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Background: The cause of lacunar ischemic stroke, a clinical feature of cerebral small vessel disease (SVD), is largely unknown. Inflammation and endothelial dysfunction have been implicated. Plasma biomarkers could provide mechanistic insights but current data are conflicting. White matter hyperintensities (WMHs) are an important imaging biomarker of SVD. It is unknown if plasma biomarkers add predictive capacity beyond age and vascular risk factors in explaining WMH., Methods: We prospectively recruited patients presenting with non-disabling ischemic stroke, classifying them clinically and with the help of MRI as lacunar or cortical. We measured biomarkers of inflammation, endothelial dysfunction and hemostasis for >1 month after stroke and compared biomarker levels between stroke subtypes. We quantitatively calculated WMH. We used multiple linear regression analysis to model WMH as a function of age, sex, hypertension and smoking (the baseline model). We fitted exploratory models using plasma biomarkers as predictor variables to assess model improvement over baseline., Results: We recruited 125 patients. The lacunar group (n = 65) had lower tissue plasminogen activator (t-PA) levels in unadjusted (7.39 vs. 8.59 ng/ml, p = 0.029) and adjusted (p = 0.035) analyses compared with the cortical group (n = 60). There were no significant differences in the other plasma biomarkers. The results for t-PA were consistent with an updated meta-analysis, although the effect remains non-significant (standardized mean difference -0.08 (95% CI -0.25 to 0.09)). The baseline regression model explained 29% of the variance in quantitative WMH (R2 0.289). Inflammatory biomarkers showed minor improvement over baseline (R2 0.291), but the other plasma biomarkers did not improve the baseline model., Conclusion: Plasma t-PA levels appear to differ between lacunar and cortical stroke subtypes, late after stroke, independent of age, sex and vascular risk factors and may reflect endothelial dysfunction. Except for a minor additional predictive effect of inflammatory markers, plasma biomarkers do not relate to WMH severity in this small stroke population., (© 2015 The Author(s) Published by S. Karger AG, Basel.)

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., (© 2012 International Society on Thrombosis and Haemostasis.)

Background: Circulating levels of C-reactive protein (CRP), fibrinogen, fibrin D-dimer, tissue plasminogen activator antigen (t-PA) and von Willebrand factor (VWF) are associated with incident coronary heart disease (CHD). However, their associations with metabolic syndrome and its components in large populations of men and women have not been well defined., Objectives: We compare the sex associations of these biomarkers with established CHD risk factors, metabolic syndrome and its components in a large cohort., Patients and Methods: 8302 men and women aged 45 years from the British 1958 birth cohort provided a blood sample. Analyses were restricted to 3457 men and 3464 women with complete data on all risk factors and no history of cardiovascular disease. Multiple regression analyses adjusted for smoking, social class, alcohol consumption and variables related to biomarker measurement error., Results: Adjusted sex differences in levels of all biomarkers (except VWF) varied according to presence/absence of metabolic syndrome, its components and obesity (BMI ≥30 kg m(-) (2)). Associations in women were up to twice as strong for CRP, fibrinogen and t-PA with markers of obesity (body mass index, waist circumference), blood pressure, blood lipids and metabolic syndrome. D-dimer showed weaker associations and less heterogeneity by sex. There was no evidence of sex interaction in associations with VWF., Conclusions: Associations between CRP, fibrinogen and t-PA and metabolic syndrome and its components were stronger in women than in men. Understanding the reasons for these differences across sex will be important in understanding the pathophysiology of cardiovascular and metabolic disease in men and women., (© 2011 International Society on Thrombosis and Haemostasis.)

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., (© 2011 International Society on Thrombosis and Haemostasis.)

Objective: To determine whether activation of hemostatic function (thrombosis and fibrinolysis) is associated with cognitive decline in older people., Methods and Results: We studied 5804 people (age, 70-82 years) in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Mean follow-up was 3.2 years, including annual measurement of speed of information processing (letter, digit coding, and Stroop), verbal memory (picture-word naming), and basic and instrumental activities of daily living. Raised levels of markers of thrombin generation (d-dimer and prothrombin fragment 1+2) were associated independently with increased rate of cognitive decline (eg, Stroop increased by 4.44 s [SEM, 0.68] in bottom tertile of d-dimer compared to 5.46 [SEM, 0.71] in highest tertile; P<0.05) and deterioration in activities of daily living. This increased rate of decline was attenuated but not removed when subjects with incident nonfatal stroke were omitted from the analysis. It also persisted when adjustments were made for inflammation (C-reactive protein and IL-6)., Conclusions: Older patients with increased markers of thrombin generation (d-dimer and prothrombin fragment 1+2) are at increased risk for cognitive decline and deterioration in ability to perform activities of daily living. This is likely attributable to increased risk of cerebral ischemic damage (including covert disease) associated with prothrombotic states.

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.

Background: Many inflammatory and haemostatic biomarkers show associations with acute ischaemic stroke outcome, but few studies compare a large range of markers., Methods: We assessed clinical status and 16 biomarkers within 24 h of onset in 180 consecutive acute ischaemic stroke patients., Results: A total of 94 patients had a poor outcome (dead or dependent at 30 days). C-reactive protein (CRP), IL-6, and fibrin D-dimer showed the strongest univariate associations with poor outcome (>2-fold increase; p < 0.01). When all biomarkers were included with clinical variables in a multivariable model, only D-dimer (OR 1.54; 95% CI 1.09-2.17), CRP (OR 1.31; 95% CI 1.03-1.68) and Scandinavian Stroke Scale (OR 0.91; 95% CI 0.88-0.95) were associated with poor outcome., Conclusions: D-dimer and CRP are independently associated with poor outcome in acute ischaemic stroke. More data is required to expand our understanding of these potential relationships with outcome.

