- Email: [email protected]
Effects of in vivo cocaine administration on human platelet aggregation
Effects Richard
of In Vivo Cocaine Administration Platelet Aggregation
on Human
Christian M. Heesch, MD, Brian H. Negus, MD, Manfred Steiner, MD, PhD, W. Snyder II, MD, Donald D. M&tire, PhD, Paul A. Grayburn, MD, Joy Ashcraft, Jo& A. Hernhndez, MD, and Eric J. Eichhorn, MD
MT,
tained 40, 80, and 120 minutes after administration of the study drug. Aggregation was tested by a turbidimetric method it is an intriguing hypothesis for the explanation of using a PAP-4 aggregometer (Bio-Data Corporation, thrombotic events in this setting, this has yet to be Hatboro, Pennsylvania). At each time point (basesubstantiated. Available data on the interaction of line, 40, 80 and 120 minutes) aggregation w.as incocaine with platelets provide contradictory and in- duced in 4 specimens using 0.5, I, 2, and 5 pg/mL conclusive answers. Very recent results from our lab- collagen (Helena Laboratories, Beaumont, Texas), in 4 specimens using adenosine diphosphate ( ADP) oratory, evaluating platelet aggregation following cocaine incubation in vitro, suggest that the direct (1, 21 4, and 10 PM), in 3 specimens with epinepheffects of cocaine inhibit rather than increase platelet rine (10, 25, and 50 ,uM) and in 1 specimen with activation.* However, platelet activation is a com- 625 PM arachidonic acid (all from Bio-Data Corplex process involving many in vivo mediators, such poration) . Aggregation testing was maintained for 4 minutes after induction with collagen and ADP, and as catecholamines, thromboxane, platelet-activating factor, and the complement system. These factors for 12 minutes after induction with epinephrine and could possibly play a counterregulatory role result- arachidonic acid. For the 2 low concentrations of ing in enhanced thrombosis rather than platelet in- collagen (0.5 and 1 pg/ml) and ADP ( 1 and 2 /AM), hibition, so that any in vitro investigation of platelet and for arachidonic acid (625 ,uM), the peak aggrefunction is bound to have significant shortcomings. gation of the curves was determined. For the 2 high Thus, this study was designed to test the hypothesis concentrations of collagen (2 and 5 ,ug/mL) and that in vivo cocaine administration increases human ADP (4 and 10 PM) and for all epinephrine con.cenplatelet aggregation. trations, aggregation was measured at the end of the ... testing period. These measurements were chosen beTwelve healthy male volunteers without his- cause with low doses of collagen and ADP as well tory of drug abuse, all nonsmokers aged 23 to 46 as with arachidonic acid, most curves will proceed years, were enrolled in this study. Written consent to a peak value of (primary) aggregation and then was obtained from each volunteer. No medica- regress as a result of disaggregation. Differences in tions were given, including over-the-counter peak aggregation were thought to be more meaningdrugs, for the 2 weeks preceding each study. All ful than differences in disaggregation for the purpose volunteers were studied twice at 6:00 4.~. in the of this study. fasting state and served as their own controls, To determine drug levels, blood samples were with a time interval of at least 2 weeks between procured 40, 80, and 120 minutes after administrastudies. The volunteers remained in a quiet room tion of the study drug, and immediately frozen at and were kept in a recumbent position for the du- -80°C for later analysis. Analysis of cocaine and ration of the study. benzoylecgonine was performed by Medtox LaboAt 30 minutes after the placement of an intrave- ratories (Saint Paul, Minnesota), using capillary gas nous cannula, blood was withdrawn for the mea- chromatography with electron-impact mass specsurement of platelet aggregation at baseline. The trometry . study substance was then administered. Each volTo analyze the data, first a doubly repeated-meaunteer received cocaine, 2 mg/kg (as a 10% cocaine sures analysis of variance (ANOVA) with the 2 reHCl solution) ) or a similar volume of saline solution peated factors of time (baseline, 40, 80, and 120 by intranasal administration in random order, after a minutes) and study drug (placebo or cocaine) was double-blinded protocol. Blood samples were ob- done. A p value 50.004 was considered significant. For the combination study drug x time, a p ~~0.008 was considered significant. The data were also anaFrom the Departments of lnternol Medicine, Divisions of Cardiology lyzed as a multivariate repeated-measuresANOVA, and Hemotoiogy, and Bioslatistics, University of Texcls Southwestern with the factors study drug and time repeated within Medico1 Center, Dallas, Texas; and the Deportment of Internal MedRhode subjects on the multivariate agonist (referring to agicine, Division of Hematology/Oncology, Brown Universi Island. Dr. Eichhorn’s address is: Cardiac Catheterization Lo“i: oratory, gregation with each individual agonist at each of the University of Texas Southwestern and Dallas Veterans Administration concentrations used). This analysis was done to exMedical Centers, 4500 South Lancaster, Dallas, Texas 752 16. Manamine whether overall aggregation results across all uscript received September 7, 1995; revised manuscript received agonists at all concentrations used were changed by and acceptedJanuary 23, 1996.
