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The vasoactive eicosanoids, prostacyclin and thromboxane, are thought to play an important role in the genesis of cardiovascular disease. Since an altered basal production of these eicosanoids among individuals exhibiting the Type A behavior pattern had previously been observed by the authors, the present study evaluated the extent to which the TABP-eicosanoid relationship would be altered by two lifestyle variables known to affect platelet activity: alcohol consumption and stressful physical activity. 55 male participants aged 18-25 years, participated in the study. They were classified as either Type A or Type B on the basis of the Structured Interview and as either moderate, heavy, or abstinent alcohol drinkers. Bleeding times were performed and bleeding time thromboxane and prostacyclin metabolites were measured in all subjects both before and following treadmill exercise. The results indicated that following exercise, Type A participants, who reported moderate alcohol intake, had decreased levels of thromboxane B2 formation relative to Type As reporting heavy consumption. Further, prostacyclin production, measured as the primary metabolite, 6-keto-prostaglandin F1 alpha, was significantly suppressed following exercise among drinkers as compared with participants reporting abstinence. These results were discussed in relation to the proposition that moderate alcohol consumption reduces coronary heart disease risk.

The relationship between bleeding and bruising and the production of prostacyclin and thromboxane was assessed in children who were to have a tonsillectomy and/or an adenoidectomy. Eicosanoids in the blood oozing from the bleeding time incision were measured and correlated with the reported frequency of bruising and epistaxis. A striking association (P = .0003) between prostacyclin production and the frequency of bruising was found; children reporting bleeding at least biweekly had the highest prostacyclin synthesis. Successively lower levels of the prostacyclin metabolite, 6-keto-prostaglandin F1 alpha, were found in children reporting less frequent bruising. Prostacyclin production in bleeding time blood was also correlated inversely with systolic blood pressure and hemoglobin level, although neither of these variables could explain the association between prostacyclin production and bruising. There was no correlation between thromboxane formation, systolic blood pressure, hemoglobin level, age, or bleeding time and the frequency of bruising. The ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha was correlated inversely with the length of the bleeding time (P = .016). It is concluded that vascular prostacyclin production may have a role in bruising symptomatology. It is suggested that prostacyclin formed at the injured vessel surface collects within the first few seconds after injury inside the tissue space at the site of the bruise and, by influencing the formation of the platelet/fibrin plug and/or the leakage of blood from the vessels, plays a significant role in modifying the development of bruising.

The authors evaluated the interaction between physical fitness and Type A behavior on vascular production of prostacyclin and platelet thromboxane in response to a standard vessel injury. Ninety-seven male university students were classified as Type A or B on the basis of the Structured Interview of Rosenman. Reactivity, as measured by changes in systolic blood pressure (SBP), and heart rate (HR), measured before and after a stressful Stroop task 1 week later, showed that Type A individuals were more reactive to the stressor than Type Bs, providing independent confirmation of the behavioral interview assessment procedure. Fitness level was determined by a graded treadmill test and was not different for Type As and Type Bs. Basal thromboxane production, measured as the primary metabolite, thromboxane B2, in blood oozing from the bleeding-time site, was highest among unfit Type A subjects. Fit Type As and Type Bs showed significantly lower thromboxane production. No significant differences in prostacyclin production were seen. This study marks the first time that behavior pattern has been linked to an adverse aspect of a thrombosis-related parameter likely to be involved in the genesis of cardiovascular disease. The present results also indicate that physical fitness may, in some fashion, ameliorate the "toxic" effects of Type A behavior.

Sixty-six male university students were classified as Type A or B on the basis of the Structured Interview of Rosenman and as hostile or non-hostile on the basis of the Cook-Medley scale. Vascular production of prostacyclin and platelet thromboxane in response to a standard vessel injury was evaluated. Basal thromboxane production, measured as the primary metabolite, thromboxane B2, in blood oozing from the bleeding-time site, was highest among hostile Type A subjects with significantly lower thromboxane production in hostile Type Bs and all non-hostile groups combined. Following an exercise treadmill test hostile subjects produced more thromboxane than non-hostile ones, and hostile Type As had significantly shorter bleeding times than hostile Type Bs. No significant differences on any measure were observed following a stressful color naming task. The observed interaction of hostility and Type A behavior on bleeding time thromboxane formation links behavior to an adverse aspect of a thrombosis-related parameter thought to be involved in the genesis of cardiovascular disease.

Exercise at a heart rate corresponding to 30% VO2max for 15 min was associated with an increase in the volume of bleeding time blood from a mean of 133 microliters before exercise to a mean of 218 microliters during and immediately after the exercise. There was similarly an increase in thromboxane B2 production from 6.40 nmol.l-1 before to 11.50 nmol.l-1. Most subjects also showed an increase in the length of the bleeding time and in the production of bleeding time 6-keto-PGF1 alpha. The extent of increase in the bleeding time and in production of 6-keto-PGF1 alpha was quite variable, with subjects showing the largest increases in bleeding time also demonstrating the greatest increases in 6-keto-PGF1 alpha (r = 0.76, P = 0.004). The ingestion of aspirin before exercise markedly inhibited basal bleeding time thromboxane B2 production and blocked the exercise-associated increments in thromboxane B2 and 6-keto-PGF1 alpha production. While the aspirin itself increased the length of the bleeding time, there was not any further increase associated with exercise. In contrast to the effects of acute short-term exercise, long-distance running was associated with a significant decrease in bleeding time, but no change in bleeding time blood volume, bleeding time thromboxane B2, or bleeding time 6-keto-PGF1 alpha. The results show that acute low-level exercise can be associated with significant changes in the volume of blood oozing from a bleeding time incision and in the amount of thromboxane production stimulated at the incisional site. Following exhaustive exercise of long duration, the above changes are no longer seen.