Background: The aim of our present study was to compare the association of a wide range of 17 biomarkers of inflammation, hemostasis, and blood rheology with incident heart disease and stroke after accounting for an indicator of subclinical atherosclerotic disease and traditional risk factors and also to determine their incremental predictive ability., Methods and Results: We used data from the Edinburgh Artery Study, a population cohort study started in 1987 that comprised 1592 men and women aged 55 to 74 years. Subjects were followed for a mean of 17 years, and 416 of them suffered at least 1 cardiovascular event. In analyses adjusted for cardiovascular risk factors and history of cardiovascular disease (CVD): C-reactive protein, interleukin-6, fibrinogen, fibrin D-dimer, tissue plasminogen activator (t-PA), leukocyte elastase, and lipoprotein(a) (all P<0.01), as well as von Willebrand factor and plasma viscosity (both P<0.05), had significant hazard ratios for incident CVD. Further adjustment for a measure of subclinical atherosclerosis (ankle brachial index) had little impact on these associations. The hazard ratios (95% CI) for incident CVD between top and bottom tertiles in the latter analysis were 1.78 (1.30 to 2.45) for C-reactive protein, 1.85 (1.33 to 2.58) for interleukin-6, and 1.76 (1.35 to 2.31) for fibrinogen. Single biomarkers provided little additional discrimination of incident CVD to that obtained from cardiovascular risk factors and the ankle brachial index. An incremental score of multiple markers [interleukin-6, t-PA, intercellular adhesion molecule 1, and lipoprotein(a)] provided some added discrimination., Conclusions: Several "novel" risk factors predicted CVD after adjustments for conventional risk factors and also for a measure of asymptomatic disease. However, their incremental predictive ability was modest and their clinical utility remains uncertain.

Background and Aim: Leptin, an adipocyte-derived protein, regulating food intake and metabolism has been implicated in the development of coronary heart disease. We have examined the relationship between leptin and vascular risk factors including insulin resistance, metabolic, inflammatory and haemostatic risk factors., Methods and Results: The study was carried out in 3640 non-diabetic men aged 60-79 years drawn from general practices in 24 British towns and who were not on warfarin. Leptin was strongly positively correlated with waist circumference (r=0.58; p<0.0001). Leptin concentrations decreased significantly with increasing physical activity and were lowered in cigarette smokers and elevated in men with pre-existing coronary heart disease and stroke; alcohol intake showed no association with leptin concentration. After adjustment for waist circumference and these lifestyle factors, increased leptin was independently associated with significant increases in insulin resistance, triglycerides, inflammatory markers (interleukin-6, C-reactive protein, fibrinogen, plasma viscosity), coagulation factor VIII, endothelial markers von Willebrand factor, tissue plasminogen activator, and fibrin D-dimer levels; and a decrease in HDL-cholesterol. No association was seen between leptin and blood pressure, total cholesterol, glucose or white cell count after adjusting for waist circumference. Further adjustment for insulin resistance abolished the relationships between leptin and triglycerides and HDL-cholesterol, weakened the associations with the haemostatic factors although they remained significant, but made minor differences to the associations with inflammatory markers., Conclusion: Plasma leptin is associated with insulin resistance, inflammation and disturbances in haemostasis independent of waist circumference, suggesting possible pathways by which leptin may influence risk of cardiovascular disease.

Background: Previous studies have suggested that several hemostatic and inflammatory variables, which are risk predictors for arterial or venous thrombosis, increase with age. However, there is a lack of data from large population studies for reliable estimates of reference ranges., Objectives: To establish reliable reference ranges of hemostatic and inflammatory variables for 5-year age groups in older men and their implications for pathogenesis and diagnosis., Patients and Methods: A total of 3861 men aged 60-79 years at the 20 years follow-up of the British Regional Heart Study., Results: Several variables increased with age. The greatest median increases between 60-64 and 75-79 years age groups were observed for fibrin D-dimer (91%) and C-reactive protein (CRP) (57%). Significant median increases were also observed for von Willebrand factor antigen (23%), tissue plasminogen activator antigen (11%), factor VIII (10%), and fibrinogen (8%). In contrast, levels of classical cardiovascular risk factors neither decreased nor increased substantially with age, with the exception of systolic blood pressure (median increase 10%)., Conclusions: The exponential increases in risk of arterial and venous thrombotic events in men between age 60 and 79 years (when most such events occur) may be related in part to increasing activation of blood coagulation, fibrinolysis, and inflammation; possibly related to the increasing inflammatory burden of both atherosclerotic and non-vascular disease. These increases also have implications for diagnosis of suspected acute venous thromboembolism (D-dimer), and recently proposed screening for prediction of coronary heart disease risk and detection of occult disease (CRP).

Background: It has been suggested that a high dietary intake and high circulating concentrations of vitamin C may protect against ischemic heart disease., Objectives: The objective was to examine the associations between dietary and plasma vitamin C concentrations, fruit and vegetable intakes, and markers of inflammation and hemostasis associated with cardiovascular disease in older men free of cardiovascular disease., Design: This cross-sectional study examined 3258 men aged 60-79 y with no physician diagnosis of myocardial infarction, stroke, or diabetes and who were drawn from general practices in 24 British towns. Fruit and vegetable intakes and dietary vitamin C were assessed by using a food-frequency questionnaire., Results: Plasma vitamin C, fruit intake, and dietary vitamin C intake were significantly and inversely associated with mean concentrations of C-reactive protein, an acute phase reactant, and tissue plasminogen activator (t-PA) antigen, a marker of endothelial dysfunction, even after adjustment for confounders. Vegetable intake was correlated significantly (inversely) only with t-PA. For plasma vitamin C (highest versus lowest quartile), the adjusted odds of elevated C-reactive protein and t-PA (highest tertile versus lowest tertile) were 0.56 (95% CI: 0.44, 0.71) and 0.79 (0.62, 1.00); for fruit intake, the corresponding odds ratios were 0.76 (0.60, 0.95) and 0.76 (0.61, 0.95). Plasma (but not dietary) vitamin C also showed inverse associations with both fibrinogen concentrations and blood viscosity. No associations were seen with von Willebrand factor or factor VIII., Conclusion: The findings suggest that vitamin C has antiinflammatory effects and is associated with lower endothelial dysfunction in men with no history of cardiovascular disease or diabetes.

