thromboxane-b2 and Alcoholism

Urinary excretion of 2,3-dinor-thromboxane B2 as a marker of in vivo thromboxane A2 (TxA2) biosynthesis was measured in six alcoholics 1 and 14 days after the cessation of heavy drinking using gas chromatography/mass spectrometry. Six non-alcoholic healthy volunteers served as controls. One day after alcohol withdrawal the excretion of the dinor metabolite was significantly higher (P < 0.01) in the alcoholics (408 +/- 42 pg mg-1 creatinine) than in the controls (180 +/- 30 pg mg-1 creatinine) and was accompanied by a significantly reduced platelet count (103.0 +/- 20.2 x 10(9) l-1 vs. 194.0 +/- 13.9 x 10(9) l-1 in controls; P < 0.01). The metabolite excretion fell then significantly (P < 0.05) to 245 +/- 53 pg mg-1 creatinine 14 days after alcohol withdrawal and this was paralleled by an increase in platelet count to 453.5 +/- 72.0 x 10(9) l-1 (P < 0.05). The present results support the hypothesis that Tx-A2 biosynthesis is increased in early alcohol withdrawal and strongly suggest platelets as a cellular origin of the increased TxA2 formation.

Topics: Adult; Alcoholism; Female; Humans; Male; Platelet Count; Substance Withdrawal Syndrome; Thromboxane B2

To investigate the effect on platelet function of the interaction between dietary cholesterol and moderate, chronic doses of ethanol, hypercholesterolemia was induced in rabbits by 8 weeks of administration of a chow diet with added (0.25% wt/wt) cholesterol; during the eighth week, a moderate amount of ethanol (6% in drinking water) was given. Blood alcohol levels were not detectable in ethanol-treated rabbits at the time of exsanguination. Ethanol did not affect plasma cholesterol levels or the cholesterol to phospholipid molar ratio in platelets. Platelet membrane fluidity, which decreased with cholesterol feeding, was not altered further by administration of ethanol. The overall fatty acid composition of platelet phospholipids was not affected by either cholesterol feeding or chronic ethanol intake. Responses of washed platelets stimulated with either ADP or thrombin were studied to determine whether ethanol administration modified platelet functions in hypercholesterolemia. Primary ADP-induced aggregation was not affected by cholesterol feeding or chronic ethanol intake, but thrombin-induced aggregation and secretion of [14C]serotonin from prelabeled platelets, which were enhanced by cholesterol feeding, were diminished by administration of ethanol to hypercholesterolemic rabbits. This reduction in thrombin-induced responses was also observed with aspirin-treated platelets, which cannot form thromboxane A2. Thus, chronic short-term administration of a moderate amount of ethanol inhibited the enhanced responses of platelets from rabbits with diet-induced hypercholesterolemia, via a thrombin-induced, thromboxane A2-independent pathway.

Topics: Adenosine Diphosphate; Alcoholism; Animal Feed; Animals; Blood Platelets; Carbon Radioisotopes; Cholesterol, Dietary; Hypercholesterolemia; Male; Platelet Aggregation; Rabbits; Serotonin; Thrombin; Thromboxane B2; Time Factors

Recently, hepatic microcirculation has been focused on as an important pathogenic factor in progression of alcoholic liver disease (ALD). Therefore, blood levels of several prostaglandins, which are associated with organ microcirculation, were determined in various liver diseases, including ALD. Blood thromboxane B2 (TXB2) level was significantly increased in ALD, when compared to other types of liver diseases, whereas both 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and prostaglandin E were not changed. These consequences resulted in the imbalance of 6-keto PGF1 alpha to TXB2, which might promote platelet aggregation and blood vessel contraction. Indeed, the increase of beta-thromboglobulin and platelet factor 4 in blood was observed in ALD. Furthermore, in ALD, the rate of arachidonate-induced platelet aggregation was prominently enhanced, and malondialdehyde production in platelet, which was well correlated with blood TXB2 levels, significantly increased. Thus, the present study may indicate that, in ALD, hyper-aggregability of platelet is produced, because of the derangement of prostaglandin metabolism and platelet dysfunction.

