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Original Investigation |

Cocaine-Induced Erythrocytosis and Increase in von Willebrand Factor:  Evidence for Drug-Related Blood Doping and Prothrombotic Effects FREE

Arthur J. Siegel, MD; Michelle B. Sholar, BA; Jack H. Mendelson, MD; Scott E. Lukas, PhD; Marc J. Kaufman, PhD; Perry F. Renshaw, MD, PhD; Jane C. McDonald, RP; Kent B. Lewandrowski, MD; Fred S. Apple, PhD; James J. Stec, BS; Izabella Lipinska, PhD; Geoffrey H. Tofler, MD; Paul M. Ridker, MD
[+] Author Affiliations

From the Department of Medicine (Dr Siegel), Alcohol and Drug Abuse Research Center (Ms Sholar and Drs Mendelson and Lukas), Brain Imaging Center (Drs Kaufman and Renshaw), and Pharmacy Department (Ms McDonald), McLean Hospital, Belmont, Mass; Department of Clinical Laboratory, Massachusetts General Hospital, Boston (Dr Lewandrowski); Department of Laboratories, Hennepin County Medical Center and University of Minnesota School of Medicine, Minneapolis (Dr Apple); Institute for the Prevention of Cardiovascular Disease, Beth Israel-Deaconess Medical Center, Boston (Mr Stec and Dr Lipinska); Royal North Shore Hospital, Sydney, Australia (Dr Tofler); Department of Cardiology, Brigham and Women's Hospital, Boston (Dr Ridker); and Harvard Medical School, Boston (Drs Siegel, Mendelson, Lukas, Kaufman, Renshaw, Lewandrowski, and Ridker).


Arch Intern Med. 1999;159(16):1925-1929. doi:10.1001/archinte.159.16.1925.
Text Size: A A A
Published online

Background  Mechanisms that mediate cocaine-induced cardiovascular events following vasoconstriction are incompletely understood.

Objective  To examine the effects of cocaine in moderate doses on hematologic and hemostatic parameters that influence blood viscosity and thrombotic potential.

Methods  Changes in hemoglobin concentration, hematocrit, and red blood cell counts were measured in human subjects who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for long-term cocaine abuse, before and sequentially after moderate intranasal and intravenous doses of cocaine. Hemostatic parameters, including von Willebrand factor, fibrinolytic activity, fibrinogen, plasminogen activator inhibitor antigen, and tissue-type plasminogen activator antigen, were sequentially measured after intravenous cocaine or saline placebo with cardiac troponin subunits T and I.

Results  Hemoglobin level (P=.002), hematocrit (P=.01), and red blood cell counts (P=.04) significantly increased from 4% to 6% over baseline from 10 to 30 minutes after intranasal (n=14) and intravenous (n=7) cocaine administration in doses of 0.9 mg/kg and 0.4 mg/kg, respectively, with no change in white blood cell or platelet counts. There was a significant increase (P=.03) in von Willebrand factor from 30 to 240 minutes, peaking at 40% over baseline following intravenous cocaine administration in a dose of 0.4 mg/kg (n=12), with no change after 0.2 mg/kg (n=3) or placebo (n=6). Other hemostatic factors, creatinine, blood urea nitrogen, and cardiac troponin subunits T and I showed no changes.

Conclusions  Cocaine induced a transient erythrocytosis that may increase blood viscosity while maintaining tissue oxygenation during vasoconstriction. An increase in von Willebrand factor without a compensatory change in endogenous fibrinolysis may trigger platelet adhesion, aggregation, and intravascular thrombosis.

Figures in this Article

AS THE MOST frequently used illicit drug among patients presenting with chest pain to hospital emergency departments,1 cocaine may trigger acute cerebral and myocardial ischemia or infarction.2,3 Beyond vasoconstrictive effects shown in human coronary and cerebral circulations,46 cocaine may also induce a blood doping effect7 and alter plasma constituents that influence thrombogenicity.8 We therefore measured changes in hematologic parameters in human subjects, before and sequentially after the administration of moderate doses of intranasal and intravenous cocaine sufficient to produce significant changes in blood pressure and heart rate. Hemostatic factors, including von Willebrand factor (vWF), fibrinolytic activity, fibrinogen, plasminogen activator inhibitor (PAI-1) antigen, and tissue-type plasminogen activator (TPA) antigen, were similarly measured after intravenous cocaine or saline placebo to assess changes in thrombotic and fibrinolytic potential. Cardiac troponin subunits T (cTnT) and I (cTnI) were sequentially measured to assess silent injury to the myocardium.

