Plasma ADAMTS-13 levels and the risk of myocardial infarction: an individual patient data meta-analysis.

BACKGROUND: Low ADAMTS-13 levels have been repeatedly associated with an increased risk of ischemic stroke, but results concerning the risk of myocardial infarction are inconclusive. OBJECTIVES: To perform an individual patient data meta-analysis from observational studies investigating the association between ADAMTS-13 levels and myocardial infarction. METHODS: A one-step meta-analytic approach with random treatment effects was used to estimate pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) adjusted for confounding. Analyses were based on dichotomous exposures, with the 5th and 1st percentiles of ADAMTS-13 antigen levels as cut-off values. Quartile analyses, with the highest quartile as a reference category, were used to assess a graded association between levels and risk ('dose' relationship). Additionally, we assessed the risk of the combined presence of low ADAMTS-13 and high von Willebrand factor (VWF) levels. RESULTS: Five studies were included, yielding individual data on 1501 cases and 2258 controls (mean age of 49 years). Low ADAMTS-13 levels were associated with myocardial infarction risk, with an OR of 1.89 (95% CI 1.15-3.12) for values below the 5th percentile versus above, and an OR of 4.21 (95% CI 1.73-10.21) for values below the 1st percentile versus above. Risk appeared to be restricted to these extreme levels, as there was no graded association between ADAMTS-13 levels and myocardial infarction risk over quartiles. Finally, there was only a minor synergistic effect for the combination of low ADAMTS-13 and high VWF levels. CONCLUSIONS: Low ADAMTS-13 levels are associated with an increased risk of myocardial infarction.

Hepatitis C infection and outcomes in the Scottish haemophilia population.

Patients with bleeding disorders previously frequently became infected with hepatitis C virus. We identified the number of patients infected in Scotland and assessed several aspects of the outcomes of HCV infection and its treatment comparing these with cohorts infected for other reasons. We calculated the number of individuals infected in Scotland (cohort A) starting with the total number of patients treated in Scottish haemophilia centres registered on the UKHCDO database between 1970 and 1989. Cases were then removed or added based on additional information from centre records. A second cohort B, consisted of 255 patients from cohort A and 47 patients HCV infected outside Scotland, but with follow-up data from Scottish centres around their HCV infection. We estimate that 455 patients with bleeding disorders became infected by coagulation factor provided by NHS Scotland. In 302 individuals with documented HCV infection, rates of natural clearance (17.4%), genotype spread (64% genotype 1) and responses to antiviral therapy (14.5% with monotherapy; 38.8% with combination therapy) were similar to those in other cohorts. Thirty-four liver biopsies were performed without adverse event and liver transplantation has been performed in 11 patients, seven for liver failure, four for hepatocellular carcinoma. Around 455 patients with bleeding disorders became HCV infected in Scotland before 1989. The natural history of HCV infection and responses to treatment are similar to those in other HCV-infected cohorts. Liver transplantation has been used successfully for the treatment of end-stage liver failure and hepatocellular carcinoma.

Sex-specific time trends in first admission to hospital for peripheral artery disease in Scotland 1991-2007.

BACKGROUND: This study examined trends for all first hospital admissions for peripheral artery disease (PAD) in Scotland from 1991 to 2007 using the Scottish Morbidity Record. METHODS: First admissions to hospital for PAD were defined as an admission to hospital (inpatient and day-case) with a principal diagnosis of PAD, with no previous admission to hospital (principal or secondary diagnosis) for PAD in the previous 10 years. RESULTS: From 1991 to 2007, 41,593 individuals were admitted to hospital in Scotland for the first time for PAD. Some 23,016 (55.3 per cent) were men (mean(s.d.) age 65.7(11.7) years) and 18,577 were women (aged 70.4(12.8) years). For both sexes the population rate of first admissions to hospital for PAD declined over the study interval: from 66.7 per 100,000 in 1991-1993 to 39.7 per 100,000 in 2006-2007 among men, and from 43.5 to 29.1 per 100,000 respectively among women. After adjustment, the decline was estimated to be 42 per cent in men and 27 per cent in women (rate ratio for 2007 versus 1991: 0.58 (95 per cent confidence interval 0.55 to 0.62) in men and 0.73 (0.68 to 0.78) in women). The intervention rate fell from 80.8 to 74.4 per cent in men and from 77.9 to 64.9 per cent in women. The proportion of hospital admissions as an emergency or transfer increased, from 23.9 to 40.7 per cent among men and from 30.0 to 49.5 per cent among women. CONCLUSION: First hospital admission for PAD in Scotland declined steadily and substantially between 1991 and 2007, with an increase in the proportion that was unplanned.