Topics: Adult; Alcoholism; beta-Thromboglobulin; Blood Platelets; Humans; Liver Diseases, Alcoholic; Malondialdehyde; Middle Aged; Platelet Aggregation; Platelet Factor 4; Prostaglandins; Thromboxane B2

Platelet aggregation, secretion of serotonin, and formation of thromboxane B2 induced by platelet-activating factor (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) were studied in plasma containing physiological concentrations of ionized calcium in eight alcoholics after cessation of heavy drinking. Responses of platelets of four nonalcoholic volunteers, matched with a subgroup of the alcoholics by age and sex, were also investigated. Aggregation of platelets from alcoholics was significantly less throughout the 6-day detoxification period compared with controls. Secretion of serotonin (5-hydroxy-tryptamine) was negligible and the production of thromboxane B2 was not detectable. Decreased platelet aggregability in response to aggregating agents, including platelet-activating factor, may be important in the development of hemorrhagic complications in alcoholics.

Topics: Adult; Aged; Alcoholism; Blood Platelets; Calcium; Ethanol; Female; Hemorrhagic Disorders; Humans; Male; Middle Aged; Platelet Activating Factor; Platelet Aggregation; Serotonin; Smoking; Stimulation, Chemical; Substance Withdrawal Syndrome; Thromboxane B2

Collagen-, arachidonate- and ADP-stimulated platelet thromboxane B2 (TXB2) formation was studied in platelet-rich plasma (PRP) of 14 alcoholics, 7 of whom had a biopsy-verified alcoholic fatty liver. On admission for detoxication, the alcoholics showed decreased platelet count and aggregability (p less than 0.001) as compared to nonalcoholic healthy controls. Platelet TXB2 formation was decreased (p less than 0.01), if PRP was stimulated by arachidonate, but not if it was stimulated by ADP or collagen. In contrast, 9-14 days after ethanol withdrawal platelet TXB2 formation had increased to markedly higher levels than those seen in nonalcoholic controls (p less than 0.01), if PRP was stimulated by ADP, but not if it was stimulated by arachidonate or collagen. Skin bleeding time was found to be prolonged (p less than 0.05) on admission in alcoholics having fatty liver, but it normalized within 2 weeks after ethanol withdrawal. We conclude that the effect of ethanol withdrawal in alcoholics on platelet TXB2 formation is influenced by platelet count, aggregability and the agonist used to induce platelet aggregation.

Topics: Adenosine Diphosphate; Adult; Alcoholism; Arachidonic Acid; Arachidonic Acids; Bleeding Time; Blood Platelets; Collagen; Ethanol; Female; Fibrinogen; Humans; Liver Diseases, Alcoholic; Male; Middle Aged; Platelet Aggregation; Platelet Count; Serum Albumin; Substance Withdrawal Syndrome; Thromboxane B2

Topics: Alcohol Withdrawal Delirium; Alcoholism; Humans; Ischemic Attack, Transient; Male; Middle Aged; Platelet Aggregation; Psychoses, Alcoholic; Thromboxane B2

To study the effect of maternal ethanol consumption on the production of prostacyclin and thromboxane, we measured urinary 6-keto-prostaglandin F1 alpha (a hydration product of prostacyclin), 2,3-dinor-6-keto-prostaglandin F1 alpha (generated from 6-keto-prostaglandin F1 alpha through beta oxidation), and thromboxane B2 (a hydration product of thromboxane A2) using consequent high-performance liquid chromatography and radioimmunoassays in 39 drinking women and 16 abstinent controls, and in their infants. Thirty-one drinkers and two control women smoked. Maternal ethanol consumption was accompanied by increased output of prostacyclin and thromboxane metabolites in the mothers, but no relationship was apparent between the increased metabolites and development of fetal alcohol effects in 22 mothers. There were no differences between smoking and nonsmoking drinkers in the excretion of these prostanoids. All the infants born to the drinkers had increased thromboxane B2 excretion, but the excretion of prostacyclin metabolites was increased only in infants with fetal alcohol effects. The ratio between prostacyclin and thromboxane was reduced in infants with fetal alcohol effects. Thus, maternal ethanol consumption is associated with enhanced prostacyclin and thromboxane synthesis, perhaps in the kidneys and/or systemic circulation and vascular bed. Similar changes may also occur in the fetus and/or newborn with fetal alcohol effects.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Alcoholism; Epoprostenol; Female; Fetal Alcohol Spectrum Disorders; Humans; Pregnancy; Pregnancy Complications; Temperance; Thromboxane B2

The effect of ethanol on the formation of platelet thromboxane B2 (TXB2), a stable metabolite of thromboxane A2 (TXA2) was studied in vitro in six chronic alcoholics, admitted for detoxification, and in six healthy volunteers. Immediately after cessation of heavy drinking platelet count and ADP-induced TXB2 formation were lower in alcoholics than in nonalcoholic volunteers (P less than 0.05). Ten days after withdrawal of ethanol platelet count increased, and skin bleeding time shortened (P less than 0.05). Ethanol had no effect on arachidonate-induced platelet TXB2 formation, whereas ethanol added to platelet suspension prior to stimulation by ADP resulted in a concentration-related inhibitory tendency in both alcoholics and nonalcoholic control subjects. This effect of ethanol may be of significance for primary hemostasis in alcoholics.

