Acute effects of retinoids on fibrinolysis before and after venous occlusion in healthy humans

The effects of acitretin and etretinate on the fibrinolytic system have been investigated in a double-blind, placebo-controlled cross-over study in twelve healthy volunteers. Euglobulin fibrinolytic activity, euglobulin clot lysis time, tissue-type plasminogen activator (t-PA) activity and antigen concentration in plasma were measured before and after 10 min of venous occlusion (VO), three hours after ingestion of the compounds. The plasminogen activator inhibitor (PAI) activity was also measured in each session before fibrinolysis stimulation. None of the parameters studied was significantly affected by the two retinoids in comparison with placebo. Our study demonstrates that a single oral dose of 100 mg of etretinate or acitretin, investigated 3 hours after drug administration does not significantly influence the fibrinolytic system in vivo in humans. This observation does not exclude an effect of retinoids after prolonged intake.     

Fibrinolysis in normal subjects--comparison between plasminogen activator inhibitor and other components of the fibrinolytic system

We analyzed fibrinolytic parameters in 20 healthy men and 20 healthy women, aged from 25 to 59, before and after 10 and 20 min venous occlusion. The 10 min post-occlusion fibrinolytic activity measured directly in diluted unfractionated plasma by a highly sensitive 125I-fibrin plate assay correlated well with the activity of euglobulins determined by the classical fibrin plate assay (r = 0.729), but pre-stasis activities determined with these two methods did not correlate (r = 0.084). The enhancement of fibrinolytic activity after venous occlusion was mainly due to an increase of t-PA in the occluded vessels (4-fold increase t-PA antigen after 10 min and 8-fold after 20 min venous occlusion). Plasminogen activator inhibitor (PAI) activity and plasminogen activator inhibitor 1 (PAI-1)1 antigen levels at rest showed considerable dispersion ranging from 1.9 to 12.4 U/ml, respectively 6.9 to 77 ng/ml. A significant increase of PAI-1 antigen levels was observed after 10 and 20 min venous occlusion. At rest no correlation was found between PAI activity or PAI-1 antigen levels and the fibrinolytic activity measured by 125I-FPA. However, a high level of PAI-1 at rest was associated with a high prestasis antigen level of t-PA and a low fibrinolytic response after 10 min of venous stasis. Since the fibrinolytic response inversely correlated with PAI activity at rest, we conclude that its degree depends mainly on the presence of free PAI.     

Effect of supplementation with dietary seal oil on selected cardiovascular risk factors and hemostatic variables in healthy male subjects

The average daily consumption of seal oil by the Inuit people is approximately 8-9 g, yet there is very little information on the effect of seal oil consumption on cardiovascular disease risk factors. In this study, 19 healthy, normocholesterolemic subjects consumed 20 g of encapsulated seal oil containing eicosapentaenoic acid (EPA; 20:5n-3), docosahexaenoic acid (DHA; 22:6n-3), and docosapentaenoic acid (DPA; 22:5n-3) or 20 g of vegetable oil (control) per day for 42 days. Levels of selected cardiovascular and thrombotic risk factors as well as fatty acid profiles of serum phospholipid and nonesterified fatty acid (NEFA) were determined. EPA levels in serum phospholipid and NEFA increased by 4.3- and 2.7-fold, respectively, in the seal oil supplemented group. DHA levels rose 1.5- and 2.1-fold, respectively, and DPA levels rose 0.5- and 0.7-fold, respectively. Arachidonic acid (AA) levels dropped by 26% in both serum phospholipid and serum NEFA. There was a significant decrease in the ratio of n-6 to n-3 fatty acids in serum phospholipid from 7.2 to 2.1 and a significant increase in the ratio of EPA/AA in NEFA. Ingestion of seal oil raised the coagulant inhibitor, protein C, values by 7% and decreased plasma fibrinogen by 18%. No alterations in other hemostatic variables, including plasma activity of Factors VII, VIII, IX, and X and antithrombin, or in the concentrations of von Willebrand Factor, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, glucose, Apo A-1, or lipoprotein(a) were observed in either group. Other risk factors for cardiovascular disease, including hematocrit, white blood cell count, plasma viscosity, systolic and diastolic blood pressures, heart rate, and platelet aggregation after stimulation with ADP or collagen did not change. Our results indicate that seal oil supplementation in healthy, normocholesterolemic subjects decreased the n-6/n-3 ratio and increased EPA, DHA, and DPA and the ratio of EPA/AA and DHA/AA in the serum phospholipid and NEFA, while exhibiting a modest beneficial effect on fibrinogen and protein C levels.     

