Correspondence.

(Letters to the Editor are welcomed. They may report new clinical or laboratory observations and new developments in medical care or may contain comments on recent contents of the Journal. They will be published, if found suitable, as space permits. Like other material submitted for publication, letters must be typewritten, double-spaced, and submitted in duplicate. They must not exceed two typewritten pages in length. No more than five references and one figure or table may be used. See "Information for Authors" for format of references, tables, and figures. Editing, possible abridgment, and acceptance remain the prerogative of the Editors.)

Proinflammatory and Hematopoietic Cytokines in Reactive and Clonal Thrombycytosis

To the Editor: Araneda et al (1) have reported the status of interleukin (IL)-3, IL-6, IL-11, IL-1[beta], tumor necrosis factor [alpha], and C-reactive protein (CRP) in clonal thrombocytosis versus reactive thrombocytosis. The authors stated that the levels of IL-1[beta], as well as IL-6 and CRP, were demonstrated for the first time to be significantly higher in reactive thrombocytosis compared with clonal thrombocytosis and controls. They also noted that, although the thrombopoietin (TPO) levels were higher in patients with reactive thrombocytosis, this did not reach statistical significance. We would like to share our experience regarding the interactions of IL-6, IL-1[beta], and TPO in pathologic thrombopoiesis.

Interleukin-1 is a potent inducer of IL-6, and the combination of IL-1 and IL-6 can act as a megakaryocyte potentiator as well. (2) In our previous study, which was not cited by the authors, we demonstrated that in patients with rheumatoid arthritis (PA) complicated by thrombocytosis, levels of IL-1[beta] were increased compared with RA patients with normal platelet counts, patients with myeloproliferative disorders with thrombocytemia, and healthy, control subjects. Moreover, there was a positive correlation between IL-1[beta] and IL-6 levels in PA patients with thrombocytosis. (3) Serum IL-1[beta] concentrations, like IL-6 concentrations, were found to be suppressed in patients with myeloproliferative disease, suggesting the autonomous character of platelet production in these neoplastic disorders. In another study, we demonstrated the association of serum IL-6 and IL-1[beta] concentrations with disease activity in RA patients (using the Stoke Index). (4)

On the other hand, thrombocytosis induced by IL-6 in mice is accompanied by enhanced hepatic TPO messenger ribonucleic acid (mRNA) expression and elevated TPO plasma levels. (5) Administration of IL-6 to cancer patients resulted in a corresponding increase in TPO levels. (5) Circulating concentrations of TPO have been studied previously in patients with reactive thrombocytosis secondary to surgical stress, malignant tumors, infectious diseases, and inflammatory conditions. (6-11) Elevated TPO levels in cases of reactive thrombocytosis have been demonstrated in some studies. (6-8) We, along with others, failed to confirm these observations, however. (9-11) Nevertheless, elevated serum TPO levels in reactive thrombocytosis should not be universally expected, because growing platelet mass can cause a reduction in peripheral blood TPO concentrations by platelet-megakaryocyte TPO receptor-mediated uptake and destruction. (12) We recently compared circulating peripheral blood TPO concentrations in patients with RA and thrombocytosis with those of RA patients with normal platelet counts, as well as healthy control subjects. (13) We demonstrated that RA patients with normal platelet counts have TPO levels comparable to healthy control subjects, but RA patients with mild thrombocytosis have significantly elevated TPO levels, while RA patients with markedly increased platelet counts have prominently decreased TPO levels. In this study, TPO levels might be increased due to ongoing inflammatory processes, possibly under the influence of inflammatory cytokines (eg, IL-6) in our patients with active RA. When platelet counts markedly increased, large platelet mass could overcome the increased production of TPO. Accordingly, TPO levels were significantly decreased.

The interactions of proinflammatory cytokines and TPO in pathologic thrombopoiesis are very complicated, and they act in concert to regulate megakaryocytopoiesis in inflammatory conditions. Clarification of the pathobiologic basis of thrombopoiesis in health and disease may help improve management of the patients with thrombocytosis and thrombocytopenia.

