Long-term effects on haemostatic variables of three ad libitum diets differing in type and amount of fat and carbohydrate:a 6-month randomised study in obese individuals

Diet is important in the prevention of CVD, and it has been suggested that a diet high in MUFA is more cardioprotective than a low-fat diet. We hypothesised that the thrombotic risk profile is improved most favourably by a high-MUFA diet compared with a low-fat diet. This was tested in a parallel randomised intervention trial on overweight individuals (aged 28·2 (sd 4·6) years) randomly assigned to a diet providing a moderate amount of fat (35–45 % of energy; &gt;20 % of fat as MUFA) (MUFA diet; n 39), to a low-fat (LF; 20–30 % of energy) diet (n 43), or to a control diet (35 % of energy as fat; n 24) for 6 months after a weight loss of about 10 %. Protein constituted 10–20 % of energy in all three diets. All foods were provided free of charge from a purpose-built supermarket. Fasting blood samples were collected before and after intervention and analysed for factor VII coagulant activity (FVII:c), fibrinogen, prothrombin fragment 1+2 (F1+2), D-dimer and plasminogen activator inhibitor (PAI). The fibrinogen concentration was significantly lowered by the LF diet, but not by the MUFA diet. Changes in fibrinogen differed significantly between diet groups. BMI and PAI concentration increased and D-dimer concentrations were reduced irrespective of the diets. No changes were observed for FVII:c and F1+2. Our findings suggest that in overweight subjects after weight loss the thrombotic risk profile is improved most favourably by the LF diet compared with the MUFA diet based on the reduction in fibrinogen concentrations.</jats:p

A case-only approach for assessing gene-sex interaction in human longevity

As one aspect of the complex feature of longevity, gene-sex interaction plays an important role in influencing human life span. With advances in molecular genetics, more studies aimed at assessing gene-sex interaction are expected. New and valid statistical methods are needed. In this paper, we introduce a nontraditional approach, the case-only design, which was originally proposed for assessing gene and disease associations, to detect gene-sex interaction in human longevity. Applications of this method to data collected from centenarian studies show that it can produce consistent results as compared with results obtained from case-control and other approaches. Important features of the application in human longevity studies are highlighted and discussed. Since centenarians constitute a special population representing successful ageing, the easily applicable case-only approach will be an important tool for screening potential major genes that contribute to human longevity. (AUTHORS)

Genetic influence on inflammation variables in the elderly

Udgivelsesdato: 2004-NovBACKGROUND: Inflammation variables (C-reactive protein [CRP], fibrinogen, and soluble intercellular adhesion molecule-1 [sICAM-1]) have been identified as risk factors for cardiovascular disease. It is still not known how much the regulation of inflammatory risk factors is determined by genetic factors, and the aim of this study was to determine the heritability of these inflammation variables and of the acute phase regulating cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) at older ages. METHODS AND RESULTS: The heritability of CRP, fibrinogen, sICAM-1, IL-6, and TNF-alpha was determined in a twin study consisting of 129 monozygotic twin pairs and 153 dizygotic same-sex twins aged 73 to 94 years who participated in the Longitudinal Study of Aging of Danish Twins. Furthermore, we determined the influence of selected genetic polymorphisms on the plasma level variations. Genetic factors accounted for 20% to 55% of the variation in plasma levels of the inflammation variables. The highest heritability was found for sICAM-1. The genetic polymorphisms we studied explained only a small, insignificant part of the heritability. CONCLUSIONS: This study in elderly twins provides evidence for a substantial genetic component of inflammatory cardiovascular risk factors among the elderly

Effects of Obesity Surgery on Blood Coagulation and Fibrinolysis:A Literature Review

OBJECTIVE:  Obesity is characterized by a disturbed hemostatic balance with increased coagulation and impaired fibrinolysis. This increases the risk of thrombosis, and the risk is lowered after obesity surgery. Over the past 25 years, several studies have contributed to understand the mechanisms behind the antithrombotic effect of obesity surgery, and this literature review summarizes the results of these studies.METHODS:  A detailed literature search on the effects of obesity surgery on the hemostatic balance was conducted.RESULTS:  The 25 relevant studies reviewed demonstrated that obesity surgery has favorable effects on many biomarkers of coagulation and fibrinolysis. The evidence is substantial for fibrinogen and plasminogen activator inhibitor type 1 with average reductions from 1 to 24 months after obesity surgery of 17 and 48%, respectively. For most other biomarkers, the evidence is moderate or weak with average effect sizes varying from 2% for fiber mass length ratio to 70% for prothrombin fragment 1 + 2 and with a large variation between studies. Many studies are small and of short duration, and the surgical techniques differ. Also, studies are confounded by changes in medication, comorbidity, diet, and exercise. It is unknown whether the hemostatic changes are mediated by weight loss alone or by the accompanying metabolic improvements.CONCLUSION:  Despite issues of confounding, this review suggests that obesity surgery shifts the hemostatic balance in the antithrombotic direction, thereby reducing the thrombotic potential of people with obesity, but more studies are needed for most of the biomarkers.</p

