Virchow's triad revisited: the importance of soluble coagulation factors, the endothelium, and platelets.
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Biomedical subjects
Publications and source records attributed to G Y Lip.
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We measured indexes of platelet activation (soluble P-selectin), endothelial dysfunction (von Willebrand factor), and fibrinogen in 54 patients who underwent aortic valve replacement (AVR): after mechanical AVR implantation, there was a significant increase in plasma levels of soluble P-selectin and von Willebrand factor levels 3 months after surgery, with no change in mean plasma fibrinogen levels. No significant changes in measured indexes were noted in patients undergoing biologic AVR, suggesting that mechanical AVR results in abnormal endothelial damage and/or dysfunction and platelet activation, which is not apparent among patients undergoing this procedure.
Raised plasma VEGF is found in some cancers but levels of its receptor soluble Flt-1 (sFlt-1) are unreported. Hypothesising increased levels to be present in haematological cancers, we measured both by ELISA in 22 patients with haematological cancer, 22 with breast cancer, and in age- and sex-matched controls. VEGF was raised in both patients groups compared to controls (P < 0.01) but was higher in haematological cancer compared to breast cancer (P = 0.0238). There was no difference in levels of sFlt-1. Our data point to changes in levels of plasma VEGF, but not sFlt-1, in haematological cancer that may have pathophysiological consequences.
BACKGROUND: Morbidity and mortality in patients with symptomatic chronic heart failure is high, it predisposes to stroke and thromboembolism which in turn contribute to high mortality in heart failure. OBJECTIVES: To determine effect of antiplatelet agents when compared to placebo or anticoagulant therapy on death and/or major thromboembolic events in adults with heart failure who are in sinus rhythm. SEARCH STRATEGY: Systematic search of electronic databases (MEDLINE, EMBASE, DARE). Abstracts from cardiology meetings and reference lists of relevant papers were searched. Authors of studies were contacted for further information. SELECTION CRITERIA: Randomised parallel group placebo or controlled trials comparing antiplatelet therapy with control or anticoagulation in adults with chronic heart failure in sinus rhythm. Treatment for at least 1 month. To assess any adverse effects cohort study & non-randomised controlled studies were assessed. Orally administered antiplatelet agents e.g. non-steroidal anti-inflammatory agents, TICLOPIDINE, CLOPIDOGREL, DIPYRIDAMOLE, ASPIRIN compared with anticoagulant agents e.g. COUMARINS, WARFARIN or placebo. DATA COLLECTION AND ANALYSIS: Data were extracted by two reviewers independently. No meta-analyses were performed as no data were available from randomised comparisons. The data extracted included data relating to the complexities of the topic area, such as patient characteristics and concomitant treatments, as well as data relating to study eligibility, quality, and outcomes. Non-randomised studies were used to identify side-effects caused by anticoagulants. MAIN RESULTS: One RCT of warfarin, aspirin versus no antithrombotic therapy was found but no definitive data have yet been published. Three retrospective, non-randomised cohort studies from the V-HeFT, SOLVD and SAVE trials examining the role of ACE inhibitors have examined the role of aspirin therapy +/- anticoagulant therapy in patients with heart failure and/or left ventricular systolic dysfunction. The results from these trials were conflicting. REVIEWER'S CONCLUSIONS: At present there is no evidence from long term RCTs to recommend use of aspirin to prevent thromboembolism in patients with heart failure in sinus rhythm. A possible interaction with ACE inhibitors may reduce the efficacy of aspirin, although this evidence is from retrospective analyses of trial cohorts. There is also no evidence to indicate superior effects from oral anticoagulation, when compared to aspirin, in patients with heart failure in sinus rhythm.
