Correspondence

Acquired Bleeding Diathesis in a Patient Taking PC-SPES

N Engl J Med 2001; 345:1213-1214October 18, 2001DOI: 10.1056/NEJM200110183451616

Article

To the Editor:

PC-SPES is a commercially available nutritional supplement containing eight herbs that is used by many patients with prostate cancer. It has potent estrogenic activity and substantial antineoplastic effects in patients with prostate cancer.1,2 We describe a patient with profound bleeding diathesis after one month of unsupervised use of this compound.

A 62-year-old man with hormone-refractory prostate cancer and nodal metastases (stage D1 disease) presented to the emergency department after an episode of syncope. This episode had been preceded by one day of epistaxis, abdominal pain, hematuria, and the passage of maroon stools. The patient denied a family history of bleeding or bruising, and the prothrombin time and activated partial-thromboplastin time had previously been normal. The only medications were 12 capsules of PC-SPES daily (twice the manufacturer's recommended dosage) for one month, in addition to multivitamins. The initial vital signs were notable for a pulse of 120 beats per minute and a blood pressure of 112/82 mm Hg. Physical examination revealed extensive ecchymoses, and a computed tomographic scan showed a large retroperitoneal hematoma. The results of laboratory analysis and mixing studies with normal plasma are shown in Table 1Table 1Hematologic and Coagulation Variables.. Hepatic-function variables were within normal limits. Initial treatment included the transfusion of 2 units of packed red cells and 6 units of fresh-frozen plasma and the administration of vitamin K. On follow-up testing three weeks and again three months later, the prothrombin time and activated partial-thromboplastin time were normal. Laboratory studies on admission also unexpectedly revealed a serum warfarin level of 0.69 μg per milliliter (therapeutic range, 2 to 8).

The use of PC-SPES has been associated with increased rates of deep venous thrombosis and pulmonary embolism, but to our knowledge its use has never been linked to hemorrhage. Two isolates of the herb Baikal skullcap (Scutellaria baicalensis Georgi ), one of the components of PC-SPES, are coumarins (compounds structurally related to warfarin, a synthetic coumarin) and have been shown to act as vitamin K reductase inhibitors in a manner similar to that of warfarin.3 In this case, the history and laboratory variables were most consistent with the presence of an acquired coagulation-factor deficiency, and the measured warfarin level was insufficient to have induced the described changes in coagulation variables.

To investigate the possibility that a phytocoumarin was contained in the PC-SPES, two mice were given the PC-SPES preparation procured from the patient at a dosage of 500 mg per kilogram of body weight per day, administered orally as previously described.4 After three days, the mean (±SD) measured serum warfarin level was 0.87 ±0.2 μg per milliliter. These results indicate that the PC-SPES preparation that this patient took contained a component that comigrates with warfarin on high-performance liquid chromatography. The transient, severe bleeding diathesis in this patient was probably the result of unsupervised use of PC-SPES and was probably related to a phytocoumarin or other compound in the PC-SPES. Patients should be counseled that PC-SPES has multiple thrombotic and hemorrhagic side effects, that these potentially harmful complications must be balanced with the antineoplastic effects of PC-SPES, and that unsupervised use of this preparation is not recommended.

Mark C. Weinrobe, M.D.
Bruce Montgomery, M.D.
University of Washington, Seattle, WA 98108
rbmontgo@u.washington.edu

4 References

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   DiPaola RS, Zhang H, Lambert GH, et al. Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 1998;339:785-791
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   Liu XF, Liu ML, Iyanagi T, Legesse K, Lee TD, Chen SA. Inhibition of rat liver NAD(P)H:quinone acceptor oxidoreductase (DT-diaphorase) by flavonoids isolated from the Chinese herb scutellariae radix (Huang Qin). Mol Pharmacol 1990;37:911-915
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   Kubota T, Hisatake J, Hisatake Y, et al. PC-SPES: a unique inhibitor of proliferation of prostate cancer cells in vitro and in vivo. Prostate 2000;42:163-171
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   F Javed, A Golagani, H Sharp. (2008) Potential effects of herbal medicines and nutritional supplements on coagulation in ENT practice. The Journal of Laryngology & Otology 122:02,
   

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   James M. Metz, Heather Jones. Complementary and Alternative Medicine. In: Abeloff's Clinical Oncology. Elsevier, 2008:545-561.
   

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   Richard Ko, Raymond D. Wilson, Susan Loscutoff. (2003) PC-SPES. Urology 61:6, 1292
   

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   Barrie R Cassileth, Andrew J Vickers. (2003) Complementary and alternative therapies. Urologic Clinics of North America 30:2, 369-376
   

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   Monte S. Willis, Frank H. Wians. (2003) The role of nutrition in preventing prostate cancer: a review of the proposed mechanism of action of various dietary substances. Clinica Chimica Acta 330:1-2, 57-83
   

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   Elizabeth M Williamson. (2003) Drug Interactions Between Herbal and Prescription Medicines. Drug Safety 26:15, 1075-1092
   

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   Leonard S Marks, Robert S DiPaola, Peter Nelson, Sophie Chen, David Heber, Arie S Belldegrun, Franklin C Lowe, John Fan, Floyd E Leaders, Allan J Pantuck, Varro E Tyler. (2002) PC-SPES: herbal formulation for prostate cancer. Urology 60:3, 369-375
   

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    HS Pandha, RS Kirby. (2002) PC-SPES: phytotherapy for prostate cancer. The Lancet 359:9325, 2213-2215
    

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    Mary L. Chavez. (2002) PC-SPES for the Treatment of Prostate Cancer?. Journal of Herbal Pharmacotherapy 2:3, 73-89
    

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    &NA;. (2001) PC-SPES overdose. Reactions Weekly &NA;:875, 10