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Biomedical subjects

P K MacCallum

Publications and source records attributed to P K MacCallum.

At least 19 recordsLinked to original sources
PubMed2006

Impairment of coagulation by commonly used resuscitation fluids in human volunteers.

BACKGROUND: This study compared the effects of two commonly used resuscitation fluids on whole blood coagulation. METHODS: 1000 ml of two resuscitation fluids each (saline and Gelofusine) were given to eight volunteers in a crossover design with a 2-week washout period. The effect on whole blood coagulation was assessed using the Sonoclot analyzer, a conventional coagulation screen and coagulation markers. RESULTS: No significant effect was found on whole blood coagulation by giving saline (time to peak clot increased by a mean of 106 s; (95% confidence interval (CI) -140 to 354), whereas Gelofusine delayed the time to peak by a mean of 845 s (95% CI 435 to 1255). By contrast, there was no change in the conventional coagulation screen with either fluid. CONCLUSION: It was concluded that some resuscitation fluids have an effect on clot formation that is not shown by the conventional coagulation screen, but is disclosed only if the whole coagulation process is studied.

Blood Coagulation↗
PubMed2003

Cumulative risk assessment in unstable angina: clinical, electrocardiographic, autonomic, and biochemical markers.

OBJECTIVES: To determine the incremental value of clinical data, troponin T, ST segment monitoring, and heart rate variability for predicting outcome in patients with non-ST elevation acute coronary syndromes. METHODS: Prospective cohort study of 304 consecutive patients. Baseline clinical and electrocardiographic data were recorded, serial blood samples were obtained for troponin T assay, and 48 hour Holter monitoring was performed for ST segment and heart rate variability analysis. End points were cardiac death and non-fatal myocardial infarction during 12 months' follow up. RESULTS: After 12 months, 7 patients had died and 21 had had non-fatal myocardial infarction. The risk of an event was increased by troponin T > 0.1 microg/l, T wave inversion on the presenting ECG, Holter ST shift, and a decrease in the standard deviation of 5 minute mean RR intervals. Positive predictive values of individual multivariate risk were low; however, analysis of all multivariate risk markers permitted calculation of a cumulative risk score, which increased the positive predictive value to 46.9% while retaining a negative predictive value of 96.9%. CONCLUSION: A cumulative approach to risk stratification in non-ST elevation coronary syndromes successfully identifies a group in whom the risk of cardiac death or non-fatal myocardial infarction approaches 50%.

Angina, Unstable↗
PubMed2002

Genetic determinants of the response to bezafibrate treatment in the lower extremity arterial disease event reduction (LEADER) trial.

Genetic determinants of baseline levels and the fall in plasma triglyceride and fibrinogen levels in response to bezafibrate treatment were examined in 853 men taking part in the lower extremity arterial disease event reduction (LEADER) trial. Three polymorphisms in the peroxisome proliferator activated receptor alpha (PPARalpha) gene were investigated (L162V, G>A in intron 2 and G>C in intron 7), two in the apolipoprotein CIII (APOC3) gene (-482C>T and -455T>C) and one in the beta-fibrinogen (FIBB) gene (-455G>A). The presence of diabetes (n=158) was associated with 15% higher triglyceride levels at baseline compared to non-diabetics (n=654) (P<0.05). Among the diabetic group, carriers of the PPARalpha intron 7 C allele had 20% lower triglyceride levels compared to homozygotes for the common G allele (P<0.05), with a similar (non-significant) trend for the L162V polymorphism, which is in linkage disequilibrium with the intron 7 polymorphism. For the APOC3 gene, carriers of the -482T allele had 13% lower baseline triglyceride levels compared to -482C homozygotes (P<0.02), but no effect was observed with the -455T>C substitution. In the non-diabetic patients, the PPARalpha V162 allele was significantly associated with 9% higher baseline triglyceride levels (P<0.03) and a similar, but non-significant trend was seen for the intron 7 polymorphism. Overall, triglyceride levels fell by 26% with 3 months of bezafibrate treatment, and current smokers showed a poorer response compared to ex/non-smokers (23% fall compared to 28% P=0.03), but none of the genotypes examined had a significant influence on the magnitude of response. Carriers of the -455A polymorphism of the FIBB gene had, as expected, marginally higher baseline fibrinogen levels, 3.43 versus 3.36 g/l (P=0.055), but this polymorphism did not affect response to treatment. Overall, fibrinogen levels fell by 12%, with patients with the highest baseline fibrinogen levels showing the greatest decrease in response to bezafibrate. For both the intron 2 and the L162V polymorphisms of the PPARalpha gene there was a significant interaction (both P<0.01) between genotype and baseline levels of fibrinogen on the response of fibrinogen levels to bezafibrate, such that individuals carrying the rare alleles in the lowest tertile showed essentially no overall decrease compared to a 0.18 g/l fall in homozygotes for the common allele. Thus while these genotypes are a minor determinant of baseline triglyceride and fibrinogen levels, there is little evidence from this study that the magnitude of response to bezafibrate treatment in men with peripheral vascular disease is determined by variation at these loci.

