Cardiovascular risk factors in vegetarians. Normalization of hyperhomocysteinemia with vitamin B(12) and reduction of platelet aggregation with n-3 fatty acids

Hyperhomocysteinemia in association with vitamin B(12) deficiency, and increased platelet aggregation, probably due to dietary lack of n-3 fatty acids, constitute cardiovascular risk factors frequently observed in vegetarians. We tested if administration of vitamin B(12) normalizes the concentration of total plasma homocysteine, and if intake of eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) fatty acids modulates platelet function in a population of lactoovovegetarians. One week after a single intramuscular injection of cyanocobalamin (10000 microg) in 18 individuals, serum vitamin B(12) increased from 149+/-63 pg/mL to 532+/-204 pg/mL (p<0.0001) and total tHcy dropped from 12.4+/-4.7 to 7.9+/-3.1 micromol/L (p<0. 0001). Ten of fourteen of these vegetarians completed an 8-week supplementation with 700 mg/day of each eicosapentaenoic and docosahexaenoic acids. Increased incorporation of these fatty acids into plasma lipids was observed in all of them, together with a significant reduction in maximum percentage or slope of platelet aggregation with all the agonists tested (ADP, epinephrin, collagen, arachidonic acid). No significant change in bleeding time was observed after n-3 fatty acid trial. Supplementation with vitamin B(12) and n-3 fatty acids corrects hyperhomocysteinemia and reduces platelet reactivity to agonists in vegetarians. Whether this supplementation improves the already reduced cardiovascular morbidity and mortality associated with vegetarian diet has yet to be demonstrated.     

Plasma homocysteine, vitamin B12 and folate in Alzheimer's patients and healthy Arabs in Israel

High plasma homocysteine (tHcy) is a risk factor for cardiovascular disease and stroke and Alzheimer's disease (AD). An inverse relationship has been reported between tHcy and plasma B12 and folate levels. Seventy-nine AD patients and 156 controls from three Arab villages in northern Israel participated. Plasma tHcy, B12 and folate levels were determined. Data were analyzed using univariate statistical tests and logistical regression with confounders. tHcy was significantly higher in AD patients (20.6+/-8.7 micromol/l) than in controls (16.4+/-6.5 micromol/l) (p=0.03) after correction for year of birth, gender and smoking status. Plasma B12 (322.9+/-136.0/350.5+/-175.3 pmol/l) and plasma folate (4.5+/-3.8/4.9+/-2.6 nmol/l) levels did not differ significantly between AD patients and controls. Subjects in the highest tHcy tertile or in the lowest B12 and folate tertiles did not have greater risk to develop AD. In this population residing in Arab villages in northern Israel, tHcy levels were significantly higher among AD patients than in controls. Plasma B12 and folate levels were lower among cases but were not significant. There was not a significant association between plasma tHcy, B12 and folate levels in controls or AD patients. High levels of tHcy may suggest the need for folate and vitamin B12 supplementation in this population.     

Coagulation factors and the increased risk of stroke in nonvalvular atrial fibrillation

We studied whether hemostatic abnormalities contribute to the increased risk of stroke in patients with nonvalvular atrial fibrillation. Hemostatic function was studied in four age-matched groups: 20 patients with nonvalvular atrial fibrillation and a previous ischemic stroke, 20 patients with nonvalvular atrial fibrillation without a previous stroke, 20 stroke patients with sinus rhythm, and 40 healthy controls. Both groups with nonvalvular atrial fibrillation had significantly higher concentrations of von Willebrand factor, factor VIII:C, fibrinogen, D-dimer (a fibrinolytic product), beta-thromboglobulin, and platelet factor 4; a significantly higher fibrinogen/antithrombin ratio; and significantly higher spontaneous amidolytic activity than the healthy controls. Prekallikrein levels were significantly lower in both groups with nonvalvular atrial fibrillation. Stroke patients with sinus rhythm had normal hemostatic function, normal concentrations of platelet-related factors, and a slightly increased concentration of fibrinopeptide A compared with the healthy controls. Both groups with nonvalvular atrial fibrillation differed from the stroke patients with sinus rhythm as they did from the healthy controls. No difference in hemostatic function was seen between the nonvalvular atrial fibrillation patients with and without a previous ischemic stroke. Thus, alterations in hemostatic function may contribute to the increased risk of stroke in patients with nonvalvular atrial fibrillation.     