Objective: Abdominal aortic aneurysms often coexist with reduced lung function and chronic obstructive pulmonary disease (COPD). These conditions are each associated with cigarette smoking, cardiovascular disease, and evidence of increased inflammatory and hemostatic activity. The aim of this study was to determine if these factors accounted for the link between aneurysms and pulmonary disease., Methods: The design was a case-control study comparing patients with an asymptomatic abdominal aortic aneurysm with population-based controls without an aneurysm. Aneurysms were diagnosed by ultrasound scan, and pulmonary function was measured by respiratory questionnaire and spirometry. Activation of inflammation and hemostasis was measured by assay of plasma interleukin-6 (IL-6), fibrinogen, von Willebrand factor (vWF), tissue plasminogen activator (tPA) antigen, fibrin D-dimer, and plasmin antiplasmin complexes., Results: Cases with an abdominal aortic aneurysm (n = 89) had more COPD and worse expiratory lung function as measured by forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) than controls (n = 98) (FEV1, 1.9 vs 2.2 L, P < .01; FEV1/FVC, 0.67 vs 0.75, P < .001) and did not differ in restrictive function (FVC, 2.9 vs 3.0 L, P = .33). Cases also had higher levels of lifetime cigarette smoking (30 vs 24 pack-years, P < 0.01), cardiovascular disease (35% vs 18%, P = .01), plasma fibrinogen (3.5 vs 3.1 g/L, P = .02), IL-6 (2.8 vs 1.8, pg/mL, P < .001), plasmin antiplasmin complexes (596 vs 384 microg/L, P = .01), and D-dimer (442 vs 93 ng/mL, P < .001). On multiple logistic regression analysis of lung function and COPD on the risk of aneurysm, both cigarette smoking and cardiovascular disease had little effect on the relationships. For the markers of activated inflammation and hemostasis, plasmin antiplasmin complexes and D-dimer had the most important confounding effect on the odds ratios. All markers combined had a substantial effect: odds ratio of aneurysm for a one standard deviation decrease in FEV1 fell from 2.3 (95% confidence interval [CI], 1.5 to 3.5) (P < .01) to 1.3 (95% CI, 0.55 to 2.4) (P > or = .05)., Conclusion: The association between reduced respiratory function and abdominal aortic aneurysm was not accounted for by cigarette smoking or cardiovascular disease. We hypothesize that activation of inflammation and hemostasis in response to injury may be an important explanation of the association between aneurysm formation and reduced respiratory function. Further studies are required to test this hypothesis.

The interplay between inflammatory and hemostatic mechanisms may play a crucial role in the development and progression of atherosclerosis. The authors evaluated the separate and joint associations of hemostatic and inflammatory variables on peripheral atherosclerotic progression in the Edinburgh Artery Study, a population cohort study of 1,592 men and women aged 55-74 years that started in 1987. Levels of fibrinogen, fibrin D-dimer, von Willebrand factor, tissue plasminogen activator antigen, factor VII, prothrombin fragment 1 + 2, urinary fibrinopeptide A, C-reactive protein, and interleukin-6 were measured at baseline. Arm and ankle blood pressures were measured, and atherosclerotic progression was assessed by computing ankle brachial index (ABI) at baseline (1,582 participants) and after 12 years of follow-up (813 participants). Fibrinogen (p = 0.05) and D-dimer (p < or = 0.05) were significantly associated with ABI change independently of baseline ABI and cardiovascular disease risk factors. However, these associations were no longer significant when analyses were adjusted for either C-reactive protein or interleukin-6. Moreover, subjects with higher levels of both D-dimer and interleukin-6 at baseline had the greatest ABI decline. In conclusion, fibrinogen and D-dimer, but not other hemostatic factors, were associated with progressive peripheral atherosclerosis. Since D-dimer and fibrinogen are acute phase reactants, these data support the hypothesis that inflammation is more related to atherosclerosis than is hypercoagulation.

Background and Purpose: Several prospective studies have shown significant associations between plasma fibrinogen, viscosity, C-reactive protein (CRP), fibrin D-dimer, or tissue plasminogen activator (tPA) antigen and the risk of primary cardiovascular events. Little has been published on the associations of these variables with recurrent stroke. We studied such associations in a nested case-control study derived from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS)., Methods: Nested case-control study of ischemic (n=472) and hemorrhagic (n=83) strokes occurring during a randomized, placebo-controlled multicenter trial of perindopril-based therapy in 6105 patients with a history of stroke or transient ischemic attack. Controls were matched for age, treatment group, sex, region, and most recent qualifying event at entry to the parent trial., Results: Fibrinogen and CRP were associated with an increased risk of recurrent ischemic stroke after accounting for the matching variables and adjusting for systolic blood pressure, smoking, peripheral vascular disease, and statin and antiplatelet therapy. The odds ratio for the last compared with the first third of fibrinogen was 1.34 (95% CI, 1.01 to 1.78) and for CRP was 1.39 (95% CI, 1.05 to 1.85). After additional adjustment for each other, these 2 odds ratios stayed virtually unchanged. Plasma viscosity, tPA, and d-dimer showed no relationship with recurrent ischemic stroke, although tPA was significant for lacunar and large artery subtypes. Although each of these variables showed a negative relationship with recurrent hemorrhagic stroke, none of these relationships achieved statistical significance., Conclusions: Fibrinogen and CRP are risk predictors for ischemic but not hemorrhagic stroke, independent of potential confounders.