drug-induced increase in platelet aggregation is now widely accepted as a significant cofactor A in cocaine-induced myocardial infarction. Although
~1996 by Excerpta Medica, All rights reserved.
Inc.
0002-9149/96/$15.00 PII SOOO2.9149(96)00267-6
237
administration of the drug. In addition, the average of the 3 values is given. Values are expressed as Concentrations mean -+ SEE. 40 Min 80 Min 120 Min Average Using a doubly repeated-measures ANOVA analysis, there was no difference in aggregation at any Cocaine 1022 15 142+-20 133 f 13 126~ 14 Benzoylecgonine 204 i 48 414 t 58 605 t 60 397 -t 53 agonist concentration used between the placebo and the cocaine group at baseline. There was a trend toData represents blood levels of cocaine and benzoylecgonine ot 40, 60, and ward decreased aggregation over time regardless of 120 minutes after cocaine administration. Dota ore presented os meon f SEE. I ’ which study drug was given, which reached statistical significance when aggrega1 tion was tested with collagen (1 pg/ml) and ADP (2 PM). In evaluating each agonist used separately, there was a trend toward decreased aggregation after administration of cocaine compared with placebo. This effect reached % Difference in Aggregatlon 0 statistical significance after cor(cocaine - saline) rection for multiple testing, when aggregation was induced with = Collagen (pgml) Baseline _, o ADP (.lO ,uM). Using a multivariate repeated- Arachidonic Acid (NM) measures ANOVA, there was a = Epinephtine (wM) q differential time effect for the -20 0.5 1 2 5 1 2 4 10 625 5 10 25 study drug variable, as repreAgonist Concentration sented by the Study drug x time interaction (p = 0.038 ) . This differential time effect was not dominated by any one particular n = Collagen (W/ml) multivariate outcome, as evidenced by the Agonist X study m = Arachidonic Acid (pM) drug X Time interaction (p = = Epinephrine (KM) 0.73). Thus, although the in% Difference in dividual agonist concentrations Aggregation o contributed to the observed de(cocaine - saline) crease in aggregation to different degrees (as evidenced by the re120 sults of the doubly repeated-meaMinutes -’ O sures ANOVA analysis), this effect was observed with all 4 of the agonists used in our study. 0.5 1 2 5 1 2 4 10 625 5 10 25 The difference in aggregation Agonist Concentration after cocaine and placebo is illustrated in Figure 1. The top panel FIGURE 1. Difference in aggregation (%) of the cocaine day and in aggregation (7%)of th shows the difference in aggregapanel) administration of placebo day before (top pane/) and 120 minutes after (6otim tion (aggregation before cocaine the study drug. All 12 individual agonists and agonist concentrations are listed. Comminus aggregation before plapared with baseline, aggregation decreased after the administration of cocaine. Values are presented as mean 2 SEE. ADP = adenosine, diphosphate. cebo) at baseline for both study days. At this time point, the study cocaine administration, and if such a change was ob- drug had not been administered. Thus, neither of the served, whether it was dominated by any of the mul- 2 sample groups had been exposed to cocaine. There tivariate outcomes. For this analysis, a p value of was no significant difference in aggregation between 0.05 ( Greenhouse-Geisser adjusted) was considered the 2 study days at this point. The bottom panel significant. Analysis of covariance was applied using shows the difference in aggregation (aggregation afthe mean level of cocaine as the covariate for the ter cocaine minus aggregation after placebo) at 120 comparison of the effect of the study drug on minutes after administration of the study drug. The cocaine covariate failed to provide an explachanges in aggregation from baseline. The mean level of cocaine was determined as the average of nation for the decrease in aggregation noted. Thus, the cocaine blood concentrations at 40, 80, and 120 at the dose given in our study, the decrease in agminutes. gregation was dependent on the presence or absence Table I lists the levels of cocaine and cocaine me- of cocaine, but did not correlate with the blood level tabolite measured 40, 80, and 120 minutes after the of the drug. TABLE I Cocaine
238
and Benzoylecgonine (rig/ml)
THE AMERICAl\I JOURNAL OF CARDIOLOGY@
VOL. 78
JULY 15, 1996
. . .