Endothelial Cell Markers in Chronic Uremia: Relationship with Hemostatic Defects and Severity of Renal Failure

Plasma von Willebrand factor antigen, soluble thrombomodulin, and tissue factor were increased in 31 patients with severe chronic renal failure (creatinine clearance <20 ml/min) under conservative treatment, whereas plasminogen activator inhibitor antigen did not differ significantly from healthy controls. No correlation among plasma levels of these proteins was found. Three patterns of relationship between endothelial cell markers and hemostatic defects were identified: 1) Plasma thrombomodulin, a marker of endothelium damage, was found an independent predictor of bleeding time and platelet aggregation, and secretion defects, and was also related to the severity of renal failure; 2) von Willebrand factor antigen, an index of endothelial cell activation and secretion, was significantly correlated with intravascular markers of thombin and plasmin generation and with platelet adenosine triphosphate content, but not with plasma creatinine levels; and 3) tissue factor and plasminogen activator inhibitor antigen levels were not statistically correlated with the diverse hemostatic defects. Activation of coagulation and fibrinolysis, secondary to endothelial cell activation, appearing early during the evolution of chronic renal failure, is pathogenically related to the platelet dysfunction, and probably to development of atherosclerosis and thrombotic events in this disease. The progression of chronic renal failure, through endothelial cell damage, would lead to aggravation of the platelet functional defect potentiating the hemorrhagic risk.     

Plasma homocyst(e)ine concentrations and the risk of subtypes of cerebral infarction. The Hisayama study.

Moderately elevated plasma total homocyst(e)ine (tHcy) levels have been linked with cardiovascular disease. However, the findings of previous studies regarding the relationship between tHcy levels and subtypes of cerebral infarction (CI) have been conflicting. The aim of the present study was to examine this issue in a community-based case-control study performed in Hisayama Town in Japan. Fasting tHcy levels were compared among 75 CI cases, of which 43 were lacunar (LI), 24 atherothrombotic (ATI) and 8 cardioembolic infarctions (CEI), and 248 age- and sex-matched healthy controls. The mean tHcy concentrations were higher in CI than in controls (13.0 vs. 11.8 micromol/l; p = 0.018). LI and CEI also had significantly higher tHcy levels than did the corresponding controls (12.3 vs. 11.3 micromol/l for LI; p = 0.037 and 16.3 vs. 12.7 micromol/l for CEI; p = 0.036). The same tendency was also observed for ATI, but the difference was only marginally significant probably due to the small number of the cases (13.4 vs. 11.9 micromol/l; p = 0.087). After adjustment for age, sex, hypertension, serum creatinine, total protein, folate and vitamin B(12) levels, the risk of LI was not significant in the second tertile of the tHcy distribution, but significantly increased in the third compared with the first tertile (adjusted odds ratio, AOR, 3.4; 95% confidence limits, CL, 1.3-8.9; p = 0.015), while the risk of ATI was significant even in the second tertile (AOR, 5.0; 95% CL, 1.0-23.7; p = 0.042) and higher in the third tertile (AOR, 7.5; 95% CL, 1.5-38.3; p = 0.015). However, the odds ratios for CEI could not be estimated, as there was no case of CEI in the first tertile. These findings suggest that elevated tHcy is an independent risk factor for all subtypes of CI, but that its impact is higher in ATI and probably in CEI than in LI.     

Inflammatory and hemostatic responses to repeated mental stress: individual stability and habituation over time

An important assumption underlying psychobiological studies relating stress reactivity with disease risk is that individuals are characterized by stable response profiles that can be reliably assessed using acute psychophysiological stress testing. Previous research has mainly focused on the stability of cardiovascular, neuroendocrine, and cellular immune responses to repeated stressors, and less attention has been given to inflammatory and platelet responses. We therefore examined both average stability and individual test-retest stability of cardiovascular, neuroendocrine, hemostatic, inflammatory, and subjective responses to mental stress over two repeated stress sessions, four weeks apart. Ninety-one healthy, non-smoking men (mean age 33.2 years) completed a 3-min speech task followed by a 5-min mirror tracing task on two separate occasions. Blood samples were taken at baseline and 10 min after the stress tasks while cardiovascular activity, saliva samples, and subjective ratings were measured repeatedly. There was significant cardiovascular and cortisol activation to the stressors and stress-induced increases in plasma C-reactive protein, von Willebrand factor antigen, and platelet activation indexed by leukocyte-platelet aggregates. The magnitude of stress responses did not differ between sessions in any variable. Significant test-retest correlations between sessions were observed for baseline and stress values of all variables (r=0.47-0.74, p<.001), but reactivity (change scores) for C-reactive protein, von Willebrand factor, cortisol, and platelet activation were not significantly correlated. Our results demonstrate that the stress-induced responses did not habituate between sessions, though the small magnitude of acute inflammatory, cortisol, and platelet responses limits the test-retest reliability of stress reactivity assessments.     