Aims: To examine the associations between cigarette smoking, pipe/cigar smoking, and years since quitting smoking, and inflammatory and haemostatic markers., Methods and Results: A study in 2920 men aged 60-79 with no history of myocardial infarction, angina, stroke, or diabetes, and who were not on warfarin, from general practices in 24 British towns. After adjustment for other major cardiovascular risk factors, compared with never smokers, current cigarette smokers showed significantly higher levels of C-reactive protein (2.53 vs. 1.35 mg/L), white cell count (7.92 vs. 6.42 x 10(9)/L), and fibrinogen (3.51 vs. 3.13 g/L). They also showed higher levels of haematocrit, blood and plasma viscosity, tissue plasminogen activator antigen, and fibrin D-dimer, and lower levels of albumin. Primary pipe/cigar smokers showed levels similar to never smokers. Ex-cigarette smokers and secondary pipe/cigar smokers showed intermediate levels although secondary pipe/cigar smokers showed higher odds of having elevated white cell count and fibrinogen than ex-cigarette smokers. Most inflammatory and haemostatic levels improved within 5 years of smoking cessation but took over 20 years to revert to levels of never smokers., Conclusion: These findings suggest that activation of inflammation and haemostasis may be potential mechanisms by which cigarette and pipe/cigar smoking increase cardiovascular risk.

Aims: We have examined the cross-sectional relationship between insulin resistance, the metabolic syndrome and haemostatic and inflammatory markers., Methods and Results: We carried out the study in 2722 non-diabetic men aged 60-79 years with no history of coronary heart disease or stroke and who were not on warfarin treatment, drawn from general practices in 24 British towns. Insulin resistance (HOMA) was significantly associated with increased inflammatory markers (C-reactive protein (CRP), white cell count), coagulation factors VII-IX, von Willebrand factor (VWF) and tissue plasminogen activator (t-PA) antigens (markers of endothelial dysfunction) and blood viscosity after adjustment for age, smoking, physical activity, alcohol intake and waist circumference. Relationships with fibrinogen and fibrin D-dimer were weak. The relationship between HOMA and CRP was abolished after adjustment for t-PA. The prevalence of the metabolic syndrome was similar using World Health Organization (WHO) and National Cholesterol Education Program definitions (26.7% and 27.0%) but associations between the metabolic syndrome and increased haemostatic markers, particularly for raised factor VIII and VWF were stronger using WHO criteria., Conclusion: Insulin resistance and the metabolic syndrome showed significant associations with markers of haemostasis and inflammation, which may be relevant to their associations with cardiovascular disease.

Background: Atrial fibrillation (AF) is associated with cognitive impairment and dementia, perhaps through encouraging a prothrombotic state and cardioembolism., Objectives: We wished to test the hypotheses that hemostatic function is altered in subjects with AF who develop dementia, and that long-term warfarin anticoagulation is protective against this complication., Patients and Methods: Recruitment was from an observational cohort study of AF. Baseline assessment included measurement of plasma fibrinogen, fibrin D-dimer, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes (TAT), von Willebrand factor and tissue plasminogen activator. We assessed cognitive function after 3 years' follow-up using the 13-item modified Telephone Interview for Cognitive Status (TICSm) and the short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)., Results: Of the 218 subjects assessed, 145 (66%) were prescribed warfarin. Forty-nine (22%) met TICSm/IQCODE criteria for dementia. D-dimer, F1+2 and TAT levels were higher in AF subjects with dementia compared with those without (medians 81 vs. 60 ng mL(-1), P = 0.008; 0.76 vs. 0.49 nmol L(-1), P = 0.006; and 1.78 vs. 1.44 microg L(-1), P = 0.003, respectively). These associations became of borderline statistical significance following adjustment for age. Logistic regression showed a trend towards warfarin use being independently associated with reduced prevalence of dementia (odds ratio 0.52, P = 0.08)., Conclusions: We found evidence of increased thrombin generation and fibrin turnover in subjects with AF and dementia compared with those without dementia. Long-term warfarin use may be protective against the development of dementia in subjects with AF.

Aims: We compare the predictive values of plasma lipids (total and HDL-cholesterol, triglycerides) and three haemostatic/inflammatory risk markers for subsequent ischaemic heart disease (IHD)., Methods and Results: Two UK populations totalling 4860 men were screened for evidence of IHD between 1979 and 1983. Men were followed over 10 years and validated coronary events were recorded. Risk estimates were made using relative odds, receiver operating characteristic (ROC) curves and deciles of risk. Regression dilution effects were also examined. By 10 years, 525 men had a coronary event (fatal, non-fatal or silent myocardial infarction, MI). Two alternative multivariate models were compared - a lipid model (total, HDL-cholesterol, triglyceride) and a haemostatic/inflammatory model (fibrinogen, viscosity and white cell count). 'Correction' for regression dilution increased relative odds for most risk factors. In the distribution of predicted risk, using established risk factors in conjunction with either lipid or haemostatic/inflammatory factors, the deciles of risk analysis showed that the observed 10-year risk of IHD was 34-35% in men in the top tenth, compared to 2-3% in the lowest tenth of the distribution., Conclusion: At the 10 years' follow-up, major, haemostatic/inflammatory risk factors showed a graded relationship to incident IHD that was at least as strong as that given by plasma lipids. Haemostatic/inflammatory factors provide possible additional targets for intervention.

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.

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.

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.