These results contradict the widely accepted hypothesis of an exclusively proaggregatory effect of cocaine. Data also show a decrease in aggregation over time for both the cocaine and placebo groups, a finding that likely reflects physiologic changes in platelet aggregation during the morning hours. Kugelmass et al2 evaluated P-selectin expression and fibrinogen binding as markers of platelet activation after incubation of whole blood samples with cocaine. There was activation of individual platelets of some but not all donors. Rezkalla et a13used a turbidimetric method to show an increase in aggregation after cocaine incubation of plasma samples from 10 volunteers. However, these effects were noted in only half the samples, and with only 1 concentration of 1 of several agonists used. In contrast to these findings, Jennings et al” reported an inhibition of aggregation in response to ADP, collagen, or arachidonic acid, when platelets of 4 donors were challenged in vitro with cocaine. Very recently, we conducted a study in our laboratory, measuring platelet aggregation by turbidimetry after incubation of platelet-rich plasma from 42 healthy volunteers with different concentrations of cocaine and cocaine metabolites.’ There was clear evidence of a dosedependent decrease in platelet aggregation with cocaine. Rinder et al5 administered double-blinded infusions of cocaine or placebo to 4 chronic cocaine abusers, measuring P-selectin expression as a marker of platelet activation. Both placebo and cocaine infusions increased the number of activated circulating platelets, without a difference between the study drugs used. Kugelmass et al6 demonstrated increased P-selectin expression after intravenous cocaine administration to dogs. The temporal association of myocardial infarction with cocaine abuse is well described. However, increased thrombogenesis after cocaine ingestion remains unproven. Other proposed mechanisms of ischemia, such as coronary vasoconstriction, microvascular injury, hemodynamic changes, or catecholamine excess, may be of greater importance than thrombosis in some myocardial injuries after cocaine use. Moreover, cocaine may interact with thrombosis and thrombolysis in more ways than one. The medical literature abounds with case series of hemorrhagic complications temporally related to cocaine use. Intracerebral hemorrhage, with and without underlying vascular pathology, may be more frequent than ischemic strokes after cocaine abuse.7-8Hemoptysis has been described after both freebasing9.” and intranasal ‘I self-administration of cocaine, and pulmonary hemorrhage is found in most of cocaine-related fatalities.12 Diffuse gastrointestinal bleedsevere bleeding after tooth extraction, I5 and ing, I3314 even intratumoral hemorrhage l6 have been linked to cocaine ingestion. A randomized double-blinded trial by Anderton et al, I7 investigating the relative efficacy and adverse effects of 3 different doses of topical cocaine used during nose surgery, found that the mean blood loss for those patients given the low-
est dose of cocaine was approximately half that of the other 2 groups. This effect is also observed with other local anesthetics, in which it has been shown to be associated with a drug-induced decrease in platelet aggregation.lS In summary, by using a turbidimetric method there is no evidence of a direct proaggregatory effect of cocaine or its metabolites on platelet function in healthy volunteers without prior exposure t’o this drug, and it may even have antiaggregatory effects in this group. Both thrombotic and hemorrlhagic events have been associated with cocaine, and its influence on thrombosis and thrombolysis is likely to be complex and multifaceted. Whereas cocaine use may promote hemorrhagic events in some persons, certain persons or subgroups of patients may be prone to develop thrombotic complications. Further research, using techniques other than the turbidimetric method, will be necessary to confirm our results and to define such possible subgroups in whom cocaine use may influence aggregation and thrombosis in a different way than that observed in our study with healthy volunteers. Acknowledgment: We thank L. David Hillis, MD, Richard A. Lange, MD, and Henry M. Rinder, MD, for their helpful suggestions and comments. We also thank Paul Orsulak, PhD, and Harry McCoy, PhD, for the analysis of cocaine and benzoylecgonine 1evel.s.