BACKGROUND: Patients with chronic heart failure (heart failure) are at risk of thromboembolic events, including stroke, pulmonary embolism and peripheral arterial embolism, whilst coronary ischaemic events also contribute to the progression of heart failure. Long-term oral anticoagulation is established in certain groups, including patients with heart failure and atrial fibrillation but there is wide variation in the indications and use of oral anticoagulation in the broader heart failure population. OBJECTIVES: To determine whether long-term oral anticoagulation reduces total deaths and/or major thromboembolic events in patients with heart failure, when compared to placebo. SEARCH STRATEGY: Reference lists of papers resulting from this search, electronic database searching (MEDLINE, EMBASE, DARE), and abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. Relevant authors of these studies were contacted to obtain further data. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing oral anticoagulants with control or placebo. Non-randomised studies were included as they may help in assessing side-effects. Duration of treatment at least 1 month, adults with heart failure due to any underlying cause. Inclusion decisions were duplicated, disagreement resolved by discussion or a third party. DATA COLLECTION AND ANALYSIS: Data were collected by two reviewers independently and where appropriate data from RCTs were meta-analysed. MAIN RESULTS: One recent pilot RCT compared warfarin, aspirin and no antithrombotic therapy, but no definitive data have yet been published. Three small prospective studies of warfarin in heart failure were also identified, but were over 50 years old with methods not considered reliable by modern standards. Anticoagulation was more efficacious than control for the reduction of all cause death (odds ratio 0.64 95% CI 0.45,0.90) and the reduction of cardiovascular events (0.26 95% CI 0.16, 0.43). Four retrospective non-randomised cohort analyses and three small observational studies of oral anticoagulation in heart failure included differing populations of heart failure patients and reported contradictory results. REVIEWER'S CONCLUSIONS: Evidence from the RCTs and observational studies found a reduction in mortality and cardiovascular events with anticoagulants compared to control. This evidence needs to be interpreted with caution. Although oral anticoagulation is indicated in certain groups of patients with heart failure (eg atrial fibrillation), the data available does not support its routine use in heart failure patients who remain in sinus rhythm. A large randomised trial of warfarin in heart failure patients in sinus rhythm is currently in progress data from which will be useful addition to this story.
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BACKGROUND: There is increasing evidence that chronic atrial fibrillation (AF) is associated with a prothrombotic or hypercoagulable state. HYPOTHESIS: This study was undertaken to determine whether short-term exercise in patients with chronic AF would shift the overall hemostatic balance toward a more prothrombotic state with a reduction in fibrinolytic potential. METHODS: We recruited 20 patients (13 men; mean age 65 years +/- 11 standard deviation [SD]) with chronic AF who were not treated with antithrombotic therapy and exercised them to exhaustion using a multistage treadmill exercise (standard Bruce) protocol. Blood samples were taken pre exercise, immediately after cessation of exercise, and at 20 min post exercise. The prothrombotic state was quantified by fibrinogen (an index of hemorheology and a coagulation factor), soluble P-selectin (sP-sel, marking platelet activation), von Willebrand factor (vWF, an index of endothelial dysfunction), and plasminogen activator inhibitor-1 (PAI-1, a regulator of fibrinolytic activity) levels. There were two groups of age- and gender-matched controls in sinus rhythm: (1) healthy controls, and (2) "hospital controls" who were patients with vascular disease. RESULTS: Baseline levels of vWf (p = 0.034) and fibrinogen (p < 0.0001), but not sP-sel (p = 0.075) were significantly elevated in patients with AF compared with both control groups in sinus rhythm. The PAI-1 levels were highest in the hospital control patients, but not in chronic AF (p = 0.041). Following treadmill exercise, achieving a mean metabolic equivalent of 4.9 METS (+/- 1.75 SD) and total exercise duration of 4.9 min (+/- 2 SD), there was a significant rise in plasma fibrinogen (repeated measures analysis of variance [ANOVA] p = 0.047) and a reduction in PAI-1 levels (p = 0.025) in patients with AF. There were no significant changes seen in vWf (p = 0.308) or sP-sel (p = 0.071) levels. No significant changes in these indices were seen in hospital controls (all p = not significant), despite a much longer duration of exercise with greater workload. CONCLUSION: Patients with chronic AF have increased vWf and fibrinogen levels compared with sinus rhythm. Exercise to exhaustion influences the hypercoagulable state in chronic AF, with a rise in plasma fibrinogen and possible increase in fibrinolytic activity. Nevertheless, acute exercise does not appear to have a significant influence on endothelial dysfunction or platelet activation in patients with AF.