Improved fibrinolysis after 1-year treatment with HMG CoA reductase inhibitors in patients with coronary heart disease

The study was aimed to investigate the effect of two different statins on the levels of haemostatic variables reflecting procoagulant and fibrinolytic activity in patients with coronary heart disease (CHD), with the hypothesis that statins might beneficially modify these levels. Fifty-eight patients were randomized to treatment with atorvastatin (n=28) or simvastatin (n=30) for 1 year. The starting dose in both groups was 20 mg/day. Fasting blood samples were collected before and after 12-month treatment for determinations of fibrinogen, prothrombin fragment 1+2 (F1+2), plasma D-dimer, soluble tissue factor, tissue plasminogen activator (tPA) antigen, tPA activity, plasminogen activator inhibitor type-1 activity (PAI-1 activity) and serum D-dimer as a global test of fibrinolytic activity. In the total population, improved fibrinolytic activity was observed after 1 year with increased levels of serum D-dimer (P=.001) and tPA activity (P=.024) and a reduction in tPA antigen (P=.048). No statistically significant changes were observed in any of the measured coagulation variables. Separately examined, an improved fibrinolytic profile was seen in the atorvastatin group with a significant increase in serum D-dimer (P=.005), a borderline increase in tPA activity (P=.083) and a borderline reduction in tPA antigen (P=.069). Within the simvastatin group, a reduction in prothrombin F1+2 was observed (P=.038). The differences in changes between the groups were statistically significant only for global fibrinolysis (serum D-dimer, P=.046). In conclusion, an improved fibrinolytic profile was observed after statin treatment, most pronounced with atorvastatin. The results indicate that the drugs promote a profibrinolytic profile, and may in part explain the benefit of statin treatment rendered in the prevention of CHD.     

A randomised, controlled study of the effects of aerobic exercise and dietary fish on coagulation and fibrinolytic factors in type 2 diabetics

Type 2 diabetes is associated with disturbances in coagulation and fibrinolysis. Prospective studies show that increased tissue plasminogen activator (tPA) antigen increases the risk of cardiovascular mortality. The present study examined the hypothesis that combining a regime of moderate aerobic exercise with one daily fish meal as part of a low-fat diet (30% total energy) would improve coagulation and fibrinolytic factors in dyslipidaemic type 2 diabetic patients. In a randomised. controlled, 8-week trial, 55 sedentary type 2 diabetic subjects with serum triglycerides >1.8 mmol/l and/or HDL-C <1.0 mmol/l were randomly assigned to a low-fat diet (30% daily energy intake) with or without one fish meal daily (3.6 g omega3 fatty acids/day) and further randomized to a moderate (55-65% VO2max) or light (heart rate <100 bpm) exercise program. Plasma levels of fibrinogen, coagulation factor VIIc, tPA and plasminogen activator inhibitor (PAI-1) antigen were measured before and after intervention. In the 49 subjects who completed the study, the fish diet alone, moderate exercise alone and the combination of fish and moderate exercise all led to significant reductions in tPA antigen concentrations (-2.1 ng/ml, p = 0.02. -1.9 ng/ml, p = 0.03, -2.0 ng/ml, p = 0.01, respectively) compared to controls. In multivariate regression, changes in fasting blood glucose (positively) and erythrocyte omega3 fatty acid composition (inversely) were independent predictors of the change in tPA antigen. The fish diet alone contributed to a significant rise in coagulation factor VIIc compared to controls (4.9%, p = 0.02), which was prevented by moderate exercise. No significant effects on PAI-1 antigen and fibrinogen were seen. In view of recent epidemiological findings, the reduction in tPA antigen with both fish and moderate exercise in these dyslipidaemic type 2 diabetic patients could reflect a reduced thrombotic potential and decreased cardiovascular risk. Furthermore, a small, albeit significant, increase in coagulation factor VIIc associated with fish can be prevented by a concomitant programme of moderate exercise.     