1. Heesch CM, Steiner M, Hem~indez IA, ilshcraft J. Eichhom EJ. Effects of cocaine and cocaine metabolites on human platelet aggregation in vitro. .I To.ricol Clin Tmicol; in press. 2. Kugelmass AD. Oda A. Monahan K, Cabral C, Ware JA. .4ctivation of human platelets by cocaine. Circulation 1993$3:876-X83. 3. Rerkalla SH. Mazza JJ. Kloner RA, Tillema V, Champ SH. Effects of cocaine on human platelets in healthy subjects. .&I J Cnrdiol 1993;72:243-216. 4. Jennings LK, White MM. Sauer CM. Mauer 4M, Robertson JT. Cocaineinduced platelet defects. Srmke 1993;24:1352- 1359. 5. Rinder HM. Ault K.4, Jarlow PI, Kosten TR, Smith BR. Platelet a-gr.%mle release in cocaine users. Cirnularion 1994;90: 1162- 1167. 6. Kugelmass AD, Shannon RP, Yea EL. Ware JA. Intravenous cocaine induces platelet activation in the conscious dog. Circrdntion 1995;91:1336- 1330. 7. Van Viet H, Chevalier P, Sereni C, Bomet P. Baotier P. Degos CF, Rulliere R. Accidents neurologiques lies B l’usage de la cocaine. Plrssr ~w&f 1990;19:10~5-1049. 8. Rinkel GJE. van Cijn J. Wijdicks EFM. Subarachnoid hemorrhage without detectable aneurysm. Swokr 1993;21:1403-1409. 9. Murray RI, Albin RJ, Mergner W. Coiner GJ. Diffuse alveolar hemorrhage temporally related to cocaine smoking. Char 1988;93:327-429. 10. Godwin JE. Haley RA, Miller KS, Heffner JE. Cocaine. pulmonary hemorrhage, and hemoptysis (letrerj. Ann hztern hfed lY89;110:843. 11. Walek JW. hbsson RG. Siddiqui M. Pulmonmy hemorrhage in a cocaine abuser (letter j. Cluzt 1989:96:22X 12. Bailey ME, Fraire AE, Greenberg SD, Barnard J, Cagle PT. Pulmolnary histopathology in cocaine abusers. H~I Path01 1994:25:203-207. 13. Riggs D. Weiblev RE. Acme hemorrhagic diarrhea and cardiovascular collapse in n young child owing to environmentally acquired cocaine. Pediatr Enwg Cm 1991;7:151-155. 14. Carlan SJ. Stromquist C, Angel JL, Harris M, O’Brien WF. Cocaine and indomethacin: fetal anuria. neonatal edema. and gastrointestinal bleeding. ObSW G~~ecol 1991;78:501-503. 15. Johnson CD, Brown RS.
How cocaine abuse affects post-extraction bleeding. JAnz Drnt Assoc 1993;121:60-62. 16. Yapor WY. Gutierrer FA. Cocaine-induced intratumoral hemorrhage: case report and review, of the literature. Nerrrosurger) 1992;30:288-291. 17. Anderton JM, Nassar WY. Topical cocaine and general anaesthesia: an imestigation of the efficxy and side effects of cocaine on the nnsal mucosae. Anaesthesia 1975;30:809-817. 18. Fe&ndez PJ. Gxcia M. Iravedm 54. Caballero J, Gonz&z de Z&ate I, Moreno Rodriguez L. Efecto de la bupivacaina epidural sobre la agregaci6n plaquetaria J’ el tiempo de hemom@. Rev Espmiola A?wsr Rem 1988:35:15-18.