Platelet activation in psoriasis

Recent epidemiological studies have suggested that psoriasis represents a risk factor for thrombotic vascular diseases. In order to evaluate the possible role of hemostatic changes in the development of thrombotic episodes in psoriasis, some parameters of the hemostatic "balance" were investigated in 22 male psoriatic patients and compared to those of 22 male control subjects. Incidence of known risk factors for vascular diseases (diabetes, hypertension, smoking, dyslipidemia) was comparable in the two study groups. There were no statistically significant differences in platelet count, circulating platelet aggregates, platelet production of malondialdehyde (MDA), total plasma antithrombin and fibrinolytic activities. In patients with psoriasis the incidence of spontaneous platelet hyperaggregability and plasma levels of beta-thromboglobulin were significantly higher than in control subjects. Platelet regeneration time, measured as MDA recovery after aspirin ingestion, was significantly shorter in psoriatic patients. These data suggest that an in vivo platelet activation occurs in patients with psoriasis and could contribute to the development of thrombotic complications. The release of mitogenic and inflammatory substances by activated platelets may play a role in the histogenesis of psoriatic lesions.     

Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid

OBJECTIVE: The aim of this study was to evaluate if multiple sclerosis (MS) is associated with vitamin B12 (cobalamin) deficiency. METHODS: We measured serum vitamin B12, plasma folate, serum methylmalonic acid (MMA), plasma homocysteine (tHcy) and also cerebrospinal fluid (CSF) MMA and tHcy in 72 patients with MS and 23 controls. RESULTS: The mean plasma tHcy level was significantly increased in MS patients (11.6 micromol/L) compared with controls (7.4 micromol/L) (P = 0.002). Seven patients showed low serum vitamin B12 levels but only one of them had concomitant high plasma tHcy. None of them showed high serum MMA. Plasma or blood folate levels did not differ between MS patients and controls. We found no significant differences in mean values or frequency of pathological tests of serum B12, serum MMA, mean corpuscular volume (MCV), haemoglobin concentration, CSF tHcy or CSF MMA between patients and healthy subjects. There were no correlations between CSF and serum/plasma levels of MMA or tHcy. Serum vitamin B12, serum MMA, plasma tHcy, CSF Hcy or CSF MMA were not correlated to disability status, activity of disease, duration of disease or age. CONCLUSIONS: The relevance of the increased mean value of plasma tHcy thus seems uncertain and does not indicate functional vitamin B12 deficiency. We can not, however, exclude the possibility of a genetically induced dysfunction of the homocysteine metabolism relevant for the development of neuroinflammation/degeneration. Our findings indicate that, regardless of a significant increase in plasma tHcy in MS patients, the MS disease is not generally associated with vitamin B12 deficiency since we did not find any other factors indicating vitamin B12 deficiency. Analysis of CSF MMA and CSF tHcy, which probably reflects the brain vitamin B12 status better than serum, are not warranted in MS. We conclude that B12 deficiency, in general, is not associated with MS.     

The effect of vitamin C supplementation on coagulability and lipid levels in healthy male subjects

Although dietary intake and plasma levels of vitamin C have been inversely associated with cardiovascular disease, the mechanism through which it may exert its effect has not been fully explained. Since thrombosis plays an important role in the onset of cardiovascular disease, we investigated the effect of vitamin C on measures of hemostasis that have been associated with cardiovascular risk. The effect of vitamin C on lipid levels was also evaluated.In a randomized, placebo-controlled, crossover study, we determined the effect of 2 g daily of vitamin C supplementation on platelet adhesion and aggregation, levels of tissue plasminogen activator antigen, plasminogen activator inhibitor, fibrinogen, plasma viscosity, von Willebrand factor, and lipid levels in 18 healthy male volunteers with low normal vitamin C levels. No striking effects of vitamin C on the hemostatic measures were observed, although tissue plasminogen activator antigen levels were inversely related to Vitamin C levels. Von Willebrand factor levels were slightly higher with vitamin C, although within the normal range. Total cholesterol levels were 10% lower when subjects were receiving vitamin C compared to placebo (167+/-7 mg/dL vs. 184+/-7 mg/dL), P=0. 007), although the total cholesterol/HDL ratio was not significantly different. Higher levels of tissue plasminogen activator antigen, which in the present study were associated with lower vitamin C levels, have been shown in prospective studies to convey an increased risk of cardiovascular events. Further studies of the effect of vitamin C on hemostatic measures are required in higher risk populations or those with known cardiovascular disease.     

