R Butt

Platelet release and thromboxane synthesis in symptomatic coronary artery disease.

The incidence and significance of platelet activation in myocardial ischemia was evaluated by serial measurement of plasma thromboxane B2 (TXB2) and β thromboglobulin (,βTG) in plasma and urine in 98 patients admitted to a coronary care unit with chest pain. All measurements were normal in the 26 patients with noncardiac chest pain. Mean plasma TXB2 and βTG concentration, but not urine βTG, were elevated in the 25 patients with myocardial infarction and the 47 patients with angina. The βTG levels remained normal in 61% of the patients with angina or infarction. The TXB2 levels were significantly higher in patients with recurrent episodes of angina at rest than in those without ischemic episodes after admission. There was a weak correlation between plasma TXB2 and plasma, βTG (r = 0.20, p < 0.01) and between plasma and urine βTG (r = 0.31, p < 0.01). Results indicate that platelets are frequently activated with myocardial ischemia or infarction. However, the measurement of βTG and TXB2 is of limited value in detecting or differentiating myocardial ischemia from infarction and therefore lacks clinical value in the management of patients with ischemic heart disease.

The sex-related differences in aspirin pharmacokinetics in rabbits and man and its relationship to antiplatelet effects

There are a number of reports which suggest that the antithrombotic effect of aspirin is limited to males. It is unclear whether this effect is due to sex-related differences in the effect of aspirin on platelets, the vessel wall, or the pharmacokinetics of aspirin. To test these possibilities we examined the sex-related differences in (1) vessel wall PGI2 release and its inhibition by and recovery from aspirin in rabbits; (2) the effects of aspirin on platelet aggregation, thromboxane B2 and beta-thromboglobulin (BTG) release in man, and (3) the pharmacokinetic characteristics of aspirin, in both rabbits and man. Vascular wall PGI2 measured as 6-keto-PGF1 alpha, was not different in male and females rabbits, and was inhibited to a similar extent by identical concentrations of aspirin. The duration of this inhibitory effect was also the same in males and females. The pattern of inhibition of collagen-induced platelet aggregation, and collagen-induced thromboxane B2 and BTG release by aspirin were not different in either sex. There was, however, a sex-related difference in a number of pharmacokinetic characteristics of aspirin both in rabbits and man. Thus, aspirin was absorbed more rapidly, distributed in larger apparent volume and was hydrolysed more rapidly in females. These observations suggest that the sex-related differences in the antithrombotic effects of aspirin seen in clinical studies are not due to differences in the effects of aspirin on the inhibition of platelet function mediated by the inhibition of cyclo-oxygenase in either the platelet or the vessel wall. An effect of aspirin on platelet function independent of the inhibition of cyclo-oxygenase has been described and it is possible that this effect may be influenced by sex-related differences in the pharmacokinetics of aspirin.

Role of lipoxygenase metabolism in platelet function: effect of aspirin and salicylate.

Aspirin inhibits thromboxane A2 (TxA2) production whereas its salicylate moiety inhibits 12-hydroxy-eicosatetraenoic acid (12-HETE) production in the platelet. The significance of the latter effect on platelet function is unclear. We examined the effects of aspirin and salicylate on (i) platelet/collagen adhesion using 3H-adenine-labelled human platelets and collagen-coated discs, (ii) platelet aggregation induced by thrombin, collagen, ADP and arachidonic acid, and (iii) platelet TxA2 and 12-HETE synthesis as measured by radioimmunoassay and high pressure liquid chromatography respectively. Aspirin (50 uM) decreased platelet aggregation and increased platelet adhesion. The decrease in aggregation was associated with inhibition of TxA2 production and the increase in adhesion was associated with enhanced 12-HETE production. Salicylate had the opposite effects. Platelet aggregation was increased and platelet adhesion decreased. The increased aggregation was associated with enhanced TxA2 production and the decrease in aggregation was associated with inhibition of 12-HETE production. These observations suggest that 12-HETE facilitates platelet adhesion which can be altered by salicylate treatment.

Platelet tests and antiplatelet drugs in coronary artery disease.

This study was designed to clarify discrepancies in the literature concerning platelet survival time and,/-thromboglobulin (I3TG) levels in patients with coronary artery disease (CAD) and the effect of platelet-suppressant drugs on these tests. Platelet survival time and plasma,/TG levels were determined in 48 patients with angiographically documented CAD. The effect of sulfinpyrazone or aspirin/dipyridamole on these measurements was investigated in a double-blind, crossover trial that included a placebo phase. In patients with CAD, the mean plasma, BTG concentration was significantly elevated, but the mean platelet survival time was not significantly different from that in controls. Treatment with sulfinpyrazone or aspirin/dipyridamole did not produce changes in platelet survival time or plasma,3TG concentration that were significantly different from the values during the placebo phase. This study demonstrates that compared with the spontaneous variation in platelet survival time or ITG concentration, there was no measurable effect of sulfinpyrazone or aspirin/dipyridamole on the results of the tests.

Plasma betathromboglobulin and serum fragment E in acute partial stroke

Plasma betathromboglobulin (BTG) and serum fragment E (FgE) were measured serially by radioimmunoassay for 7 d in 67 patients admitted with acute partial stroke. Twelve patients progressed within 7 d of admission. Plasma BTG was not different from normal in patients with acute partial stroke and did not increase significantly with stroke progression. Serum FgE was elevated in patients with acute partial stroke compared with normal values, and was significantly higher in patients who progressed compared with those who remained stable. The results indicate that fibrin formation may be more important in the process of stroke progression than activation of platelets.

