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Soy protein favorably alters serum lipids and lipoproteins in hypercholesterolemic individuals, thereby reducing cardiovascular disease risk. The primary purpose was to determine the effect of soy protein (40 g/d) on circulating lipids and lipoproteins or coagulation and fibrinolytic factors in normocholesterolemic and mildly hypercholesterolemic perimenopausal women. We also determined the contribution of coagulation and fibrinolytic and other factors (e.g., body size and composition; serum estrogens, ferritin, iron; dietary intake) to lipid profiles. Subjects were randomly assigned to treatment: isoflavone-rich soy (n = 24), isoflavone-poor soy (n = 24), or whey control (n = 21) protein. We measured circulating lipids and lipoproteins at baseline, wk 12 and wk 24, and coagulation/fibrinolytic factors at baseline and wk 24. Coagulation and fibrinolytic factors were not adversely affected by treatment. Treatment did not alter lipid profiles in mildly hypercholesterolemic (n = 30) or in all subjects combined. Time significantly (P < 0.001) affected serum total cholesterol, triacylglycerol, LDL cholesterol and HDL cholesterol concentrations. We could not attribute changes over time to various factors, but at baseline accounted for 57% of the variability in HDL cholesterol (P < or = 0.0001) and for 50% in the total to HDL cholesterol ratio (P < or = 0.0001). Dietary vitamin E and % energy from fat had positive effects, whereas plasma plasminogen activator inhibitor-1, fibrinogen, body weight and serum ferritin had negative effects on HDL and total to HDL cholesterol. Isoflavone-rich or isoflavone-poor soy protein had no effect on lipid profiles or coagulation and fibrinolytic factors, whereas the effect of time suggested that the hormonal milieu during the menopausal transition may have overridden any detectable treatment effect on lipids. The relationship between coagulation factors and serum lipids should be examined further as indices of cardiovascular disease risk in midlife women.

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BACKGROUND AND PURPOSE: The ex vivo effect of aspirin (ASA) on platelet aggregation, the platelet component of thrombosis, was studied at repeated intervals in a cohort of patients taking aspirin for recurrent ischemic stroke prevention to define the maintenance of efficacy over time. METHODS: We administered increasing doses of aspirin (from 325 to 1300 mg/d) to patients with previous ischemic stroke and determined the extent of inhibition of platelet aggregation after 2 weeks and thereafter at approximately 6-month intervals. RESULTS: Over 33 months, 306 patients had platelet aggregation studies performed to define their initial response to ASA therapy. Of these, 228 had complete and 78 had partial inhibition of platelet aggregation at initial testing. To date, 119 of those who had complete inhibition and 52 who had partial inhibition have undergone repeat testing at least once. At repeat testing 39 of the 119 (32.7%) with complete inhibition at initial testing had lost part of the antiplatelet effect of ASA and converted from complete to partial inhibition without change in ASA dosage. Of the 52 with partial inhibition at initial testing, 35 achieved complete inhibition either by ASA dosage escalation (in 325 mg/d increments) or fluctuation of response at the same dosage, but 8 of those 35 (22.8%) had reverted to partial inhibition when tested again. Overall, 8.2% of patients ultimately exhibited ASA resistance to 1300 mg/d-8 of 52 (15.4%) with partial inhibition and 6 of 119 (5.0%) with complete inhibition at initial testing. CONCLUSIONS: The antiplatelet (and presumably the antithrombotic) effect of a fixed dose of ASA is not constant over time in all individuals. The mechanisms by which increased dosage requirement or ASA resistance develops and the clinical significance of this development are currently undefined.

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We periodically obtained blood samples from mildly hypercholesterolemic, but otherwise healthy, premenopausal women who were recruited to participate in a study of a long-term, cholesterol-lowering diet. All meals were prepared and most meals were consumed in the study center dining facility. Tests performed on blood samples included fibrinogen, cholesterol, factor VII coagulant activity (VIIc), and other measures of factor VII. We found that when women switched from a typical American diet (37% fat, polyunsaturated fatty acid to saturated fatty acid [P/S] ratio 0.5, 300 mg cholesterol/d) to a diet lower in fat and cholesterol (American Heart Association phase 2 diet: 30% fat, P/S ratio of 1, 150 to 200 mg cholesterol/d) and maintained that diet for 20 weeks, their plasma cholesterol levels decreased by approximately 6% after 4 weeks and remained at that level until study termination. Likewise, VIIc decreased by approximately 11% while factor VII antigen, total factor VII activity, and fibrinogen concentration did not change appreciably from baseline values. Our results show that premenopausal women benefit from a diet lower in total and saturated fat by a reduction in blood cholesterol and VIIc. Extrapolation from data on men in the Northwick Park Heart Study indicates that the 11% decrease in VIIc activity would correspond to an approximately 30% decrease in risk of mortality from coronary heart disease.

