Platelet activation: assessment and quantification.
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Biomedical subjects
Publications and source records attributed to G Y Lip.
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BACKGROUND: Atrial fibrillation is associated with increased risk of stroke and thromboembolism, possibly by conferring a prothrombotic or hypercoagulable state. However, it is unclear whether or not this differs in the clinical subgroups of chronic atrial fibrillation patients, that is, in those with paroxysmal, persistent or permanent atrial fibrillation. We therefore hypothesized that: (i) there are differences in the prothrombotic state between these patients; and (ii) reduction in indices of hypercoagulability would follow elective electrical cardioversion of persistent atrial fibrillation and the return of left atrial function. PATIENTS AND METHODS: We studied 69 patients with chronic atrial fibrillation: 23 with paroxysmal atrial fibrillation (16 males; mean age 65 years+/-SD 13); 23 with persistent atrial fibrillation (16 males; 65 years+/-13), with a mean duration of atrial fibrillation of 3 months (range 2 to 6 months); and 23 with permanent atrial fibrillation (16 males; 67 years+/-10). Blood results were compared to 20 age- and sex-matched healthy controls. The patients with persistent atrial fibrillation then underwent elective DC cardioversion, with Doppler echocardiographic examinations and bloods tests performed prior to cardioversion, and at 3 and 12 weeks afterwards. The prothrombotic state was quantified by measurement of plasma levels of fibrinogen, soluble P-selectin (an index of platelet activation) and von Willebrand factor (a marker of endothelial dysfunction). RESULTS: Permanent atrial fibrillation was associated with significantly raised levels of von Willebrand factor, soluble P-selectin and fibrinogen (all P<0.001); paroxysmal atrial fibrillation with significantly elevated levels of plasma von Willebrand factor (P=0.0067) and fibrinogen (P=0.0001) but not soluble P-selectin (P=0.472); and persistent atrial fibrillation with normal levels of fibrinogen, von Willebrand factor and soluble P-selectin when compared to healthy controls (all P=ns). Stepwise multiple regression analyses demonstrated that the presence of atrial fibrillation was an independent predictor of abnormal von Willebrand factor, fibrinogen and soluble P-selectin levels. Electrical cardioversion of the patients with persistent atrial fibrillation did not significantly alter levels of von Willebrand factor (P=0.766), soluble P-selectin (P=0.726) or fibrinogen (P=0.50) despite maintenance of sinus rhythm and a significant return of left atrial systolic function (as quantified by the presence of A wave on Doppler echocardiography) at 3 months. CONCLUSION: There were significant differences in the prothrombotic state when patients with paroxysmal and permanent atrial fibrillation are compared to matched patients with persistent atrial fibrillation or controls in sinus rhythm. Cardioversion of persistent atrial fibrillation did not significantly alter indices of hypercoagulability even after 3 months maintenance of sinus rhythm, despite the return of atrial systole.
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Many cross-sectional and follow-up studies of large numbers of patients with hypertension have demonstrated an increased prevalence and mortality from renal cancer. We report the details of three patients with renal cell carcinoma from a series of 254 consecutive patients with malignant phase hypertension, an excess over the expected number reported from several large published series with non-malignant hypertension. In view of this excess we investigated the prevalence of hypertension in a series of 192 consecutive patients who presented with a diagnosis of renal cell carcinoma, in comparison with a local unselected population screening survey. Hypertension was found in 43% of the renal carcinoma patients and 20% of the local population, also a clear excess. The mechanism of the association between renal cancer and malignant and non-malignant hypertension is unclear.
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We surveyed Accident and Emergency (A&E) consultants in England by questionnaire, on their management of patients presenting with AF. Completed questionnaires were received from 124 (45%). Most (42%) would use digoxin as first-line treatment for rate control of AF; 28% would not treat AF acutely but would refer the patient to the medical team; 59% would cardiovert a patient with AF in A&E, if there was evidence of cardiovascular compromise. Some 51% would not routinely initiate any anticoagulation therapy. Faced with a patient in fast AF who was haemodynamically unstable, 67% would immediately opt for electrical cardioversion, 13% would refer the patient directly to the medics and 15% would initially treat with intravenous digoxin. Given a patient in fast AF and cardiac failure, 55% would treat with digoxin. Asked about AF related to Wolff-Parkinson-White syndrome, 37% would initially give adenosine, 23% would opt for immediate DC cardioversion and 25% would refer directly to the medics; however, a minority would still give a rate-limiting calcium antagonist or digoxin. The majority (79%) would not treat AF in a known alcoholic with acute intoxication who was haemodynamically stable. Consultants were more likely to initiate treatment if the patient had signs of shock or heart failure. Where there were underlying medical problems they were more likely to refer the patient directly to the medical team. There was a general reluctance to initiate anticoagulation, and some difference in opinion over how long AF should have persisted for anticoagulation to be necessary in the context of electrical cardioversion. Given the current evolution of A&E as an acute speciality, A&E clinicians should at least initiate management of patients with AF and be prepared to care for them for some time in A&E.