BRIEF REPORTS 239
of In Vivo Cocaine Administration Platelet Aggregation
on Human
Christian M. Heesch, MD, Brian H. Negus, MD, Manfred Steiner, MD, PhD, W. Snyder II, MD, Donald D. M&tire, PhD, Paul A. Grayburn, MD, Joy Ashcraft, Jo& A. Hernhndez, MD, and Eric J. Eichhorn, MD
MT,
tained 40, 80, and 120 minutes after administration of the study drug. Aggregation was tested by a turbidimetric method it is an intriguing hypothesis for the explanation of using a PAP-4 aggregometer (Bio-Data Corporation, thrombotic events in this setting, this has yet to be Hatboro, Pennsylvania). At each time point (basesubstantiated. Available data on the interaction of line, 40, 80 and 120 minutes) aggregation w.as incocaine with platelets provide contradictory and in- duced in 4 specimens using 0.5, I, 2, and 5 pg/mL conclusive answers. Very recent results from our lab- collagen (Helena Laboratories, Beaumont, Texas), in 4 specimens using adenosine diphosphate ( ADP) oratory, evaluating platelet aggregation following cocaine incubation in vitro, suggest that the direct (1, 21 4, and 10 PM), in 3 specimens with epinepheffects of cocaine inhibit rather than increase platelet rine (10, 25, and 50 ,uM) and in 1 specimen with activation.* However, platelet activation is a com- 625 PM arachidonic acid (all from Bio-Data Corplex process involving many in vivo mediators, such poration) . Aggregation testing was maintained for 4 minutes after induction with collagen and ADP, and as catecholamines, thromboxane, platelet-activating factor, and the complement system. These factors for 12 minutes after induction with epinephrine and could possibly play a counterregulatory role result- arachidonic acid. For the 2 low concentrations of ing in enhanced thrombosis rather than platelet in- collagen (0.5 and 1 pg/ml) and ADP ( 1 and 2 /AM), hibition, so that any in vitro investigation of platelet and for arachidonic acid (625 ,uM), the peak aggrefunction is bound to have significant shortcomings. gation of the curves was determined. For the 2 high Thus, this study was designed to test the hypothesis concentrations of collagen (2 and 5 ,ug/mL) and that in vivo cocaine administration increases human ADP (4 and 10 PM) and for all epinephrine con.cenplatelet aggregation. trations, aggregation was measured at the end of the ... testing period. These measurements were chosen beTwelve healthy male volunteers without his- cause with low doses of collagen and ADP as well tory of drug abuse, all nonsmokers aged 23 to 46 as with arachidonic acid, most curves will proceed years, were enrolled in this study. Written consent to a peak value of (primary) aggregation and then was obtained from each volunteer. No medica- regress as a result of disaggregation. Differences in tions were given, including over-the-counter peak aggregation were thought to be more meaningdrugs, for the 2 weeks preceding each study. All ful than differences in disaggregation for the purpose volunteers were studied twice at 6:00 4.~. in the of this study. fasting state and served as their own controls, To determine drug levels, blood samples were with a time interval of at least 2 weeks between procured 40, 80, and 120 minutes after administrastudies. The volunteers remained in a quiet room tion of the study drug, and immediately frozen at and were kept in a recumbent position for the du- -80°C for later analysis. Analysis of cocaine and ration of the study. benzoylecgonine was performed by Medtox LaboAt 30 minutes after the placement of an intrave- ratories (Saint Paul, Minnesota), using capillary gas nous cannula, blood was withdrawn for the mea- chromatography with electron-impact mass specsurement of platelet aggregation at baseline. The trometry . study substance was then administered. Each volTo analyze the data, first a doubly repeated-meaunteer received cocaine, 2 mg/kg (as a 10% cocaine sures analysis of variance (ANOVA) with the 2 reHCl solution) ) or a similar volume of saline solution peated factors of time (baseline, 40, 80, and 120 by intranasal administration in random order, after a minutes) and study drug (placebo or cocaine) was double-blinded protocol. Blood samples were ob- done. A p value 50.004 was considered significant. For the combination study drug x time, a p ~~0.008 was considered significant. The data were also anaFrom the Departments of lnternol Medicine, Divisions of Cardiology lyzed as a multivariate repeated-measuresANOVA, and Hemotoiogy, and Bioslatistics, University of Texcls Southwestern with the factors study drug and time repeated within Medico1 Center, Dallas, Texas; and the Deportment of Internal MedRhode subjects on the multivariate agonist (referring to agicine, Division of Hematology/Oncology, Brown Universi Island. Dr. Eichhorn’s address is: Cardiac Catheterization Lo“i: oratory, gregation with each individual agonist at each of the University of Texas Southwestern and Dallas Veterans Administration concentrations used). This analysis was done to exMedical Centers, 4500 South Lancaster, Dallas, Texas 752 16. Manamine whether overall aggregation results across all uscript received September 7, 1995; revised manuscript received agonists at all concentrations used were changed by and acceptedJanuary 23, 1996.