Fibrinolytic proteins and progression of coronary artery disease in relation to gemfibrozil therapy

Impaired fibrinolytic function, mainly due to increased plasma plasminogen activator inhibitor-1 (PAI-1) activity, is common in patients with manifest coronary artery disease (CAD) and a predictor of recurrent cardiovascular events. We investigated the relationships of plasma tissue-type plasminogen activator (tPA) and PAI-1 antigen levels, plasma PAI-1 activity and PAI 4/5-guanosine (4G/5G) genotype to CAD progression in 203 middle-aged men participating in the Lopid Coronary Angiography Trial (LOCAT). A higher tPA antigen concentration, whether baseline or on-trial, was associated with a more severe global angiographic response (p < 0.05), an association mainly accounted for by progression of diffuse lesions in graft-affected segments (change in per-patient means of average diameters of segments haemodynamically related to bypass grafts). Plasma PAI-1 activity and mass concentration and 4G/5G PAI-1 genotype were unrelated to angiographic outcome measurements. tPA and PAI-1 antigen increased significantly in the gemfibrozil group (+11.3% and + 16.4%, respectively, p < 0.001), whereas there was no treatment effect on PAI-1 activity (median change 0.0%). It is concluded that fibrinolytic function does not substantially influence progression of CAD as assessed by angiography in middle-aged men. Furthermore, pronounced long-term lowering of serum triglycerides by gemfibrozil treatment does not significantly affect the plasma PAI-1 activity level but increases the plasma tPA and PAI-1 antigen concentrations.     

Fibrinolytic activity in Chinese patients with diabetes or hyperlipidemia in comparison with healthy controls

Plasma tissue-type plasminogen activator (tPA), plasminogen activator inhibitor (PAI) and euglobulin lysis time (ELT) were determined before and after the venous occlusion test (VOT) in 3 groups of patients with mean age about 60 years: 29 diabetic patients (D group), 8 hyperlipidemic patients (H group) and 19 healthy controls (C group). In the D and H groups, the mean of morning tPA was significantly higher than that of the C group, but the means of PAI were not significantly different among the 3 groups. ELT was significantly shortened and tPA was markedly increased after the VOT in all 3 groups whereas PAI had not significantly changed. In conclusion, high tPA activity and good fibrinolytic response without significant change of PAI activity were found in the diabetic and hyperlipidemic patients, and no definite impairment of the fibrinolytic activity could be found in the Chinese patients with diabetes and hyperlipidemia. This might be one of the reasons why the Chinese has low incidence of thromboembolic diseases.     

Changes in endothelial-related coagulation proteins in response to venous occlusion

One hundred patients with a history of thrombophilia were divided into two groups based on fibrinolytic response to venous occlusion. Good responders with a euglobulin clot lysis time less than or equal to 105 min showed significant release of tPA, PAI and vWF. Of the poor responders with an ECLT greater than 105 min, 24% showed a subnormal increase in tPA, and a significant proportion of these also showed a reduced or absent rise in vWF. We have shown poor fibrinolytic response was related to either raised levels of PAI, poor release of both tPA and vWF, or poor release of tPA or vWF alone suggesting different mechanisms of fibrinolytic impairment. Protein S levels were not significantly changed in either group following occlusion.     

Short-term effect of surgical trauma on rat peritoneal fibrinolytic activity and its role in adhesion formation

