Correspondence
BOSTONMEDICAL
URGICAL
JOURNA
Prevention of Type 2 Diabetes Mellitus by Changes in Lifestyle
To the Editor: Tuomilehto et al. (May 3 issue)1 reported that counseling subjects at high risk for type 2 diabetes mel- litus to reduce weight and the intake of fat and to increase physical exercise and the intake of fiber reduced the risk of diabetes by 58 percent, as compared with the risk in a usual- care group. We would like to know whether the weight loss in the intervention group was maintained throughout the follow-up period (i.e., at six years of follow-up). Most sub- jects in weight-loss programs have been unable to sustain weight loss, and in several studies more than 90 percent of subjects who lost weight eventually returned to their origi- nal weight.2,3
We also wonder what kind of antihypertensive drugs were prescribed in the intervention and control groups. In par- ticular, we would like to know how many of the patients in the two groups received an angiotensin-converting-enzyme (ACE) inhibitor, which according to the Heart Outcomes Prevention Evaluation (HOPE) trial is associated with a de- crease in the incidence of diabetes mellitus.4
J. GEORGE FODOR, M.D., PH.D. KRISTI B. ADAMO, M.SC. University of Ottawa Heart Institute Prevention and Rehabilitation Centre Ottawa, ON K1Y 4W7, Canada gfodor@ottawaheart.ca
1. Tuomilehto J, Lindström J, Eriksson J, et al. Prevention of type 2 dia- betes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50.
2. Friedman JM. Obesity in the new millennium. Nature 2000;404:632-4.
3. Wadden TA. Treatment of obesity by moderate and severe caloric re- striction: results of clinical research trials. Ann Intern Med 1993;119:688- 93.
4. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-53. [Erratum, N Engl J Med 2000;342:748, 1376.]
To the Editor: More than two thirds of the subjects in the study by Tuomilehto et al. were women, and therefore the role of gestational diabetes, a major risk factor for the subsequent development of type 2 diabetes, should not be overlooked.1 How many women in the study had a history of gestational diabetes, and were these women equally dis- tributed between the intervention and usual-care groups?
OREN FRUCHTER, M.D. 29 Greenbaum St. 34987 Haifa, Israel oren_md@inter.net.il
1. Kjos SL, Buchanan TA. Gestational diabetes mellitus. N Engl J Med 1999;341:1749-56.
The authors reply:
To the Editor: We agree that the maintenance of weight loss is difficult. The subjects in the intervention group did regain some weight in the later years of our study, but they remained leaner than the control group. Thus, the difference in weight loss between the intervention and control groups was 2.7 kg after two years and 2.1 kg after five years of fol- low-up.
Post hoc analyses of trials with the ACE inhibitor ramipril1 and the 3-hydroxy-3-methylglutaryl coenzyme A (HMG- CoA) reductase inhibitor pravastatin have suggested that treatment with these drugs reduces the risk of diabetes mel- litus.2 In our study, the proportion of subjects receiving any antihypertensive drug at base line was 30 percent in the in- tervention group and 31 percent in the control group. The proportion of subjects receiving cholesterol-lowering drugs at base line was also similar in the two groups. The number of subjects in both groups who were receiving both types of drug increased during the study; 13 percent of the sub-
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jects received an ACE inhibitor and 15 percent received an HMG-COA reductase inhibitor in the intervention group, as compared with 14 percent and 15 percent, respectively, in the control group. Thus, the outcome in our trial was not confounded by differences in treatment with antihyperten- sive or cholesterol-lowering drugs.
The prevalence of gestational diabetes was similar in the two groups. A total of 37 women (13 percent), 20 in the intervention group and 17 in the control group, reported a history of gestational diabetes.
JAAKKO TUOMILEHTO, M.D., PH.D. JAANA LINDSTRÖM, M.S. TIMO T. VALLE, M.D. National Public Health Institute 00300 Helsinki, Finland jaakko.tuomilehto@ktl.fi
1. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-53. [Erratum, N Engl J Med 2000;342:748, 1376.]
2. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001;103:357-62.