drug-induced increase in platelet aggregation is now widely accepted as a significant cofactor A in cocaine-induced myocardial infarction. Although
~1996 by Excerpta Medica, All rights reserved.
Inc.
0002-9149/96/$15.00 PII SOOO2.9149(96)00267-6
237
administration of the drug. In addition, the average of the 3 values is given. Values are expressed as Concentrations mean -+ SEE. 40 Min 80 Min 120 Min Average Using a doubly repeated-measures ANOVA analysis, there was no difference in aggregation at any Cocaine 1022 15 142+-20 133 f 13 126~ 14 Benzoylecgonine 204 i 48 414 t 58 605 t 60 397 -t 53 agonist concentration used between the placebo and the cocaine group at baseline. There was a trend toData represents blood levels of cocaine and benzoylecgonine ot 40, 60, and ward decreased aggregation over time regardless of 120 minutes after cocaine administration. Dota ore presented os meon f SEE. I ’ which study drug was given, which reached statistical significance when aggrega1 tion was tested with collagen (1 pg/ml) and ADP (2 PM). In evaluating each agonist used separately, there was a trend toward decreased aggregation after administration of cocaine compared with placebo. This effect reached % Difference in Aggregatlon 0 statistical significance after cor(cocaine - saline) rection for multiple testing, when aggregation was induced with = Collagen (pgml) Baseline _, o ADP (.lO ,uM). Using a multivariate repeated- Arachidonic Acid (NM) measures ANOVA, there was a = Epinephtine (wM) q differential time effect for the -20 0.5 1 2 5 1 2 4 10 625 5 10 25 study drug variable, as repreAgonist Concentration sented by the Study drug x time interaction (p = 0.038 ) . This differential time effect was not dominated by any one particular n = Collagen (W/ml) multivariate outcome, as evidenced by the Agonist X study m = Arachidonic Acid (pM) drug X Time interaction (p = = Epinephrine (KM) 0.73). Thus, although the in% Difference in dividual agonist concentrations Aggregation o contributed to the observed de(cocaine - saline) crease in aggregation to different degrees (as evidenced by the re120 sults of the doubly repeated-meaMinutes -’ O sures ANOVA analysis), this effect was observed with all 4 of the agonists used in our study. 0.5 1 2 5 1 2 4 10 625 5 10 25 The difference in aggregation Agonist Concentration after cocaine and placebo is illustrated in Figure 1. The top panel FIGURE 1. Difference in aggregation (%) of the cocaine day and in aggregation (7%)of th shows the difference in aggregapanel) administration of placebo day before (top pane/) and 120 minutes after (6otim tion (aggregation before cocaine the study drug. All 12 individual agonists and agonist concentrations are listed. Comminus aggregation before plapared with baseline, aggregation decreased after the administration of cocaine. Values are presented as mean 2 SEE. ADP = adenosine, diphosphate. cebo) at baseline for both study days. At this time point, the study cocaine administration, and if such a change was ob- drug had not been administered. Thus, neither of the served, whether it was dominated by any of the mul- 2 sample groups had been exposed to cocaine. There tivariate outcomes. For this analysis, a p value of was no significant difference in aggregation between 0.05 ( Greenhouse-Geisser adjusted) was considered the 2 study days at this point. The bottom panel significant. Analysis of covariance was applied using shows the difference in aggregation (aggregation afthe mean level of cocaine as the covariate for the ter cocaine minus aggregation after placebo) at 120 comparison of the effect of the study drug on minutes after administration of the study drug. The cocaine covariate failed to provide an explachanges in aggregation from baseline. The mean level of cocaine was determined as the average of nation for the decrease in aggregation noted. Thus, the cocaine blood concentrations at 40, 80, and 120 at the dose given in our study, the decrease in agminutes. gregation was dependent on the presence or absence Table I lists the levels of cocaine and cocaine me- of cocaine, but did not correlate with the blood level tabolite measured 40, 80, and 120 minutes after the of the drug. TABLE I Cocaine
238
and Benzoylecgonine (rig/ml)
THE AMERICAl\I JOURNAL OF CARDIOLOGY@
VOL. 78
JULY 15, 1996
. . .