Performance related factors are the main determinants of the von Willebrand factor response to exhaustive physical exercise

Background: Physical stress triggers the endothelium to release von Willebrand Factor (VWF) from the Weibel Palade bodies. Since VWF is a risk factor for arterial thrombosis, it is of great interest to discover determinants of VWF response to physical stress. We aimed to determine the main mediators of the VWF increase by exhaustive physical exercise. Methods: 105 healthy individuals (18-35 years) were included in this study. Each participant performed an incremental exhaustive exercise test on a cycle ergometer. Respiratory gas exchange measurements were obtained while cardiac function was continuously monitored. Blood was collected at baseline and directly after exhaustion. VWF antigen (VWF:Ag) levels, VWF collagen binding (VWF:CB) levels, ADAMTS13 activity and common variations in Syntaxin Binding Protein-5 (STXBP5, rs1039084 and rs9399599), Syntaxin-2 (STX2, rs7978987) and VWF (promoter, rs7965413) were determined. Results: The median VWF:Ag level at baseline was 0.94 IU/mL [IQR 0.8-1.1] and increased with 47% [IQR 25-73] after exhaustive exercise to a median maximum VWF:Ag of 1.38 IU/mL [IQR 1.1-1.8] (p<0.0001). VWF:CB levels and ADAMTS13 activity both also increased after exhaustive exercise (median increase 43% and 12%, both p<0.0001). The strongest determinants of the VWF:Ag level increase are performance related (p<0.0001). We observed a gender difference in VWF:Ag response to exercise (females 1.2 IU/mL; males 1.7 IU/mL, p = 0.001), which was associated by a difference in performance. Genetic variations in STXBP5, STX2 and the VWF promoter were not associated with VWF:Ag levels at baseline nor with the VWF:Ag increase. Conclusions: VWF:Ag levels strongly increase upon exhaustive exercise and this increase is strongly determined by physical fitness level and the intensity of the exercise, while there is no clear effect of genetic variation in STXBP5, STX2 and the VWF promoter

The effects of sampling from a peripheral venous catheter compared to repeated venepunctures on markers of coagulation, inflammation, and endothelial function

Peripheral venous (PV) catheters are often used for serial blood sampling, but studies suggest that PV catheters increase markers of coagulation activation and inflammation. Whether the increase is caused by irritation of the vessel wall or diurnal variation is unknown. We therefore compared the effects of a PV catheter and repeated venepunctures on markers of coagulation, inflammation, and endothelial function. A PV catheter was inserted at 07:45 in a hand vein in 10 healthy subjects, and blood samples were collected at 8:00, 10:00, 12:00, and 14:00. In the contralateral arm, blood was simultaneously obtained by venepunctures. Measures of coagulation, i.e., activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen, prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin (TAT), inflammation, i.e., interleukin 6 (IL-6) and C-reactive protein (CRP), and endothelial function, i.e., plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), von Willebrand factor (vWF), and tissue factor (TF) were measured in plasma. The concentrations of TAT and F1 + 2 were significantly increased (10:00; p  &lt; .01, 12:00; p  &lt; .05, and 14:00; p  &lt; .01) in PV catheter samples compared with venepuncture samples. There was a minor increase in PT and INR and no increase in APTT, fibrinogen, CRP, PAI-1, tPA, vWF, and TF, with no differences between sampling methods. IL-6 concentrations increased in many PV catheter samples and venepuncture samples, but the response varied between the subjects. Blood collection through a PV catheter induces coagulation activation, whereas endothelial function is not affected. More studies are needed to disclose the effect of blood sampling on IL-6. </p

Increased contact system activity three months after starting combined oral contraceptives