Hemoglobin level (P=.002), hematocrit (P=.01), and red blood cell (RBC) counts (P=.04) significantly increased, from 4% to 6% over baseline following intranasal (n=14) and intravenous (n=7) administration of cocaine in doses of 0.9 mg/kg and 0.4 mg/kg, respectively (Figure 1). Significant elevations in hemoglobin and hematocrit occurred 10 minutes after both routes of cocaine administration and in RBC counts coinciding with peak plasma cocaine concentrations of 476.5±57.8 nmol/L (144.4±17.5 ng/mL) and 774.2±56.8 nmol/L (234.6±17.2 ng/mL) after intranasal and intravenous routes, respectively. There were no changes in white blood cell or platelet counts after either route of cocaine administration. Cardiovascular parameters, including heart rate (P=.001) and systolic (P=.01) and diastolic blood pressures (P=.03), increased significantly following both routes of cocaine administration without cardiorespiratory symptoms or electrocardiographic changes of ischemia.

Place holder to copy figure label and caption
Figure 1.

Hematologic effects of cocaine. Changes in hematologic parameters are shown before and sequentially after intranasal (IN) or intravenous (IV) administration of cocaine hydrochloride in doses of 0.9 mg/kg (n=14) and 0.4 mg/kg (n=7), respectively, or saline placebo (n=7). Peaks in plasma cocaine concentrations of 476.5±57.8 nmol/L (144.4±17.5 ng/mL) and 774.2±56.8 nmol/L (234.6±17.2 ng/mL) at 28 and 8 minutes after IN and IV routes, respectively, are shown by arrowheads. Data points represent mean percent changes from baseline±SEM with significant increases in hemoglobin level (P=.002), hematocrit (P=.01), and red blood cell counts (P=.04) after IN and IV administration of cocaine. Single asterisk indicates P<.05 for the 0.4-mg/kg dose of cocaine (IV) vs placebo; double asterisk, P<.05 for the 0.9-mg/kg dose of cocaine (IN) vs placebo.

Graphic Jump Location

There was a significant increase (P=.03) in vWF after intravenous administration of cocaine hydrochloride in a dose of 0.4 mg/kg (n=12), with no change after 0.2 mg/kg (n=3) or saline placebo (n=6) (shown as change in mean percent activity±SEM in Figure 2). The increase in vWF peaked at 40%±18.5% over baseline and lasted from 30 to 240 minutes. Changes were similar among 6 male and 6 female subjects matched for age and body mass index, although baseline values were slightly higher in women. Fibrinolytic activity, fibrinogen, PAI-1 antigen, and TPA antigen showed no significant changes, although a circadian increase in fibrinolytic activity and decrease in PAI-1 were uniformly observed. Levels of cTnT remained within normal limits (<0.10 µg/L) and cTnI was undetectable (<0.35 µg/L) up to 4 hours after cocaine administration, with no changes in creatinine or blood urea nitrogen levels.

Place holder to copy figure label and caption
Figure 2.

Effects of cocaine on hemostatic factors. Significant increase in von Willebrand factor (P = .03) following intravenous (IV) administration of cocaine hydrochloride in a dose of 0.4 mg/kg (n=12) from 30 to 240 minutes, with no change after a 0.2-mg/kg dose or saline placebo (n=6). Plasma cocaine level shown with peak of 774.2±56.8 nmol/L (234.6±17.2 ng/mL) after the 0.4-mg/kg IV cocaine dose.

Graphic Jump Location

Subjects aged 21 to 35 years who met criteria for long-term cocaine abuse, as described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,9 provided informed consent for participation in studies in the Alcohol and Drug Abuse Research Center of McLean Hospital, Belmont, Mass, under protocols approved by the hospital's institutional review board and funded by the National Institute on Drug Abuse. Results of comprehensive medical and laboratory examinations were normal, and urine screens for substances of abuse were negative before participation using urine screening kits (Triage; Biosite Diagnostics, San Diego, Calif).

Double-blind studies were conducted with continuous noninvasive cardiovascular monitoring under direct supervision by a physician, with subjects in a resting semirecumbent position. Cocaine hydrochloride (Mallincrodt, St Louis, Mo) in powder form was used for nasal insufflation or dissolved in sterile water for intravenous injection after processing through a 0.22-µm millipore filter with negative results of testing for pyrogens using a limulus lysate test (Limulus Amebocyte Lysate assay; Whittaker Bioproducts, Walkersville, Md). Subjects received cocaine hydrochloride, either intranasally in a dose of 0.9 mg/kg using a modified snort-stick device,10 or intravenously in doses of 0.2 or 0.4 mg/kg in a 1-mL bolus for 1 minute, or saline placebo.

Blood samples were drawn through an indwelling intravenous catheter (Kowarski-Cormed Thrombo-resistant Blood Withdrawal Butterfly Needle and Tubing Set; DakMed, Inc, Buffalo, NY) in the opposite arm. Hematologic parameters were measured at baseline and at 10, 20, 30, 40, and 60 minutes in tubes with 15% EDTA solution and additionally at 2, 4, 8, 12, 16, 20, 120, 180, and 240 minutes for plasma cocaine levels using tubes containing sodium fluoride. Hemostatic factors were assayed at baseline and at 30, 60, 120, 180, and 240 minutes after intravenous cocaine using tubes containing sodium citrate. Blood samples for hemostatic factors and cocaine were centrifuged immediately, and plasma was frozen at −70°C until analyses were performed.

