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Biomedical subjects

A J Catto

Publications and source records attributed to A J Catto.

27 records · Page 2Linked to original sources
PubMed1998

Platelet GP IIIa PlA and GP Ib variable number tandem repeat polymorphisms and markers of platelet activation in acute stroke.

A number of polymorphisms of the platelet glycoprotein (GP) Ib-V-IX and IIb/IIIa complexes have been described, and the PlA polymorphism of GP IIIa has been associated with coronary thrombosis. We determined the levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) and the genotype distributions of PlA and a variable number tandem repeat (VNTR) polymorphism of GP 1b in subjects with acute stroke (n=609) and healthy control subjects (n=435). Levels of beta-TG were higher in patients both initially (47.4 [44.7 to 50.2] ng/mL, P<0.0001) and after 3 months (42.9 [40.3 to 45.7] ng/mL, P=0.03) compared with control subjects (39.4 [37.7 to 41.2] ng/mL). Initial levels of beta-TG were significantly higher in those who subsequently died (58.7 [52.3 to 65.8] ng/mL) compared with those still alive (42.7 [40.1 to 45.5] ng/mL, P<0.0001). In a logistic regression model, beta-TG remained an independent predictor of poststroke mortality, with an odds ratio for an increase in 10 ng/mL of 1.12 (1.03 to 1.21, P=0.006). In subjects who had never smoked, there was a significant difference in the genotype distributions of patients with atherothrombotic stroke (A1/A1=147, A1/A2=70, and A2/A2=2) compared with controls (A1/A1=165, A1/A2=47, and A2/A2=5, P=0.03). The PlA distribution of subjects with atherothrombotic stroke before the age of 50 years (A1/A1=19 and A1/A2+A2/A2=18) was also significantly different from age- and sex-matched controls (A1/A1=54 and A1/A2+A2/A2=20, P=0.02). We found no association of VNTR with stroke or poststroke mortality. These data indicate that there is a persistent state of enhanced platelet activation in subjects with acute stroke, which is associated with poststroke mortality. The increased frequency of the PlA2 allele in young subjects with atherothrombotic stroke lends further support for a role of the PlA polymorphism in acute thrombosis.

Aged↗
PubMed1998

Factor XIII Val 34 Leu: a novel association with primary intracerebral hemorrhage.

BACKGROUND AND PURPOSE: A common G-to-T point mutation (Val 34 Leu) in exon 2 of the alpha-subunit of the factor XIII is strongly negatively associated with the development of myocardial infarction. This result suggests that factor XIII Val 34 Leu is interfering with the formation of cross-linked fibrin. The role of factor XIII Val 34 Leu in the pathogenesis of cerebral infarction and primary intracerebral hemorrhage is unknown. METHODS: Six hundred twelve patients with acute stroke, defined by World Health Organization criteria and cranial CT, and 436 age-matched control subjects free of cerebrovascular disease were genotyped for the factor XIII Val 34 Leu mutation. Venous blood was drawn for the determination of hemostatic variables and lipids. Factor XIII genotype was determined through a single-stranded conformational polymorphism technique and plasminogen activator inhibitor (PAI)-1 4G/5G promoter genotype by allele-specific polymerase chain reaction. RESULTS: The mutation was more frequent in patients with primary intracerebral hemorrhage (n=62) (54.8%; P=.05) than in control subjects (41.7%) or in patients with cerebral infarction (n=529) (46.5%; P=.22). There was no relationship between PAI-1 levels and the PAI-1 4G/5G genotype. CONCLUSIONS: There was a slightly higher incidence of factor XIII Val 34 Leu in patients with PICH. This may be related to impaired cross-linking of fibrin and/or coagulation proteins.

Aged↗
PubMed1998

Determinants of tPA antigen and associations with coronary artery disease and acute cerebrovascular disease.