BACKGROUND: Chronic heart failure (CHF) is associated with an increased risk of thrombosis and thromboembolic events, including stroke and venous thromboembolism. which may be related to a prothrombotic or hypercoagulable state. Acute vigorous exercise has been associated with activation of hemostasis, and this risk may well be particularly increased in patients with CHF. HYPOTHESIS: The study was undertaken to determine whether acute exercise would adversely affect abnormalities of hemorheological (fibrinogen, plasma viscosity, hematocrit), endothelial (von Willebrand factor), and platelet markers (soluble P selectin) in patients with CHF. METHODS: We studied 22 ambulant outpatients (17 men; mean age 65+/-9 years) with stable CHF (New York Heart Association class II-III and a left ventricular ejection fraction of < or =40%) who were exercised to exhaustion on a treadmill. Results were compared with 20 hospital controls (patients with vascular disease, but free of CHF) and 20 healthy controls. RESULTS: Baseline von Willebrand factor (p = 0.01) and soluble P-selectin (p = 0.006) levels were significantly elevated in patients with CHF when compared with controls. In the patients with CHF who were exercised, plasma viscosity, fibrinogen, and hematocrit levels increased significantly, both immediately post exercise and at 20 min into the recovery period (repeated measures analysis of variance, all p<0.05). There was a positive correlation between exercise workload and the maximal changes in plasma viscosity in the patients with CHF (Spearman r = 0.5, p = 0.02). Plasma viscosity levels increased with exercise in the hospital control group, although no other exercise-induced changes were noted in this group. CONCLUSION: The present study indicates that the hemorheological indices. fibrinogen, and hematocrit specifically increase during acute exercise in patients with CHF. Although moderate exercise should be encouraged in patients with CHF, vigorous exercise should probably be avoided in view of its potential prothrombotic effects in this high-risk group of patients.
Recent guidelines for the treatment of hypertension place great emphasis on tighter blood pressure control, especially in the presence of hypertensive target organ damage and diabetes. In order to achieve these treatment targets, more patients will require a combination of antihypertensive medications. However, resistant hypertension may have many possible underlying causes, and clinicians should appreciate how to detect and tackle these potential problems. Effective and synergistic combinations are therefore of vital importance, especially in patients with resistant hypertension. The choice of rational first- and second-line drugs that act in synergy could lead to better blood pressure management as well as significant financial savings for health care resources. The use of the Birmingham Hypertension Square for the optimum choice of add-in drugs for the treatment of resistant hypertension may aid management.
OBJECTIVE: The purpose of this study was to determine predictors of attendance at cardiac rehabilitation after myocardial infarction (MI). METHODS: Various demographic, behavioural, and clinical variables were measured during hospitalisation in 288 MI patients. Of these, 263 were available to attend outpatient-based cardiac rehabilitation: 108 actually attended. RESULTS: Multiple logistic regression analyses indicated that nonattenders lived in more deprived areas and were less likely to have paid employment. Nonattenders also registered more symptoms of depression and anxiety and exercised less frequently prior to their MI, although only the last of these variables were predicted in a multivariate model. In terms of clinical status, whether patients had been thrombolysed or not was the strongest predictor of attendance. CONCLUSIONS: Attendance at cardiac rehabilitation is not an arbitrary matter. Strategies should be developed for encouraging greater attendance among those not in paid employment, those from deprived areas, and those who exercise infrequently.