Plasma homocysteine concentration relates to the severity but not to the duration of Alzheimer's disease

BACKGROUND: It has been reported that plasma tHcy concentration is elevated in patients with Alzheimer's disease (AD) and relates to the progress or the development of AD. In the present study we have compared plasma tHcy concentrations at different times during the course of AD and with measures corresponding to the severity and the progress rate of AD. METHODS: The study population consisted of 159 patients with AD. Three measures corresponding to the progress rate of AD were created by dividing the actual scores of the severity of the dementia, the Berger scale and the Katz index by the estimated duration. RESULTS: AD patients without a history of cardiovascular disease did not show a significant increase of plasma tHcy concentration compared to the control subjects, whereas AD patients with cardiovascular disease exhibited a significant increase of plasma tHcy concentration compared to both control subjects and patients without cardiovascular disease. However, after creatinine adjustment of plasma tHcy in control subjects and AD patients a significant increase of plasma tHcy was observed also in AD patients without cardiovascular disease compared to controls. The concentration of plasma tHcy in AD patients with and without cardiovascular history did not increase with time after disease onset. Plasma tHcy concentration correlated with the severity of the disease. The correlations between plasma tHcy and measures of rate progression of AD did not improve compared with the correlations between plasma tHcy and the severity of dementia. CONCLUSION: An interpretation of these findings may be that plasma tHcy is additionally increased in AD patients when a complication occurs, such as folate/cobalamin deficiency or a cardiovascular disease.     

Relation between plasma homocysteine and Alzheimer's disease

OBJECTIVE: Several studies have shown that plasma total homocysteine (tHcy) concentration is elevated in Alzheimer's disease (AD). However, it is not clear whether elevated plasma tHcy is a primary cause or a consequence of AD. METHOD: To elucidate this question, we have analysed plasma homocysteine and its determinants in patients with early (EOAD)- and late-onset AD (LOAD) and compared the findings with those in vascular dementia (VaD) and age- and sex-matched control subjects. RESULTS: One of the main findings in the present study is that in EOAD there is no change in the levels of either plasma tHcy or its determinants compared with an age- and sex-matched control group. The fact that plasma tHcy concentration is normal in EOAD thus indicates that elevated plasma tHcy is not the primary cause of the disease. Another main finding is that patients with mixed dementia (AD and VaD) and patients with VaD showed significantly increased plasma tHcy concentration compared with controls and that plasma tHCy concentration in patients with LOAD and a history of additional cardiovascular disease was elevated compared both with AD patients without such a history and with the controls. Thus, there is an association between elevated plasma tHcy and vascular disease. A third main finding is that patients with AD who were followed up for several years showed a clinical deterioration of dementia and an elevation of plasma tHcy concentration. This finding likewise supports the notion that elevated plasma tHcy is not the primary cause of the disease. CONCLUSIONS: The findings suggest that elevated plasma tHcy is not the primary cause of the disease. Furthermore, the findings indicate that elevated plasma tHcy might be a reflection of concomitant vascular disease in AD patients.     

Increased plasma levels of total homocysteine but not asymmetric dimethylarginine in Hispanic subjects with ischemic stroke FREC-VI sub-study