The aim of this study was to determine the association of tPA antigen levels with CAD and ischaemic stroke and whether associations are independent of levels of PAI-1 antigen. In subjects with CAD (n = 247) tPA was associated with the number of coronary arteries with > or = 50% stenosis, but this association was lost after adjustment for PAI-1, which was found to be the largest determinant of tPA levels in linear regression models and accounted for as much as 38% of the variation in levels. Levels of tPA were significantly higher in patients with a history of MI compared with those without, even after adjustment for covariates and PAI-1 (MI: 10.0 [9.4-10.6] ng/ml; no MI: 8.9 [8.5-9.4] ng/ml, p = 0.004). In a logistic regression model comparing patients with MI to patients without MI, the odds ratio for tPA levels in the upper quartile compared with the lowest quartile was 2.03 (1.33-3.10). Levels of tPA in subjects with ischaemic stroke (n = 338) were significantly higher than age matched healthy control subjects (n = 366) and again this difference remained after adjustment (patients: 10.4 [9.9-10.9] ng/ml; controls: 9.0 [8.7-9.3] ng/ml, p <0.0001). In a logistic regression model comparing patients with ischaemic stroke to healthy control subjects the odds ratio for tPA in the upper quartile compared with the lowest quartile was 4.23 (3.02-5.92). These data suggest that the associations of tPA with acute thrombosis are independent of levels of PAI-1 but the mechanisms whereby enhanced fibrinolysis may predispose to thrombosis remain unclear.

Biomarkers↗
PubMed1997

Gender-specific associations of the fibrinogen B beta 448 polymorphism, fibrinogen levels, and acute cerebrovascular disease.

Fibrinogen is an independent risk factor for the development of stroke. Factors influencing circulating levels of fibrinogen include age, smoking, gender, and genetic factors. The aim of this study was to determine the relationship between a polymorphism at position 448 of the B beta fibrinogen gene, fibrinogen levels, gender, and the risk of stroke. Fibrinogen levels were determined in 305 patients with stroke, taken within 10 days of the acute event and 3 months later, and in 197 control subjects. Initial fibrinogen levels in patients (4.49 g/L) were significantly higher than at 3 months (3.85 g/L, P < .0001), consistent with resolution of the acute-phase response. At 3 months, levels were only significantly higher than for control subjects in the male patients (3.86 g/L versus 3.31 g/L, P < .0001). Fibrinogen levels were associated with B beta 448 genotype in male patients at 3 months (1/1 = 3.62 g/L, 1/2 + 2/2 = 4.27 g/L, P = .01). There was a significant difference in the genotype distribution in female patients and control subjects (patients: 1/1 = 95, 1/2 = 34, 2/2 = 6; control subjects: 1/1 = 61, 1/2 = 50, 2/2 = 3, P = .008). These data suggest that the mechanisms linking fibrinogen and the development of cerebrovascular disease are different in males and females. In male patients, the increase in fibrinogen levels may be influenced by environmental factors, while in females there may be a functional difference in the fibrinogen molecule unrelated to fibrinogen levels.

Acute Disease↗
PubMed1997

Polymorphisms of the factor VII gene and circulating FVII:C levels in relation to acute cerebrovascular disease and poststroke mortality.

BACKGROUND AND PURPOSE: FVII:C has been shown to be an independent risk factor for myocardial infarction and is related to environmental and genetic factors. This study sought to investigate FVII:C levels and factor VII (FVII) gene polymorphisms in relation to stroke and disease outcome. METHODS: To examine the association of FVII:C and the Msp I and promoter insertion polymorphisms of the FVII gene in acute stroke, 317 patients and 198 age-matched control subjects were studied. RESULTS: FVII:C levels were significantly lower in patients at onset than 3 months later (119% versus 135%, respectively; P < .0005). Levels were significantly lower in patients at onset than in control subjects (124% [95% confidence interval, 120% to 129%] versus 141% [95% confidence interval, 135% to 148%], respectively; P < .0005) but were not significantly different at 3 months (135% [95% confidence interval, 128% to 141%] versus 141% [95% confidence interval, 135% to 148%], respectively). We found no difference in genotype distribution for either polymorphism between patients and control subjects, no difference in FVII:C level or genotype distribution between pathological types of stroke, and no relationship with poststroke mortality. Both polymorphisms were significantly associated with FVII:C levels in patients and control subjects. In a multiple regression model for patients, Msp I genotype, cholesterol, and smoking remained as independent predictors of FVII:C levels, accounting for 32% of interindividual variation. CONCLUSIONS: These results suggest that neither FVII:C levels nor FVII gene polymorphisms are associated with cerebrovascular disease. There were no genotype-specific correlations of environmental factors with FVII:C, but there was evidence of an acute-phase or consumptive fall in FVII:C levels at the time of stroke, whereas levels increased to those similar for healthy age-matched control subjects by 3 months, when the acute phase had presumably subsided.

Acute Disease↗
PubMed1997

Plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter polymorphism and levels in subjects with cerebrovascular disease.