OBJECTIVE: To investigate laboratory evidence of abnormal angiogenesis, hemorheologic factors, endothelial damage/dysfunction, and age-related macular degeneration (ARMD). DESIGN: Comparative cross-sectional study. PARTICIPANTS: We studied 78 subjects (26 men and 52 women; mean age 74 years; standard deviation [SD] 9.0) with ARMD attending a specialist referral clinic. Subjects were compared with 25 healthy controls (mean age, 71 years; SD, 11). INTERVENTION AND OUTCOME MEASURES: Levels of vascular endothelial growth factor (VEGF, an index of angiogenesis), hemorheologic factors (plasma viscosity, hematocrit, white cell count, hemoglobin, platelets), fibrinogen (an index of rheology and hemostasis), and von Willebrand factor (a marker of endothelial dysfunction) were measured. RESULTS: Median plasma VEGF (225 vs. 195 pg/ml, P = 0.019) and mean von Willebrand factor (124 vs. 99 IU/dl, P = 0.0004) were greater in ARMD subjects than the controls. Mean plasma fibrinogen and plasma viscosity levels were also higher in the subjects (both P < 0.0001). There were no significant differences in other indices between cases and controls. When "dry" (drusen, atrophy, n = 28) and "exudative" (n = 50) ARMD subjects were compared, there was no significant differences in VEGF, fibrinogen, viscosity, or von Willebrand factor levels. There were no significant correlations between the measured parameters. Stepwise multiple regression analysis did not demonstrate any significant clinical predictors (age, gender, smoking, body mass index, history of vascular disease, or hypertension) for plasma VEGF or fibrinogen levels, although smoking status was a predictor of plasma von Willebrand factor levels (P < 0.05). CONCLUSIONS: This study suggests an association between markers of angiogenesis (VEGF), hemorheologic factors, hemostasis, endothelial dysfunction, and ARMD. The interaction between abnormal angiogenesis and the components of Virchow's triad for thrombogenesis may in part contribute to the pathogenesis of ARMD.
To test the hypothesis that the hypercoagulable state in hypertension is significantly altered by anti-hypertensive therapy, we conducted a pilot prospective randomised double-blind trial of 40 untreated hypertensive patients (30 males, mean age 59 years) who were treated with either enalapril (10-20 mg per day) or losartan (50-100 mg per day) for 8 weeks. Thrombogenicity was assessed by measurement of plasma fibrinogen, soluble P-selectin (an index of platelet activation), plasminogen activator inhibitor 1 (PAI-1, an index of fibrinolysis) and von Willebrand factor (an index of endothelial dysfunction). Baseline von Willebrand factor alone was significantly higher in untreated hypertensive patients compared to controls (P<0.001). Following 8 weeks treatment with enalapril (mean dose 17 mg/day) or losartan (mean dose 77 mg/day), there was a significant reduction in mean blood pressure from 169+/-11/94+/-8 mmHg (baseline) to 147+/-14/84+/-7 mmHg (post-treatment) (P<0.001). However, there were no statistically significant changes in the levels of haemostatic markers (von Willebrand factor, fibrinogen, s-Psel and PAI-1). Our pilot study confirms previous observations of endothelial dysfunction in hypertensives. However, plasma fibrinogen and indices of platelet activation, fibrinolysis or endothelial dysfunction were not significantly affected by antihypertensive treatment with enalapril or losartan, despite satisfactory blood pressure control.
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An interaction between homocyst(e)ine and the endothelium in hypertensive patients may promote thrombogenesis and atherogenesis, leading to adverse cardiovascular events. We hypothesized that homocyst(e)ine levels are abnormal in patients with essential hypertension, and that this may be related to an adverse effect on the vascular endothelium. Accordingly, we compared plasma levels of homocyst(e)ine and von Willebrand factor (marking endothelial damage) in 83 patients (43 men; mean age 54 +/- standard deviation 15.9 years) with essential hypertension (> 160/90 mm Hg), with levels in 25 healthy normotensive controls (13 men; mean age 56+/-11.8 years). Baseline levels of the markers and other clinical indices were then related to adverse cardiovascular events at follow-up. Plasma homocyst(e)ine (P = .0001) and von Willebrand factor (P = .031) levels were significantly higher in hypertensives compared to controls. After a mean follow-up of 76 patients for 45 months (range, 1 to 66 months), 17 subjects experienced an end point of either cardiovascular death (n = 10) or adverse cardiovascular event (n = 7). Comparing these 17 with the 59 free of an end point, the former were older (P = .0002) and had a longer duration of known hypertension (P = .018). There was a nonsignificant trend toward higher median plasma homocyst(e)ine levels in the patients sustaining a vascular end point (P = .07). In this pilot study, we suggest that essential hypertension may be associated with increased plasma homocyst(e)ine levels, but that this amino acid is unrelated to endothelial damage (von Willebrand factor), clinical indices, or prognosis.