Hematologic parameters were determined using a blood cell analyzer (Miles/Bayer H2 System; SmithKline Beecham Clinical Laboratories, Waltham, Mass). Fibrinolytic activity was assayed using a fibrin plate assay, fibrinogen levels were determined using the Clauss method, commercially available immunoassay kits (Biopool International Inc, Ventura, Calif) were used to measure PAI-1 and TPA antigens, and vWF was measured using an immunoassay method of Penny et al.11 Plasma cocaine levels were measured in duplicate using a solid-phase extraction method with gas chromatography and mass spectroscopy (Hewlett-Packard 5890 Series II; Hewlett-Packard, Palo Alto, Calif).12 Serum creatinine and blood urea nitrogen were sequentially measured using a commercially available autoanalyzer (Beckman Astra 8; Beckman, Brea, Calif). Cardiac TnI was determined using an immunoassay analyzer (Elecsys 1010 Analyzer; Roche Boehringer Mannheim, Indianapolis, Ind) using Enzymun Troponin T reagents (Roche Boehringer Mannheim). Cardiac TnI was determined using an immunoassay analyzer (Stratus II Analyzer; Dade Behring, Newark, Del). Hematologic parameters, hemostatic factors, and plasma cocaine and cardiovascular measurements were analyzed using repeated-measures analysis of variance. If significant main effects were detected, 1-way analysis of variance was performed to identify the time points that differed significantly.

Although the practice of chewing coca leaf (Erythroxylon coca) spans centuries—as illustrated by the Andean Indians who measure distance across mountains by the number of "cochitas" required for a given journey13—the toxic potential of cocaine has emerged in the modern era, with rapid systemic absorption after smoking, nasal insufflation, and intravenous injection.14,15 Since cocaine has been shown to alter hematologic parameters in animals and humans,7,16,17 we investigated sequential changes in complete blood cell counts in human subjects following moderate intranasal and intravenous doses of cocaine sufficient to produce significant changes in blood pressure and heart rate. The increase in hemoglobin levels, hematocrit, and RBC counts of 4% to 6% over baseline after both routes of cocaine administration was quantitatively similar to infusion of 2 units of packed RBCs,18 use of erythropoietin every other day for 6 weeks in doses of 20 U/kg,19 or chewing coca leaf during exercise.20

Cocaine administration has been shown to induce splenic constriction in humans, with a 20% reduction in volume, as assessed by magnetic resonance imaging, which is temporally concordant with altered hematologic parameters.21 This constrictive effect contributes to a rapid expansion of the circulating RBC pool, in contrast to gradual splenic emptying during exercise,22 and may account for reported complications such as cocaine-induced intracapsular bleeding23 and infarction.24 Serum creatinine and blood urea nitrogen levels remained unchanged for 4 hours in our subjects, suggesting a true erythrocytosis, which is consistent with the finding that chewing of coca leaf attenuated dehydration during exercise.25 Although we cannot exclude a contribution of plasma volume contraction in the absence of direct blood volume measurements, the resultant erythrocytosis is similar to other blood doping effects such as RBC transfusion18 or long-term use of erythropoietin,19 which are risk factors for intravascular thrombosis during exercise.26,27 Changes in whole blood viscosity from cocaine may contribute to exertional collapse and cardiovascular events,28 as reported with sickle cell trait,29,30 although we did not directly measure changes in viscosity.

Because cocaine-induced coronary vasospasm4,5 and a decrease in cerebral blood flow31 may trigger ischemic events as a prelude to thrombosis, we assessed the effects of cocaine on hemostatic parameters related to thrombotic and fibrinolytic potential. There was a significant increase (P=.03) in vWF from 30 to 240 minutes, peaking at 40%±18.5% over baseline following intravenous cocaine hydrochloride in a dose of 0.4 mg/kg (n=12), using the same assay for vWF as shown to predict recurrence of myocardial infarction in coronary heart disease.32

Cocaine-induced coronary vasoconstriction may disrupt unstable atherosclerotic plaques,33 causing release of vWF from damaged vascular endothelium. This process may be mediated by stimulants such as catacolamines, thrombin, vasopressin,34 and cocaine, including production of high-molecular-weight multimers of vWF,35 which were not measured in our study. Cocaine may promote the adhesion and aggregation of platelets that release vWF from α granules36,37 to form bridges between exposed collagen fibrils and glycoprotein Ib/IX receptors on platelets.38 Pharmacokinetic analysis of plasma cocaine and adrenocorticotrophic hormone suggests that the increase in vWF has a direct effect on vascular endothelium39 similar to the release of immunoreactive endothelin.40

