D-dimer, tissue plasminogen activator antigen, C-reactive protein, and white cell count, even after adjustment for possible confounders. The effects were similar in men with and without prevalent cardiovascular disease. No relationship was seen with activated partial thromboplastin time, activated protein C resistance, hematocrit, or factor VII. An examination of changes in physical activity between baseline and 20 years later showed that inactive men who took up at least light physical activity had levels of blood variables approaching those who remained at least lightly active. Those who became inactive showed levels more similar to those who remained inactive. CONCLUSIONS: These data suggest that the benefit of physical activity on cardiovascular disease may be at least partly a result of effects on hemostasis and inflammation.

Aged↗
PubMed2002

Interleukin-6 -174G>C polymorphism and risk of coronary heart disease in West of Scotland coronary prevention study (WOSCOPS).

Interleukin (IL)-6 plays an important role in the pathogenesis of coronary heart disease (CHD). Two functional polymorphisms in the IL-6 promoter have been identified (-174G>C and -572G>C), with both the rare alleles being associated with higher plasma levels of IL-6 after bypass surgery and one of them (-174G>C) associated with CHD risk. We have studied the contribution of these polymorphisms to CHD risk in the West of Scotland Coronary Prevention Study (WOSCOPS), a primary prevention trial that demonstrated the effectiveness of pravastatin in reducing morbidity and mortality from CHD. Four hundred ninety-eight cases (consisting of individuals experiencing a cardiovascular event during 4.8 years of follow-up) and 1109 controls (individuals matched for age and smoking habits) were genotyped. In the placebo group, there was no significant evidence of higher risk associated with the -174CC genotype compared with the GG+GC group. However, in the pravastatin-treated group, CC homozygotes had a significantly lower risk of CHD compared with the GG+GC placebo group (odds ratio 0.46, 95% CI 0.27 to 0.79), and this remained statistically significant after adjustment for classic risk factors. Compared with the GG+GC group, men with the CC genotype had modestly, but not significantly, higher baseline levels of IL-6, C-reactive protein, or fibrinogen but showed a significantly greater fall in LDL cholesterol with statin treatment (P=0.036). The -572G>C polymorphism was not significantly associated with any plasma trait or CHD risk. Thus, in subjects under pravastatin treatment, the -174CC genotype was associated with a lower risk of CHD. These results demonstrate the importance of the inflammatory system in determining the risk of CHD and support the nonlipid effect of statins on risk.

Anticholesteremic Agents↗
PubMed2002

Association of the factor XII 46C>T polymorphism with risk of coronary heart disease (CHD) in the WOSCOPS study.

AIM: To evaluate the contribution of the 46C>T polymorphism of the Factor XII (FXII) gene to risk for coronary heart disease (CHD) in the West of Scotland Coronary Prevention Study (WOSCOPS) of men with high cholesterol. BACKGROUND: WOSCOPS is a primary prevention trial that demonstrated the effectiveness of pravastatin in reducing morbidity and mortality from CHD. FXII is a protein of the contact system that plays a key role in both coagulation and fibrinolysis. Elevated activated FXII (FXIIa) levels have been previously associated with CHD. Plasma FXIIa levels are strongly determined by a 46C>T polymorphism in the FXII gene. RESULTS: 441 CHD cases and 990 controls were genotyped. The frequency of TT homozygotes was 8.3% in controls and 11.8% in cases (P=0.04). When compared with the CC+CT group (after adjustment for age, blood pressure, BMI, fibrinogen and lipid levels) the TT genotype was an independent risk factor for CHD (OR 1.48 95% CI 1.01-2.17), an effect that was only significant in the pravastatin group (OR 1.95 95% CI 1.09-3.47) and not in the placebo group (OR 1.20, 95%CI 0.72-2.02). Compared with risk in the placebo group as a whole (reference group), and after adjustment for other risk factors, men with the CC or CT genotype, but not the TT genotype showed a significant benefit from pravastatin treatment (OR, respectively, 0.61 (0.46-0.81) and 0.56 (0.40-0.79) compared with 1.10 (0.64-1.96). In a subgroup of these men, subjects with the TT genotype had, as expected, baseline levels of FXIIa that were 50% lower than those with the CC genotype, with CT subjects having intermediate levels (P<0.001 by Kruskal-Wallis test). CONCLUSIONS: The TT genotype of the FXII 46C>T polymorphism is associated with a high risk of CHD in men with high cholesterol. We hypothesise that reduced fibrinolysis in these men, as a consequence of lower plasma FXIIa, may be the mechanism leading to higher risk, and that pravastatin treatment may enhance this effect.

Case-Control Studies↗
PubMed2002

The need for risk factor assessment in atherothrombotic vascular disease.

Risk factors for cardiovascular disease are characteristically associated with an increased likelihood of disease. Prospective studies of incident disease are less prone to bias than cross-sectional or case-control studies of prevalent disease. Meta-analyses of prospective studies provide more reliable estimates of the strength of association of risk factors with risk of disease than individual studies. Meta-analyses of intervention studies provide the most reliable estimates of reversibility of disease risk through prolonged reduction of classical risk factors (e.g., blood pressure, serum cholesterol). Emerging potential risk factors include markers of infection, inflammation, and thrombosis; their possible roles in causation and in risk prediction require much further study.

Arteriosclerosis↗
PubMed2002

Hemostatic and rheological variables and risk of cardiovascular disease.

Increasing blood levels of hemostatic variables may increase the risk of thrombosis, while increasing levels of rheological variables which reduce blood flow may increase the risk of ischemic events. Systematic reviews of prospective cohort studies of hemostatic and rheological variables suggest that increasing blood levels of fibrinogen, von Willebrand factor, tissue plasminogen activator antigen, fibrin D-dimer, hematocrit, viscosity, and erythrocyte sedimentation rate may be predictors of risk of coronary heart disease (CHD), but their causal relevance is unknown. At present, data for the associations of other hemostatic variables with CHD, and for the associations of hemostatic variables with stroke, venous thromboembolism, and mortality, is relatively sparse and inconclusive. More detailed syntheses of existing prospective data (such as the Fibrinogen Studies Collaboration), observational studies of CHD and the genetic determinants of these plasma components, as well as large-scale randomized trials should help to determine whether or not these associations are (1) useful in prediction of cardiovascular risk and/or (2) of causal significance.

Blood Coagulation↗