Prospective study of seasonal patterns in hemostatic factors in older men and their relation to excess winter coronary heart disease deaths.

BACKGROUND: In England and Wales, approximately 20% extra deaths from coronary heart disease (CHD) occur between December and March, among older people. Circulating concentrations of tissue plasminogen activator (t-PA), von Willebrand factor (VWF) and fibrin D-dimer are associated with arterial disease, and tend to peak in winter. The potential contributions of these hemostatic activation measures to excess winter mortality are unknown. OBJECTIVES: To estimate contributions of hemostatic factors to excess winter mortality. METHODS: Seasonal patterns in t-PA, VWF and D-dimer were investigated in 4088 men aged 60-79 years from 24 British towns. Data on established coronary risk factors were collected by questionnaire, physical examination and blood sampling. The adjusted mean increase in hemostatic markers during winter months, after adjustment for a range of coronary risk factors, was combined with associations of each marker with CHD mortality obtained from 9 years' follow-up of participants, to predict degree of excess CHD winter mortality. Associations of hemostatic markers with CHD incidence from large meta-analyses were also used. RESULTS: All three markers showed peaks in winter; the adjusted mean increases during winter months were 0.21, 0.15 and 0.12 standard deviations for t-PA, VWF and log(D-dimer), respectively. Predicted excess hazard ratios for winter CHD mortality were 3.0%, 2.4% and 3.1%, respectively, in combination, representing an 8.6% excess. This increased to 14% when applying meta-analysis estimates. CONCLUSIONS: Seasonal patterns in three hemostatic markers predict at least 8.6% excess CHD mortality in winter in Great Britain, potentially accounting for over half the excess observed in recent years.

Prospective study of circulating soluble CD40 ligand concentrations and the incidence of cardiovascular disease in a nested prospective case-control study of older men and women.

BACKGROUND: CD40 ligand(CD40L) is implicated in atherosclerotic plaque formation. OBJECTIVES: We investigated prospective associations between circulating soluble CD40L and myocardial infraction (MI) or stroke in an older general population cohort, accounting for established and novel cardiovascular risk factors. METHODS: Baseline serum CD40L (sCD40L) was measured in incident MI (n = 368) and stroke (n = 304) cases and two controls per case, 'nested' in prospective UK studies of 4252 men and 4286 women aged 60-79 years, sampled from general practices in Britain in 1998-2000, with 7-year follow-up for fatal and non-fatal MI and stroke. RESULTS: sCD40L was higher in smokers and negatively associated with lung function and positively associated with total cholesterol and markers of inflammation, but not with other established cardiovascular disease (CVD) risk factors. Geometric mean sCD40L levels did not differ between MI cases and controls (5.94 ng mL(-1) vs. 5.82 ng mL(-1); P = 0.5) or between stroke cases and controls (5.61 ng mL(-1) vs. 5.28 ng mL(-1), P = 0.1). There was no strong evidence for elevated risk of MI or stroke in multivariable models comparing participants in the top to those in the bottom third of sCD40L. Age-adjusted odds ratios (ORs) were 1.39 [95% confidence interval (CI) 0.98, 1.96] for MI and 1.16 (0.78, 1.73) for stroke. These attenuated to 1.24 (95% CI 0.86, 1.79) and 1.18 (0.78, 1.78), respectively, after adjustment for established and novel CVD risk factors. CONCLUSIONS: sCD40L is associated with other inflammatory markers but is not itself a strong independent risk marker for either stroke or MI.