There has been a tendency to treat paroxysmal atrial fibrillation (PAF) in a similar way to sustained AF, but treatment objectives may be very different. We discuss current definitions, epidemiology, pathophysiology and natural history of PAF, and review evidence for its treatment and management. PAF comprises between 25% and 62% of cases of AF, with similar underlying causes to those in sustained AF. The main objective of management is prevention of paroxysms and long-term maintenance of sinus rhythm, and Class 1c drugs are highly effective, although beta-blockers are useful alternatives. If patients have severe coronary artery disease or poor ventricular function, amiodarone is probably the drug of choice. Although randomized controlled trials of thromboprophylaxis in patients with paroxysmal AF per se are lacking, the approach to patients with paroxysmal AF should be similar to that in patients with sustained AF, with warfarin for 'high risk' patients and aspirin for those at 'low risk'. Non-pharmacological therapeutic options, including pacemakers, electrophysiological techniques and the implantable atrial defibrillator, show great promise. Despite paroxysmal AF being a common condition, management strategies are limited by evidence from small randomized trials, with inconsistencies over the definition of the arrhythmia and the inclusion of only symptomatic subjects. Evidence for antithrombotic therapy is also based on epidemiological studies and subgroup analyses of the large randomized trials.
Low-density lipoprotein (LDL) consists of a heterogeneous group of particles of differing size, density and electrophoretic mobility, smaller particles being more atherogenic. A high proportion of small LDL particles is an independent risk factor for cardiovascular disease. We hypothesized that patients with malignant phase hypertension (MHT), the most severe form of hypertension, would demonstrate a more atherogenic LDL subfraction profile than either non-malignant hypertension (NMHT) or normotensive controls. We compared 16 patients with MHT to 41 patients with untreated NMHT and 45 normotensive controls. LDL subfraction profile was measured by disc polyacrylamide gel electrophoresis using a validated scoring system to calculate the mean size (locus) and heterogeneity (spread) of LDL subfraction mobilities. A higher LDL locus indicates a greater proportion of small LDL subfractions. LDL cholesterol levels were similar in all three groups (p=0.23). High-density lipoprotein cholesterol (HDL-C) levels were significantly lower (p<0.001) and serum triglyceride concentrations significantly higher (p=0.02) in the MHT group, compared to normotensive controls. LDL locus was greater in the NMHT group than in the normotensive controls and intermediate in the MHT group (p=0.008). There was no significant difference in LDL spread (p=0.26). Serum triglyceride concentrations were not significantly higher after adjusting for confounding variables. MHT is associated with an abnormal lipid profile, characterized by low HDL-cholesterol concentration. This dyslipidaemia may be partly responsible for the vascular complications and the poor prognosis of these patients.
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Abnormal platelet activation and an increased risk of thrombosis are frequent findings in cancer. As soluble adhesion molecule P-selectin is being increasingly recognized as reflecting increased platelet activation, we hypothesized raised levels in patients with cancer, obtaining plasma from 24 patients with a cross-section of haematological cancers, 41 with breast cancer, and from an equal number of healthy controls for each patient group. Levels of soluble P-selectin were compared with those of von Willebrand factor (vWf), plasminogen activator inhibitor-1 (PAI-1) activity and fibrinogen (markers of endothelial integrity, fibrinolysis and coagulation, respectively). We found raised soluble P-selectin, fibrinogen and vWf in both patient groups compared with their controls (P < 0.01). vWf and soluble P-selectin were higher in the haematological cancers than in breast cancer patients (by 30 and 74%, respectively; both P < 0.01). There was no significant difference in levels of PAI-1 between any group. There were no differences in soluble P-selectin or vWf when the data from the women with breast cancer were classified according to tumour size, lymph node involvement or presence of vascular invasion. We conclude that the platelet marker soluble P-selectin is raised in both haematological and breast cancer, and is higher in the former, but is unrelated to the type or stage of breast cancer.