Abnormalities of coagulation and fibrinolysis may play an important role in the pathogenesis of ischaemic stroke and vascular dementia. We aimed to determine whether haemostatic function is altered in acute recent-onset or chronic ischaemic cerebrovascular disease. We studied consecutive patients with ischaemic stroke (n = 74) and vascular dementia (n = 42) compared with healthy controls (n = 40) in a case-control study. The ischaemic stroke group was assessed twice, 3-10 days after the acute stroke and at 1-3 months. Fibrinogen, fibrin D-dimer (marker of fibrin turnover) and von Willebrand factor (vWF) (marker of endothelial disturbance) were elevated acutely (P < 0.0001) and in the convalescent phase after ischaemic stroke (P < 0.0001, P < 0.0001, and P < 0.01 respectively, compared with controls). Similar results were seen in the vascular dementia group. Stepwise multivariate regression analyses showed that cerebrovascular disease correlated independently with fibrinogen (P < 0.001) and fibrin D-dimer levels (P < 0.001), while vWF correlated independently with electrocardiograph evidence of ischaemic heart disease (P = 0.004). Changes between acute and convalescent phases in ischaemic stroke were slightly inconsistent. However, in the acute stage there were tendencies for fibrinogen, D-dimer and vWF to be increased, and factor VIII was significantly higher. Abnormalities of haemostasis, including increased fibrin turnover and endothelial disturbance, are found in both acute and chronic cerebral ischaemia. Many of these patients have co-existent ischaemic heart disease and this may contribute to some of these changes. Acute ischaemic stroke is associated with transient changes in haemostatic factors; however, most abnormalities persist into the convalescent phase, and are also demonstrable in subjects with vascular dementia.

Despite much research, the aetiology of venous disease is still poorly understood. Since haemostatic factors are involved in the processes of fibrinolysis and platelet aggregation, it is conceivable that such processes may be implicated in the pathology of varicose veins and chronic venous insufficiency (CVI). The Edinburgh Vein Study examined 1566 men and women aged 18-64 years that were randomly selected from the lists of 12 general practitioners. Each subject completed a questionnaire, underwent a comprehensive clinical examination and had a blood sample taken for the analysis of plasma fibrinogen, tissue plasminogen activator (t-PA) and von Willebrand factor (vWF) antigens. Subjects with trunk varicose veins and those with CVI had higher levels of each haemostatic factor compared with those with no trunk varices and no CVI. Although unit increases in t-PA and vWF were initially associated with a significantly increased risk of CVI in men, and both factors with an elevated risk of trunk varices in women, multiple adjustment for age, smoking status and body mass index reduced the odds ratios to non-significance. However, this does not entirely rule out the possibility of a pathogenic role for haemostatic factors in venous disease, but rather indicates the need for further experimental and epidemiological studies.

We have recently shown that fibrin D-dimer, tissue plasminogen activator (tPA) antigen, von Willebrand factor antigen, fibrinogen, plasma viscosity, and white cell count are associated with subsequent ischemic heart disease (IHD) in men aged 49 to 65 years in the Caerphilly Study from South Wales. We now report the contribution of major lifestyle factors to plasma levels of these new risk predictors for IHD. Results were available for up to 2188 men. The contribution of factors associated with lifestyle (smoking, alcohol, body mass index, leisure and work activity, social class, and use of prescribed medicines) to variation in plasma levels of 8 hemostatic variables was examined. All results were adjusted for other lifestyle variables, age, and time of day. Most hemostatic variables increased with age and smoking habit. Increasing levels of alcohol consumption were associated with increases in tPA and plasminogen activator inhibitor (PAI-1) activity and with decreases in fibrinogen and white cell count. tPA, PAI-1, fibrinogen (nephelometric), and viscosity were positively associated with body mass index. Increasing levels of leisure activity were inversely associated with D-dimer, von Willebrand factor, nephelometric fibrinogen, and viscosity. Use of prescribed medicines (a marker for chronic illness) was associated with adverse levels of D-dimer, fibrinogen, plasma viscosity, and white cell count. tPA, PAI-1, and plasma viscosity were associated with blood pressure, cholesterol, and triglycerides but not with lipoprotein(a) or homocysteine. We conclude that several lifestyle factors are associated with hemostatic risk predictors for IHD. Lifestyle modifications may reduce IHD risk partly by altering hemostatic function; large intervention studies are required to test this hypothesis.

The European Concerted Action on Thrombosis (ECAT) DVT Study was a collaborative study of preoperative haemostatic tests in prediction of DVT (diagnosed by routine bilateral venography) after elective hip replacement. 480 patients were recruited in 11 centres across Europe. Clinical risk factors were assessed, and stored citrated plasma aliquots were centrally assayed for 29 haemostatic factors according to the ECAT methodology. 120 (32%) of 375 evaluable patients had DVT, and 41 (11%) had proximal DVT. Among clinical variables, DVT was significantly associated with increased age, obesity, and possibly non-use of stockings. Of the 29 haemostatic factors, mean preoperative levels were significantly higher in patients with subsequent DVT (on univariate analyses) for factor VIII activity, prothrombin fragment F1+2, thrombin-antithrombin complexes, and fibrin D-dimer; and significantly lower for APTT and APC sensitivity ratio. Factor V Leiden was also associated with DVT. Most of these variables were also associated with age, while D-dimer was higher in patients with varicose veins. On multivariate analyses including clinical variables, only a shorter APTT (locally but not centrally performed) and APC resistance showed a statistically significant association with DVT. We conclude that (a) DVT is common after elective hip replacement despite prophylaxis; (b) the study provides some evidence that DVT is associated with a preoperative hypercoaguable state; and (c) preoperative haemostatic tests do not add significantly to prediction of DVT from clinical variables, with the possible exception of APC resistance.