Thrombophilia
To the Editor: Seligsohn and Lubetsky (April 19 issue)1 justify not routinely testing white women for inherited thrombophilia before prescribing oral contraceptives, since “it would deny contraceptives to about 5 to 10 percent of white women … while preventing very few fatal throm- boembolisms.” This is not acceptable. No woman should die unnecessarily from complications of contraceptive use, nor should any woman be subjected to a possible stroke, pulmonary embolism, or deep venous thrombosis when the occurrence of these complications could have possibly been prevented by a simple and accurate blood test. Other accept- able forms of birth control are available. Not offering wom- en an informed choice and thus perhaps significantly increas-
ing their risk of a preventable complication associated with substantial morbidity should not be the standard of care.
NINA CAPLIN, M.D. Mount Sinai School of Medicine Elmhurst, NY 11373 ninacaplin@aol.com
LAURIE EDELMAN, M.D. Mount Sinai School of Medicine New York, NY 10029
1. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001;344:1222-31.
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To the Editor: Seligsohn and Lubetsky propose an algo- rithm for identifying a congenital state of hypercoagulabil- ity in patients with thromboembolic disease. When my col- leagues and I used this algorithm in 87 patients with venous thrombosis and thrombophilia, 12 cases were not detected, in 4 because the process was limited to superficial veins and in 8 because the patients had distal deep-vein thrombosis after surgery or immobilization (Table 1). Although subcla- vian thrombosis is not mentioned in the article, we found three patients with this condition, in all three cases second- ary to venous-catheter implantation or effort. A history of superficial thrombophlebitis is not rare in patients with thrombophilia. Thus, we recommend extending testing for thrombophilia to all patients with secondary distal deep- vein thrombosis, secondary subclavian thrombosis, or ex- tended superficial-vein thrombosis.1
FRANCESC J. CASALS SOLE, M.D. Hospital Clinic 08036 Barcelona, Spain casals@compuserve.com
1. Casals FJ. Trombosis venosa. Barcelona, Spain: Masson, 1999:75-82.
| CONDITION | HYPERHOMO- CYSTEINEMIA | RESISTANCE TO ACTIVATED PROTEIN C | DEFICIENCY OF PROTEIN S | DEFICIENCY OF PROTEIN C OR ANTITHROMBIN | Two ASSOCIATED RISK FACTORS | TOTAL |
|---|---|---|---|---|---|---|
| Proximal deep-vein thrombosis, idiopathic distal deep-vein thrombosis, or pulmonary embolism | 20 | 23 | 9 | 6 | 14 | 72 |
| Subclavian-vein thrombosis | 2 | 0 | 0 | 0 | 1 | 3 |
| Distal deep-vein thrombosis due to surgery or immobilization* | 4 | 3 | 1 | 0 | 0 | 8 |
| Superficial-vein thrombosis* | 0 | 2 | 1 | 0 | 1 | 4 |
| Total | 26 | 28 | 11 | 6 | 16 | 87 |
*The patients with this condition were not identified with use of the proposed algorithm.
To the Editor: Seligsohn and Lubetsky define criteria for assessing the likelihood of inherited thrombophilia. Ac- cording to these criteria, thrombophilia is likely in a patient 45 years of age or older in whom proximal-vein thrombosis has been provoked by surgery, trauma, or immobilization. Most patients with a first episode of venous thrombosis meet these criteria, but in such cases the thrombosis is due to un- derlying diseases.1-3 Therefore, these patients should be cat- egorized as unlikely to have thrombophilia, without the need for further testing. Doing so would improve the diagnostic yield of thrombophilia screening and would reduce costs.
In addition, the authors recommend lifelong oral anti- coagulant therapy for a subgroup of patients who are char- acterized by a high risk of recurrence. At present, however, no clinical trials support such a treatment regimen. With regard to the risk of major bleeding complications that is directly related to the duration of anticoagulant therapy,4 we suggest restricting the initial treatment period to five years, even in these high-risk patients. Thereafter, the decision as to whether warfarin therapy should be continued or stopped should be reconsidered.