BACKGROUND: Fibrin deposition, the primary step in the formation of post-surgical adhesions, is the result of a disbalance between the fibrin-forming and the fibrin-dissolving capacity of the peritoneum. Literature data suggest a transient reduction in local plasminogen activator activity after peritoneal trauma, which results in a reduction of fibrinolysis and permits deposited fibrin to become organized into fibrous, permanent adhesions. In the present study, the fibrinolytic parameters tissue-type plasminogen activator (tPA; antigen and activity) and plasminogen activator inhibitor type-1 (PAI-1; antigen and activity) were measured in peritoneal fluid, in peritoneal biopsies and in plasma to establish the time course of changes in fibrinolytic activity. DESIGN: A standardized peritoneal adhesion model in the rat. OUTCOME MEASURES: Analysis, over a 72-h period following surgical trauma. of the main fibrinolytic parameters in peritoneal lavage, in biopsies of damaged and undamaged peritoneum, and in plasma, and determination of fibrin and fibrin(ogen)-degradation products in peritoneal lavage fluid. RESULTS: At all time intervals, tPA antigen was found to be about six-fold increased in peritoneal lavage after surgical trauma. This significant rise in tPA antigen was accompanied by a large increase in its main inhibitor PAI-1, resulting in tPA activity levels similar to, or slightly higher than, those found in control animals. tPA activity was lowest at 4 h and increased thereafter. Also in biopsies from damaged peritoneum, tPA antigen was significantly increased. Tissue tPA activity was also lowest at 4 h, after which it increased, significantly so at 24 and 72 h. Similar, though smaller, changes were seen in the biopsies from undamaged areas of the peritoneal wall in operated rats. PAI-1 (antigen and activity) was not detected in peritoneal biopsies. Fibrin-related material (especially fibrin monomer/fibrinogen, an indicator of forming fibrin) in peritoneal fluid was slightly increased at 4 h, and abundantly present at 16 and 24 h, returning to control levels at 72 h. Fibrin degradation products were always present. From 2 h onward, adhesions were found. CONCLUSIONS: In contrast to the view that adhesions are formed as a result of a reduced fibrinolytic activity, our results demonstrate that tPA activity remained unchanged or slightly increased after surgical trauma, and point to increased fibrin formation rather than diminished fibrinolytic activity as the main cause of fibrin deposition after peritoneal trauma. Therapies directed at prevention of adhesion formation should therefore aim at avoiding massive fibrin production and at promoting fibrinolytic activity during the early period after trauma.     

Fibrinolytic response in normal subjects to venous occlusion and DDAVP infusion

A set of fibrinolytic parameters was measured in 40 healthy subjects before and after a venous occlusion (VO) test lasting 10 min. After VO, plasma levels of tissue-type plasminogen activator (t-PA) antigen increased in all subjects, t-PA activity increased only in 25 subjects who were considered responders and remained unchanged in 15 (non-responders). High levels of plasminogen activator inhibitor (PAI) in the non-responder group explain this discrepancy. The non-responders had basal levels of PAI activity and t-PA antigen higher than responders (p less than 0.0001) and their basal levels of t-PA activity were lower (p less than 0.001). DDAVP infusion elicited good responses in 7 of 9 non-responders to VO with a fall of PAI activity to 0. Our data indicate that a high proportion of healthy subjects do not have a fibrinolytic response after VO, that a lack of fibrinolytic response to VO is due to high plasma levels of PAI and that DDAVP infusion appear to be more selective than VO for detecting non-responders.     

Tissue plasminogen activator and plasminogen activator inhibitor in patients with acute ischemic stroke: relation to stroke etiology

Recent studies suggest that high plasma levels of tissue-type plasminogen activator (tPA) and its inhibitor (plasminogen activator inhibitor-1, PAI-1) are markers of an increased risk of atherothrombotic ischemic events such as stroke and myocardial infarction. In this prospective study, we measured tPA antigen, PAI-1 antigen and activity, as well as tPA/PAI-1 complex in patients with acute stroke. Stroke subtypes were classified according to the TOAST criteria. From 132 consecutively screened patients, 89 (100%) were enrolled in this study, including 42 patients (47%) with large artery atherosclerosis (LAA), 32 (36%) with small vessel occlusion (SVO), and 15 (17%) with cardioembolism (CE). Nineteen age-matched neurologic patients without manifestations of cerebrovascular disease served as control subjects (CS). Patients with acute stroke had significantly higher plasma levels of tPA antigen (p < 0.001), PAI-1 antigen (p < 0.05) and PAI activity (p < 0.05) than patients in the control group. t-PA antigen, PAI activity and tPA/PAI-1 complex levels were similar regardless of stroke etiology. Only PAI-1 antigen was lower in patients with cardioembolic stroke than in stroke patients with LAA (p < 0.05). Plasma tPA antigen, PAI-1 antigen, and PAI activity are significantly increased in patients with acute ischemic stroke. Except for PAI-1 antigen, this increase appears not to be related to the underlying stroke etiology.     