Increased activation of both blood coagulation and fibrinolysis occurs during normal pregnancy. The responsible mechanisms are unclear, but may include increases in both oestradiol and blood lipids. We, therefore, studied the associations between fasting serum oestradiol, plasma cholesterol and triglyceride, and Factor VII activity, PAI activity, t-PA antigen, fibrin D-dimer, and vWF antigen in 10 women, each sampled on 6 occasions between 10 weeks and 35 weeks during normal pregnancy. Strong and similar individual correlations were observed between increases in FVII, PAI, t-PA and D-dimer (but not vWF) and increases in both oestradiol and triglyceride. Associations between increments in plasma cholesterol and haemostatic factors (except for FVII), were somewhat weaker. We, therefore, suggest that oestradiol-induced hypertriglyceridaemia may be a cause of elevations in plasma Factor VII activity, PAI and t-PA, and fibrin turnover (D-dimer) during normal pregnancy, but is poorly related to the increase in vWF antigen.

The role of hemostatic variables (which promote hemostatic plugs and thrombi) and rheological variables (which affect blood flow) in the pathogenesis of vascular diseases (ischemic heart disease, stroke, and peripheral arterial disease) is reviewed, with emphasis on epidemiological studies. Rheological variables are consistently associated with both prevalent and incident cardiovascular disease. These associations are only partly explained by conventional risk factors. The predictive value of plasma viscosity for cardiovascular events is partly explained by fibrinogen, and partly by lipoproteins. The associations of whole blood viscosity with cardiovascular disease are partly explained by plasma viscosity and partly by hematocrit. White cell count, but not platelet count, predicts ischemic heart disease events. Cigarette smokers have higher levels of rheological variables than non-smokers, these increases are partly or wholly reversible in ex-smokers. Lipoprotein reduction by pravastatin lowers plasma and whole-blood viscosity, which may be one mechanism through which lipid lowering produces an early reduction in cardiovascular events. Data from the Edinburgh Artery Study suggest that viscosity is related both to the extent of atherosclerosis, and to ischemia in the presence of a given degree of atherosclerotic stenoses. Among hemostatic variables, fibrinogen, factor VIII: vWF complex, tpA antigen, and fibrin D-dimer are associated with both prevalent and incident cardiovascular disease. Again, these associations are only partly explained by conventional risk factors They suggest that endothelial disturbance and increased fibrin turnover may play roles in cardiovascular disease. Hemostatic and rheological variables are therefore associated with both prevalent and incident cardiovascular disease, and may be mechanisms through which risk factors such as smoking, hyperlipidemia and infections (including oral infections) promote vascular events.

Atherothrombosis is a systemic disease, hence it is difficult to prove the specificity of haemostasis abnormality for any single vascular phenotype. Associations between haemostatic variables and any given phenotype, e.g. (vascular) dementia, should be interpreted with caution, given the overlaps of vascular disease phenotypes, risk factors, and haemostatic variables.

The prediction of patients who are at sufficiently high risk of postoperative deep venous thrombosis to indicate perioperative antithrombotic prophylaxis has traditionally used only clinical risk factors. The associations of preoperative and/or postoperative haemostatic tests with postoperative deep venous thrombosis are reviewed. In general, the results support the biological concept of a preoperative and postoperative prothrombotic tendency in patients who develop deep venous thrombosis. Increased levels of coagulation activation markers and decreased assays of fibrinolytic potential show consistent relationships to postoperative deep venous thrombosis. At present, however, the clinical utility of such tests is unproven; so that at present they cannot be advocated for routine preoperative or postoperative screening.

Abdominal aortic aneurysms have traditionally been thought to be a consequence of severe atherosclerosis of the arterial wall. To date, the role of haemostatic factors in aneurysmal disease has not been extensively researched. The aim of this study was to see if such factors were independently related to the occurrence of aortic aneurysm. Furthermore, were the associations maintained after taking into account the presence of underlying atherosclerotic disease? Using data from the Edinburgh Artery Study, a nested case-control design was used involving 40 cases of aortic aneurysm, each being matched to five controls by sex and within a 5-year age band. After adjustment for age and sex, both fibrinogen (P < or = 0.01) and fibrin D-dimer (P < or = 0.001) were each associated with a significant increased risk of aneurysm. Further adjustment for packyears, history of cardiovascular disease and the ankle brachial pressure index resulted in odds ratios of 1.51 (95% CI 1.05 to 2.16, P < or = 0.05) for fibrinogen and 3.75 (95% CI 1.80 to 7.82, P < or = 0.001) for fibrin D-dimer. These associations probably arise as a consequence of fibrin deposition and turnover within the aneurysmal sac, although further prospective studies are needed before thrombotic factors can be used in the identification of a group who are at high risk of developing an abdominal aortic aneurysm.

Patients with intermittent claudication have been reported to have disturbances in blood rheology and haemostasis. Whether these disturbances are a result of, or largely independent of, smoking history and arterial narrowing has not yet been established. The levels of whole blood and plasma viscosity, haematocrit, von Willebrand factor antigen, fibrin D-dimer antigen and urinary fibrinopeptide A antigen were compared in 617 claudicants and 722 controls from two epidemiological studies in Edinburgh. After adjustment for age and sex, all factors, except whole blood viscosity and haematocrit, were significantly higher in the claudicants compared to controls (P < or = 0.001). The risk of intermittent claudication was significantly raised for unit change in each factor, except for whole blood viscosity and haematocrit. Adjustment for lifetime smoking had little effect on the odds ratios. After further adjustment for the ankle brachial pressure index (as a measure of the extent of peripheral arterial disease), haematocrit, von Willebrand factor and urinary fibrinopeptide A showed a significant independent relationship with the risk of intermittent claudication. We conclude that the association between selected rheological and haemostatic factors and leg ischaemia is largely independent of both smoking history and the extent of arterial narrowing, and may be directly related to microvascular ischaemia.