Fibrinolytic activity, fibrinogen, TPA antigen, and PAI-1 antigen were unchanged after cocaine administration, indicating a lack of a compensatory rise in endogenous fibrinolysis, which has been shown to accompany exercise-enhanced levels of vWF.4143 Such an imbalance in hemostatic factors, occurring as a consequence of cocaine, has been observed as an independent risk factor for the development of coronary artery disease44 and acute ischemic cardiovascular events.4547

Recent evidence supports the improved detection of ischemic myocardial injury using cTnT and cTnI.4850 The diagnostic utility of cardiospecific troponins for myocardial injury has been demonstrated in patients with unstable coronary artery disease5153 and in cocaine-associated chest pain.54,55 Levels of cTnT remained within normal limits (<0.10 µg/L), and cTnI was undetectable (<0.35 µg/L) up to 4 hours after cocaine in these asymptomatic subjects, providing biochemical evidence against silent myocardial injury. Recent reports that an early rise in vWF predicts adverse outcome in patients with unstable angina and that enoxaprin has protective effects by reducing its release56,57 suggest a valve for low-molecular-weight heparin in cocaine-induced myocardial ischemia in addition to conventional treatments.58

Based on the small sample size of our study, the hypothesis that cocaine promotes thrombogenesis mediated by altered blood viscosity and an increase in vWF should be regarded as preliminary. Areas for further study regarding cocaine include the measurement of changes in whole blood viscosity, in vitro effects on platelets, vascular endothelium, metabolism of vWF multimers,35 and assessment of drug tolerance.59 Clinical studies of enoxaprin in patients with cocaine-associated cerebral or myocardial ischemia may be of value. Cocaine-induced changes in blood viscosity from erythrocytosis, and a selective increase in vWF following vasoconstriction, may contribute to the abrupt and transient increase in risk for acute MI associated with its use.2

Accepted for publication January 9, 1999.

This study was supported in part by grants DA09448, DA04059, DA00064, DA00329, DA00343, DA03994, and DA10757 from the National Institute on Drug Abuse, National Institutes of Health, Bethesda, Md.

We thank Susan Currier for her excellent assistance in preparation of the manuscript.

Reprints: Arthur J. Siegel, MD, Department of Internal Medicine, McLean Hospital, 115 Mill St, Belmont, MA 02478 (e-mail: AJSIEGEL@mclean.harvard.edu).