Association between circulating hemostatic measures and dementia or cognitive impairment: systematic review and meta-analyzes.

BACKGROUND AND OBJECTIVES: Hemostasis and thrombosis may be important contributors to cognitive decline and dementia. Certain blood markers may assist in diagnosis or management. OBJECTIVES: To collate evidence for the association of circulating hemostatic variables and dementia or cognitive impairment. METHODS: A systematic review of studies describing blood markers of hemostatic function and cognition/dementia. Abstracts were reviewed by two independent assessors and studies selected based on pre-specified criteria. We described methodological quality and performed meta-analyzes where data allowed. RESULTS: From 7103 titles, 485 abstracts and included 21 studies (n = 32,773) were assessed. In two longitudinal studies, the incident of vascular dementia risk was greater for higher D-dimer [hazard ratio (HR): 1.50, 95% confidence interval (CI): 1.15-1.96]. For case-control data, we calculated standardized mean differences (SMD) and 95% CI. Higher levels of: factor (F)VII (SMD: 0.93; 95% CI: 0.60-1.26), fibrinogen (SMD: 1.53; 95% CI: 1.17-1.87), prothrombin fragment 1 and 2 (SMD: 0.64; 95% CI: 0.32-0.96), plasminogen activator inhibitor (SMD: 0.68; 95% CI: 0.26-1.10), D-dimer (SMD: 2.00; 95% CI: 1.59-2.40) and von Willebrand factor (VWF) (SMD: 1.68; 95% CI: 1.30-2.06) showed modest but significant associations with vascular dementia. For patients with any dementia diagnosis, associations were with higher D-dimer (SMD: 0.36; 95% CI: 0.15-0.56) and VWF (SMD: 0.31; 95% CI: 0.11-0.51). For specific cognitive domains, significant (P < 0.001) positive correlations were fibrinogen and speed of processing (0.76; 95% CI: 0.67-0.84), verbal memory (0.69; 95% CI: 0.59-0.79) and non-verbal reasoning (0.57; 95% CI: 0.49-0.65). CONCLUSIONS: The present results suggest a modest association between hemostasis and vascular dementia including increased levels of thrombin generation markers (D-dimer and prothrombin fragment 1 + 2) and endothelial dysfunction (VWF and plasminogen activator inhibitor). Associations are weaker for specific cognitive tests and when all dementias are combined.

Management of deep vein thrombosis to reduce the incidence of post-thrombotic syndrome.

The post-thrombotic syndrome (PTS) is the major chronic sequel of deep vein thrombosis (DVT) of the leg, and is a major socioeconomic challenge. In addition to systematic prophylaxis of DVT in hospitalized patients, effective management of DVT is important to reduce the incidence of PTS. Thrombolysis and thrombectomy are not indicated routinely. Optimal anticoagulation, usually with heparins initially and then with oral warfarin, is important to prevent recurrent DVT, which is a major risk factor for PTS. Following a routine three-month period of anticoagulation, patients with proximal idiopathic DVT should be individually assessed for the benefits and risks of continued oral anticoagulation, including patient preferences. Risk factors for recurrent DVT include active cancer, pregnancy, continued use of oral oestrogens, male sex, obesity, recurrent thrombosis, established PTS, permanent inferior vena caval filters, residual DVT, high fibrin d-dimer and other thrombophilias. Early walking, continued high levels of physical activity and wearing compression stockings for up to two years may also reduce the risk of PTS.

Haemorheological predictors of cognitive decline: the Edinburgh Artery Study.