To determine relationships between haemostatic and rheological factors and severity of peripheral atherosclerosis and differences by site, an angiographic cross-sectional survey was carried out on 192 men and women with intermittent claudication or rest pain. 34 patients were classified as having aorto-iliac disease, 85 femoro-popliteal disease and 73 dual-site disease. Mean levels of haemostatic or rheological factors did not differ significantly between the three site groups. In all 192 patients, disease severity in the femoro-popliteal segments was correlated with plasma nephelometric fibrinogen (r = 0.20, p < or = 0.01), von Willebrand factor (r = 0.14, p < or = 0.05) and fibrin D-dimer (r = 0.22, p < or = 0.001). On multiple regression analyses, fibrinogen was independently associated with disease severity in the femoro-popliteal segments (p < or = 0.05), but not in the aorto-iliac segments. Adjustment for packyears or serum thiocyanate had little effect on the association of fibrinogen with severity of disease. An inverse relationship between plasminogen activator inhibitor and disease severity in the femoro-popliteal segments was found only in men (r = 0.24, p < or = 0.01). We conclude that elevated fibrinogen and disturbed fibrinolytic activity may be related to the extent of disease within the femoro-popliteal arteries, more so than in the aorto-iliac arteries.

We investigated the relationships between the angiographic severity of peripheral arterial occlusive disease (PAOD) and haemostasis, fibrinolytic, and rheological variables in 219 patients with symptomatic peripheral arterial occlusive disease (PAOD). White cell count, fibrinogen, cross-linked fibrin degradation products (FDP), von Willebrand factor, and plasminogen activator inhibitor levels were all elevated in comparison with age-matched population controls (all p < 0.0001, Mann-Whitney U test), while fibrinogen (Spearman r = 0.30), von Willebrand factor (r = 0.40), and log (FDP) (r = 0.56), (all p < 0.0001) showed a strong correlation with the angiographic extent of PAOD. Multivariate analysis indicated that log (FDP) was a strong independent predictor of the angiographic severity of PAOD (p < 0.0001), in addition to increasing age (p < 0.0001), presence of tissue sepsis (p < 0.02), prior vascular surgery (p = 0.007), and other vascular pathology (p = 0.007). These results confirm that increase in fibrinogen, von Willebrand factor, plasminogen activator inhibitor and fibrin turnover, are strongly associated with the presence of symptomatic peripheral arterial disease, and suggest that there may be a causal link between fibrin turnover, as determined by FDP levels, and the extent of peripheral arterial occlusive disease.

We investigated the relationships between the angiographic severity of peripheral arterial occlusive disease (PAOD) and haemostasis, fibrinolytic, and rheological variables in 219 patients with symptomatic peripheral arterial occlusive disease (PAOD). White cell count, fibrinogen, cross-linked fibrin degradation products (FDP), von Willebrand factor, and plasminogen activator inhibitor levels were all elevated in comparison with age-matched population controls (all p < 0.0001, Mann-Whitney U test), while fibrinogen (Spearman r = 0.30), von Willebrand factor (r = 0.40), and log (FDP) (r = 0.56), (all p < 0.0001) showed a strong correlation with the angiographic extent of PAOD. Multivariate analysis indicated that log (FDP) was a strong independent predictor of the angiographic severity of PAOD (p < 0.0001), in addition to increasing age (p < 0.0001), presence of tissue sepsis (p < 0.02), prior vascular surgery (p = 0.007), and other vascular pathology (p = 0.007). These results confirm that increases in fibrinogen, von Willebrand factor, plasminogen activator inhibitor and fibrin turnover, are strongly associated with the presence of symptomatic peripheral arterial disease, and suggest that there may be causal link between fibrin turnover, as determined by FDP levels, and the extent of peripheral arterial occlusive disease.

We aimed to determine whether levels of plasma fatty acids are correlated with other potential risk factors for cardiovascular disease, using a sample of patients from a cross-sectional survey of the general population, in the City of Edinburgh. 306 men and women aged 55-74 years of whom half had clinical evidence of arterial disease were tested. The main outcome measures were plasma fatty acids and potential risk factors for cardiovascular disease (age, sex, smoking, blood pressure, serum cholesterol, HDL cholesterol (HDL-C), triglycerides (TGs), lipid peroxides (LPx), plasma fibrinogen, von-Willebrand factor (vWf), beta-thromboglobulin (beta TG), cross-linked fibrin degradation products (FIBDP) and plasminogen activator inhibitor PAI). High levels of several known risk factors for cardiovascular diseases were associated with low levels of certain essential fatty acids. Eicosapentaenoic (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) were negatively associated with smoking and TG levels. High levels of certain haemostatic factors, including plasma fibrinogen, blood viscosity and LPx were also associated with low levels of EPA, DHA, AA and HDL-C. In conclusion, plasma fatty acids show strong correlations with many potential risk factors for cardiovascular disease, emphasising their possible importance in pathogenesis.

The aim of this study was to determine differences between cases of peripheral arterial disease and healthy controls in levels of haemostatic factors and lipid peroxides and the influence of cigarette smoking. The study groups were selected from the Edinburgh Artery Study which is a random sample survey of men and women aged 55-74 years. Mean levels of plasma fibrinogen, von Willebrand factor, beta-thromboglobulin, plasminogen activator inhibitor (type I), cross-linked fibrin degradation products and lipid peroxides were markedly elevated in 121 study cases compared with 126 age- and sex-matched controls. For example, cross-linked fibrin degradation products had a geometric mean of 106.8 ng/ml (95% confidence interval (CI) 95.3, 119.8) in study cases and 74.7 ng/ml (95% CI 67.0, 83.4) in controls (P < 0.001). Inclusion of smoking in logistic regressions of each factor on peripheral arterial disease significantly reduced the odds of disease for von Willebrand factor and for cross-linked fibrin degradation products, but had little effect on the increased odds associated with fibrinogen, beta-thromboglobulin, plasminogen activator inhibitor and lipid peroxides. We conclude that, in men and women in Edinburgh, peripheral atherosclerosis is associated with lipid peroxidation, endothelial disturbance, platelet activation, elevated fibrinogen, fibrin formation and increased inhibition of fibrinolysis. The most important effects of cigarette smoking in promoting atherosclerosis may be endothelial disturbance and fibrin formation.