The exact role of the fibrinolytic system in the pathogenesis of stroke remains to be established. Elevated circulating levels of plasminogen activator inhibitor-1, the principle inactivator of the fibrinolytic system, have been related to the development of myocardial infarction. There is evidence that a polymorphism in the promoter region of the PAI-1 gene is associated with circulating PAI-1 levels. We studied a common single nucleotide insertion/deletion (4G/5G) polymorphism by PCR in 558 patients with stroke, the pathological type of which was established by cranial computed tomography, and in 172 controls. 4G/5G genotype and PAI-1 activity were investigated in relation to 1) stroke type and 2) mortality occurring within four weeks, three months and six months of the stroke. No difference in genotype frequency was observed when all cases of stroke were compared with controls nor between the clinically determined subtypes of cerebral infarction. PAI-1 activity was significantly higher in patients with stroke (n = 245) both at presentation (11.6 U/ml) and after three months (11.8 U/ml), in paired samples, than in control subjects (8.8 U/ml, p < 0.0001). Thirty-seven (6.2%), 86 (14.5%) and 122 (20.5%) patients had died within one, three and six months of admission, respectively. PAI-1 activity was independently associated with all-cause mortality at one and three months after stroke (p = 0.02 and p = 0.03 respectively), but not after six months. In this population the 4G/5G promoter polymorphism is not associated with an increased risk of stroke. PAI-1 levels were elevated at the time of acute stroke which persisted after three months. PAI-1 level but not genotype was associated with early mortality following stroke.

Aged↗
PubMed1997

von Willebrand factor and factor VIII: C in acute cerebrovascular disease. Relationship to stroke subtype and mortality.

BACKGROUND: Elevated von Willebrand factor (vWF) is a risk factor in the development of acute myocardial infarction. The importance of vWF and factor VII:C in the pathogenesis of cerebrovascular disease (CVD) is poorly defined. METHODS AND RESULTS: We studied 208 cases of stroke whose pathological type was defined by cranial computed tomography. Cerebral infarcts were grouped according to the Oxfordshire Community Stroke Project (OCSP) clinical classification. The results in patients were compared with 184 healthy reference subjects. In patients, vWF and FVIII:C levels were determined initially and after three months. Patients were followed prospectively for six months or until death. Levels of vWF and FVIII:C were elevated initially (1.86 IU/ml and 2.20 U/ml respectively) and after 3 months (1.51 IU/ml and 1.90 U/ml) compared with a healthy reference population (1.26 IU/ml and 1.49 U/ml p = 0.0001). In the initial sample, vWF was associated with age (p = 0.01). FVIII:C was related to age (p = 0.04), gender (p = 0.007 higher for females) and a history of diabetes mellitus (2.56 U/ml vs. 2.16 U/ml in non-diabetics, p = 0.008). Initial vWF levels were higher in subjects with large vessel disease (TACI/PACI) group compared with the small vessel disease (LACI) group [2.12 IU/ml, (n = 112) vs. 1.48 IU/ml (n = 59) respectively, p = 0.0001] and similarly in initial FVIII:C levels (2.43 U/ml vs. 1.87 U/ml, p = 0.0001). Analysis of six-month case fatality, vWF levels were associated with risk of death [p = 0.01, OR 1.73 (1.12, 2.66) for an increase of I U/ml], even after allowing for stroke type. CONCLUSION: The relationship of vWF with stroke mortality has not previously been described. Although we have not demonstrated a causal role for vWF in the pathogenesis of CVD, elevated circulating levels of vWF may be associated with increased risk of death following stroke. A prospective study would be required to establish whether vWF is predictive for the development of CVD.

Acute Disease↗
PubMed1995

Risk factors for cerebrovascular disease and the role of coagulation and fibrinolysis.

Cerebrovascular disease is one of the major causes of morbidity and mortality in the developed world. A number of important risk factors have been identified with the occurrence of stroke, including advancing age, hypertension, smoking and diabetes mellitus, but the mechanisms that link these risk factors to the development of cerebrovascular disease are unclear. The pathogenesis of cerebrovascular disease includes syndromes of atherothrombotic brain infarction and intracerebral hemorrhage. The role of abnormalities of the coagulation and fibrinolytic systems in these processes has not been properly evaluated with regard to clinical outcome, although there is evidence that raised concentrations of fibrinogen are associated with an increased risk of stroke. Smaller studies have identified increases in FVIII/vWF in association with acute stroke and raised levels of tissue plasminogen activator. Although factor VII is considered a risk factor for coronary artery disease, little is known regarding its role in the development of cerebrovascular disease. Improved understanding of the pathogenesis of stroke and the potential to predict patients at risk of stroke should herald the beginning of new approaches in stroke management.

Blood Coagulation↗