Adult↗
PubMed2000

Minimum effective intensity of oral anticoagulant therapy in primary prevention of coronary heart disease.

BACKGROUND: There is mounting evidence that low-intensity oral anticoagulation is effective, particularly in primary prevention of thrombosis, with important implications for safety and the practicalities of using warfarin. Because it is desirable to know possible benefits for different indications so that optimal therapy can be administered in as wide a range of conditions as possible, we analyzed data from the Thrombosis Prevention Trial, a factorial trial that compared treatment with low-intensity, dose-adjusted warfarin and low-dose aspirin separately and together, to determine the minimum effective intensity of oral anticoagulation in the primary prevention of coronary heart disease. METHODS: The international normalized ratio (INR) most recent to an event and overall time at each INR were used to calculate the INR-related event rate for coronary events, strokes, and major and minor bleeding episodes in 2545 men receiving warfarin with or without aspirin (75 mg/d) and followed up for a total of 9952 person-years. RESULTS: Compared with placebo, warfarin alone at a dose that maintained the INR at 1.4 or more significantly reduced the risk of a coronary event by 47% (95% confidence interval, 4%-70%; P =.03), whereas the risk of a coronary event was not reduced at INRs below 1. 4. Coronary events, strokes, and major bleeding episodes combined were significantly reduced by 45% (95% confidence interval, 9%-67%; P =.02) in the warfarin group compared with the placebo group when the INR was 1.4 or more. Minor bleeding episodes increased as the INR rose above about 2.0. No significant association of INR with coronary events was observed with combined warfarin and aspirin, possibly reflecting the small number of such events that occurred in this group, therefore limiting the power to detect an association with INR. CONCLUSIONS: Warfarin alone is effective in the primary prevention of coronary heart disease when the dose is adjusted to maintain an INR of 1.4 or more. The results add to the evidence that low-intensity, dose-adjusted oral anticoagulation is effective for a range of conditions.

Aged↗
PubMed2000

Influence of previous aspirin treatment and smoking on the electrocardiographic manifestations of injury in acute myocardial infarction.

OBJECTIVE: To examine demographic and clinical characteristics of patients with acute myocardial infarction in order to identify factors affecting the electrocardiographic evolution of injury. METHODS: Prospective cohort study of 1399 consecutive patients with a first myocardial infarction. Baseline clinical data associated with ST elevation and Q wave development were identified and 12 month survival was estimated. RESULTS: Smoking had complex effects on the evolution of injury, increasing the odds of ST elevation (odds ratio (OR) 1.61; 95% confidence interval (CI) 1.08 to 2.36), but reducing the odds of Q wave development (OR 0.69, 95% CI 0.49 to 0.96). The effects of previous aspirin treatment were more consistent with reductions in the odds of ST elevation (OR 0.57, 95% CI 0.35 to 0.94) and Q wave development (OR 0.53, 95% CI 0.34 to 0. 84). ST elevation and Q wave development were both associated with an adverse prognosis, with estimated 12 month survival rates of 80. 6% (95% CI 78.2% to 83.1%) and 80.0% (95% CI 77.5% to 82.5%), respectively, compared with 86.5% (95% CI 81.2% to 91.9%) and 89.9% (95% CI 86.2% to 93.7%) for patients without these ECG changes. CONCLUSIONS: The thrombogenicity of the blood may be a major determinant of infarct severity. Smoking increases thrombogenicity and the likelihood of ST elevation, but because coronary occlusion is relatively more thrombotic in smokers, responses to both endogenous and exogenous thrombolysis are better, reducing the risk of Q wave development. Previous aspirin treatment reduces thrombogenicity, protecting against ST elevation and Q wave development.

Aged↗
PubMed2000

Haemostatic and lipid determinants of prothrombin fragment F1.2 and D-dimer in plasma.