Background and purpose: Despite sharing some metabolic and pathological mechanisms, the reported association between total homocysteine (tHcy), asymmetric dimethylarginine (ADMA) and stroke remains controversial, particularly in Hispanic populations from developing countries in which genetic, socioeconomic, and nutritional factors are different to those described in developed countries. Our objectives were to determine the relationships of these factors to stroke and to each other independent of other cardiovascular risk factors, and to explore potential sex differences. Methods: This national (Colombia) multicenter case–control study included 238 cases and 238 controls to evaluate traditional and emerging risk factors for ischemic stroke including tHcy and ADMA plasma levels. Results: The median plasma levels of tHcy were 8.48 μM for controls and 10.01 μM for cases (P < 0.0001). Plasma levels of tHcy between 12 and 50 μM were considered moderate hyperhomocysteinemia (HtHcy). There were no differences in plasma ADMA concentration between groups (P = 0.40). Plasma levels of ADMA and creatinine were not correlated (P = 0.47). After adjusting for confounding factors, the presence of HtHcy was strongly associated with stroke (OR 8.97; P < 0.0001). The adjusted association between HtHcy and stroke in men (OR 9.98) was comparable to that in women (OR 8.98) (P = 0.41). Conclusions: In this Hispanic population, with relatively normal renal function, plasma levels of tHcy but not ADMA were associated with stroke independent of other cardiovascular risk factors.     

Effect of the methylenetetrahydrofolate reductase gene polymorphisms on homocysteine, folate and vitamin B12 in patients with bipolar disorder and relatives

We investigated the effect of polymorphic variants of c.1298A>C (Glu429Ala) and c.677C>T (Ala222Val) in methylenetetrahydrofolate (MTHFR) gene on the total homocysteine (tHcy), folate and B12 levels in patients with bipolar disorder, first-degree relatives of patients, and controls. The c.677C>T and c.1298A>C polymorphisms in MTHFR were determined by polymerase chain reaction-restriction fragment length polymorphism in 197 bipolar patients, 278 relatives and 238 controls. tHcy and folate and vitamin B12 levels were measured by Fluorescence Polarization Immunoassay and Electrochemiluminescence, respectively. The tHcy was significantly increased in patients and relatives. In contrast, folate and B12 were significantly lower in patients and relatives. Gender was not considered as a significant determinant in the multivariate analysis. Genotypes of c.1298A>C and c.677C>T were correlated with tHcy, folate and B12. Patients and relatives carrying TT and/or AA and AC genotypes had elevated tHcy and reduced folate and B12 levels. High tHcy but low folate and vitamin B12 levels may be a risk factor for development of bipolar disorder.     

The influence of a vegetarian diet on haemostatic risk factors for cardiovascular disease in Africans.

Dietary habits have been implicated in the occurrence of cardiovascular diseases. Elevated plasma fibrinogen levels and decreased fibrinolytic activity have been identified as major independent cardiovascular risk factors. In this study, we compared the blood pressure, plasma fibrinogen concentration, and fibrinolytic activity of 40 nonvegetarians (NON-VEGs) with 36 vegetarians (8 VEGs and 28 SEMI-VEGs). The latter group consisted of students and lecturers of the Adventist Seminary Institute of West Africa, Ilishan Remo. All subjects had blood pressures below 140/90 mmHg, no underlying haemostatic disorders and were not on any medical treatment. The NON-VEGs had significantly decreased fibrinolytic activity (p<0.001) and increased plasma fibrinogen levels (p<0.001) compared with the SEMI-VEGs and VEGs. There were no significant differences between the blood pressure levels of the three groups, although the NON-VEGs had lower diastolic blood pressures. It is concluded that black African Seventh-Day Adventists who follow a vegetarian diet may be protected against premature cardiovascular disease because of beneficial dietary effects on plasma fibrinogen levels and fibrinolytic activity.     

Homocysteine as a risk factor for cognitive impairment in stroke patients

BACKGROUND: Elevated total homocysteine (tHcy) levels are associated with an increased risk of cerebrovascular disease. It is uncertain whether tHcy is also an independent risk factor for cognitive impairment. METHODS: We examined 95 stroke subjects 3 months after their strokes, and 55 healthy comparison subjects, with a detailed neuropsychological assessment, and MRI brain scans in a proportion (n = 97). Baseline measurements of tHcy, serum folate and B(12), creatinine and plasma fibrinogen levels were obtained. RESULTS: tHcy levels were higher in the stroke subjects by a mean 34%. These levels were significantly correlated with the first factor of a principal component analysis of the neuropsychological data, after controlling for age, folate, B(12) and creatinine levels. The correlation of Hcy levels was particularly significant with frontal-executive functioning and attention. tHcy levels were significantly correlated with number of infarcts and total stroke volume in the stroke group, but not with T(2)-weighted deep white matter hyperintensity scores, after correction for age. In the control group, tHcy levels were significantly correlated with ventricle-to-brain ratios as measures of brain atrophy. CONCLUSION: This study provides evidence that high tHcy levels are associated with cognitive impairment, in particular that of frontal-executive function. The major component of this association is accounted for by small and large strokes, but non-vascular neurotoxic effects of tHcy also appear to play a role. tHcy must receive greater attention as a risk factor for cognitive impairment.     