Hollander  JETodd  KHGreen  G  et al.  Chest pain associated with cocaine: an assessment of prevalence in suburban and urban emergency departments. Ann Emerg Med. 1995;26671- 676
Link to Article
Hollander  JEHoffman  RSBurstein  JLShih  RDThode  HC Cocaine-associated myocardial infarction: mortality and complications. Arch Intern Med. 1995;1551081- 1086
Link to Article
Mittleman  MAMintzer  DMaclure  M  et al.  Triggering of myocardial infarction by cocaine. Circulation. 1999;992737- 2741
Link to Article
Brogan  WCLange  RAGlamann  DBHillis  LD Recurrent coronary vasoconstriction caused by intranasal cocaine: possible role for metabolites. Ann Intern Med. 1992;116556- 561
Link to Article
Moliterno  DJWillard  JELange  RA  et al.  Coronary-artery vasoconstriction induced by cocaine, cigarette smoking, or both. N Engl J Med. 1994;331454- 459
Link to Article
Kaufman  MJLevin  JMRoss  MH  et al.  Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography. JAMA. 1998;278376- 380
Link to Article
Shannon  RPManders  WTShen  YT Role of blood doping in the coronary vasoconstrictor response to cocaine. Circulation. 1995;9296- 105
Link to Article
Moliterno  DJLange  RAGerard  RDWillard  JELackner  CHillis  LD Influence of intranasal cocaine on plasma constituents associated with endogenous thrombosis and thrombolysis. Am J Med. 1994;96492- 496
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;223- 224
Lukas  SESholar  MLundahl  LH  et al.  Sex differences in plasma cocaine levels and subjective effects after acute cocaine administration in human volunteers. Psychopharmacology. 1996;125346- 354
Link to Article
Penny  WWeinstein  MSalzman  EW  et al.  Correlation of circulating von Willebrand factor levels with cardiovascular hemodynamics. Circulation. 1991;831630- 1636
Link to Article
Jacob  PElias-Baker  GAJones  RTBenowitz  NL Determination of benzoylecgonine and cocaine in biologic fluids by automated gas chromatography. J Chromatogr. 1987;417277- 286
Link to Article
Musto  DF Opium, cocaine and marijuana in American history. Scientific American. 1991;July40- 47
Link to Article
Marzuk  PMTardiff  KLeon  AC  et al.  Fatal injuries after cocaine use as a leading cause of death among young adults in New York City. N Engl J Med. 1995;3321753- 1757
Link to Article
Verebey  KGold  MS From coca leaves to crack: the effects of dose and routes of administration in abuse liability. Psychiatr Ann. 1988;18513- 520
Link to Article
Spielvogel  HCaceres  EKoubi  H  et al.  Effects of coca chewing on metabolic and hormonal changes during graded incremental exercise to maximum. J Appl Physiol. 1996;80643- 649
Favier  RCaceres  EKoubi  H  et al.  Effects of coca chewing on hormonal and metabolic responses during prolonged submaximal exercise. J Appl Physiol. 1996;80650- 655
Sawka  MNYoung  AJMuza  SRGonzalez  RRPandolf  KB Erythrocyte reinfusion and maximal aerobic power. JAMA. 1987;2571496- 1498
Link to Article
Casoni  IRicci  GBallarin  E  et al.  Hematological indices of erythropoietin administration in athletes. Int J Sports Med. 1993;14307- 311
Link to Article
Favier  RCaceres  ESempore  B  et al.  Fluid regulatory hormone response to exercise after coca-induced body fluid shifts. J Appl Physiol. 1997;83376- 382
Kaufman  MJSiegel  AJMendelson  JH  et al.  Cocaine administration induces human splenic constriction and altered hematologic parameters. J Appl Physiol. 1998;851877- 1883
Laub  MHvid-Jacobsen  KHovind  PKanstrup  IChristensen  NJNielsen  SL Spleen emptying and venous hematocrit in humans during exercise. J Appl Physiol. 1993;741024- 1026
Homler  HJ Nontraumatic splenic hematoma related to cocaine abuse. West Med J. 1995;163160- 162
Novielli  KDChambers  CV Splenic infarction after cocaine use. Ann Intern Med. 1991;114251- 252
Link to Article
Spielvogel  HRodriguez  ASempore  B  et al.  Body fluid homeostasis and cardiovascular adjustments during submaximal exercise: influence of chewing coca leaves. Eur J Appl Physiol Occup Physiol. 1997;75400- 406
Link to Article
Sawka  MNJoyner  MJMiles  DS  et al.  The use of blood doping as an ergogenic aid: American College of Sports Medicine Position Paper. Med Sci Sports Exerc. 1996;28i- vii
Link to Article
United States Olympic Committee, Drug Control Education, Doping Methods, Peptide and Glycoprotein Hormones, Position statements as of January 18, 1998. Available at: http://www.olympic-usa.org. Accessed June 19, 1998.
Cantwell  JDRose  FD Cocaine and cardiovascular events. Phys Sports Med. 1986;1477- 82
Link to Article
Kark  JAPosey  DMSchumacher  HRRuehle  CJ Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med. 1987;317781- 787
Link to Article
Kerle  KKNishimura  KD Exertional collapse and sudden death associated with sickle cell trait. Am Fam Phys. 1996;54237- 239
Kaufman  MJLevin  JMMaas  LC  et al.  Cocaine decreases relative cerebral blood volume in humans: a dynamic susceptibility contrast magnetic resonance imaging study. Psychopharmacology. 1998;13876- 81
Link to Article
Jansson  JHNilsson  TKJohnson  O Von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J. 1991;66351- 355
Link to Article
Muller  JEAbela  GSNesto  RWTofler  GH Triggers, acute risk factors and vulnerable plaques: the lexicon of a new frontier. J Am Coll Cardiol. 1994;23809- 813
Link to Article
Sporn  LAMarder  VWagner  DD Inducible secretion of large, biological potent vWF multimers. Cell. 1996;46185
Link to Article