Increased blood fibrinolytic activity after physical exercise: comparative study in individuals with different sporting activities and in patients after myocardial infarction taking part in a rehabilitation sports program

The activation of fibrinolysis during bicycle ergometry was studied in two pairs of age-matched groups. Group A: 18 healthy male competitive athletes (23 +/- 3.5 years of age, mean +/- SD), Group B: 18 healthy male volunteers (25.7 +/- 2.7) not engaged in any sports, Group C: 17 healthy male volunteers (50.6 +/- 7.7) regularly practicing sports, and Group D: 18 male survivors from myocardial infarction (MI-patients, 54.2 +/- 7.9) who took part in a rehabilitation sports program. Before ergometry, healthy participants with regular sporting activities showed significantly lower plasma plasminogen activator inhibitor capacities (PAI cap) than the members of the respective age-matched control groups: Group A 13.9 +/- 2.6 AU/ml, Group B 18.5 +/- 5.5, p less than 0.005; Group C 15.2 +/- 2.9, Group D 20.7 +/- 5.5, p less than 0.05. During ergometry the release of tPA antigen did not differ significantly between the age-matched groups, however, tissue plasminogen activator (tPA) activities after ergometry were higher in groups presenting lower pre-test PAI cap values. Group A 5.5 +/- 6.4 AU/ml, Group B 1.1 +/- 2.9 AU/ml, p less than 0.05; Group C 2.9 +/- 3.3, Group D 0.2 +/- 0.7, p less than 0.05. Levels of the fibrin split product (D-dimer) did not change in any of the groups. This investigation indicates that (1) regular vigorous sporting activities enhance blood fibrinolysis by reducing blood PAI cap in healthy individuals, (2) rehabilitation sport is not capable of reducing blood PAI cap in MI-patients to values measured in age matched healthy individuals regularly practicing sports and (3) the activation of fibrinolysis during physical exercise has no systemic fibrinolytic effect.     

Effects of recombinant plasminogen activator inhibitor type 1 on fibrinolysis in vitro and in vivo

A biologically active recombinant PAI-1 (rPAI-1) was evaluated for its effects on clot lysis in vitro and in vivo. At concentrations of 0.5 to 10 micrograms/ml, the rPAI-1 significantly prolonged the time to lysis of rabbit euglobulin clots both in the presence and absence of exogenous tissue plasminogen activator. To examine the effects of PAI in vivo, we infused rPAI-1 into conscious rabbits after i.v. injection of homogenized fibrin clots, and assessed fibrinolysis by measuring the appearance of d-dimer fibrin degradation products (FDP). Plasma fibrinolytic activity, PAI activity and antigen were also measured in plasma samples taken during and after infusion of rPAI-1. In control rabbits, endogenous fibrinolytic activity resulted in a significant and continual generation of FDP, reaching 32.6 +/- 13.6 ng/ml 90 minutes after fibrin injection. Infusion of 1, 2, or 5 micrograms/kg/min rPAI-1 led to dose dependent increases in PAI activity and antigen, while FDP levels at 90 minutes were only 8.8 +/- 2.9, 5.7 +/- 2.4, and 0.3 +/- 0.3 ng/ml, respectively. Complete inhibition of fibrinolysis was observed with 10 micrograms/kg/min rPAI-1. These studies directly demonstrate that increases in PAI-1 impair the fibrinolytic system, and support indirect observations of an association between elevated levels of this protein and thromboembolic diseases.     