To investigate the hypothesis that abnormalities of thrombogenesis and endothelial damage/dysfunction are greater in malignant hypertension (MHT) compared with uncomplicated nonmalignant essential hypertension (EHT) > 160/90 mm Hg), we measured markers of endothelial function (von Willebrand factor) platelet activation (soluble P-selectin) and fibrinogen in 18 consecutive patients with MHT, 50 patients with untreated EHT, and 34 healthy control subjects. We also investigated whether there was any diurnal variation in the measured indices, as well as the effects of good blood pressure (BP) control after 6-month follow-up. Mean plasma fibrinogen and von Willebrand factor levels were both highest in the MHT group, intermediate in the nonmalignant hypertension group and lowest in the normotensive control subjects (P < .001). Similarly, mean soluble P-selectin levels were higher in both hypertensive groups compared to normotensive control subjects (P = .033). There was no significant diurnal variation in plasma fibrinogen, soluble P-selectin, and von Willebrand factor levels over the 24-h study period among the MHT patients. At 6-month follow-up and a reduction in mean BP, there was no significant change in mean plasma fibrinogen levels (P = .25), but both soluble P-selectin (P < .001) and von Willebrand factor (P = .0025) were significantly reduced. In conclusion, malignant hypertension is associated with abnormal endothelial damage (elevated von Willebrand factor), platelet activation (soluble P-selectin), and fibrinogen levels, which may be related to the pathogenesis of this condition, as well as the development of complications. These abnormalities do not undergo any significant diurnal variation and may be beneficially altered by BP reduction.
OBJECTIVE: The primary aim of medical care and surgery for mitral valve disease is to improve the overall functional capacity and health of patients. AIM: To assess whether there was an actual improvement in quality of life (QOL) of patients 3 months following primary mitral valve repair (MRr) or mitral valve replacement (MVR). METHODS: Prospective study of 61 consecutive patients (34 males, mean age 64+/-12) who underwent primary, isolated mitral valve repair (MRr, n=40) or mitral valve replacement (MVR, n = 21) from April 1997 to October 1998. QOL parameters using the validated short form 36 (SF-36) questionnaire were determined before and at 3 months after surgery and analysed using the Wilcoxon matched pairs rank test. RESULTS: Mean QOL scores (scale 0-100) for all patients following mitral valve surgery showed clinical and statistically significant improvement in seven of eight QOL parameters, namely (i) physical function (post, 60+/-31 vs. pre, 44+/-29; P = 0.0001); (ii) role limitation due to physical function (50+/-42 vs. 23+/-36; P = 0.0002); (iii) social function (76+/-31 vs. 59+/-36; P = 0.0006); (iv) role limitation due to emotional problems (65+/-42 vs. 44+/-45; P = 0.003); (v) energy (57+/-24 vs. 40+/-24; P < 0.0001); (vi) mental health (73+/-20 vs. 66+/-21; P = 0.007); and (vii) general health perception (68+/-19 v 56+/-22; P = 0.0001); but not pain (73+/-29 v 71+/-30; P = 0.4). Following MRr there was significant improvement in seven of eight QOL parameters and following MVR there was significant improvement in three of eight QOL parameters. Whilst patients with ejection fraction > or = 50% showed significant improvement in seven of eight QOL parameters, there was no significant improvement in any QOL parameters in patients with impaired left ventricular (LV) function. Similarly, patients with mitral regurgitation with end-systolic dimensions of > or = 45 mm showed no significant improvement in any QOL parameters at 3 months follow-up. CONCLUSIONS: Our study suggests that following mitral valve surgery there was significant improvement in the QOL of patients especially in those patients requiring mitral valve repair. However, patients with impaired LV function and those with MR with end-systolic dimensions > or = 45 mm were unlikely to demonstrate a significant improvement in QOL at 3 months follow-up.
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