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BACKGROUND AND PURPOSE: Although warfarin and perhaps aspirin may be effective in preventing thromboembolism in patients with nonvalvular atrial fibrillation, some patients develop cerebral infarction despite these therapies. The purpose of this study was to determine inhibition of platelet aggregation in patients on aspirin and platelet reactivity in those on warfarin in the Stroke Prevention in Atrial Fibrillation study. METHODS: Twenty-four patients in the Stroke Prevention in Atrial Fibrillation study at the University of Illinois at Chicago, 17 on enteric-coated aspirin 325 mg/d and 7 on warfarin to produce an International Normalized Ratio of 2.0 to 4.5, had platelet aggregation studies performed during a 10-month period and interpreted by an investigator blinded to therapy. Epinephrine, adenosine diphosphate, collagen, and arachidonic acid were used as aggregating agents. Compliance was determined by pill count for those patients on aspirin. RESULTS: Seven patients taking aspirin had partial and 10 had complete inhibition of platelet aggregation. Three of seven patients on warfarin had hyperaggregable platelets. Compliance was 80% or greater for those patients taking aspirin. One patient on warfarin had partial inhibition of platelet aggregation. CONCLUSIONS: Some patients in the Stroke Prevention in Atrial Fibrillation trial on aspirin 325 mg/d did not achieve complete inhibition of platelet aggregation. Others had hyperaggregable platelets. These findings suggest platelet-dependent mechanisms for aspirin and warfarin failure to prevent stroke in these patients.

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BACKGROUND AND PURPOSE: The purpose of this study was to assess the biological effect of aspirin as measured by the inhibition of platelet aggregation in patients taking aspirin for stroke prevention and in patients with acute stroke. METHODS: We administered increasing doses of aspirin (325, 650, 975, and 1,300 mg daily) to 113 patients for stroke prevention and measured the inhibition of platelet aggregation in these patients and in 33 patients with acute stroke taking aspirin before stroke onset. RESULTS: Eighty-five patients on < or = 325 and six on > or = 650 mg aspirin had complete inhibition of platelet aggregation. Increase of the dose by 325 mg in nine of the 22 patients with partial inhibition of platelet aggregation produced complete inhibition in five patients at 650 mg and in one at 975 mg. At 1,300 mg, three patients still had only partial inhibition of platelet aggregation (aspirin resistance). Of the 33 inpatients with acute stroke, 24 had platelet aggregation studies done before further administration of aspirin. Of these, 19 had complete inhibition of platelet aggregation and three had partial inhibition, with production of complete inhibition of platelet aggregation at dose escalation; one patient was aspirin-resistant and the other noncompliant. CONCLUSIONS: How the inhibition of platelet aggregation relates to stroke prevention remains unclear. The ability of aspirin and the dose required to inhibit platelet aggregation may depend upon the individual.

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The ability of a low-fat, low-cholesterol diet to improve the risk-factor profiles of moderately hypercholesterolemic, premenopausal women was evaluated. Nineteen women were fed a typical American diet for 1 mo, after which a low-fat diet consisting of 21% of total energy (en%) as fat, 59 en% carbohydrates, 19 en% protein, and 96 mg cholesterol/d (P:S 1.8) was given. After 5 months, total and low-density lipoprotein (LDL) cholesterol was decreased by 7% and 11%, respectively, and total triglycerides increased by approximately 30%. High-density-lipoprotein (HDL) cholesterol was decreased by 12% at month 2 and 5% at month 5 (P less than 0.05). Although HDL2 cholesterol decreased progressively throughout the diet period to -35% by month 5, HDL3 cholesterol, which decreased to -5% at month 1, increased to +7% by month 5. Of the plasma apolipoproteins only apo A-II was altered (+15%) by the diet. Body mass index correlated to baseline values and affected response to diet; only the leanest women had significant decreases in total, LDL, and HDL2 cholesterol in response to the low-fat diet.

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We have previously shown that unmodified heparin (bovine lung or porcine mucosal) and a low molecular weight heparin fraction, PK 10169, cause platelet aggregation in a dose and molecular weight-dependent manner. In this report, we show that two other low molecular weight heparin fractions, CY 216 and CY 222, also cause platelet aggregation in a dose and molecular weight-dependent manner. Utilizing heparin and defined fractions of CY 216 and CY 222 separated on the basis of molecular weight, we determined dose/response (D/R) relationships for each of these agents and their individual fractions. In comparison to an unmodified porcine mucosal heparin, CY 216 yielded a D/R curve that was shifted down and to the right, indicating that this agent is less potent in causing platelet aggregation. The D/R curve for CY 222, which has a lower molecular weight that CY 216, was shifted further down and to the right, indicating that it was less potent than CY 216. The D/R curves obtained with the fractions of CY 216 and CY 222 demonstrate that as the molecular weight of the fractions decrease, they become progressively less potent in causing platelet aggregation. Fractions with molecular weights of less than approximately 3,000 daltons are essentially without activity in causing platelet aggregation. Platelet aggregation studies with CY 216 and CY 222 fractions separated on the basis of affinity for antithrombin III (AT III) indicate that the platelet aggregating activity of these agents may not be related to their affinity for AT III. However, these latter results are not conclusive and need to be expanded.