1. The effects of acute hypoglycaemia on haemostasis, fibrinolysis, blood viscosity and erythrocyte aggregation were examined after acute insulin-induced hypoglycaemia in six normal male subjects and in six male patients with poorly controlled insulin-dependent diabetes. In the control subjects hypoglycaemia caused a significant increase in the concentration of von Willebrand factor, with no change in the concentrations of fibrinogen and cross-linked fibrin degradation products. Fibrinolysis was enhanced, as indicated by significant increases in tissue plasminogen activator concentration and the fibrin plate lysis area, with a fall in plasminogen-activator inhibitor activity, suggesting complex formation. Whole-blood and plasma viscosity increased significantly after hypoglycaemia, but there was no significant change in erythrocyte aggregation tendency. 2. In diabetic patients the increase in the concentration of von Willebrand factor was significantly greater than in the control group (analysis of variance, P less than 0.02). The basal concentration of tissue plasminogen activator was reduced at 3.7 +/- 0.7 mg/l (mean +/- SEM) in the diabetic group compared with 8.5 +/- 1.3 mg/l in the control group (Student's t-test, P less than 0.01), but thereafter the increase in response to hypoglycaemia was similar. The changes in the other variables were not significantly different from the changes in the control group. 3. During acute hypoglycaemia in poorly controlled diabetic patients there is promotion of haemostasis with a greater increase in the concentration of von Willebrand factor, which, in association with the increase in viscosity, might reduce perfusion in diabetic microangiopathy, leading to aggravation of the microvascular complications of diabetes.

The predictive value for cancer recurrence of five measurements of haemostatic activity was studied in 89 patients with operable breast cancer. Neither preoperative nor sequential measurements up to 9 months postoperatively of fibrinopeptide A, fibrin fragment B beta 15-42, fibrinogen and serum fibrin(ogen) degradation products nor the fibrin plate lysis assay correlated with early recurrent disease. B beta 15-42 values were higher preoperatively in patients with oestrogen receptor positive tumours (P = 0.017). Mean B beta 15-42 values rose postoperatively (P = 0.003), largely because of an increase in patients with oestrogen receptor negative tumours.

We have previously shown abnormalities of haemostasis suggestive of intravascular coagulation in patients with malignant hypertension, a condition associated with retinopathy and renal fibrin deposition. To determine whether such abnormalities are specific to malignant hypertension, we have measured several haemostatic and haemorheological variables in 18 patients with malignant hypertension (Group 1), 18 matched healthy controls (Group 2), and 18 patients with non-malignant hypertension (Group 3) matched for renal pathology, blood pressure and serum creatinine with Group 1. Both Groups 1 and 3 had increased mean levels of fibrinogen, factor VIIIc, beta-thromboglobulin, plasma viscosity and blood viscosity (corrected for haematocrit); and decreased mean levels of haematocrit, antithrombin III and platelet count. Mean levels of fast antiplasmin and alpha2-macroglobulin were elevated in Group 1 but not in Group 3. We conclude that most blood abnormalities are not specific to malignant hypertension; are also present in patients with non-malignant hypertension who have similar levels of blood pressure and renal damage; and might result from renal damage as well as promoting further renal damage by enhancing fibrin deposition. However increased levels of fibrinolytic inhibitors in malignant hypertension merit further investigation in relation to removal of renal fibrin.

Blood viscosity and its major determinants (haematocrit, plasma viscosity and fibrinogen) as well as several haemostatic variables were measured in 21 patients with the nephrotic syndrome, and 21 controls matched for age, sex, smoking habit and serum creatinine. Blood viscosity was significantly increased in the nephrotic group, measured at a low shear rate (mean increase 41%, p less than 0.01) and at a high shear rate (mean increase 25%, p less than 0.01). Haematocrit was not significantly increased, but plasma viscosity was significantly higher (p less than 0.01), associated with increased plasma macroglobulins especially fibrinogen, which was increased to double the plasma concentration of the control group (p less than 0.01). Nephrotic subjects also had increased plasma levels of alpha 2-macroglobulin, factor VIII activity, factor VIII antigen and beta-thromboglobulin; differences in antithrombin III, fibrin degradation products, plasminogen, and platelet count were not significant. We suggest that increased blood and plasma viscosity may play a role in the vascular complications of the nephrotic syndrome.

Disorders of haemostasis and altered platelet activity have been documented in patients with malignant disease but their relation to response to treatment and prognosis are not known. Thrombin activity (fibrinopeptide A (FpA), plasmin mediated fibrinolysis (B beta 15-42) antigen), and platelet alpha granule release (beta thromboglobulin) were studied in 37 patients with small cell lung cancer to find out whether these indices show a relationship to chemoresponse. There was evidence of considerably increased thrombin activity, with a median fibrinopeptide A concentration of 13.2 (normal less than 4) pmol/ml, but only modestly increased fibrinolysis, with a median B beta 14-42 antigen concentration of 5.6 (normal less than 3) pmol/ml. Thus the ratio of fibrinopeptide A to B beta 15-42 concentration (FpA:B beta) was raised, with a median value of 2.2 (normal less than 1.33). In addition, 57% of patients had increased platelet alpha granule release, the median beta thromboglobulin concentration being 50 (normal less than 50) ng/ml. There was a significant association between increased thrombin generation and lack of response to chemotherapy. Furthermore, non-responders had higher FpA:B beta ratios. The same haemostatic markers were studied in nine patients who have been in complete remission for at least two years after chemotherapy for small cell lung cancer. There was a significant difference in thrombin activity and also in the ratio of thrombin activity to lysis between the pretreatment group and the group of two year survivors. Lack of response to chemotherapy appears to be related to increased thrombin activity. Such an association has not previously been reported in patients with malignant disease.