INTRODUCTION: Combined oral contraceptives (COC) are associated with an increased risk of venous thromboembolism (VTE). The contact system (CAS) can, when activated, stimulate coagulation, and may play a role in thrombus formation. Our recent case-control study showed increased CAS capacity and in vivo activity in COC users, indicating a systemic activation that could contribute to VTE risk during COC treatment. Aim This study investigates intraindividual changes in CAS in women before and after start of COC treatment.MATERIALS AND METHODS: Twenty-four women aged between 15 and 34 years, who were starting treatment with COC, were included in the study. A baseline blood sample was drawn before start of COC, and a follow-up blood sample 3-4 months later. The capacity and activity of CAS, i.e. factor XII (FXII), prekallikrein (PK), H-kininogen (HK), C1-esterase inhibitor (C1inh), cleaved HK (cHK) and endogenous kallikrein potential (EKP), were analyzed.RESULTS: Our study showed significantly increased levels of FXII (median 29.4 vs 42.9 mg/L; p &lt; 0.0001) and decreased levels of C1inh (0.21 vs 0.20 g/L; p = 0.005). Increased EKP (1859 vs 2203 nmol/L*min; p = 0.0004) demonstrated an increased capacity of CAS, and increased levels of cHK (0.70 vs 0.96 μg/L; p &lt; 0.0001) indicated an increased activity of CAS in vivo. The levels of PK and HK showed no significant changes.CONCLUSION: This study demonstrates an increased intraindividual CAS capacity as well as an increased CAS activity during treatment with COC supporting the previous research. These effects on CAS may contribute to the increased thrombotic risk caused by COC.</p

Testosterone therapy increases the anticoagulant potential in men with opioid-induced hypogonadism:a randomized, placebo-controlled study

Introduction: Hypogonadism is prevalent during opioid treatment, and low testosterone concentrations are associated with cardiovascular disease. The effect of testosterone replacement therapy (TRT) on the coagulation system in men with hypogonadism is not clarified. We investigate the effects of TRT on the tissue factor (TF) and contact activation pathways of coagulation in opioid-treated men. Materials and methods: This was a double-blinded, placebo-controlled study in 37 men with total testosterone &lt; 12 nmol/L randomized to 24 weeks of testosterone injections (n = 17) or placebo (n = 20). Variables of the coagulation system were analysed at baseline and after 24 weeks. Measurements included the TF pathway (endogenous thrombin potential (ETP) and peak thrombin), the contact activation pathway (endogenous kallikrein potential (EKP) and peak kallikrein), coagulation factors (FVII, FX, prothrombin, and FXII), and inhibitors (tissue factor pathway inhibitor (TFPI), protein C, protein S, antithrombin, and C1 esterase inhibitor (C1inh)). Between-group differences at 24 weeks were determined with analysis of covariance. Within-group changes in TRT and placebo were analysed with paired t-test. Results: Between-group differences at 24 weeks were observed for ETP (P = 0.036), FVII (P = 0.044), FX (P = 0.015), prothrombin (P = 0.003), protein C (P = 0.004), and protein S (P = 0.038). Within the TRT group, ETP, peak thrombin, FVII, FX, prothrombin, TFPI, protein C, FXII, and C1inh decreased and protein S increased (all P &lt; 0.05). Within the placebo group, coagulation outcomes were unchanged. Conclusion: TRT affects the coagulation system in an anticoagulant direction through suppressed TF pathway in men with opioid-induced hypogonadism.</p

High-fat meals do not affect thrombin formation and fibrin clot lysis in individuals with obesity during intentional weight loss

Repeated weight loss cycles are associated with increased cardiovascular morbidity. Meal-induced thrombin formation, measured as prothrombin fragment 1+2 (F1+2), is observed in individuals with overweight after weight loss, and postprandial effects can be one of the mechanisms underlying harmful effects during intentional weight loss. We hypothesize that consumption of high-fat meals during intentional weight loss triggers a prothrombotic state by increasing postprandial F1+2 or decreasing fibrin clot lysis in individuals with obesity, and that the response associates with the gut bacteria composition. A cross-over meal study was conducted in patients admitted to bariatric surgery during dietary weight loss (N = 20) and surgical weight loss (N = 16) (weight loss groups). High-fat (67 E%) and low-fat (16 E%) meals were served at 08:15 and 10:00 on 2 study days. Blood samples collected at 08:00 (fasting), 12:00, and 14:00 were analyzed for triglycerides, activated factor VII (FVIIa), F1+2, D-dimer, fibrinogen, tissue factor, and fibrin clot lysis. The proportion of Gram-negative bacteria and bacterial diversity were analyzed in fecal samples obtained less than 24 hours before the meal test. Triglyceride and FVIIa increased after high-fat meals in both weight loss groups, whereas D-dimer (dietary group) and F1+2 decreased and tissue factor and fibrin clot lysis did not change. There was a negative association between the proportion of Gram-negative bacteria and changes in FVIIa in the surgery group. Postprandial FVII activation after high-fat meals is not accompanied by increased F1+2, irrespective of the weight loss intervention, but might be associated with the proportion of Gram-negative gut bacteria.</p