These results contradict the widely accepted hypothesis of an exclusively proaggregatory effect of cocaine. Data also show a decrease in aggregation over time for both the cocaine and placebo groups, a finding that likely reflects physiologic changes in platelet aggregation during the morning hours. Kugelmass et al2 evaluated P-selectin expression and fibrinogen binding as markers of platelet activation after incubation of whole blood samples with cocaine. There was activation of individual platelets of some but not all donors. Rezkalla et a13used a turbidimetric method to show an increase in aggregation after cocaine incubation of plasma samples from 10 volunteers. However, these effects were noted in only half the samples, and with only 1 concentration of 1 of several agonists used. In contrast to these findings, Jennings et al” reported an inhibition of aggregation in response to ADP, collagen, or arachidonic acid, when platelets of 4 donors were challenged in vitro with cocaine. Very recently, we conducted a study in our laboratory, measuring platelet aggregation by turbidimetry after incubation of platelet-rich plasma from 42 healthy volunteers with different concentrations of cocaine and cocaine metabolites.’ There was clear evidence of a dosedependent decrease in platelet aggregation with cocaine. Rinder et al5 administered double-blinded infusions of cocaine or placebo to 4 chronic cocaine abusers, measuring P-selectin expression as a marker of platelet activation. Both placebo and cocaine infusions increased the number of activated circulating platelets, without a difference between the study drugs used. Kugelmass et al6 demonstrated increased P-selectin expression after intravenous cocaine administration to dogs. The temporal association of myocardial infarction with cocaine abuse is well described. However, increased thrombogenesis after cocaine ingestion remains unproven. Other proposed mechanisms of ischemia, such as coronary vasoconstriction, microvascular injury, hemodynamic changes, or catecholamine excess, may be of greater importance than thrombosis in some myocardial injuries after cocaine use. Moreover, cocaine may interact with thrombosis and thrombolysis in more ways than one. The medical literature abounds with case series of hemorrhagic complications temporally related to cocaine use. Intracerebral hemorrhage, with and without underlying vascular pathology, may be more frequent than ischemic strokes after cocaine abuse.7-8Hemoptysis has been described after both freebasing9.” and intranasal ‘I self-administration of cocaine, and pulmonary hemorrhage is found in most of cocaine-related fatalities.12 Diffuse gastrointestinal bleedsevere bleeding after tooth extraction, I5 and ing, I3314 even intratumoral hemorrhage l6 have been linked to cocaine ingestion. A randomized double-blinded trial by Anderton et al, I7 investigating the relative efficacy and adverse effects of 3 different doses of topical cocaine used during nose surgery, found that the mean blood loss for those patients given the low-
est dose of cocaine was approximately half that of the other 2 groups. This effect is also observed with other local anesthetics, in which it has been shown to be associated with a drug-induced decrease in platelet aggregation.lS In summary, by using a turbidimetric method there is no evidence of a direct proaggregatory effect of cocaine or its metabolites on platelet function in healthy volunteers without prior exposure t’o this drug, and it may even have antiaggregatory effects in this group. Both thrombotic and hemorrlhagic events have been associated with cocaine, and its influence on thrombosis and thrombolysis is likely to be complex and multifaceted. Whereas cocaine use may promote hemorrhagic events in some persons, certain persons or subgroups of patients may be prone to develop thrombotic complications. Further research, using techniques other than the turbidimetric method, will be necessary to confirm our results and to define such possible subgroups in whom cocaine use may influence aggregation and thrombosis in a different way than that observed in our study with healthy volunteers. Acknowledgment: We thank L. David Hillis, MD, Richard A. Lange, MD, and Henry M. Rinder, MD, for their helpful suggestions and comments. We also thank Paul Orsulak, PhD, and Harry McCoy, PhD, for the analysis of cocaine and benzoylecgonine 1evel.s.