While the blood vessels are exposed to high pressures in hypertension, the main complications of hypertension (stroke and myocardial infarction) are paradoxically thrombotic rather than haemorrhagic. To investigate abnormalities of haemorheology (plasma viscosity, fibrinogen), endothelial dysfunction (von Willebrand factor), platelet activation (soluble P-selectin) and thrombogenesis (plasminogen activator inhibitor and fibrin D-dimer) in stroke and the effects of concurrent hypertension, we studied 86 consecutive patients (58 male, 28 female) aged < 75 years (mean age +/- SD, 64.2 +/- 9.2 years) with acute stroke (ictus < 12 h). Baseline blood tests on admission were compared with 46 'hospital controls' (patients with uncomplicated essential hypertension; mean age +/- SD, 65.9 +/- 3.8 years) and 24 healthy normotensive controls (mean age +/- SD, 65 +/- 14.0 years). Further comparisons were made between stroke patients with hypertension (systolic blood pressure > 160 mmHg and/or diastolic > 90 mmHg) on admission and those without hypertension. Mean plasma viscosity (one-way analysis of variance, P = 0.026) and fibrinogen levels (P = 0.016) were significantly higher in stroke patients and hospital controls, when compared with healthy controls. The von Willebrand factor, plasminogen activator inhibitor soluble P-selectin and fibrin D-dimer levels were highest in the acute stroke patients, intermediate in hospital controls and lowest in healthy controls (all P < or = 0.001). There were no significant differences in measured indices of haemorheology, endothelial dysfunction and thrombogenesis between the three stroke pathological subtypes (ischaemic/thrombotic, haemorrhagic or transient ischaemic attack). There were also no significant differences in the measured parameters for stroke patients with or without systolic blood pressure > 160 mmHg or diastolic blood pressures > 90 mmHg using clinical (manual) readings or mean daytime or night-time ambulatory blood pressure monitoring recordings. There were no statistically significant differences between the measured parameters on admission and at 3 months follow-up in 26 patients (all P = not significant). Plasma viscosity was significantly correlated with mean daytime systolic blood pressure (r = 0.314, P = 0.021) and mean night-time systolic blood pressure (r = 0.309, P = 0.025). This study of hypertension and haemostasis in acute stroke has demonstrated clear abnormalities of haemorheology, endothelial dysfunction, platelet activation and thrombogenesis, which do not appear to be affected by the height of the blood pressure or the presence of hypertension. This is despite the known hypercoagulable state found in hypertension and the relationship of haemostatic abnormalities to vascular complications.
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Coronary bypass grafts using the internal mammary artery usually have an excellent record of success and long term patency. We report a 42 year old man who initially presented with a history of atypical left sided chest pain, who had coronary artery bypass surgery for a severe stenosis in his proximal left anterior descending coronary artery (LAD) and moderate stenosis of his proximal circumflex artery, with his LIMA being grafted to his mid-LAD and a saphenous venous graft to the proximal LAD. He subsequently developed multiple stenoses in the LIMA graft which required coronary augioplasty and stenting, on more than one occasion, in view of very rapid restenosis within the LIMA graft.
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The aim of this article is to provide an overview of the available data linking antihypertensive drug therapy to cancer risk. In recent years, a number of mainly retrospective studies have reached different conclusions on the risk of cancer in patients with hypertension being treated with different antihypertensive drugs. At some point or another nearly all antihypertensive drugs have been suggested to increase the risk of cancer. Some studies have even found an association between hypertension itself and increased carcinogenesis. For calcium channel antagonists, beta-blockers and alpha-blockers, the available evidence seems to favour a neutral effect on cancer development and death rate. For ACE inhibitors, the overall data suggest a similar neutral effect on cancer or, possibly, a small protective effect. Perhaps the strongest evidence in favour of a link, although probably weak, between cancer and antihypertensive drugs is with the diuretics. Until further solid data are available from prospective clinical trials, we suggest that the management of hypertension should continue according to current treatment guidelines with little fear of any substantial cancer risk.