Furlan  MRobles  RLammie  B Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood. 1996;874223- 4234
Rinder  HMAult  KAJatlow  PIKosten  TRSmith  BR Platelet alpha-granule release in cocaine users. Circulation. 1994;901162- 1167
Link to Article
Heesch  CMNegus  BHSteiner  M  et al.  Effects of in vivo cocaine administration on human platelet aggregation. Am J Cardiol. 1996;78237- 239
Link to Article
Handin  RI Bleeding and thrombosis. Fauci  ASBraunwald  EIsselbacher  KJ  et al. eds.Harrison's Principles of Internal Medicine. New York, NY McGraw-Hill1998;60339- 345
Sholar  MBMendelson  JHMello  NK  et al.  Concurrent pharmacokinetic analysis of plasma cocaine and adrenocorticotropic hormone in men. J Clin Endocrinol Metab. 1998;83966- 968
Wilbert-Lampen  USeliger  CZilker  TArendt  RM Cocaine increases the endothelial release of immunoreactive endothelin and its concentrations in human plasma and urine. Circulation. 1998;98385- 390
Link to Article
Arai  MYorifuji  MIkematsu  S  et al.  Influences of strenuous exercise (triathlon) on blood coagulation and fibrinolytic system. Thromb Res. 1990;57465- 471
Link to Article
Boman  KHellsten  GBruce  AHallmans  GNilsson  TK Endurance physical activity, diet and fibrinolysis. Atherosclerosis. 1994;10665- 74
Link to Article
Eliasson  MAsplund  KEvrin  P Regular leisure time physical activity predicts high activity of tissue plasminogen activator: The Northern Sweden MONICA Study. Am J Epidemiol. 1996;251182- 1188
Green  DRuth  KJFolsom  ARKiang  L Hemostatic factors in the coronary artery risk development in young adults (CARDIA) study. Arterioscler Thromb. 1994;14686- 693
Link to Article
Thompson  SGKienast  JPyke  SDHaverkate  Fvan de Loo  JC Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med. 1995;332635- 641
Link to Article
Smith  FBLee  AJFowkes  FGRPrice  JFRumley  ALowe  GDO Haemostatic factors as predictors of ischaemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler Thromb. 1997;173321- 3325
Link to Article
Rosito  GBATofler  GH Hemostatic factors as triggers of cardiovascular events. Cardiol Clin. 1997;14239- 250
Link to Article
Baum  HBraun  SGerhardt  W  et al.  Multicenter evaluation of a second-generation assay for cardiac troponin T. Clin Chem. 1997;431977- 1884
Apple  FSFalahati  APaulsen  PR  et al.  Improved detection of minor ischemic myocardial injury with measurement of serum cardiac troponin I. Clin Chem. 1997;432047- 2051
Tucker  JFCollins  RAAnderson  AJ  et al.  Early diagnosis efficiency of cardiac troponin I and troponin T for acute myocardial infarction. Acad Emerg Med. 1997;413- 21
Link to Article
Antman  EMTanasijevic  MJThompson  B Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med. 1996;3351342- 1349
Link to Article
Hamm  CWGoldmann  BUHeeschen  C  et al.  Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med. 1997;3371648- 1653
Link to Article
Polanczyk  CALee  THCook  EF  et al.  Troponin I is predictor of cardiac events in acute chest pain patients. J Am Coll Cardiol. 1998;328- 14
Link to Article
Hollander  JELevitt  MAYoung  GP  et al.  Effect of recent cocaine use on the specificity of cardiac markers for diagnosis of acute myocardial infarction. Am Heart J. 1998;135245- 252
Link to Article
McLaurin  MApple  FSHenry  TD  et al.  Cardiac troponin I and T concentrations in patients with cocaine-associated chest pain. Ann Clin Biochem. 1996;33183- 186
Link to Article
Montalescot  GPhilippe  FAnkri  A  et al.  Early increase of von Willebrand factor predicts adverse outcome in unstable coronary artery disease: beneficial effects of enoxaparin. Circulation. 1998;98294- 299
Link to Article
Antman  EMHandin  R Low-molecular-weight heparins: an intriguing new twist with profound implications. Circulation. 1998;98287- 289
Link to Article
Hollander  J The management of cocaine-associated myocardial ischemia. N Engl J Med. 1995;3331267- 1272
Link to Article
Mendelson  JHSholar  MMello  NTeoh  SKSholar  JW Cocaine tolerance: behavioral, cardiovascular, and neuroendocrine function in men. Neuropsychopharmacology. 1998;18263- 271
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Hematologic effects of cocaine. Changes in hematologic parameters are shown before and sequentially after intranasal (IN) or intravenous (IV) administration of cocaine hydrochloride in doses of 0.9 mg/kg (n=14) and 0.4 mg/kg (n=7), respectively, or saline placebo (n=7). Peaks in plasma cocaine concentrations of 476.5±57.8 nmol/L (144.4±17.5 ng/mL) and 774.2±56.8 nmol/L (234.6±17.2 ng/mL) at 28 and 8 minutes after IN and IV routes, respectively, are shown by arrowheads. Data points represent mean percent changes from baseline±SEM with significant increases in hemoglobin level (P=.002), hematocrit (P=.01), and red blood cell counts (P=.04) after IN and IV administration of cocaine. Single asterisk indicates P<.05 for the 0.4-mg/kg dose of cocaine (IV) vs placebo; double asterisk, P<.05 for the 0.9-mg/kg dose of cocaine (IN) vs placebo.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Effects of cocaine on hemostatic factors. Significant increase in von Willebrand factor (P = .03) following intravenous (IV) administration of cocaine hydrochloride in a dose of 0.4 mg/kg (n=12) from 30 to 240 minutes, with no change after a 0.2-mg/kg dose or saline placebo (n=6). Plasma cocaine level shown with peak of 774.2±56.8 nmol/L (234.6±17.2 ng/mL) after the 0.4-mg/kg IV cocaine dose.