Relationship between smoking and fibrinolytic system with special reference to t-PA and PA inhibitor

Recently tissue plasminogen activator (t-PA) has been clinically applied to the thrombolytic therapy of myocardial infarction. We investigated relationship between cigarette smoking and fibrinolytic system, namely the plasma level of t-PA antigen, plasminogen activator inhibitor (PAI), and PA activity. Nineteen healthy volunteers were asked to smoke for 10 min. The plasma levels of t-PA antigen, PAI activity, PA activity and catecholamine were measured together with measurement of blood pressure and heart rate before, soon after or 30 min after cigarette smoking. Plasma t-PA antigen after cigarette smoking increased to 8.83 +/- 3.11 ng per ml, significantly higher (p less than 0.005) than 6.35 +/- 1.7 ng/ml before cigarette smoking. Plasma PAI activity after cigarette smoking was 5.52 +/- 2.03 u/ml, significantly higher (p less than 0.05) than 4.18 +/- 1.06 u/ml before smoking. Plasma PA activity after smoking was 6.28 +/- 3.85 u/ml significantly higher (p less than 0.05) than 4. 49 +/- 2.74 u/ml. Furthermore, plasma epinephrine level after smoking increased to 59.1 +/- 52.4 pg/ml (p less than 0.1), compared with 36.2 +/- 22.5 pg/ml before smoking. There was a positive correlation between the rate of increase in plasma t-PA antigen and the rate of increase in plasma epinephrine after smoking. It is suggested that plasma epinephrine was related to the mechanism of increased plasma levels of t-PA in cigarette smoking.     

Coagulation and fibrinolysis during laparoscopic cholecystectomy

Laparoscopic surgery appears to be less traumatic to the patient than open surgery, but its influence upon coagulation and fibrinolysis is incompletely elucidated. Our aim was to measure markers of coagulation and fibrinolysis before, during. and after laparoscopic cholecystectomy (LC). Blood samples drawn on admission, on four occasions during operation as well as 2 hours after operation and on the first postoperative day in 50 patients undergoing elective LC were analyzed for prothrombin fragment 1+2 (F1+2), soluble fibrin (SF), D-dimer (DD), fibrin degradation products (FbDP), tissue-type plasminogen activator (tPA) activity and antigen, and plasminogen activator inhibitor (PAI) activity and antigen. F1+2, SF, DD, and FbDP levels increased significantly after LC. Differences between pre- and postoperative PAI and tPA levels were not significant apart from a transient increase in tPA antigen levels. tPA activity was significantly increased during operation.     

Determination of plasminogen activator inhibitor (PAI) activity of human plasma after dilution in a PAI-depleted plasma

A simple and discriminating assay for the determination of the fast-acting plasminogen activator inhibitor (PAI) activity in human plasma is described. The method is based on the inhibition of purified tissue plasminogen activator (tPA) by plasma diluted with a PAI-depleted plasma and the subsequent measurement of residual tPA in the presence of CNBr-fibrinogen fragments, purified plasminogen and a plasmin sensitive chromogenic substrate CBS 10.65. This assay does not require any acidification step, and allows PAI determination directly on plasma. Since dilutions are made in PAI-depleted plasma, all the serine-protease inhibitors, except PAI, are kept constant in their effect on the assay. Thus, any detectable degree of inhibition can only be ascribed to PAI. Under these conditions, parallel titration curves of tPA are obtained in plasma and the values of PAI are reproducible when measured at different dilutions. The PAI levels of 31 normal volunteers ranged from 0.3 to 8.7 IU/ml (mean: 3.5 IU/ml). After venous occlusion, variations of PAI were associated with the release of tPA. A marked increase of PAI levels was observed in the post-operative period and in pregnancy. In this case both PAI-1 and PAI-2 related activities were measured. Due to its simplicity, the assay can be easily used for the screening of patients with thrombotic diseases.     

Maternal dietary fish oil enriches docosahexaenoate levels in brain subcellular fractions of offspring