INTRODUCTION: vascular risk factors and diseases can negatively impact cognitive function. Determinants of blood flow are implicated in thrombogenesis and ischaemic events, yet little is known about their relationship with cognition. METHODS: blood rheology data were collected in 1987/88, and cognitive testing was performed in 1998/99 when the mean (+ or - standard deviation) age of the study sample was 73.1 years (+ or - 5.0). Follow-up assessment was performed 4 years later. Information was collected on verbal declarative memory, non-verbal reasoning, verbal fluency, information processing speed and a general cognitive factor representing the variance common to the individual test scores. RESULTS: after controlling for age, sex and cognitive performance in 1998/99, blood viscosity (BV) (P < 0.05) and fibrinogen (P < 0.05) predicted decline in non-verbal reasoning over 4 years. When estimated from pre-morbid level, decline in general cognition (P < 0.05), non-verbal reasoning (P < 0.05) and information processing speed (P < 0.01) was associated with BV levels. Haematocrit (HCT) had similar effects (P < 0.01 to P < 0.001). All associations persisted after control for multiple confounders. When examined together, HCT but not BV independently predicted cognitive decline. CONCLUSIONS: blood rheology is independently related to cognitive decline in older people. The value of strategies aimed at preserving cognition through influencing blood rheology needs investigation.

Secondhand smoke (SHS) exposure is associated with circulating markers of inflammation and endothelial function in adult men and women.

AIMS: Secondhand smoke (SHS) exposure is associated with elevated CHD risks. Yet the pathways through which this may operate have not been investigated in epidemiologic studies with objective SHS exposure measures and a wide range of CHD risk factors associated with active smoking. Therefore we investigate associations between SHS exposure and CHD risk factors, to clarify how SHS exposure may raise risk of CHD. METHODS: Cross-sectional population-based study of 5029 men and women aged 59-80 years from primary care practices in Great Britain. Smoking, behavioural and demographic information was reported in questionnaires; nurses made physical measurements and took blood samples for analysis of serum cotinine and markers of inflammation, hemostasis and endothelial dysfunction. RESULTS: Active cigarette smokers had lower albumin and higher triglycerides, CRP, IL-6, white cell count, fibrinogen, blood viscosity, factor VIII, VWF and t-PA than non-smokers. Among non-smokers, serum cotinine levels were independently positively associated with CRP, fibrinogen, factor VIII, VWF and t-PA and inversely associated with albumin, after adjustment for age, gender, social and behavioural factors. The differences in CRP, fibrinogen and albumin between cotinine < or =0.05 and >0.7 ng/ml were one-third to one half the size of differences between cotinine < or =0.05 ng/ml and current smokers, but were of similar magnitude for VWF and t-PA. CONCLUSIONS: Endothelial, inflammatory and haemostatic markers related to CHD risk showed independent associations with SHS exposure in the same direction as those for active smoking. Results aid understanding of the associations between SHS exposure and elevated CHD risks.

Circulating inflammatory and hemostatic biomarkers are associated with risk of myocardial infarction and coronary death, but not angina pectoris, in older men.

AIMS: The extent to which hemostatic and inflammatory biomarkers are related to angina pectoris as compared with myocardial infarction (MI) remains uncertain. We examined the relationship between a wide range of inflammatory and hemostatic biomarkers, including markers of activated coagulation, fibrinolysis and endothelial dysfunction and viscosity, with incident myocardial infarction (MI) or coronary heart disease (CHD) death and incident angina pectoris uncomplicated by MI or CHD death in older men. METHODS: A prospective study of 3217 men aged 60-79 years with no baseline CHD (angina or MI) and who were not on warfarin, followed up for 7 years during which there were 198 MI/CHD death cases and 220 incident uncomplicated angina cases. RESULTS: Inflammatory biomarkers [C-reactive protein (CRP), interleukin-6, fibrinogen], plasma viscosity and hemostatic biomarkers [von Willebrand factor (VWF) and fibrin D-dimer] were associated with a significant increased risk of MI/CHD death but not with uncomplicated angina even after adjustment for age and conventional risk factors. Adjustment for CRP attenuated the relationships between VWF, fibrin D-dimer and plasma viscosity with MI/CHD death. Comparisons of differing associations with risk of MI/CHD deaths and uncomplicated angina were significant for the inflammatory markers (P < 0.05) and marginally significant for fibrin D-dimer (P = 0.05). In contrast, established risk factors including blood pressure and high-density lipoprotein (HDL)-cholesterol were associated with both MI/CHD death and uncomplicated angina. CONCLUSION: Circulating biomarkers of inflammation and hemostasis are associated with incident MI/CHD death but not incident angina uncomplicated by MI or CHD death in older men.

Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study.

BACKGROUND: A lack of longitudinal studies has made it difficult to establish the direction of associations between circulating concentrations of low-grade chronic inflammatory markers, such as C-reactive protein and interleukin-6, and cognitive symptoms of depression. The present study sought to assess whether C-reactive protein and interleukin-6 predict cognitive symptoms of depression or whether these symptoms predict inflammatory markers. METHOD: In a prospective occupational cohort study of British white-collar civil servants (the Whitehall II study), serum C-reactive protein, interleukin-6 and cognitive symptoms of depression were measured at baseline in 1991-1993 and at follow-up in 2002-2004, an average follow-up of 11.8 years. Symptoms of depression were measured with four items describing cognitive symptoms of depression from the General Health Questionnaire. The number of participants varied between 3339 and 3070 (mean age 50 years, 30% women) depending on the analysis. RESULTS: Baseline C-reactive protein (beta=0.046, p=0.004) and interleukin-6 (beta=0.046, p=0.005) predicted cognitive symptoms of depression at follow-up, while baseline symptoms of depression did not predict inflammatory markers at follow-up. After full adjustment for sociodemographic, behavioural and biological risk factors, health conditions, medication use and baseline cognitive systems of depression, baseline C-reactive protein (beta=0.038, p=0.036) and interleukin-6 (beta=0.041, p=0.018) remained predictive of cognitive symptoms of depression at follow-up. CONCLUSIONS: These findings suggest that inflammation precedes depression at least with regard to the cognitive symptoms of depression.

Serum matrix metalloproteinase-9 and coronary heart disease: a prospective study in middle-aged men.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) has a potential role in arterial plaque rupture, but its relation to risk of coronary heart disease (CHD) is uncertain. AIM: To determine whether circulating levels of serum MMP-9 are prospectively related to the risk of CHD in the general population. METHODS: We measured baseline MMP-9 levels in stored serum samples of subjects in a case-control study nested within a prospective study of 5661 men followed up for 16 years for CHD events (465 cases, 1076 controls). RESULTS: MMP-9 values were associated with cigarette smoking, and with several inflammatory and haemostatic markers, but not with age, body mass index, blood pressure or lipid measurements. Men in the top third of baseline MMP-9 levels had an age-adjusted odds ratio (OR) for CHD of 1.37 (95% CI 1.04-1.82) compared with those in the bottom third. Adjustment for conventional risk factors (smoking in particular) reduced the odds ratio to borderline significance: OR 1.28 (95% CI 0.95-1.74), while additional adjustment for two markers of generalized inflammation, interleukin-6 and C-reactive protein, further attenuated the association: OR 1.13 (0.82-1.56). CONCLUSION: Serum MMP-9 has a modest association with incident CHD in the general population, which is not independent of cigarette smoking exposure and circulating markers of generalized inflammation. MMP-9 is unlikely to be a clinically useful biomarker of CHD risk, but may still play a role in the pathogenesis of CHD.

Early life growth and hemostatic factors: the Barry Caerphilly Growth study.

Associations between early life growth trajectories and a range of adult (aged approximately 25 years) hemostatic factors were assessed in the Barry Caerphilly Growth study (N = 517) in South Wales, 1974-1999. Associations of birth weight, birth length, and weight and height velocities during three periods ("immediate": 0-<5 months, "infant": 5 months-<1 year 9 months, and "childhood": 1 year 9 months-5 years) with adult levels of hemostatic factors were assessed. Birth weight was inversely associated with fibrinogen (beta per 1-unit change in z score = -0.08, 95% confidence interval (CI): -0.15, -0.02). Immediate weight velocity was inversely associated with factor VII (beta = -1.88, 95% CI: -3.84, 0.09), factor VIII (beta = -2.58, 95% CI: -4.07, -0.45), and von Willebrand factor antigen (beta = -4.07, 95% CI: -7.25, -0.89). Birth length was inversely associated with fibrinogen (beta = -0.07, 95% CI: -0.14, -0.01). Evidence was weaker for an inverse association of immediate height velocity with factor VIII (beta = -2.16, 95% CI: -4.62, 0.29) and von Willebrand factor antigen (beta = -2.85, 95% CI: -6.52, 0.81). Childhood height velocity was positively associated with D-dimer (ratio of geometric means = 1.11, 95% CI: 1.01, 1.23). Results support the view that the immediate postnatal period may be particularly important, possibly through impaired liver development and/or infection in early life, in determining cardiovascular disease risk.