BERND PÖTZSCH, M.D. University of Bonn 53105 Bonn, Germany bernd.poetzsch@ukb.uni-bonn.de
KATHARINA MADLENER, M.D. Kerckhoff Clinic 61231 Bad Nauheim, Germany
1. Baron JA, Gridley G, Weiderpass E, Nyrén O, Linet M. Venous throm- boembolism and cancer. Lancet 1998;351:1077-80. [Erratum, Lancet 2000;355:758.]
2. White RH, Gettner S, Newman JM, Trauner KB, Romano PS. Predic- tors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty. N Engl J Med 2000;343:1758-64.
3. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Mel- ton LJ III. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000;160:809-15.
4. Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with war- farin. Am J Med 1998;105:91-9.
To the Editor: Seligsohn and Lubetsky present decision trees that may help clinicians who are caring for patients with thrombophilia. However, some points need clarification. In Figure 2A of their article, the distinction between patients in whom thrombophilia is “highly likely” and those in whom it is “likely” is not clear. In particular, when thrombosis oc- curs during pregnancy in a woman less than 45 years old (as is the case in general), do the authors consider throm- bophilia “likely” or “highly likely”? We think it is reason- able to screen for a deficiency of antithrombin, protein C, or protein S in such a situation. In Figure 2B, some consid- erations regarding therapy do not meet standard recommen- dations. For instance, the recommended duration of treat- ment in patients with cerebral-vein thrombosis, in the absence of thrombophilia, is six months.1 Do the authors have evidence to support a prolongation of this duration?
The question of the international normalized ratio in the antiphospholipid syndrome is also controversial and could have been addressed in the discussion. Finally, as mentioned by the authors, an increased level of homocysteine may be caused by vitamin B12 deficiency. This deficiency is rarely
of dietary origin and most often reflects malabsorption of various causes.2
BERNARD GOICHOT, M.D., PH.D. EMMANUEL ANDRÈS, M.D. Hôpitaux Universitaires de Strasbourg 67098 Strasbourg CEDEX, France bernard.goichot@chru-strasbourg.fr
1. Bousser MG. Cerebral venous thrombosis: diagnosis and management. J Neurol 2000;247:252-8.
2. Andrès E, Goichot B, Schlienger JL. Food cobalamin malabsorption: a usual cause of vitamin B12 deficiency. Arch Intern Med 2000;160:2061-2.
The authors reply:
To the Editor: Caplin and Edelman should note that the estimated risk of fatal venous thromboembolism in women who are heterozygous for factor V Leiden and use contra- ceptives is 1 in 90,000.1 Thus, to prevent 1 death it would be necessary to test 1,800,000 women for factor V Leiden (assuming a prevalence of 5 percent in the population) and even more if testing for the prothrombin G20210A muta- tion were included. Furthermore, withholding oral contra- ceptives from 90,000 carriers would result in an increased number of unwanted pregnancies associated with compli- cations and stigmatize persons bearing an inherited disorder, a result that could affect the cost of their health insurance. For these reasons, a consensus team recently recommended against screening for factor V Leiden in asymptomatic wom- en contemplating the use of or using oral contraceptives, unless they have a personal or family history of thrombo- embolism or other risk factors.2
With regard to Casals Sole’s comments: distal deep-vein thrombosis secondary to surgery, trauma, or immobiliza- tion is associated with a low rate of recurrence and therefore does not warrant testing for thrombophilia. Superficial- vein thrombosis is indeed one of the manifestations of in- herited thrombophilia but is more frequently related to other causes. We limited our investigation to those patients who had recurrent events or an extension from the superficial to the deep veins. Upper-extremity venous thrombosis is rela- tively rare and in approximately 75 percent of cases is pro- voked by indwelling venous catheters, cancer, or an unusu- ally strenuous effort. In approximately 25 percent of cases, the event is unprovoked; for these patients, we advocate high- priority and intermediate-priority tests. In one series, the prevalence of thrombophilia was 42 percent among patients with unprovoked cases and 15 percent among those with provoked cases.3
With regard to the comments of Pötzsch and Madlener: it has repeatedly been shown that approximately 50 percent of patients with inherited thrombophilia present with venous thrombosis after surgery, trauma, or immobilization. This rate is sufficiently high for these patients to be considered likely to have a thrombophilia and to undergo high-priority testing. We agree that only long-term, prospective, random- ized studies will determine whether patients with a high risk of recurrence should be treated indefinitely or for five years.