The determinants of plasma levels of prothrombin fragment F1.2 (F1.2) and D-dimer in different populations are unclear and this may complicate their interpretation as predictors of thrombotic risk, particularly in the case of D-dimer. We therefore measured F1.2 and D-dimer levels together with a number of other haemostatic and lipid variables in a cross-sectional community-based study of 150 healthy adults (73 male, 77 female), age range 23-80 years, identified from the list of a general practice by stratified random sampling within sex and decade of age. Plasma F1.2 was significantly higher in females than males and was independently and positively associated with age, factor VII activity (FVIIc) and C1 inhibitor, and inversely associated with high density lipoprotein (HDL) cholesterol. Plasma D-dimer showed a quadratic association with age (p <0.0001). In those < or =55 years D-dimer was inversely associated with dilute clot lysis time (DCLT) and activated protein C (APC) ratio. In those >55 years it was significantly higher in females than males and associated positively with age, fibrinogen and, in males, activated factor XII (FXIIa). In a multiple-linear model which combined both age groups, F1.2 and D-dimer were independently associated with each other (r = 0.22, p = 0.03). Thus, thrombin generation and fibrin turnover/fibrinolysis are associated in healthy subjects. HDL cholesterol (inversely) and FVIIc are associated with basal thrombin generation (i.e. F1.2). Determinants of D-dimer differ according to age and interpretation of the biological significance of D-dimer levels in epidemiological studies may therefore not be straightforward.

Adult↗
PubMed2000

Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels.

BACKGROUND: Respiratory tract infections may acutely increase risk from coronary heart disease (CHD), though the mechanisms have not been defined. Patients with chronic obstructive pulmonary disease (COPD) are prone to repeated exacerbations that are often associated with respiratory infections. These patients also have increased cardiovascular morbidity and mortality. We hypothesized that transient acute increases in plasma fibrinogen, an independent risk factor for CHD, could occur at COPD exacerbation (mediated through a rise in IL6) and thereby provide a mechanism linking respiratory infection to risk of coronary heart disease. METHODS: 93 COPD patients [mean (SD) age 66.8 (8.1) years] were followed regularly over one year, with daily diary card monitoring of respiratory symptoms and peak expiratory flow rate (PEFR); 67 patients [mean FEV1 1.06 (0.44) l, FVC 2.43 (0.79) l] were seen during 120 exacerbations. At each visit spirometry was measured and blood samples taken for plasma fibrinogen and Interleukin-6 (IL-6) levels. RESULT: At baseline, the mean (SD) plasma fibrinogen was elevated at 3.9 (0.67) g/l in the 67 patients with exacerbations during the study and the median (IQR) IL-6 at 4.3 (2.4 to 6.8) pg/ml. Plasma fibrinogen increased by 0.36 (0.74) g/l at exacerbation (p <0.001). with IL-6 levels rising by 1.10 (-2.73 to 6.95) pg/ml (p = 0.008). There was a relation between the changes in fibrinogen at exacerbation and IL-6 levels (r = 0.348, p <0.001). Multiple regression revealed significantly greater rises in fibrinogen when exacerbations were associated with purulent sputum (b = 0.34 g/l; p = 0.03), increased cough (b = 0.31 g/l, p = 0.019) and symptomatic colds (b = 0.228; p = 0.024). CONCLUSIONS: Plasma fibrinogen levels were elevated in stable patients with COPD and may contribute to the increased cardiovascular morbidity and mortality in these patients. COPD exacerbations increased serum IL-6 levels, leading to a rise in plasma fibrinogen. Thus acute rather than chronic infection may have a role in predisposing to coronary heart disease or stroke.

Aged↗
PubMed1999

Haemostatic function, arterial disease and the prevention of arterial thrombosis.

Recent years have seen the expansion of information linking raised plasma levels of individual clotting factors and evidence of disturbances of fibrinolytic activity with the risk of thrombotic manifestations of arterial disease, both in community-based, apparently healthy populations and in patients with known atherosclerosis. Some of these prothrombotic changes in the haemostatic system may result partly from underlying chronic inflammation or acute infection and may, in turn, contribute substantially to the thrombotic risk which accompanies these underlying processes. The importance of the coagulation system in the pathogenesis of arterial thrombosis is further illustrated by the benefit in the Thrombosis Prevention Trial of low-intensity, dose-adjusted warfarin in the primary prevention of ischaemic heart disease. Clinical trials of bezafibrate, which is being used for its fibrinogen-lowering as well as lipid-modifying properties, are in progress.

Animals↗
PubMed1998

Multicentre randomised study of computerised anticoagulant dosage. European Concerted Action on Anticoagulation.

