Modulation of Thrombophilia Genes by Environmental Factors.
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Journal Article↗
Biomedical subjects
Gordon D O Lowe
Publications and source records attributed to Gordon D O Lowe.
A specific elevation in tissue plasminogen activator antigen in women with polycystic ovarian syndrome.
There is increasing evidence that elevated plasma levels of hemostatic factors [fibrinogen, factor VII, von Willebrand factor, fibrin D-dimer, and tissue plasminogen activator (t-PA) antigen] are independently linked to risk for coronary heart disease (CHD). Women with polycystic ovary syndrome (PCOS) are insulin-resistant and have increased risk for CHD and type 2 diabetes, but there are few data on hemostatic markers in women with PCOS. Seventeen women with PCOS (defined on the basis of elevated testosterone and oligomenorrhea) and 15 healthy women matched as a group for body mass index (BMI) were recruited. Insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique. Factor VIIc was determined by a clotting assay; fibrinogen was determined by nephelometry; and t-PA, D-dimer, and von Willebrand factor antigens were measured by ELISA techniques. Of these hemostatic markers, only t-PA concentration was significantly (P = 0.013) elevated in women with PCOS relative to controls. t-PA correlated with BMI in both PCOS and controls (r = 0.428, P < 0.1; and r = 0.686, P < 0.01) and inversely with the insulin sensitivity index (r = -0.590, P < 0.05; and r = -0.620, P < 0.05, respectively). After further adjustment for BMI and insulin sensitivity, there remained a significant difference in t-PA between cases and controls (P = 0.017). Together, age and insulin sensitivity explained 39% of the variance in t-PA in women with PCOS (P < 0.05). Total testosterone did not correlate significantly with t-PA in either group. We conclude that women with PCOS have significantly increased t-PA concentrations relative to women with normal menstrual rhythm and normal androgens. We suggest that elevated t-PA and dysfibrinolysis may be a factor in the increased cardiovascular morbidity seen in PCOS.
Adult↗
C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study.
Accumulating evidence implicates inflammation as a potential pathway in the pathogenesis of type 2 diabetes. The objective of the present study was to assess the ability of C-reactive protein (CRP) to predict the development of diabetes in middle-aged men in the West of Scotland Coronary Prevention Study. Baseline plasma samples for CRP measurement were available for 5,245 men of whom 127 were classified as having a transition from normal glucose control to overt diabetes during the study, based on American Diabetes Association criteria. Baseline CRP was an important predictor of the development of diabetes in univariate analysis (hazard ratio [HR] for an increase of 1 SD = 1.55; 95% CI 1.32-1.82; P < 0.0001). In multivariate analysis, CRP remained a predictor of diabetes development (HR 1.30; 95% CI 1.07-1.58; P = 0.0075) independent of other clinically employed predictors, including baseline BMI and fasting triglyceride and glucose concentrations. Moreover, there was a graded increase in risk across CRP quintiles throughout the study, evident at even 1 year of follow-up. The highest quintile (CRP >4.18 mg/l) was associated with a greater than threefold risk of developing diabetes (HR 3.07; 95% CI 1.33-7.10) in a multivariate analysis at 5 years. Thus, CRP predicts the development of type 2 diabetes in middle-aged men independently of established risk factors. Because CRP, the most commonly used acute-phase protein in clinical practice, is very stable in serum, our observations have clinical potential in helping to better predict individuals destined to develop type 2 diabetes. They also add to the notion that low-grade inflammation is important in the pathogenesis of type 2 diabetes.
Acute-Phase Reaction↗
Influence of socioeconomic status and job control on plasma fibrinogen responses to acute mental stress.
OBJECTIVE: An elevation in plasma fibrinogen may be one of the pathways through which low socioeconomic status increases cardiovascular disease risk. This study assessed the influence of socioeconomic status, job control, and social isolation on fibrinogen responses to acute stress. METHODS: The study was conducted with 125 white men and 96 white women aged 47 to 58 years, drawn from the Whitehall II cohort. Socioeconomic status was indexed by grade of employment, with 82 high, 75 intermediate, and 64 low grade participants. Plasma fibrinogen and hematocrit were assessed at baseline, immediately after performance of color-word and mirror tracing tasks, and 45 minutes later. RESULTS: Plasma fibrinogen increased from baseline to stress (from 2.85 +/- 0.57 to 2.92 +/- 0.58 g/liter), remaining elevated 45 minutes after stress (2.89 +/- 0.58 g/liter, p <.001). Fibrinogen concentration was greater in the low than in the high or intermediate employment grade groups, independently of sex, age, body mass index, smoking status, and hematocrit. Fibrinogen responses to acute stress did not differ across employment grades. Women had higher fibrinogen levels than men, but this pattern was abolished in women taking hormone replacement therapy. Men experiencing low job control showed greater fibrinogen responses to acute stress than did those with high job control (p =.003). Fibrinogen levels were greater in socially isolated individuals, but social isolation did not affect responses to acute stress. CONCLUSIONS: Socioeconomic status and acute stress had independent effects on the plasma fibrinogen level. Low job control may influence cardiovascular disease risk in men partly through provoking greater fibrinogen stress responses.
Acute Disease↗
Virchow's triad revisited: abnormal flow.
Virchow rightly recognised that blood flow plays an important role in thrombosis. The roles of blood flow in haemostasis, and in arterial, intra-cardiac, and venous thrombosis are reviewed. In streamline (laminar) flow, shear stresses are maximal at the vessel wall, and affect endothelial cell morphology and function (e.g. secretion of NO, prostacyclin,t-PA and vWF). Platelets are also concentrated at the vessel wall (due to axial concentration of red cells)where they can be activated by high shear stresses and are well-placed to interact with vWF and subendothelium,resulting in platelet adhesion and the initial stages of haemostasis. On the other hand, increasing wall shear forces increase removal of thrombin and fibrin monomer, hence stasis (induced by internal or external pressure) is required to allow fibrin formation and secondary haemostasis. Atherogenesis occurs in areas of arterial flow separation,which promotes platelet, leucocyte, LDL and fibrinogen adhesion and wall infiltration. Rheological variables (e.g. wall shear stress, viscosity, haematocrit,fibrinogen, LDL) have been correlated with the extent of ultrasonic carotid intima-media thickening. Arterial thrombosis usually follows rupture of atherosclerotic plaques and intra-plaque haemorrhage: high intra-stenotic shear stresses may activate platelets,promoting the initial platelet-rich "white-head" of arterial thrombi, while low post-stenotic shear stresses may promote the subsequent, fibrin--and red cell-rich "red tail". Blood viscosity, platelet microemboli, and activated leucocytes may each reduce post-stenotic microcirculatory blood flow, promoting infarction. Such mechanisms may explain the associations of increased levels of blood and plasma viscosity, haematocrit, white cell count, fibrinogen and vWF with risk and outcome of myocardial, cerebral and limb infarction. Areas of recirculating blood flow under low shear stresses predispose to intracardiac thromboembolism(e.g. atrial fibrillation, in which elevated fibrin D-dimer levels are normalised after cardioversion) and venous thromboembolism (fibrin D-dimer levels are associated with most risk factors). There is good evidence that reduction of venous stasis in the legs reduces the risk of venous thromboembolism. There is increasing evidence that regular exercise and avoidance of immobility reduces the risk of both arterial and venous thrombosis and also has systemic antithrombotic and anti-inflammatory effects. So: "Go with the flow!"
Blood Platelets↗