Oxidative stress and platelet activation in subjects with moderate hyperhomocysteinaemia due to MTHFR 677 C →T polymorphism

The methylenetetrahydrofolate reductase (MTHFR) 677 C→T polymorphism may be associated with elevated total homocysteine (tHcy) levels, an independent risk factor for cardiovascular disease. It was the study objective to evaluate in vivo lipid peroxidation and platelet activation in carriers of the MTHFR 677 C→T polymorphism and in non-carriers, in relation to tHcy and folate levels. A cross-sectional comparison of urinary 8-iso-prostaglandin (PG)F2α and 11-dehydro-thromboxane (TX)B2 (markers of in vivo lipid peroxidation and platelet activation, respectively) was performed in 100 carriers and 100 non-carriers of the polymorphism. A methionine-loading test and folic acid supplementation were performed to investigate the causal relationship of the observed associations. Urinary 8-iso-PGF2α and 11-dehydro-TXB2 were higher in carriers with hyperhomocysteinaemia than in those without hyperhomocysteinaemia (p<0.0001). Hyperhomocysteinaemic carriers had lower folate levels (p=0.0006), higher urinary 8-iso-PGF2α (p<0.0001) and 11-dehydro-TXB2 (p<0.0001) than hyperhomocysteinaemic non-carriers. On multiple regression analysis, high tHcy (p<0.0001), low folate (p<0.04) and MTHFR 677 C→T polymorphism (p<0.001) independently predicted high rates of 8-iso-PGF2α excretion. Methionine loading increased plasma tHcy (p=0.002), and both urinary prostanoid metabolites (p=0.002). Folic acid supplementation was associated with decreased urinary 8-iso-PGF2α and 11-dehydro-TXB2 excretion (p<0.0003) in the hyperhomocysteinaemic group, but not in the control group, with substantial inter-individual variability related to baseline tHcy level and the extent of its reduction. In conclusion, hyperhomocysteinaemia due to the MTHFR 677 C→T polymorphism is associated with enhanced in vivo lipid peroxidation and platelet activation that are reversible, at least in part, following folic acid supplementation. An integrated biomarker approach may help identifying appropriate candidates for effective folate supplementation.     

Similar effects of atorvastatin, simvastatin and pravastatin on thrombogenic and inflammatory parameters in patients with hypercholesterolemia

BACKGROUND: Previous studies have suggested that statins exert beneficial effects beyond their favorable lipid lowering effect. Particularly, the modification of thrombus formation and degradation, alteration in inflammatory response, plaque stabilization and improved endothelial function are thought to be responsible for additional reduction of morbidity and mortality due to cardiovascular events. To date, however, it is still unclear whether these effects are elicited by all statins. METHODS AND RESULTS: We set out to compare in a controlled, randomized, double-blind study design the effects of almost equieffective cholesterol lowering doses of three chemically and pharmacokinetically different statins (atorvastatin, simvastatin, pravastatin) on hemostatic and inflammatory markers in 99 hypercholesterolemic patients. At entry and 3 months after onset of statin therapy plasma cholesterol and von Willebrand factor antigen (vWf-Ag), fibrinogen, d-dimer, prothrombin fragment 1+2 (F1.2) and C-reactive protein (CRP) were measured. The effect on plasma values of F1.2, vWf-Ag, d-dimer and CRP was not significantly different between the three treatment groups. The effect of simvastatin on fibrinogen (p = 0.005) was more pronounced than the effects of atorvastatin (p = 0.48 n.s.) and pravastatin (p = 0.15 n.s.). Plasma levels of F1.2 and vWf-Ag (when data of all statins were pooled) were significantly reduced by 7% and 10% versus baseline, respectively. No significant reduction was observed for d-dimer (p = 0.26) and CRP (p = 0.5). Total plasma cholesterol levels decreased significantly (p < 0.0001 in all groups) between 22% and 29% compared to baseline. CONCLUSION: The present study shows similar short-term (3 months) effects of atorvastatin, simvastatin and pravastatin on selected hemostatic and inflammatory parameters in plasma in patients with hypercholesterolemia. Thus, chemical and pharmacological differences between statins appear to exert no major influence on these parameters.     