In order to provide an overview of the relative contribution of platelet, von Willebrand factor, and other abnormalities to patients with clinical bleeding difficulties, we performed a retrospective survey of coagulation studies on 569 individuals referred to the University of Manitoba coagulation laboratory because they, or a closely related family member, showed clinical evidence of a bleeding disorder. There was a highly significant (p less than 0.001) negative correlation between the bleeding time and each of the following parameters: the platelet count; the hematocrit; the percent aggregation to collagen, epinephrine, ADP, and arachidonic acid; and the logarithm of von Willebrand factor antigen and a measure of its activity (ristocetin cofactor). A significant and independent inverse relationship between the length of the bleeding time and the extent of platelet adhesion to glass beads, patient age, and prothrombin consumption were also observed. Multivariate analysis of the ability of all parameters to predict the bleeding time showed an r2 of only 0.33. Bleeding time thromboxane B2, in a second smaller study of 70 patients, showed a negative correlation with the length of the bleeding time (p = 0.0001), and, when used together with the above parameters, significantly enhanced the ability to predict the length of the bleeding time (r2 = 0.55). Defects in platelet function, as measured in vitro, and significant enough to have an effect on the bleeding time, occurred with greater frequency than defects in von Willebrand factor in the Manitoba patients evaluated.

We altered platelet cholesterol by incubating the cells with either "cholesterol-rich" or "cholesterol-poor" liposomes. These platelets were then used to study the influence of cholesterol content on the metabolism of arachidonic acid, a fatty acid that serves as the critical precursor in the platelet for formation of the potent aggregating agent thromboxane A2. After addition of the aggregating agent thrombin, cholesterol-enriched platelets released 18.1 +/- 0.6 per cent (mean +/- 1 S.E.M.) [14C]arachidonic acid from prelabeled platelet phospholipids. This value was higher (P less than 0.001) than that for cholesterol-depleted platelets (14.6 +/- 1.0 per cent). Conversion of released arachidonic acid to platelet thromboxane B2 (the stable end product of thromboxane A2) was also higher in cholesterol-rich platelets (22.6 +/- 3.9 per cent) than in cholesterol-depleted platelets (13.8 +/- 2.7 per cent). These studies show that changes in the cholesterol content of human platelets in vitro have a significant effect on platelt metabolism of arachidonic acid. N Engl J Med 302:6-10, 1980).

The body's ability to produce prostacyclin and thromboxane by blood vessels and platelets may be important in hemostatic and thrombotic disorders and in blood pressure regulation. There are limitations to the information that can be derived from measurement of the active substances or metabolites in plasma and urine. Assays for thromboxane and prostacyclin in bleeding time blood reflect production in response to a single standardized vascular injury, and show considerable promise in furthering our understanding of the production of these chemicals in vivo. These assays may improve the assessment of risk of developing thrombotic disorders and improve the ability to monitor treatment. Studies to date have focused largely on the influences of various doses of aspirin on the production of prostacyclin and thromboxane in bleeding time blood, but also suggest that smokers are high thromboxane producers. In addition, individuals who exhibit type A behavior, a behavior pattern characterized by a relatively high level of ambitiousness, hostility, and competitive drive and a chronic sense of urgency appear to be low prostacyclin producers. Diets enriched in sunflower oil were found to diminish thromboxane production, while diets high in canola oil enhanced prostacyclin formation.

The effects of smoking, aspirin ingestion, and sex differences on bleeding times and bleeding time thromboxane B2 and 6-keto-prostaglandin (PG)F1 alpha production were examined. Nonsmoking men produced more thromboxane B2 (3.99 +/- 0.76 ng/ml) than nonsmoking women (2.13 +/- 0.24 ng/ml). Female smokers produced more thromboxane B2 (5.01 +/- 0.97 ng/ml) than nonsmoking women. Twenty-four hours after a single dose of 600 mg aspirin, in vitro production of thromboxane B2 in response to collagen fell by 95%, whereas in vivo production of thromboxane B2 and 6-keto-PGF1 alpha in bleeding time blood fell by 87% and 66%, respectively. Subjects with the lowest absolute levels of thromboxane B2 24 hours after aspirin were also those with the longest postaspirin bleeding times. Recovery of 6-keto-PGF1 alpha production was faster than recovery of thromboxane B2 production, but 6-keto-PGF1 alpha production for most subjects was still below basal 72 hours after aspirin. The influence of two different doses of long-term aspirin (80 mg every other day and 325 mg daily) on the in vivo production of thromboxane B2 and 6-keto-PGF1 alpha was studied in normals and diabetics. After 14 days of 80 mg aspirin every other day, thromboxane B2 and 6-keto-PGF1 alpha production were both substantially inhibited (93% and 78%, respectively). After 14 days of 325 mg aspirin daily, thromboxane B2 production was similarly substantially inhibited (93%), whereas 6-keto-PGF1 alpha was significantly less affected (only 45% inhibition). Study of a second group of five normal subjects confirmed that 6-keto-PGF1 alpha production was significantly inhibited 24 hours after the first dose of 325 mg aspirin but was not significantly less than basal after 14 days of 325 mg aspirin. The results suggest that 325 mg aspirin daily is more antithrombotic compared with 80 mg every other day due to the superior preservation of prostacyclin production.