We regard women less than 45 years old who present with an unprovoked venous thrombosis, whether or not they are pregnant or use female hormones, as highly likely to have a thrombophilia. As Goichot and Andrès suggest,
such women should be examined for high-priority and in- termediate-priority tests. No prospective studies have ade- quately addressed the issue of the desirable duration of oral anticoagulant therapy in patients with cerebral-vein throm- bosis. In patients whose event is unprovoked or in patients who are affected by an inherited thrombophilia, we recom- mend indefinite treatment because of the 17 to 26 percent rate of recurrence of cerebral or noncerebral thrombotic events,4,5 particularly in patients bearing factor V Leiden.5
URI SELIGSOHN, M.D. AHARON LUBETSKY, M.D. Chaim Sheba Medical Center Tel Hashomer 52621, Israel zeligson@post.tau.ac.il
1. Creinin MD, Lisman R, Strickler RC. Screening for factor V Leiden mutation before prescribing combination oral contraceptives. Fertil Steril 1999;72:646-51.
2. Grody WW, Griffin JH, Taylor AK, Korf BR, Heit JA. American Col- lege of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med 2001;3:139-48.
3. Heron E, Lozinguez O, Alhenc-Gelas M, Emmerich J, Fiessinger JN. Hypercoagulable states in primary upper-extremity deep vein thrombosis. Arch Intern Med 2000;160:382-6.
4. Preter M, Tzourio C, Ameri A, Bousser MG. Long-term prognosis in cerebral venous thrombosis: follow-up of 77 patients. Stroke 1996;27:243- 6.
5. Ludemann P, Nabavi DG, Junker R, et al. Factor V Leiden mutation is a risk factor for cerebral venous thrombosis: a case-control study of 55 pa- tients. Stroke 1998;29:2507-10.
Meningococcal Disease
To the Editor: Rosenstein et al. (May 3 issue)1 mention infectious syndromes associated with meningococcal disease. We would like to draw attention to the importance of con- sidering meningococcal disease in patients who present with septic arthritis and rash.
A 20-year-old heterosexual man presented with a painful, swollen left knee. There were no other symptoms. His last sexual contact had involved unprotected intercourse with a casual female partner two years earlier. On examination he was afebrile, with a swollen, inflamed left knee and a vas- culitic rash on his legs and arms. The white-cell count was 19.9×109 per liter; knee radiography showed a joint effusion.
The patient was given intravenous cefotaxime for probable septic arthritis. During arthroscopy and washout, a translu- cent greenish-brown, nonpurulent, viscous fluid was aspi- rated from the left knee. Gram’s staining revealed intracellu- lar gram-negative diplococci, and a presumptive diagnosis of disseminated gonococcal infection was made.
Genitourinary tract examination showed no urethral dis- charge, but microscopy of a urethral smear showed poly- morphonuclear leukocytes and gram-negative diplococci. A urethral culture was negative, but the aspirate from the joint grew Neisseria meningitidis group B. The public health department was notified, and prophylaxis was provided for the patient’s contacts.
Primary septic arthritis and urethritis are uncommon manifestations of meningococcal infection. The negative ure- thral culture in this case is assumed to be a result of previous antibiotic treatment. In a relatively sexually permissive era, it is interesting to note the patient’s relief on receiving the
diagnosis of meningococcal disease rather than the previ- ously presumed gonorrhea.
IAN LAURENSON, M.D. MEHARPAL SANGRA, M.R.C.S. CAROLYN THOMPSON, F.R.C.P. Fife Acute Hospitals NHS Trust Kirkcaldy, Fife KY2 5AG, United Kingdom ian.laurenson@faht.scot.nhs.uk
1. Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JM. Me- ningococcal disease. N Engl J Med 2001;344:1378-88.