Graphic Jump Location

Tables

References

Hollander  JETodd  KHGreen  G  et al.  Chest pain associated with cocaine: an assessment of prevalence in suburban and urban emergency departments. Ann Emerg Med. 1995;26671- 676
Link to Article
Hollander  JEHoffman  RSBurstein  JLShih  RDThode  HC Cocaine-associated myocardial infarction: mortality and complications. Arch Intern Med. 1995;1551081- 1086
Link to Article
Mittleman  MAMintzer  DMaclure  M  et al.  Triggering of myocardial infarction by cocaine. Circulation. 1999;992737- 2741
Link to Article
Brogan  WCLange  RAGlamann  DBHillis  LD Recurrent coronary vasoconstriction caused by intranasal cocaine: possible role for metabolites. Ann Intern Med. 1992;116556- 561
Link to Article
Moliterno  DJWillard  JELange  RA  et al.  Coronary-artery vasoconstriction induced by cocaine, cigarette smoking, or both. N Engl J Med. 1994;331454- 459
Link to Article
Kaufman  MJLevin  JMRoss  MH  et al.  Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography. JAMA. 1998;278376- 380
Link to Article
Shannon  RPManders  WTShen  YT Role of blood doping in the coronary vasoconstrictor response to cocaine. Circulation. 1995;9296- 105
Link to Article
Moliterno  DJLange  RAGerard  RDWillard  JELackner  CHillis  LD Influence of intranasal cocaine on plasma constituents associated with endogenous thrombosis and thrombolysis. Am J Med. 1994;96492- 496
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;223- 224
Lukas  SESholar  MLundahl  LH  et al.  Sex differences in plasma cocaine levels and subjective effects after acute cocaine administration in human volunteers. Psychopharmacology. 1996;125346- 354
Link to Article
Penny  WWeinstein  MSalzman  EW  et al.  Correlation of circulating von Willebrand factor levels with cardiovascular hemodynamics. Circulation. 1991;831630- 1636
Link to Article
Jacob  PElias-Baker  GAJones  RTBenowitz  NL Determination of benzoylecgonine and cocaine in biologic fluids by automated gas chromatography. J Chromatogr. 1987;417277- 286
Link to Article
Musto  DF Opium, cocaine and marijuana in American history. Scientific American. 1991;July40- 47
Link to Article
Marzuk  PMTardiff  KLeon  AC  et al.  Fatal injuries after cocaine use as a leading cause of death among young adults in New York City. N Engl J Med. 1995;3321753- 1757
Link to Article
Verebey  KGold  MS From coca leaves to crack: the effects of dose and routes of administration in abuse liability. Psychiatr Ann. 1988;18513- 520
Link to Article
Spielvogel  HCaceres  EKoubi  H  et al.  Effects of coca chewing on metabolic and hormonal changes during graded incremental exercise to maximum. J Appl Physiol. 1996;80643- 649
Favier  RCaceres  EKoubi  H  et al.  Effects of coca chewing on hormonal and metabolic responses during prolonged submaximal exercise. J Appl Physiol. 1996;80650- 655
Sawka  MNYoung  AJMuza  SRGonzalez  RRPandolf  KB Erythrocyte reinfusion and maximal aerobic power. JAMA. 1987;2571496- 1498
Link to Article
Casoni  IRicci  GBallarin  E  et al.  Hematological indices of erythropoietin administration in athletes. Int J Sports Med. 1993;14307- 311
Link to Article
Favier  RCaceres  ESempore  B  et al.  Fluid regulatory hormone response to exercise after coca-induced body fluid shifts. J Appl Physiol. 1997;83376- 382
Kaufman  MJSiegel  AJMendelson  JH  et al.  Cocaine administration induces human splenic constriction and altered hematologic parameters. J Appl Physiol. 1998;851877- 1883
Laub  MHvid-Jacobsen  KHovind  PKanstrup  IChristensen  NJNielsen  SL Spleen emptying and venous hematocrit in humans during exercise. J Appl Physiol. 1993;741024- 1026
Homler  HJ Nontraumatic splenic hematoma related to cocaine abuse. West Med J. 1995;163160- 162
Novielli  KDChambers  CV Splenic infarction after cocaine use. Ann Intern Med. 1991;114251- 252
Link to Article
Spielvogel  HRodriguez  ASempore  B  et al.  Body fluid homeostasis and cardiovascular adjustments during submaximal exercise: influence of chewing coca leaves. Eur J Appl Physiol Occup Physiol. 1997;75400- 406
Link to Article
Sawka  MNJoyner  MJMiles  DS  et al.  The use of blood doping as an ergogenic aid: American College of Sports Medicine Position Paper. Med Sci Sports Exerc. 1996;28i- vii
Link to Article
United States Olympic Committee, Drug Control Education, Doping Methods, Peptide and Glycoprotein Hormones, Position statements as of January 18, 1998. Available at: http://www.olympic-usa.org. Accessed June 19, 1998.
Cantwell  JDRose  FD Cocaine and cardiovascular events. Phys Sports Med. 1986;1477- 82
Link to Article
Kark  JAPosey  DMSchumacher  HRRuehle  CJ Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med. 1987;317781- 787
Link to Article
Kerle  KKNishimura  KD Exertional collapse and sudden death associated with sickle cell trait. Am Fam Phys. 1996;54237- 239