Topics: Adenosine Diphosphate; Adult; Alcoholism; Blood Platelets; Ethanol; Humans; Male; Middle Aged; Substance Withdrawal Syndrome; Thromboxane B2

Changes in the kinetic variables of the platelet serotonin uptake, Km and Vmax, were studied in 7 male alcoholics, admitted for detoxification and in sex- and age-matched volunteers. On admission the alcoholics had lower Km values than reference subjects (p less than 0.05). During detoxification the Km values normalized. Vmax was normal throughout the study in spite of the changes in platelet count. The results of the study suggest that the affinity of serotonin to its uptake receptor is transiently increased after a period of heavy drinking.

Topics: Adult; Alcoholism; Blood Platelets; Carbon Radioisotopes; Ethanol; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Count; Receptors, Cell Surface; Serotonin; Substance Withdrawal Syndrome; Thromboxane B2

1. The rates of secretion into the circulation of prostaglandin E, prostacyclin, and thromboxane A2 were estimated in male alcoholics on the third day of withdrawal and in control subjects by measuring appropriate metabolites in urine. 2. Urinary levels of tetranor-5,11-diketo-7 alpha-hydroxyprostane-1,16-dioic acid (the major urinary metabolite of prostaglandins E1 and E2), of 2,3-dinor-6-keto-prostaglandin F1 alpha (the major urinary metabolite of prostacyclin) and of 6-keto-prostaglandin F1 alpha (the stable hydrolysis product of prostacyclin) were significantly different from the normal subjects in the alcoholic group. In contrast, 2,3-dinor-thromboxane B2 (the major urinary metabolite of thromboxane A2) and thromboxane B2 (the stable hydrolysis product of thromboxane A2) were not significantly different between the groups. 3. These data suggest that the ratio of the vasodilator prostanoids prostaglandin E and prostacyclin and the vasoconstrictor prostanoid thromboxane A2 is lower than in normal subjects, in alcoholics during withdrawal. This may be one causal factor for the higher incidence of hypertension observed in withdrawing alcoholics compared with control subjects.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Alcoholism; Epoprostenol; Ethanol; Humans; Male; Middle Aged; Prostaglandins E; Prostanoic Acids; Substance Withdrawal Syndrome; Thromboxane B2; Thromboxanes

The excretion of 2,3-dinor-6-keto prostaglandin F1 alpha, a major urinary metabolite of prostacyclin, and the formation of thromboxane B2, a stable metabolite of thromboxane A2, by platelets stimulated by adenosine diphosphate, were studied in alcoholics, who had been admitted for detoxification. Once prolonged heavy drinking had stopped, platelet count and thromboxane formation, calculated either per 10(7) platelets or per litre of blood, significantly increased (p less than 0.05), while the skin bleeding time and urinary excretion of the metabolite of prostacyclin decreased (p less than 0.05). The balance between prostacyclin and thromboxane therefore seemed to favour the excretion of prostacyclin while it shifted to favour thromboxane formation about a week later.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Alcoholism; Bleeding Time; Blood Platelets; Humans; Male; Middle Aged; Platelet Count; Substance Withdrawal Syndrome; Thromboxane B2; Time Factors

Platelet phosphatidylinositol and phosphatidylcholine composition, ADP-induced platelet aggregation and associated thromboxane B2 formation were studied in alcoholics after a period of heavy drinking and in healthy non-alcoholic volunteers. The composition of these phospholipids in alcoholics was different from that seen in the control subjects. The most prominent change was a decrease in the relative amount of stearoyl-arachidonoyl species in the phosphatidylinositol fraction. Particularly this species of PI might be involved in the transmission of transmembrane signals. During detoxification changes were also observed in the extent of ADP-induced platelet aggregation and the amount of thromboxane B2 produced. Changes in platelet phospholipid composition might influence platelet reactivity in alcoholics.