To the Editor: The review by Rosenstein and colleagues omits an important approach to the rapid diagnosis of me- ningococcal septicemia. In 1919, Herrick1 began his impor- tant article with the following sentence: “The meningeal pic- ture resulting from meningococcus infection has so fixed the attention of clinicians and pathologists that the possibilities of extrameningeal infection by the organism have had scant notice.” As it turns out, in cases of sepsis the meningococ- cus is more likely to be found in the petechial and purpu- ric skin lesions than in cerebrospinal fluid. In 1917, Netter et al. described Gram’s staining of skin lesions as a rapid method of detecting negative diplococci.2 This diagnostic approach was again highlighted in 1947, when Hill and Kin- ney stated that “it is surprising that biopsy as a diagnostic adjunct has not gained more widespread recognition.”3
More recently, in a study of 51 patients, Gram’s staining of biopsy or needle-aspiration specimens from skin lesions provided a diagnosis within less than an hour in patients with meningococcal septicemia.4 Examination of the cerebrospi- nal fluid was inconclusive in most cases.
Furthermore, as the authors remarked, cultures of cere- brospinal fluid and blood are often falsely negative after the initiation of antibiotic treatment. In contrast, results for bi- opsy specimens are not affected immediately by antibiotics: Gram’s staining gave positive results up to 45 hours after the start of treatment, and positive cultures could be obtained up to 13 hours after the start of treatment.4
MARCEL VAN DEUREN, M.D. University Medical Center St. Radboud 6500 HB Nijmegen, the Netherlands
JACQUES F.G.M. MEIS, M.D. Canisius-Wilhelmina Hospital 6500 GS Nijmegen, the Netherlands j.meis@cwz.nl
1. Herrick WW. Extrameningeal meningococcus infections. Arch Intern Med 1919;23:409-18.
2. Netter A, Salanier M, Blanchier M. Two fresh cases of meningococcal infection with presence of the meningococcus in the purpuric eruption: cultivation of the meningococcus from the serum of a vesicle in one of the cases: occurrence of a strain of meningococci differing from the typical meningococcus. Br J Childr Dis 1917;14:264-6.
3. Hill WR, Kinney TD. The cutaneous lesions in acute meningococce- mia. JAMA 1947;134:513-8.
4. van Deuren M, van Dijke BJ, Koopman RJJ, et al. Rapid diagnosis of acute meningococcal infections by needle aspiration or biopsy of skin le- sions. BMJ 1993;306:1229-32.
To the Editor: The excellent review of Neisseria meningi- tidis disease failed to mention cellulitis as a possible clinical manifestation of meningococcal infection. Whereas skin le- sions (e.g., petechial and ecchymotic rash) are quite common and are an important early diagnostic clue to N. meningi- tidis infection, cases of meningococcal cellulitis have been described only rarely. My colleagues and I recently pub- lished a comprehensive review of this entity.1
Particular features of meningococcal cellulitis include a predilection for involvement of the periorbital area in chil- dren, the presence of underlying conditions in most adults, and a favorable outcome after administration of suitable an- tibiotic therapy. Meningitis was typically not present in these patients.
As Rosenstein et al. correctly point out, one of the chal- lenges of diagnosing meningococcal disease is that its clin- ical manifestations are difficult to distinguish from those of more common but less serious illnesses. Cellulitis may serve as an example of such a condition.
MIGUEL CARRASCOSA PORRAS, M.D. Hospital of Laredo 39770 Laredo, Cantabria, Spain mcarrascosap@nexo.es
1. Porras MC, Martinez VC, Ruiz IM, et al. Acute cellulitis: an unusual manifestation of meningococcal disease. Scand J Infect Dis 2001;33:56-9.
Giant, Nonfunctioning Carcinoma of the Adrenal Cortex
To the Editor: A 61-year-old man with no symptoms was found to have an enormous mass that occupied the entire right flank and pushed the right kidney down. A preoper- ative cytologic specimen obtained from a computed tomog- raphy-guided fine-needle biopsy showed many huge epi- thelial cells, with naked or doubled nuclei, suggesting a diagnosis of a clear-cell carcinoma of the right kidney.