M. Akif Ozturk, MD

Sedat Kiraz, MD

Ihsan Ertenli, MD

Meral Calguneri, MD

Department of Rheumatology 

Ibrahim C. Haznedaroglu, MD

Department of Hematology

Hacettepe University School of Medicine

Yenimahalle, Ankara, Turkey 06170

References

(1.) Araneda M, Krishnan V, Hall K, et al: Reactive and clonal thrombocytosis: proinflammatory and hemaotpoietic cytokines and acute phase proteins. South Med J 2001; 94:417-420

(2.) Warren MK, Conroy LB, Rose JS: The role of interleukin-6 and interleukin-1 in megakaryocyte development. Exp Hematol 1989; 17:1095-1099

(3.) Haznedaroglu IC, Ertenli I, Ozcebe OI, et al: Megakaryocyte-related interleukins in reactive thrombocytosis versus autonomous thrombocytemia. Acta Haematol 1996; 95:107-111

(4.) Ertenli I, Haznedaroglu IC, Kiraz S, et al: Cytokines affecting megakaryocytopoiesis in rheumatoid arthritis with thrombocytosis. Rheumatol Int 1996; 16:5-8

(5.) Kaser A, Brandacher G, Steurer W, et al: Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood 2001; 98:2720-2725

(6.) Hsu HC, Tsai WH, Jiang ML, et al: Circulating levels of thrombopoietic and inflammatory cytokines in patients with clonal and reactive thrombocytosis. J Lab Clin Med 1999; 134:392-397

(7.) Cerutti A, Custodi P, Duranti M, et al: Thrombopoietin levels in patients with primary and reactive thrombocytosis. Br J Haematol 1997; 99:281-284

(8.) Heits F, Stahl M, Ludwig D, et al: Elevated serum thrombopoietin and interleukin-6 concentrations in thrombocytosis associated with inflammatory bowel disease. J Interferon Cytokine Res 1999; 19:757-760

(9.) Wang JC, Chen C, Novetsky AD, et al: Blood thrombopoietin levels in clonal thrombocytosis and reactive thrombocytosis. Am J Med 1998; 104:451-455

(10.) Choe EI, Kasabian AK, Kolker AR, et al: Thrombocytosis after major lower extremity trauma: mechanism and possible role in free flap failure. Ann Plast Surg 1996; 36:489-494

(11.) Karakus S, Ozcebe OI, Haznedaroglu IC, et al: Circulating thrombopoietin in clonal versus reactive thrombocytosis. Hematology (In press)

(12.) Kuter DJ, Rosenberg RD: The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood 1995; 85:2720-2730

(13.) Kiraz S, Ertenli I, Haznedaroglu IC, et al: Circulating thrombopoietin in rheumatoid arthritis with thrombocytosis [abstract]. Arthritis Rheum 1999; 42:744a

Diabetic Foot: Evaluation and Management

To the Editor: Melissa Green et al (1) have written an excellent review article on the evaluation and management of the diabetic foot. Two areas in this article require revision, however.

In the Key Points, a yearly foot examination is recommended. It is my strong recommendation that the foot of the diabetic patient be examined at each regular office visit, every 3 to 4 months, not just once a year. This is especially important for patients who have lost protective sensation and, therefore, have a high-risk foot. It is also important to do foot examinations more than once a year to evaluate callus build-up, which frequently leads to ulceration, to detect new foot lesions, to detect developing foot and toe deformities, and to repeat foot-care instructions at these visits. I agree that it is reasonable to do a neurologic and vascular examination once a year.

It should be stressed that the acute phase of Charcot's foot, characterized by a history of minor trauma to the foot, followed by redness, swelling, and increased warmth, is not a sign of fracture. Initial x-rays taken during the acute phase of Charcot's foot rarely confirm fracture. It is in the acute inflammatory stage of Charcot's foot that the patient should be placed on non--weight-bearing status in order to help prevent fracture.

Marvin E. Levin, MD

Department of Medicine Division of Endocrinology

Washington University School of Medicine 

St. Louis, MO 63110

Reference

(1.) Green MF, Aliabadi Z, Green BT: Diabetic foot: evaluation and management. South Med J 2002; 95:95-101