BACKGROUND: The demand for anticoagulant treatment is increasing. We compared the benefits of computer-generated anticoagulant dosing with traditional dosing decided by experienced medical staff in achieving target international normalised ratios (INRs). METHODS: In five European centres we randomly assigned 285 patients in the stabilisation period and stabilised patients to the computer-generated-dose group (n=137) or traditional-dose group (n=148). Centres had a specialist interest in oral anticoagulation but no previous experience with computer-generated dosing. The computer program calculated doses and times to next visit. Our main endpoint was time spent in target INR range (Rosendaal method). FINDINGS: For all patients combined, computer-generated dosing was significantly beneficial overall in achieving target INR (p=0.004). The mean time within target INR range for all patients and all ranges was 63.3% (SD 28.0) of days in the computer-generated-dose group compared with 53.2% (27.7) in the traditional-dose group. For the stabilisation patients alone, computer-generated doses led to a non-significant benefit in all INR ranges (p=0.06), whereas in the stable patients the benefit was significant (p=0.02). INTERPRETATION: The computer program gave better INR control than the experienced medical staff and at least similar standards to the specialised centres should be generally available. Clinical outcome and cost effectiveness remain to be assessed.

Administration, Oral↗
PubMed1998

Clinical characteristics determining the mode of presentation in patients with acute coronary syndromes.

OBJECTIVES: The purpose of this study was to examine clinical characteristics of patients with acute coronary syndromes to identify factors that influence the mode of presentation. BACKGROUND: In acute coronary syndromes, presentation with myocardial infarction or unstable angina has major prognostic implications, yet clinical factors affecting the mode of presentation are not well defined. METHODS: A prospective cohort study was made of 1,111 patients with acute coronary syndromes. Baseline demographic, clinical and biochemical data were compared in groups with myocardial infarction (n = 633) and unstable angina (n = 478). RESULTS: The risk of myocardial infarction relative to unstable angina was increased by age >70 years (odds ratio [OR] 2.21; 95% confidence interval [CI] 1.33 to 3.66), male gender (OR 1.56; CI 1.13 to 2.16) and cigarette smoking (OR 1.49; CI 1.09 to 2.03). A rise in admission creatinine from the 10th to the 90th centile of the distribution also increased the odds of myocardial infarction (OR 1.30; CI 1.05 to 1.94). Conversely, the risk of myocardial infarction relative to unstable angina was reduced by previous treatment with aspirin (OR 0.37; CI 0.27 to 0.52), hypertension (OR 0.64; CI 0.47 to 0.86) and previous acute coronary syndromes (OR 0.36; CI 0.26 to 0.51) and revascularization procedures (OR 0.36; CI 0.21 to 0.62). CONCLUSIONS: The clinical presentation of acute coronary syndromes may be influenced by various factors that have the potential to influence the coagulability of the blood, the collateralization of the coronary circulation and myocardial mass. Myocardial infarction is favored by cigarette smoking, advanced age and renal impairment, while unstable angina is favored by treatment with aspirin, hypertension, previous revascularization and previous coronary syndromes.

Aged↗
PubMed1998

Associations of protein C and protein S with serum lipid concentrations.

Difficulties in the laboratory measurement of protein C and protein S levels cause problems in the diagnosis of deficiency states in individual patients and may complicate estimation of the prevalence of these states in the general population. Some difficulties may be due to unappreciated influences affecting the measured levels of proteins C and S. We measured protein C activity and antigen, total and free protein S antigen, and serum total cholesterol, high-density cholesterol and triglyceride in a community-based study of 150 adults (73 male, 77 female), age range 23-80 years. Participants were identified from the list of a single general practice by stratified random sampling within sex and decade of age. Protein C activity and antigen were strongly associated with serum lipids, mean levels increasing by approximately 0.25 u/ml as total cholesterol and triglyceride concentration each rose from the 5th to 95th centile. Total protein S antigen concentration was associated with total cholesterol, the mean rising by over 0.1 u/ml as total cholesterol increased from the 5th to the 95th centile, whilst a similar rise in triglyceride was associated with an increase in mean free protein S of more than 0.3 u/ml. Overall, physiological variation in total cholesterol and triglyceride concentration was associated with significant variation in protein C and protein S levels, independent of age and sex, suggesting that it is important to take serum lipids into account when investigating patients for protein C or protein S deficiency. Failure to do so may be misleading in some circumstances.

Adult↗
PubMed1998

Sex differences in the determinants of fibrinolytic activity.