ARCTIC: Assessment of haemodynamic Response in patients with Congestive heart failure to Telmisartan: A multicentre dose-ranging study In Canada

BACKGROUNDnThe aim of this study was to examine the acute hemodynamic and neurohormonal effects of the angiotensin II antagonist telmisartan relative to placebo in patients with chronic symptomatic (New York Heart Association class II to III) congestive heart failure and to explore the dose-response relation for these effects.nnnMETHODS AND RESULTSnAfter baseline hemodynamic and neurohormonal measurements made with the use of a pulmonary artery and radial arterial catheter, 82 patients were randomly assigned to placebo or 10, 20, 40, or 80 mg of telmisartan in a double-blind fashion. Hemodynamic and neurohormonal measurements were carried out over 24 hours. Telmisartan caused significant decreases in systemic arterial, pulmonary arterial, and pulmonary capillary wedge pressures with evidence of a dose-response relation for each of these parameters. The drug had no significant effects on heart rate, cardiac index, or systemic vascular resistance. Telmisartan did not have consistent effects on either plasma norepinephrine or plasma atrial natriuretic peptide levels, although it did cause significant increases in both plasma renin activity and angiotensin II levels at higher doses.nnnCONCLUSIONSnThe acute administration of the angiotensin II antagonist telmisartan was associated with significant dose-dependent reductions in systemic arterial blood pressure and pulmonary pressures. Long-term follow-up studies are required to translate changes in hemodynamic parameters into a clinical benefit.

Beta-thromboglobulin radioimmunoassay. A laboratory characterization and evaluation.

Platelets release beta-thromboglobulin from alpha-granules when they are activated by various stimuli. An evaluation and optimization of a radioimmunoassay for beta-thromboglobulin is described. The optimum conditions for the reaction have been characterized, and the use of second antibody and polyethylene glycol allows completion of the assay within 24 hours. Similar BTG concentrations were obtained using a 1-hour non-equilibration assay but the 1-hour assay was inefficient for processing large volumes of specimens and has the potential for cross reactivity. BTG standards were unstable but the shelf-life was prolonged with aprotinin or by storage at -70 degrees C. Plasma BTG concentration in 80 normal individuals was 28 +/- 18 ng/ml. (mean +/- 2 S.D.).

Effect of nafazatrom on platelet function and release: Relationship to symptomatic episodes in patients with peripheral vascular disease

We studied the effect of nafazatrom on plasma prostacyclin (PGI2) levels, platelet function, and thromboxane B2 (TxB2), and 12-hydroxy-eicosatetraenoic acid (12-HETE) production and clinical improvement in 12 patients with peripheral vascular disease (PVD) by means of a double-blind crossover trial of placebo, 800 or 1600 mg of nafazatrom four times daily for 1 week, with intervening 2-week washout periods. Plasma PGI2 levels were measured as 6-keto-PGF1 alpha by radioimmunoassay. Platelet function ex vivo was measured as collagen and adenosine diphosphate (ADP)-induced platelet aggregation, release of 12-HETE and thromboxane A2 (measured as TxB2), and was determined by high-pressure liquid chromatography (HPLC) and radioimmunoassay, respectively. The plasma 6-keto-PGF1 alpha levels were unaffected by nafazatrom treatment (p greater than 0.25). Nafazatrom treatment had no effect on TxB2 production, but significantly altered the production of the platelet 12-HETE (p less than 0.05). There was a significant association between the changes in 12-HETE production and clinical improvement. These results suggest that the mechanism of action of nafazatrom is in part related to the inhibition of platelet function via the lipoxygenase pathway, independent of PGI2 stimulation.

Effect of suloctidil on platelet function in patients with shortened platelet survival time.

The effect of suloctidil (600 mg/day) on platelet survival time (PST) and plasma and urine betathromboglobulin (BTG) was studied in a double-blind, placebo-controlled six-week crossover trial in 13 patients with shortened PST (less than 110 hrs, exponential model). Mean PST after suloctidil (110.6 hrs) was significantly higher than in the placebo phase (94.5 hrs) (p = 0.04). Mean plasma BTG was significantly lower during the suloctidil phase (42.8 ng/ml) compared with the placebo phase (65.8 ng/ml) (p = 0.02), but there was no significant difference in urine BTG. These results suggest that suloctidil provides a platelet protective effect and therefore may be of benefit in reducing the frequency of platelet mediated thromboembolic events.

Evaluation of a commercial kit for the radioimmunoassay of fibrinopeptide A.

Measurement of fibrinopeptide A (FpA) provides a sensitive and specific marker of thrombin generation and is important in the investigation of the mechanisms involved in thrombosis and hemostasis. However, current methods available for determination of FpA by radioimmunoassay (RIA) require rigorous method development. Recently, a commercial kit (Mallinckrodt Corp: M-Kit) for the RIA of FpA has become available which contains all the necessary reagents for the assay. We evaluated this kit and compared it to an assay prepared from a commercial kit (IMCO Corp: I-Kit) which contains only the raw materials. Both assays had similar characteristics and duplicate plasma samples assayed using both methods were not significantly different. Separation of FpA from fibrinogen using bentonite slurry (M-Kit) proved superior to the ethanol precipitation method (I-Kit). The complete kit (M-Kit) will provide the routine hemostasis laboratory with an RIA for FpA which is immediately available.