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Addition of heparin or heparin derivatives to citrate anticoagulated platelet-rich plasma caused platelet aggregation in a dose-dependent manner. Utilizing heparin, a low molecular weight heparin derivative (PK 10169) and its various subfractions, we determined dose/response relationships for platelet aggregation and found that the ability of these agents to cause platelet aggregation was dependent upon the molecular weight of the individual subfraction used. In comparison to unmodified porcine mucosal heparin, the lower molecular weight derivative (PK 10169) yielded a dose/response curve that was shifted down and to the right, and indicated that this agent was less potent in causing platelet aggregation. In addition, as the molecular weight of PK 10169 subfractions decreased, their dose/response curves were progressively shifted down and to the right. The lowest molecular weight subfraction was essentially without platelet aggregating activity. We also measured the anti IIa and anti Xa activities of these agents and concluded that these activities did not appear to correlate with platelet aggregating activity. Platelet aggregation studies with PK 10169 subfractions of high and low affinity for antithrombin III (AT III) indicated that the platelet aggregating activity of these compounds may not be related to their affinity for AT III, but results were not definitive.

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The interactions of heparin or its fractions with platelets that cause heparin-induced thrombocytopenia or in vitro platelet activation are poorly understood. We have shown that a low molecular weight derivative of heparin (PK 10169) and its subfractions can cause in vitro activation of platelets from normal human donors. This activation process is molecular-weight-dependent and involves the generation of thromboxane. We have also examined the effect of the serum from a patient with immune heparin-induced thrombocytopenia on normal donors' platelets incubated with heparin, PK 10169 or subfractions of PK 10169. It was found that the patient's serum induced aggregation of normal donor platelets in the presence of heparin, PK 10169 or certain subfractions of PK 10169. This process also appears to be mediated by thromboxane generation.

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We previously demonstrated that thromboxane A2 and/or prostaglandin H2 (TXA2/PGH2), ADP, and A23187 cause calcium mobilization in intact human platelets. Other studies have also shown that platelet shape change and aggregation induced by a variety of platelet agonists can be reversed by specific antagonists. In the present study, we used the fluorescent calcium probe chlortetracycline to evaluate whether the reversal of platelet activation involves a resequestration of intraplatelet calcium. It was found that the TXA2/PGH2 receptor antagonist 13-azaprostanoic acid (13-APA) reversed calcium mobilization and shape change induced by AA but not that induced by ADP. A similar specificity of action was observed using the specific ADP receptor antagonist, ATP, in that ATP only reversed ADP-induced calcium release and shape change. In contrast, prostacyclin reversed both AA and ADP-induced calcium redistribution and shape change. In the latter experiments, a net calcium sequestration was actually observed on prostacyclin addition. These findings indicate that the resequestration of released calcium leads to platelet deactivation. Furthermore, there appear to be at least two mechanisms by which a reduction in cytosolic calcium can be produced: specific interruption of the agonist-receptor interaction, for example, 13-APA antagonism of TXA2/PGH2; and stimulation of platelet adenosine 3',5'-cyclic monophosphate production by prostacyclin and consequent calcium sequestration.

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The present study investigated the mechanism by which thromboxane A2/prostaglandin H2 (TXA2/PGH2) stimulates platelet activation. Previous studies in isolated platelet vesicles have suggested that TXA2/PGH2 functions to release calcium from intraplatelet stores. On this basis, we investigated whether TXA2/PGH2 causes mobilization of calcium in intact platelets. Calcium redistribution was measured using the fluorescent probe, chlortetracycline (CTC), and a photon-counting microspectrofluorometer. Human platelet-rich plasma was incubated with CTC (50 microM) for 40 min at 25 degrees C. Shape change was induced with arachidonic acid (AA, 100 microM) or ADP (0.75-1.0 microM). It was found that AA addition resulted in a significant release of intraplatelet calcium. This release was blocked by inhibition of the cyclooxygenase with indomethacin (20 microM) or the specific TXA2/PGH2 antagonist, 13-azaprostanoic acid (13-APA, 100 microM). On the other hand, neither indomethacin nor 13-APA had any effect on calcium release stimulated by ADP. However, prostacyclin (13 nM) inhibited both AA- and ADP-induced calcium release. These findings provide evidence that cyclooxygenase products of AA, i.e., TXA2 and/or PGH2 directly caused the mobilization of intraplatelet calcium. Furthermore, this calcium mobilization appears to be mediated through a specific TXA2/PGH2 receptor interaction.

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We have shown that heparin and heparin fractions cause in vitro platelet aggregation in a large portion of a normal population. Furthermore, this aggregation occurs in a concentration-dependent manner and is not related to the anti-Xa activity of heparin or its fractions. In addition, it appears that at least part of the mechanism by which heparin induces aggregation is through the production of thromboxane. However, this is not the sole mechanism, since approximately 20% aggregation still occurs when thromboxane production is totally inhibited or the thromboxane receptor is completely blocked. Furthermore, although protamine (at the concentrations used) completely neutralizes the anticoagulant activity of heparin, it does not always completely inhibit the platelet aggregating activity of heparin. Finally, we have shown that heparin alone promotes thromboxane production and PF4 release in a whole blood system. Additional studies are needed to characterize further the mechanisms of heparin-induced platelet aggregation.

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