Evidence that high von Willebrand factor and low ADAMTS-13 levels independently increase the risk of a non-fatal heart attack.

BACKGROUND: A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) may influence von Willebrand factor (VWF) levels and consequently the risk of myocardial infarction (MI). Moreover, ADAMTS-13 influences hemostatic plug formation in mouse models. We therefore studied their associations in the Glasgow MI Study (GLAMIS). METHODS AND RESULTS: We measured ADAMTS-13 and VWF antigen levels by ELISAs in stored plasma from a case-control study of 466 MI cases and 484 age- and sex-matched controls from the same north Glasgow population. There was no correlation between ADAMTS-13 and VWF levels in cases or controls. ADAMTS-13 levels correlated positively with serum cholesterol and triglycerides and body mass index, and negatively with high-density lipoprotein-cholesterol. VWF levels correlated with age, fibrinogen and C-reactive protein. In multivariable analyses including risk factors, VWF correlated positively with risk of MI, and ADAMTS-13 correlated negatively with risk of MI. These associations were independent of each other. The association of ADAMTS-13 with risk of MI was observed only in multivariable analysis. CONCLUSIONS: VWF and ADAMTS-13 levels were not associated in this study, and showed associations with MI risk in opposite directions but of similar strength. The association of ADAMTS-13 with MI is influenced by lipid levels, and consequently requires further investigation.

Blood interactions with plasticised poly (vinyl chloride): influence of surface modification.

Surface modification of plasticised poly (vinyl chloride) (PVC), with di-(2-ethylhexyl) phthalate (DEHP) as plasticiser, for the improvement of blood compatibility in potential clinical use such as cardiopulmonary bypass was achieved by heparinisation. The influence of surface modification on blood compatibility was assessed in terms of the influence on fibrinogen and factor XII adsorption in vitro, and the generation of thrombin-antithrombin III complex (TAT) and the complement component C3a, in vitro and ex vivo. Electron spectroscopy for chemical analysis (ESCA) was used to characterise the heparinised surface in order to correlate the surface properties with the blood response. Results indicate that at the plasticised PVC surface there is a higher content of heparin than that of the PVC and the DEHP content is lower than that present at the surface of standard plasticised PVC. The blood compatibility assessment confirms the importance of surface modification for the improvement of blood compatibility.

Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant meta-analysis of 154,211 adults in 31 prospective studies: the fibrinogen studies collaboration.

Long-term increases in plasma fibrinogen levels of 1 g/liter are associated with an approximate doubling of risk of major cardiovascular disease outcomes, but causality remains uncertain. To quantify cross-sectional associations of fibrinogen levels with established risk factors and other characteristics, the investigators combined individual data on 154,211 apparently healthy adults from 31 prospective studies conducted between 1967 and 2003, using a linear mixed model that included random effects at the cohort level. Fibrinogen levels increased with age and showed continuous, approximately linear relations with several risk markers and slightly curvilinear associations with log triglycerides, albumin, and tobacco and alcohol consumption. Female sex, Black ethnicity, lower socioeconomic status, and alcohol abstinence were each associated with modestly higher fibrinogen levels. Approximately one third of the variation in fibrinogen levels was explained by cohort, age, and sex. An additional 7% was explained by established risk factors (notably, positive associations with smoking and body mass index and an inverse association with high density lipoprotein cholesterol), and a further 10% was explained by inflammatory markers (notably, a positive association with C-reactive protein). The association with body mass index was twice as strong in women as in men, whereas the association with smoking was much stronger in men. These findings substantially advance understanding of the correlates and possible determinants of fibrinogen levels.