Impaired whole blood fibrinolytic activity (FA), measured by the dilute clot lysis time (DCLT), is associated with first episodes of ischaemic heart disease (IHD) in the Northwick Park Heart Study in men, especially under 55 years, and in women. In a community-based study to investigate possible determinants of the DCLT, and therefore to assess which fibrinolytic components might be predictors of first IHD events, we measured fibrinolytic variables in a sub-sample of 150 healthy adults (73 males, 77 females) randomly selected from a single general practice. Most of the variance in DCLT (68% in men, 63% in women) was explained by tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) activities. In multiple regression analysis there was a significant difference in the strength of the association of t-PA activity with DCLT in men compared to women (test for interaction p = 0.05), the association of t-PA activity with DCLT being significant in males but not in females. Plasma PAI-1 activity was strongly associated with DCLT in both sexes. There was no independent association of DCLT with plasma fibrinogen, t-PA antigen, other fibrinolytic inhibitors, body mass index, serum lipids or C-reactive protein. Plasma PAI-1 activity in females and both t-PA and PAI-1 activities in males are the main determinants of whole blood FA measured by DCLT. It is therefore likely that these modulators of the plasma fibrinolytic system are associated with the onset of first clinical episodes of IHD. Elevated levels of t-PA antigen were positively associated with DCLT after adjustment for age and sex and therefore indicate impaired rather than enhanced FA. Further studies of the association of FA with risk of IHD should include not only "global" measures but also assessment of t-PA and PAI-1 activities, particularly as our results suggest that their associations with IHD may differ in men and women.

Adult↗
PubMed1995

Mitoxantrone and cytosine arabinoside as treatment for acute myeloblastic leukemia in older patients.

The majority of patients with acute myeloid leukemia (AML) are elderly, and their response to chemotherapy is poorer than that of younger patients. The combination of mitoxantrone (MTN) and cytosine arabinoside (Ara-C) is a possible alternative to an anthracycline/Ara-C combination for the treatment of AML in these patients. Of 52 older patients (> 59 years) referred over a 3.5-year period, 33 patients (age range 60-78 years, median 67 years) received MTN and Ara-C as therapy for newly diagnosed AML. MTN was administered at a dose of 12 mg/m2/day, intravenously, for 3 days (23 patients), or 10 mg/m2/day for 5 days (10 patients), and Ara-C at a dose of 100 mg/m2 twice daily, intravenously, for 7 days. Complete remission (CR) was achieved in 16/33 patients (48%). The median remission duration was 6 months (range 1-37 months). The median survival was 14 months for those who achieved CR compared with 9 months for those with resistant disease. Two patients remain in first CR after 13 and 37 months, but three patients died whilst receiving consolidation therapy. In selected elderly patients with AML, the combination of MTN and Ara-C provides an acceptable alternative to an anthracycline/Ara-C regimen, with a higher CR rate than historical controls. However, the CR rate and remission duration remain low compared with those of younger patients, supporting the need to investigate new approaches to treatment in this population.

Age Factors↗
PubMed1993

Mitoxantrone and cytosine arabinoside as treatment for acute myelogenous leukemia (AML) at first recurrence.

A total of 107 patients with newly diagnosed acute myeloblastic leukemia (AML) were referred to the ICRF Department of Medical Oncology at St Bartholomew's Hospital between August 1986 and July 1989. Of those referred, 92 (87%) were treated with remission induction chemotherapy comprising: Adriamycin, cytosine arabinoside (ara-C) and 6-thioguanine if aged < 60 years (57 patients) or mitoxantrone (MTN) and ara-C if aged > 60 years (35 patients). Of those treated, 54 (58%) entered complete remission (CR). Recurrent AML developed in 38 out of these 54 patients (70%) of whom 25 aged 19-73 years (median 50 years) subsequently received MTN and ara-C as reinduction therapy. The 19 younger patients (under 60 years old) received MTN at 12 mg/m2, intravenously, daily for 5 days and ara-C at 100 mg/m2, intravenously, twice daily for 7 days. The six older patients received the same ara-C schedule but the dose of MTN was reduced to 10 mg/m2 for 5 days. Second CR was achieved in 16 out of 25 patients (64%) [12/19 (63%) and 4/6 (67%) for patients aged under or over 60 years, respectively]. Eight of the patients in whom second CR was achieved were aged under 50 years and were thus eligible for additional consolidation comprising myeloablative therapy with autologous bone marrow transplantation (ABMT). Four patients actually received the latter treatment: two remain in second CR at 21 and 46 months. Three of the remaining eight patients aged > 50 years in whom second CR was achieved remain in second CR 8 to 43 months later. Censored for myeloablative therapy + ABMT, the overall median duration of second CR was 5 months. Although remissions tended to be short, in younger patients the possibility of proceeding to myeloablative therapy with autologous bone marrow support makes the regimen worthwhile and, even in older patients, it was sometimes possible to achieve prolonged second remissions.

Adolescent↗