Erythropoietin and Painful Leg Ulcers:Thrombosis or Vasculitis?ANDREW GIBSON, JACQUI GARDNER, AND JOHN O’DONNELL

IntroductionRecombinant human erythropoietin (rHuEPO) is used rou-tinely in the management of anemia in end-stage renalfailure. We report a case of thrombotic leg ulceration as-sociated with rHuEPO use in a 69-year-old man with long-standing but inactive proteinase 3 antineutrophil cyto-plasmic antibody–positive Wegener’s granulomatosis,nondialysis-dependent renal failure, and secondary trans-fusion-dependent anemia.

Case ReportThe patient developed painful leg ulcers 12 weeks afterstarting rHuEPO. While receiving rHuEPO treatment thepatient’s hemoglobin gradually increased over 8 weeksfrom 70 gm/dl to 120 gm/dl. Other medical history in-cluded dilated cardiomyopathy with atrial fibrillation, hy-pertension, and late-onset diabetes mellitus, all of whichwere well controlled with treatment.

Histology of an initial biopsy sample from an ulcer cra-ter and adjacent tissue suggested an acute necrotizing vas-culitis. Because there were no clinical or laboratory signsof vasculitic disease related to Wegener’s granulomatosis,a second biopsy sample from a more recent nonulceratedlesion was obtained. This second histology report read:“. . . Beneath the infarcted epidermis there is marked vas-cular congestion within the superficial dermis accompa-nied by fresh hemorrhage. Many of these capillaries areoccluded by apparent thrombus. There are no significantassociated inflammatory changes . . . This biopsy showsinfarction of the skin secondary to occlusion of superficialcapillaries by apparent thrombus . . .”

No coagulopathy or cryoglobulinemia was detected. Thepatient was started on warfarin therapy and his ulcershealed. He returned to working on his farm and has had noulcer recurrence while continuing rHuEPO therapy.

DiscussionAlthough the etiology of thrombotic ulceration in thispatient was probably multifactorial, the prothrombotic ef-fects of rHuEPO were likely to have contributed becausehis comorbid conditions were controlled. Rapid increasesin hematocrit and direct effects on platelet aggregationhave been postulated as potential prothrombotic mecha-nisms of rHuEPO (1–4) along with changes in proteinconcentrations including factor VIII, von Willebrand fac-tor–associated coagulant activity (5), protein C, and pro-tein S. In vitro, EPO induces endothelial secretion of sol-uble adhesion molecules, E-selectin, and vascular celladhesion molecule, suggesting that EPO therapy may alsoactivate vascular endothelium in vivo. In susceptible in-dividuals these changes may combine to put the individ-ual into a prothrombotic state.

Chronic ulceration of varying etiology is frequently as-sociated with accumulation of acute and chronic inflam-matory cells around vessels. It is important to not obtainbiopsy specimens from within or immediately adjacent toan ulcer to minimize the risk of misinterpretation. Onreview, the first biopsy specimen had the same pattern ofthrombosed vessels as seen on the second biopsy speci-men, but this finding was partially obscured by a nonvas-culitic inflammatory infiltrate. This aspect of the case alsoillustrates the importance of obtaining appropriate biopsymaterial to avoid confusion between primary thromboticand primary vasculitic disease.

REFERENCES

1. Lage JM, Panizo C, Madeu J, Roch E. Cyclist’s doping associ-ated with cerebral sinus thrombosis. Neurology 2002;58:665.

2. Wakeen M, Zimmerman SW. Association between human re-combinant EPO and peripheral vascular disease in diabeticpatients receiving peritoneal dialysis. Am J Kidney Dis 1998;32:488–93.

3. Wun T, Law L, Harvey D, Sieracki B, Scudder SA, Ryu JK.Increased incidence of symptomatic venous thrombosis in pa-tients with cervical carcinoma treated with concurrent chemo-therapy, radiation, and erythropoietin. Cancer 2003;98:1514–20.

4. Mingoli A, Sapienza P, Puggioni A, Modini C, Cavallaro A. Apossible side-effect of human erythropoietin therapy: thrombo-sis of peripheral arterial reconstruction. Eur J Vasc EndovascSurg 1999;18:273–4.

5. Smith KJ, Bleyer AJ, Little WC, Sane DC. The cardiovasculareffects of erythropoietin. Cardiovasc Res 2003;59:538–48.

Andrew Gibson, MbChB, Jacqui Gardner, FRCPA, JohnO’Donnell, FRACP, FRCPA: Canterbury District Health Board,Christchurch, New Zealand.

Address correspondence to John O’Donnell, FRACP,FRCPA, Department of Rheumatology Immunology and Al-lergy, Canterbury Health Laboratories, PO Box 151, Christ-church, New Zealand. E-mail: john.odonnell@cdhb.govt.nz.

Submitted for publication December 21, 2004; accepted inrevised form April 26, 2005.

Arthritis & Rheumatism (Arthritis Care & Research)Vol. 53, No. 5, October 15, 2005, pp 792DOI 10.1002/art.21449© 2005, American College of Rheumatology

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