Prompted by the speculated essentiality of docosahexaenoic acid (DHA) for neural development, this study was undertaken to investigate the incorporation of (n-3) fatty acids in the maternal diet into various phospholipids of infant rat brain subcellular fractions: microsomes (Ms), synaptosomes (Sy), myelin (My), and mitochondria (Mt). Two groups of infant rats were nourished by dams fed diets containing 20% of either corn oil (CO) or menhaden oil (MO) from 2 until 12 days of age. DHA but not eicosapen taenoic acid (EPA) was distributed to all subcellular fractions of infant rats in the CO group. The levels of DHA were higher in Ms and Mt than Sy and My, and higher in phosphatidylethanolamine (PE) and phosphatidylserine (PS) than phosphadylcholine (PC) and phosphatidylinositol (PI). The MO feeding enriched DHA in PE of all subcellular fractions, PS of all subcellular fractions, except My, PC of Sy, My and Mt, and PI of My. EPA was enriched in phospholipids in all subcellular fractions, except mitochondrial PS of the MO group. In the MO group, the ratios of EPA/ DHA, ranging from 0.01 to 0.85, in all subcellular phospholipids were markedly lower than that found in the mother-s milk (i.e., 1.5), suggesting an ability to elongate and desaturate EPA to DHA and/or disproportional uptake of the fatty acids by the brain. In PE of all subcellular fractions, the increased levels of DHA and EPA, with a concomitant reduction of arachidonic and/or linoleic acid, yielded higher ratios of total (n?3)/(n?6) fatty acids in the MO than the CO group. The inclusion of preformed DHA and EPA in the maternal diet provides an effective means to enrich these fatty acids in developing brains. © 1993 Wiley-Liss, Inc.     

Persistent impairment of platelet aggregation following cessation of a short-course dietary supplementation of moderate amounts of N-3 fatty acid ethyl esters.

The duration of the effect of a short-course (1-mo twice-daily) supplementation of moderate amounts (2.28 g) of n-3 fatty acid ethyl esters (FA) on platelet lipid composition and aggregation was compared with that of olive oil (3 g/d) supplementation in 14 healthy volunteers. The FA preparation employed contained eicosapentaenoic acid (EPA) and docosahexaenoic acids (DHA) in a ratio of 1:1.4. A marked rise (p <0.05) in the plasma and platelet content of EPA and DHA, and minimal changes in the content of arachidonic acid (AA) were documented at withdrawal of the n-3 FA supplementation. EPA/AA and DHA/AA ratios in platelet phospholipids showed that the FA accumulation persisted 8-12 wks after stopping the supplementation (p <0.05). The aggregation of platelets in response to collagen or ADP, and thromboxane B2 (TXB2) formation were impaired at withdrawal. The impaired aggregation lasted 8-12 weeks (p always <0.05), whereas TXB2 formation returned to basal values 4 weeks after stopping the n-3 supplementation. No correlation was found between impaired aggregation and TXB2 formation. In contrast, the impaired sensitivity to ADP (p = 0.036) and, to a lesser extent, to collagen (p = 0.068) were related to changes in the intracellular pH (pHi) of the Na+/H+ reverse transport. No changes in platelet composition or function were observed either during or following olive oil supplementation. These results document a long-lasting impairment of platelet sensitivity to ADP and collagen; changes in the pHi values of the Na+/H+ reverse transport, and a simultaneous persistent accumulation of EPA and DHA in platelet phospholipids, after stopping a short-course dietary supplementation of moderate amounts of n-3 fatty acid ethyl esters.     

Vegetarians and cardiovascular risk factors: hemostasis, inflammatory markers and plasma homocysteine.

We studied hemostatic and inflammatory cardiovascular risk factors (CVRF), and total plasma homocysteine (tHcy) in 26 vegetarians (23 lacto- or ovolactovegetarians and 3 vegans), matched by age, sex and socioeconomic status with omnivorous controls. Vegetarians had significantly lower proportion of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids in plasma lipids, significantly shortened bleeding time, and increased blood platelet count and in vitro platelet function (aggregation and secretion). Plasma levels of all coagulation or fibrinolytic factors and natural inhibitors synthesized in the liver were lower in vegetarians than in controls. Whereas for some factors this decrease was statistically significant (fibrinogen, factor VIIc, antithrombin III, protein S, plasminogen) for the remaining (factors VIIIc, Vc, prothrombin, protein C) a trend in the same direction was found. For hemostatic proteins of predominantly extrahepatic origin (von Willebrand factor. tPA, PAI-1) this tendency was not present. No significant differences in inflammatory proteins (C-reactive protein and alpha1-protease inhibitor) were detected in both groups. tHcy was significantly increased in vegetarians, and correlated only with cobalamin levels. The increased platelet function and tHcy found in vegetarians may counteract the known cardiovascular health benefits of vegetarian diet (VD).