1. Heesch CM, Steiner M, Hem~indez IA, ilshcraft J. Eichhom EJ. Effects of cocaine and cocaine metabolites on human platelet aggregation in vitro. .I To.ricol Clin Tmicol; in press. 2. Kugelmass AD. Oda A. Monahan K, Cabral C, Ware JA. .4ctivation of human platelets by cocaine. Circulation 1993$3:876-X83. 3. Rerkalla SH. Mazza JJ. Kloner RA, Tillema V, Champ SH. Effects of cocaine on human platelets in healthy subjects. .&I J Cnrdiol 1993;72:243-216. 4. Jennings LK, White MM. Sauer CM. Mauer 4M, Robertson JT. Cocaineinduced platelet defects. Srmke 1993;24:1352- 1359. 5. Rinder HM. Ault K.4, Jarlow PI, Kosten TR, Smith BR. Platelet a-gr.%mle release in cocaine users. Cirnularion 1994;90: 1162- 1167. 6. Kugelmass AD, Shannon RP, Yea EL. Ware JA. Intravenous cocaine induces platelet activation in the conscious dog. Circrdntion 1995;91:1336- 1330. 7. Van Viet H, Chevalier P, Sereni C, Bomet P. Baotier P. Degos CF, Rulliere R. Accidents neurologiques lies B l’usage de la cocaine. Plrssr ~w&f 1990;19:10~5-1049. 8. Rinkel GJE. van Cijn J. Wijdicks EFM. Subarachnoid hemorrhage without detectable aneurysm. Swokr 1993;21:1403-1409. 9. Murray RI, Albin RJ, Mergner W. Coiner GJ. Diffuse alveolar hemorrhage temporally related to cocaine smoking. Char 1988;93:327-429. 10. Godwin JE. Haley RA, Miller KS, Heffner JE. Cocaine. pulmonary hemorrhage, and hemoptysis (letrerj. Ann hztern hfed lY89;110:843. 11. Walek JW. hbsson RG. Siddiqui M. Pulmonmy hemorrhage in a cocaine abuser (letter j. Cluzt 1989:96:22X 12. Bailey ME, Fraire AE, Greenberg SD, Barnard J, Cagle PT. Pulmolnary histopathology in cocaine abusers. H~I Path01 1994:25:203-207. 13. Riggs D. Weiblev RE. Acme hemorrhagic diarrhea and cardiovascular collapse in n young child owing to environmentally acquired cocaine. Pediatr Enwg Cm 1991;7:151-155. 14. Carlan SJ. Stromquist C, Angel JL, Harris M, O’Brien WF. Cocaine and indomethacin: fetal anuria. neonatal edema. and gastrointestinal bleeding. ObSW G~~ecol 1991;78:501-503. 15. Johnson CD, Brown RS.
How cocaine abuse affects post-extraction bleeding. JAnz Drnt Assoc 1993;121:60-62. 16. Yapor WY. Gutierrer FA. Cocaine-induced intratumoral hemorrhage: case report and review, of the literature. Nerrrosurger) 1992;30:288-291. 17. Anderton JM, Nassar WY. Topical cocaine and general anaesthesia: an imestigation of the efficxy and side effects of cocaine on the nnsal mucosae. Anaesthesia 1975;30:809-817. 18. Fe&ndez PJ. Gxcia M. Iravedm 54. Caballero J, Gonz&z de Z&ate I, Moreno Rodriguez L. Efecto de la bupivacaina epidural sobre la agregaci6n plaquetaria J’ el tiempo de hemom@. Rev Espmiola A?wsr Rem 1988:35:15-18.
BRIEF REPORTS 239