Platelet function and plasma fibrinogen and their relations to gender, smoking habits, obesity and beta-blocker treatment in young survivors of myocardial infarction

Seventy-three (58 men and 15 women) survivors of myocardial infarction below 45 years of age and 73 healthy matched controls were investigated regarding in vitro platelet aggregability to ADP and collagen, platelet sensitivity to prostacyclin and plasma levels of beta-thromboglobulin, platelet factor 4 and fibrinogen. The patients, studied 3-6 months after the acute event, had a reduced platelet sensitivity to prostacyclin. They did not differ from the controls regarding the other platelet function tests. Females had higher platelet reactivity than men. Smoking, obesity or beta-blocker treatment did not influence platelet function. The patients had higher fibrinogen levels than the controls. Gender did not influence, while smoking and obesity increased plasma fibrinogen. Patients on beta-blockade had lower fibrinogen levels than patients without this therapy. The high fibrinogen level and the low platelet sensitivity to prostacyclin might indicate an increased thrombotic liability in young myocardial infarction patients.     

Hyperhomocysteinemia and hypofibrinolysis in young adults with ischemic stroke

BACKGROUND AND PURPOSE: Data from epidemiological and case-control studies suggest that increased total homocysteine (tHcy) levels are associated with increased risk for thromboembolic disease. The mechanisms by which hyperhomocysteinemia contributes to thrombogenesis are incompletely understood. The main objectives of this study of young ischemic stroke patients were (1) to examine fasting and post-methionine load levels of tHcy, (2) to ascertain the genotype frequency of the C677CT mutation in the methylenetetrahydrofolate reductase gene (TT genotype), and (3) to study the possible interaction between plasma tHcy levels and fibrinolytic factors. METHODS: This case-control study was based on 80 consecutive patients aged 18 to 44 years admitted between January 1992 and May 1996 as a result of a first-ever ischemic stroke. Forty-one healthy control subjects were recruited. Measurement of fasting tHcy and post-methionine load levels and evaluation of the fibrinolytic system were undertaken at least 3 months (mean, 5.1+/-1. 9 months) after admission. Genotyping of the methylenetetrahydrofolate reductase gene was performed. RESULTS: Although the increase after methionine loading (ie, postload tHcy minus fasting-level tHcy) was significantly higher among patients, there was no difference in fasting and postload tHcy levels. After adjustment for conventional risk factors, elevated postload increase tHcy levels were associated with a 4.8-fold increased risk of ischemic stroke. There was no difference between patients and control subjects in either TT genotype frequency or T allele frequency. Abnormal response to methionine loading was associated with higher tissue plasminogen activator (tPA) mass concentration, higher plasminogen activator inhibitor-1 levels, and lower tPA activity. After adjustment for age, sex, body mass index, serum cholesterol, and triglycerides, an abnormal increase in postload tHcy levels remained significantly associated with tPA mass concentration levels (P=0.03). CONCLUSIONS: A moderately elevated increase in tHcy levels after methionine loading was associated with an increased risk for ischemic stroke in young adults. In contrast, fasting tHcy levels did not differ between patients and controls. A moderately elevated increase in tHcy after methionine loading may provide a additional thrombogenic risk mediated in part by interactions with the fibrinolytic system. In young stroke patients, a methionine loading test to detect hyperhomocysteinemia should always be considered in the convalescent phase of the disease.     

Influence of Valproate Monotherapy on Platelet Activation and Hematologic Values

Summary: Purpose: Valproate (VPA) has been linked to coagulation disturbances, with both impaired and exaggerated clotting, which has been attributed to an effect of VPA on platelets or hemostatic proteins. Additional thrombocytic function testing may help to identify patients at risk of increased bleeding caused by platelet dysfunction.
Methods: We evaluated the influence of VPA on hematologic routine values and platelet activation by using immunostaining and flow cytometry in 30 patients receiving long-term VPA therapy and in 30 controls.
Results: The fraction of activated platelets was similar in both groups; however, the general extent of platelet activation was significantly lower in the patient group, with considerable interindividual variability. In addition, patients had a significantly lower platelet count, prolonged thrombin time, and higher mean corpuscular hemoglobin.
Conclusions: Our data confirm the previously reported hematologic changes caused by VPA and additionally suggest that VPA impairs procoagulatory thrombocytic function, which is reflected by reduced platelet activation and increased thrombin time. Possible mechanisms of VPA-platelet interaction are discussed.