Effect of Cocaine on Plasma Constituents Involved in Endogenous Thrombosis

With an estimated 25 million Americans having used cocaine, and 5 million Americans using cocaine regularly, research efforts are being directed towards the possible mechanisms by which cocaine may adversely affect the cardiovascular system. [1,14] Cocaine use has been associated with sudden cardiac death and myocardial ischernia. Its effect of myocardial oxygen supply and demand is well-established. Cocaine blocks the presynaptic reuptake of the neurotransmitters, epinephrine, norepinephrine, dopamine, and serotonin, resulting in an excess of these substances at postsynaptic receptor sites. The resultant adrenergic stimulation increases heart rate, blood pressure, and left ventricular contractility and, therefore, myocardial oxygen demand. Cocaine also causes coronary arterial vasoconstriction and, subsequently, decreased myocardial oxygen supply. [2,9] Additional pathophysiological bases for cocaine-induced myocardial infarction may include endothelial dysfunction, accelerated atherosclerosis, and thrombogenesis especially involving plateletrich coronary thrombi in otherwise normal vessels. More than 1/3 of patients who have sustained cocaine-related myocardial infarction and, subsequently, have undergone either angiographic or pathological examination did not have coronary artery stenosis. [10] Few recent studies have addressed the association between cocaine ingestion and endogenous thrombosis. The mechanisms by which cocaine promotes thrombus formation have not been well-defined. One study found that cocaine (in concentrations similar to those found clinically) when added to individual platelets in whole blood from drug-naive donors intermittently induced platelet activation in vitro. [7] In contrast, another study published during the same year suggested that cocaine and its carrier has a direct inhibitory effect on the activation and aggregation of human platelets in vitro. [5] David Hillis and colleagues at the University of Texas South Western Medical Center reported on cocaine's effect on plasma constituents involved in endogenous hemostasis. Their methodology involved procuring blood samples from drug-naive patients undergoing cardiac catheterization before and 15 minutes after the administration of intranasal saline or cocaine, and then measuring the plasma concentrations of fibrinogen, plasminogen, and lipoprotein(a), as well as tissue plasminogen activator activity and plasminogen activator inhibitor (PAI-1) activity. They found that intranasal cocaine administration was associated with an increase only in plasma PAI-1 activity and that this may be "important in recreational users of cocaine who experience vascular thrombosis. " [11] Similarly, Kugelmass et al. established that individual circulating platelets are activated by intravenous cocaine in vivo. Here, the cocaine was administered intravenously to conscious, chronically instrumented dogs and the expression of P-selectin (an antigen found on the external cell membrane of platelets only after stimulation) in whole blood arterial samples was found to be elevated. [8] Notably, Kugelmass found a delayed increase in the detection of activated platelets after treatment with IV cocaine, and postulated that this may have been due to adhesion and subsequent detachment of activated platelets or, alternatively, due to activation by cocaine metabolites rather than the drug itself. Examining the extent of platelet P-selectin expression in humans with cocaine use was the next logical study. Rinder et al. found that long-term cocaine use in some subjects was intermittently associated with high basal levels of P-selectin, or equivalently, circulating activated platelets. Interestingly, this study also looked at the effects of intravenous cocaine and its metabolites (at concentrations that produce the cocaine "high" in long-term users) on platelet Pselectin expression in vitro , and found no increase in platelet activation or aggregation, either directly or in concert with platelet agonists. [13]