At surgery, an ovoid mass (24 by 18 cm) distinct from the right kidney was found. After the mass was removed (Fig. 1), the appearance of the kidney was normal. A defin-
itive histologic examination showed adrenocortical carcino- ma (Fig. 2). The patient is well 14 months after surgery.
ANTONIO FIMMANÒ, M.D. GUIDO PETTINATO, M.D. CLAUDIO BONUSO CLAUDIA CIRILLO ROSANNA DI CARLO
Federico II University of Naples School of Medicine 80131 Naples, Italy fimmano@unina.it
Severe Coagulopathy as a Consequence of Smoking Crack Cocaine Laced with Rodenticide
To the Editor: We wish to report the development of a severe coagulopathy in a patient who smoked “crack” co- caine mixed with brodifacoum, a rodenticide. The patient, a 37-year-old man, presented to an emergency room with epistaxis of several hours’ duration. He had elevated pro- thrombin and activated partial-thromboplastin times and a normal platelet count. After nasal packing, he was trans- ferred to our facility, and the following laboratory values were obtained: a prothrombin time of 65.8 seconds (nor- mal range, 9.7 to 12.5), an international normalized ratio of 5.8, an activated partial-thromboplastin time of 46.4 seconds (normal range, 21.0 to 30.6), a fibrinogen level of 337 mg per deciliter (normal range, 200 to 450), a D-dimer level of less than 0.5 µg per milliliter (normal range, less than 0.5), and a platelet count of 175,000 per cubic millimeter (normal range, 150,000 to 440,000). Mix- ing studies done with a 1:1 ratio of the patient’s plasma to pooled normal plasma demonstrated prothrombin times of 65.8 seconds (patient) and 13.9 seconds (mix) and activat- ed partial-thromboplastin times of 52.3 seconds (patient) and 27.0 seconds (mix). The results of coagulation-factor assays are shown in Table 1.
The patient reported no ingestion of warfarin or other anticoagulant compounds and no use of or exposure to ro-
| COAGULATION FACTOR | VALUE (NORMAL RANGE) |
|---|---|
| % | |
| I | 14 (50-150) |
| V | 82 (50-150) |
| VII | <3 (>50) |
| VIII | 163 (55-145) |
| IX | <10 (>50) |
| X | 9 (45-155) |
denticides. Transfusion of fresh-frozen plasma and admin- istration of vitamin K normalized the coagulation values and resolved the hemorrhage. A serum sample was sent to a reference laboratory for chromatographic measurement of warfarin and warfarin-like compounds; the serum level of brodifacoum (D-Con, Talon-G) was 680 ng per milliliter. Before these results were known, 50 mg of oral vitamin K per day was prescribed and the patient was discharged. He sub- sequently left the state and was lost to follow-up.
The patient was readmitted several months later with a retroperitoneal hemorrhage and a serum prothrombin time of 72.5 seconds, an international normalized ratio of 6.4, and an activated partial-thromboplastin time of 42.4 sec- onds. He required a transfusion of packed red cells and ad- ministration of fresh-frozen plasma and vitamin K. He ad- mitted to smoking crack cocaine laced with rat poison in an attempt to potentiate the effects of the cocaine.
Adulteration of cocaine or “lacing” has been reported with a variety of substances. Occasionally, rodenticides and insecticides containing organophosphate compounds have been ingested or mixed with cocaine in an effort to poten- tiate the actions of the drug. These compounds are cholin- esterase inhibitors and presumably enhance cocaine by slow- ing its metabolism or intensifying its neurologic effects. Our case demonstrates superwarfarin toxicity as a consequence of smoking crack cocaine and represents yet another ex- ample of an adulterating agent potentiating the deadly ef- fects of cocaine.
SAIQUA A. WAIEN, M.D. DON HAYES, JR., M.D.
JAMES M. LEONARDO, M.D., PH.D. East Carolina University Greenville, NC 27858-4354 leonardoj@mail.ecu.edu
Correspondence Copyright @ 2001 Massachusetts Medical Society.
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