Kaufman  MJLevin  JMMaas  LC  et al.  Cocaine decreases relative cerebral blood volume in humans: a dynamic susceptibility contrast magnetic resonance imaging study. Psychopharmacology. 1998;13876- 81
Link to Article
Jansson  JHNilsson  TKJohnson  O Von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J. 1991;66351- 355
Link to Article
Muller  JEAbela  GSNesto  RWTofler  GH Triggers, acute risk factors and vulnerable plaques: the lexicon of a new frontier. J Am Coll Cardiol. 1994;23809- 813
Link to Article
Sporn  LAMarder  VWagner  DD Inducible secretion of large, biological potent vWF multimers. Cell. 1996;46185
Link to Article
Furlan  MRobles  RLammie  B Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood. 1996;874223- 4234
Rinder  HMAult  KAJatlow  PIKosten  TRSmith  BR Platelet alpha-granule release in cocaine users. Circulation. 1994;901162- 1167
Link to Article
Heesch  CMNegus  BHSteiner  M  et al.  Effects of in vivo cocaine administration on human platelet aggregation. Am J Cardiol. 1996;78237- 239
Link to Article
Handin  RI Bleeding and thrombosis. Fauci  ASBraunwald  EIsselbacher  KJ  et al. eds.Harrison's Principles of Internal Medicine. New York, NY McGraw-Hill1998;60339- 345
Sholar  MBMendelson  JHMello  NK  et al.  Concurrent pharmacokinetic analysis of plasma cocaine and adrenocorticotropic hormone in men. J Clin Endocrinol Metab. 1998;83966- 968
Wilbert-Lampen  USeliger  CZilker  TArendt  RM Cocaine increases the endothelial release of immunoreactive endothelin and its concentrations in human plasma and urine. Circulation. 1998;98385- 390
Link to Article
Arai  MYorifuji  MIkematsu  S  et al.  Influences of strenuous exercise (triathlon) on blood coagulation and fibrinolytic system. Thromb Res. 1990;57465- 471
Link to Article
Boman  KHellsten  GBruce  AHallmans  GNilsson  TK Endurance physical activity, diet and fibrinolysis. Atherosclerosis. 1994;10665- 74
Link to Article
Eliasson  MAsplund  KEvrin  P Regular leisure time physical activity predicts high activity of tissue plasminogen activator: The Northern Sweden MONICA Study. Am J Epidemiol. 1996;251182- 1188
Green  DRuth  KJFolsom  ARKiang  L Hemostatic factors in the coronary artery risk development in young adults (CARDIA) study. Arterioscler Thromb. 1994;14686- 693
Link to Article
Thompson  SGKienast  JPyke  SDHaverkate  Fvan de Loo  JC Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med. 1995;332635- 641
Link to Article
Smith  FBLee  AJFowkes  FGRPrice  JFRumley  ALowe  GDO Haemostatic factors as predictors of ischaemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler Thromb. 1997;173321- 3325
Link to Article
Rosito  GBATofler  GH Hemostatic factors as triggers of cardiovascular events. Cardiol Clin. 1997;14239- 250
Link to Article
Baum  HBraun  SGerhardt  W  et al.  Multicenter evaluation of a second-generation assay for cardiac troponin T. Clin Chem. 1997;431977- 1884
Apple  FSFalahati  APaulsen  PR  et al.  Improved detection of minor ischemic myocardial injury with measurement of serum cardiac troponin I. Clin Chem. 1997;432047- 2051
Tucker  JFCollins  RAAnderson  AJ  et al.  Early diagnosis efficiency of cardiac troponin I and troponin T for acute myocardial infarction. Acad Emerg Med. 1997;413- 21
Link to Article
Antman  EMTanasijevic  MJThompson  B Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med. 1996;3351342- 1349
Link to Article
Hamm  CWGoldmann  BUHeeschen  C  et al.  Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med. 1997;3371648- 1653
Link to Article
Polanczyk  CALee  THCook  EF  et al.  Troponin I is predictor of cardiac events in acute chest pain patients. J Am Coll Cardiol. 1998;328- 14
Link to Article
Hollander  JELevitt  MAYoung  GP  et al.  Effect of recent cocaine use on the specificity of cardiac markers for diagnosis of acute myocardial infarction. Am Heart J. 1998;135245- 252
Link to Article
McLaurin  MApple  FSHenry  TD  et al.  Cardiac troponin I and T concentrations in patients with cocaine-associated chest pain. Ann Clin Biochem. 1996;33183- 186
Link to Article
Montalescot  GPhilippe  FAnkri  A  et al.  Early increase of von Willebrand factor predicts adverse outcome in unstable coronary artery disease: beneficial effects of enoxaparin. Circulation. 1998;98294- 299
Link to Article
Antman  EMHandin  R Low-molecular-weight heparins: an intriguing new twist with profound implications. Circulation. 1998;98287- 289
Link to Article
Hollander  J The management of cocaine-associated myocardial ischemia. N Engl J Med. 1995;3331267- 1272
Link to Article
Mendelson  JHSholar  MMello  NTeoh  SKSholar  JW Cocaine tolerance: behavioral, cardiovascular, and neuroendocrine function in men. Neuropsychopharmacology. 1998;18263- 271
Link to Article

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