Search

Introduction: Tissue factor (TF)-induced thrombin generation (TG) ex vivo has been suggested to be an important method to assess thrombotic risk. No studies have investigated the impact of postprandial lipemia on TF-induced TG. Since myocardial infarction (MI) is associated with elevated postprandial levels of triglycerides, we hypothesized a differential impact of postprandial lipemia on coagulation activation in MI-patients and healthy controls., Material and Methods: Elderly survivors of acute MI (n=44) and healthy age-and sex matched controls (n=43) underwent a fat tolerance test (1 gram per kg body weight) to assess coagulation activation during postprandial lipemia., Results: The incremental area under the curve (AUCi) for serum triglycerides was higher in MI-patients than in healthy age-and sex matched controls (5.64±0.52 mmol/L*h and 3.94±0.39 mmol/L*h, p=0.012) during the postprandial phase. Subsequent endogenous activation of coagulation, assessed by FVIIa and thrombin generation (F1+2), was similar among groups and not related to levels of triglycerides during the postprandial phase. Healthy individuals had a gradual decline in TF-induced thrombin generation ex vivo, assessed by endogenous thrombin potential (ETP) (AUCi=-542.4±71.4 nM*min*h, p<0.001), whereas MI-patients retained their ETP (AUCi=127.4±89.0 nM*min*h, p=0.47) in plasma during the postprandial phase (p for group difference=0.005)., Conclusions: MI-patients had elevated postprandial lipemia and retained their ability for TF-induced TG in plasma ex vivo in the postprandial phase, whereas the capacity gradually decreased in healthy individuals. Further studies are warranted to reveal underlying mechanism(s) and clinical implications., (Copyright © 2009 Elsevier B.V. All rights reserved.)

Men have a higher incidence of cardiovascular disease (CVD) than women of similar age, and it has been suggested that testosterone may influence the development of CVD. Recently, we demonstrated that elderly men with low testosterone levels had lower plasma levels of free tissue factor pathway inhibitor (TFPI) Ag associated with shortened tissue factor (TF)-induced coagulation initiation in a population based case-control study. Our hypothesis was that one year of testosterone treatment to physiological levels in elderly men would increase the levels of free TFPI Ag in plasma and have a favorable effect on TF-induced coagulation. Twenty-six men with low testosterone levels (< or =11.0 nM) were randomly assigned to treatment with intramuscular testosterone depot injections (testosterone undecanoate 1,000 mg) or placebo in a double-blinded study. Each participant received a total of five injections, at baseline, 6, 16, 28 and 40 weeks, and TF-induced thrombin generation ex vivo and plasma free TFPI Ag were measured after one year. At the end of the study total and free testosterone levels were significantly higher in the testosterone treated group (14.9 +/- 4.5 nM vs. 8.1 +/- 2.4 nM; p < 0.001, and 363.3 +/- 106.6 pM vs. 187.3 +/- 63.2 pM; p < 0.001, respectively). Testosterone treatment for one year did neither cause significant changes in TF-induced thrombin generation ex vivo nor changes in plasma levels of free TFPI Ag. In conclusion, normalising testosterone levels by testosterone treatment for 12 months in elderly men did not affect TF-induced coagulation or plasma TFPI levels. The potential antithrombotic role of testosterone therapy remains to be elucidated.

The purpose of this study was to investigate the impact of recombinant glycosylated TFPI (rg-TFPI) from BHK cells, nonglycosylated TFPI (r-TFPI) from Escherichia coli, and truncated TFPI (1-161) on thrombin generation (TG) in plasma treated with and without heparin in vitro and ex vivo. Fasting plasma samples were collected from 6 healthy persons. TG was assessed by the calibrated automated thrombography (CAT) method. The addition of increasing concentrations (0-200 ng/mL) of different TFPI caused a 5% to 30% prolongation of lag time for TF (3.0 pM) induced TG, with the most pronounced effect for rg-TFPI and the least pronounced effect for truncated TFPI, but without affecting endogenous thrombin potential (ETP) in TF-induced coagulation. Removal of native TFPI from plasma by anti-TFPI IgG treatment shortened lag time by 35 +/- 4% without affecting ETP. Increasing concentrations (0-200 ng/mL) of various TFPI in the presence of low heparin concentrations (0.1 IU/mL) prolonged lag time and decreased ETP by 25% to 75% with the most prominent effect promoted by glycosylated full-length TFPI. The effect of neutralizing antibodies against TFPI and antithrombin (AT) was studied in plasma in the presence of heparin administered in vitro or ex vivo. The results revealed that TFPI and AT acted in synergy as inhibitors of coagulation in terms of the effect on both initiation (lag time) and propagation (ETP). Our data demonstrated that the CAT assay appropriately assessed the impact of TFPI on initiation and propagation of TG in a physiological plasma milieu with and without heparin. TFPI contributed significantly to regulation of coagulation initiation (lag time). The C-terminal region and, to a lesser extent, glycosylation of the TFPI molecule were essential for its anticoagulant function in the absence and presence of heparin.

Platelet microparticles (PMPs) are highly procoagulant and might therefore be important in the pathogenesis of arterial thrombotic diseases. The aim of this study was to determine plasma levels of PMPs in survivors of myocardial infarction (MI) and their relation to activation of primary (sCD40L) and secondary (thrombin-antithrombin (TAT) complexes) haemostasis. An observational, population-based case control study was conducted in 61 MI patients 1-4 years after the MI and 61 age-matched and sex-matched healthy controls. PMPs were quantified using an immunoassay that discriminates between small and large PMPs. MI patients had significantly higher total PMPs (314.3 µg/L, 273.1-361.4 µg/L versus 225.8 µg/L, 168.8-273.1 µg/L, p = 0.009) (geometric mean and 95% CI) and larger PMPs (181.3 µg/L, 160.7-204.3 µg/L versus 134.3 µg/L, 104.6-174.9 µg/L) than controls. The differences between groups remained significant after adjustments for use of cardiovascular drugs, body mass index, blood pressure and serum lipids, but were weakened when smoking was included in the analysis. Multiple regression analysis revealed a significant independent association between large PMPs and plasma TAT and soluble CD40 ligand (sCD40L) in MI patients, but not in healthy controls. The independent association between large PMPs and thrombin generation supports the concept that formation of PMPs is important for increased coagulation activation in MI patients. [ABSTRACT FROM AUTHOR]