benzoylecgonine and Thrombosis

To determine whether there is evidence of platelet activation following in vivo cocaine administration in humans, as cocaine abuse is associated with myocardial infarction and stroke, and platelet activation leading to thrombosis is a possible mechanism.. University hospital.. Following a randomised, double blind crossover design, 14 healthy volunteers were studied twice, receiving cocaine (2 mg/kg intranasally) once and placebo once. Flow cytometric analysis of P-selectin expression (an alpha granule membrane protein found on the surface of activated platelets), quantification of the platelet specific proteins platelet factor 4 and beta thromboglobulin, and measurement of platelet containing microaggregate and platelet microparticle (fragment) formation were used to assess platelet activation. Circulating von Willebrand factor antigen (vWF) was measured to evaluate a possible role of endothelial stimulation concurrent with platelet activation.. There was an increase in both platelet factor 4 (mean (SD), 16 (7) to 39 (22) IU/ml, p = 0. 04) and beta thromboglobulin (70 (20) to 98 (26) IU/ml, p < 0.01) at 120 minutes following cocaine administration. Platelet containing microaggregate formation was increased at 40 minutes (from 47 (3.2)% to 54 (2.0)%, p < 0.001) and 80 minutes (55 (2.5)%, p = 0.04). Bleeding time decreased following cocaine from 10 (1) to 9 (1) minutes (p = 0.07). No changes in any of the measured variables were noted following placebo administration.. Cocaine exposure causes platelet activation, alpha granule release, and platelet containing microaggregate formation. These data support the view that cocaine, even at the relatively low doses commonly self administered by occasional abusers, may promote thrombosis and predispose healthy individuals to ischaemic events. Platelet inhibitors should be considered early in any patient with suspected cocaine related ischaemia.

Topics: Adult; beta-Thromboglobulin; Bleeding Time; Blood Platelets; Cocaine; Cross-Over Studies; Double-Blind Method; Female; Flow Cytometry; Humans; Male; P-Selectin; Platelet Activation; Platelet Factor 4; Statistics, Nonparametric; Thrombosis; von Willebrand Factor

Cocaine use is associated with arterial thrombosis, including myocardial infarction and stroke. Cocaine use results in increased plasma von Willebrand factor (VWF), accelerated atherosclerosis, and platelet-rich arterial thrombi, suggesting that cocaine activates the endothelium, promoting platelet-VWF interactions.. Human umbilical vein endothelial cells, brain microvasculature endothelial cells, or coronary artery endothelial cells were treated with cocaine or metabolites benzoylecgonine, cocaethylene, norcocaine, or ecgonine methylester. Supernatant VWF concentration and multimer structure were measured, and platelet-VWF strings formed on the endothelial surface under flow were quantified. Cocaine, benzoylecgonine, and cocaethylene induced endothelial VWF release, with the 2 metabolites being more potent than the parent molecule. Brain microvasculature endothelial cells were more sensitive to cocaine and metabolites than were human umbilical vein endothelial cells or coronary artery endothelial cells. Coronary artery endothelial cells released VWF into the supernatant but did not form VWF-platelet strings. Intracellular cAMP concentration was not increased after treatment with cocaine or its metabolites.. Both cocaine and metabolites benzoylecgonine and cocaethylene induced endothelial VWF secretion, possibly explaining thrombotic risk after cocaine ingestion. VWF secretion is likely to vary between vascular beds, with brain endothelial cells being particularly sensitive. These results suggest that clinical management of cocaine-induced ischemia may benefit from therapies aimed at disrupting the VWF-platelet interaction.

Topics: Brain; Cells, Cultured; Cocaine; Coronary Vessels; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; P-Selectin; Sensitivity and Specificity; Thrombosis; von Willebrand Factor

A temporal relationship has been established between cocaine ingestion and myocardial infarction, and a cocaine-induced increase in platelet aggregation has been suggested as a possible explanation. However, the mechanisms of cocaine associated coronary thrombosis have yet to be completely elucidated. For this reason, we examined the in vitro effect of cocaine and its metabolites on platelet aggregation.. Platelet aggregation was tested by obtaining platelet rich plasma from 42 healthy volunteers and incubating the platelet rich plasma in six concentrations of cocaine (ranging from 1.47 to 2940 nmol) for 10 minutes prior to aggregation with ADP 1 microM. The same procedure was used to test the effect of two cocaine metabolites, benzoylecgonine and ecgonine methyl ester, on platelet aggregation. Abnormal results were confirmed by inducing aggregation with ADP at higher concentrations (2.4 and 10 microM) and with arachidonic acid (624 microM).. At increasing concentrations, cocaine progressively inhibited ADP and arachidonic acid induced platelet aggregation. No effect was seen with benzoyl ecgonine or ecgonine methyl ester as compared to saline.. These data suggest that under certain conditions cocaine may negatively affect hemostasis by decreasing platelet aggregation.

Topics: Adenosine Diphosphate; Adult; Blood Platelets; Cocaine; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Middle Aged; Narcotics; Platelet Aggregation; Thrombosis