Topics: Adenosine Diphosphate; Adult; Alcoholism; Blood Platelets; Ethanol; Humans; In Vitro Techniques; Male; Middle Aged; Phosphatidylcholines; Phosphatidylinositols; Phospholipids; Platelet Aggregation; Substance Withdrawal Syndrome; Thromboxane B2

Platelet function in alcoholic patients was assessed on admission and during abstinence in hospital. On admission platelets from these patients were significantly less responsive (percentage aggregation and thromboxane A2 release) to conventional in vitro aggregating agents (adrenaline, adenosine diphosphate, and collagen) than platelets from healthy, moderate drinkers. Initially, platelet counts in platelet rich plasma tended to be low and the Simplate II bleeding times frequently prolonged. Platelet aggregation and thromboxane A2 release, however, were inhibited even in patients with normal platelet counts on admission. Platelet aggregation and thromboxane A2 release returned to normal or became hyper-responsive during two to three weeks of abstinence. Platelet counts rose during this period, the largest responses occurring in those patients with the lowest counts on admission. Bleeding times reverted to normal during abstinence and correlated significantly with changes in platelet aggregation, thromboxane A2 release, and platelet count and with the estimated ethanol consumption during the week before admission. Chronic, heavy alcohol ingestion evidently exerts an inhibitory effect on platelet function even in the absence of alcohol in the blood, and this phenomenon is reversible on abstaining. The impaired platelet function, together with the reduced platelet count, may contribute to the bleeding diathesis associated with chronic alcoholism and to the increased incidence and recurrence of gastrointestinal haemorrhage associated with excessive alcohol intake.

Topics: Adult; Alcohol Drinking; Alcoholism; Bleeding Time; Blood Platelets; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Count; Thromboxane A2; Thromboxane B2

To study the effects of chronic alcohol consumption on platelet functions, the rate of arachidonate-induced platelet aggregation, the production of malondialdehyde in platelets, and plasma levels of prostaglandin endoperoxide metabolites were examined in 88 chronic alcoholics and 24 healthy controls. The rate of platelet aggregation and the production of malondialdehyde in platelets were greater in chronic alcoholics both on admission and 1 week after. However, these alterations returned to the level of healthy controls within 4 weeks of abstinence from alcohol and were independent of the number of circulating platelets. Furthermore, on admission, plasma levels of thromboxane B2 were significantly increased in chronic alcoholics when compared with those of healthy controls (400.8 +/- 36.5 versus 241.7 +/- 28.9 pg/ml plasma; p less than 0.025) and were also significantly correlated with malondialdehyde production in washed platelet debris (r = 0.6049; p less than 0.001). In contrast, plasma levels of 6-keto prostaglandin F1 alpha and prostaglandin E were not altered after chronic alcohol consumption. As a result, the ratio of 6-keto prostaglandin F1 alpha to thromboxane B2 was markedly decreased in chronic alcoholics (0.31 +/- 0.03 versus 0.62 +/- 0.13; p less than 0.001). These results strongly suggest that the imbalance in prostaglandin endoperoxide metabolites is produced by chronic alcohol ingestion. Moreover, a significant correlation was observed between platelet aggregation rate and malondialdehyde production during platelet aggregation (r = 0.559; p less than 0.005). Thus, we conclude that chronic alcohol consumption alters platelet thromboxane metabolism, which is likely associated with the increased ability of platelets to aggregate.

Topics: Adult; Alcoholism; Blood Platelets; Humans; Male; Malondialdehyde; Middle Aged; Platelet Aggregation; Platelet Count; Prostaglandin Endoperoxides; Prostaglandins; Thromboxane A2; Thromboxane B2

Platelet count, mean volume, aggregation and associated thromboxane (TXB2) formation, circulating platelet aggregates and bleeding time were examined in 19 noncirrhotic male alcoholic cigarette smokers for four weeks following cessation of prolonged heavy drinking, and in 24 nonalcoholic healthy male volunteers (10 smokers and 14 nonsmokers). The alcoholics showed a 9-fold increase (p less than 0.001) in ADP-stimulated platelet thromboxane formation one to two weeks after ethanol withdrawal. The effect was transient and coincided with a significant (p less than 0.01) shortening of skin bleeding time and a slight increase in circulating platelet aggregates suggesting proneness to thrombosis. No differences were seen between the smoking and nonsmoking healthy volunteers. We conclude that the recovery phase after prolonged heavy drinking is characterized by a transient increase in platelet reactivity which may lead to increased spontaneous formation of circulating platelet aggregates and shortening of bleeding time.

Topics: Adult; Alcoholism; Bleeding Time; Blood Platelets; Blood Volume; Ethanol; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Count; Reference Values; Smoking; Substance Withdrawal Syndrome; Thromboxane B2