It has been shown that the clinical course of sickle cell (SS) patients can be ameliorated by administration of hydroxyurea (HU). Induction of hemoglobin F (HbF) is thought to be the mechanism responsible for clinical improvement in some patients. However, HU has a variable effect on HbF production and there exists no good correlation between the extent of HbF increase and clinical response. On the other hand, the degree of adherence of SS to vascular endothelium and neutrophil counts correlate well with clinical severity. Being a cytotoxic drug, used in myeloproliferative diseases, HU may alter proliferation among various cell lines. Moreover, HU has been reported to reduce red blood cell (RBC) adhesion receptor expression in young SS individuals and induces changes in endothelial cells in vitro. It should be conceived that in addition to its effects on HbF production, HU may change the clinical symptoms of SS patients by affecting the degree of adherence of different blood cells, by influencing the activity of endothelium as well as the activity of white blood cells (WBC) and platelets. To analyze whether several of the determinants of adhesion are modulated by HU treatment we studied the levels of endothelial activity (soluble vascular adhesion molecule-1, (sVCAM-1), interleukin-8 (IL-8), fibronectin, neutrophil activity (sL-selectin, sIL-6 receptor-α, myeloperoxidase) and platelet activity (von Willebrand factor) in relation to clinical symptoms, hematological data and HbF levels in 8 SS patients before and during 5 months of HU therapy. Steady state sVCAM-1 levels are increased compared to normal controls and a significant decrease is noted during HU treatment, suggesting a decrease in the interactions between RBC and vascular endothelium. The IL-8 levels are comparable to those in normal controls and remain unaffected by HU therapy. Intercurrent infection and crises reveal striking increases in IL-8 which are accompanied by leukocytosis, but otherwise the IL-8 levels do not correlate with hematological data. HU has no demonstrable effect on fibronectin or soluble neutrophil adhesion molecules, but the levels of myeloperoxidase decrease significantly while WBC counts do not, implying a reduction in neutrophil activity which may help attenuate the propagation phase of a vasoocclusive crisis.

Keywords:
Fibronectin, Hemoglobin F, Hydroxyurea, Interleukin-8, Interleukin-6 receptor-α, L-selectin, soluble, Myeloperoxidase, Sickle cell anemia, Vascular adhesion molecule-1, soluble
1.
Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR, Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia: Effect of hydroxyurea on the frequency of painfull crises in sickle cell anemia. N Engl J Med 1995;332:1317–1322.
2.
Vichinsky EP, Lubin BH: A cautionary note regarding hydroxyurea in sickle cell disease. Blood 1994;83:1124–1128.
3.
Saleh AW, Velvis H, Hillen HFP, Gu L-H, Huisman THJ: Hydroxyurea therapy in sickle cell anemia patients in Curaçao, The Netherlands Antilles. Acta Haematol 1997;98:125–129.
4.
Adragna NC, Fonseca P, Lauf PK: Hydroxyurea affects cell morphology, cation transport, and red blood cell adhesion in cultured vascular endothelial cells. Blood 1994;83:553–560.
5.
Swerlick RA, Eckman JR, Kumar A, Jeitler M, Wick TM: Reticulocytes from patients with sickle cell anemia express the a4b1-integrin complex and bind to TNF-a stimulated endothelial cells via a VCAM-1-a4b1 dependent mechanism. Blood 1993;82:1891–1899.
6.
Kaul DK, Fabry ME, Nagel RL: Microvascular sites and characteristics of sickle cell adhesion to vascular endothelium in shear flow conditions: Pathophysiological implications. Proc Natl Acad Sci USA 1989;86:3356–3360.
7.
Juneja HS: Pathophysiology and management of sickle cell pain crisis. Lancet 1995;346:1408–1411.
8.
Vordermeier S, Singh S, Biggerstaff J, Harrison P, Grech H, Pearson TC, Dumonde DC, Brown KA: Red blood cells from patients with sickle cell disease exhibit an increased adherence to cultured endothelium pretreated with tumor necrosis factor (TNF). Br J Haematol 1992;81:591–597.
9.
Antonucci R, Walker R, Herion J, Orringer E: Enhancement of sickle erythrocyte adherence to endothelium by autologous platelets. Am J Hematol 1990;34:44–48.
10.
Fadlon E, Vordemeier S, Pearson TC, Mire-Sluis AR, Dumonde DC, Phillips J, Fishlock K, Alun Brown K: Blood polymorphonuclear leucocytes from the majority of sickle cell patients in the crisis phase of the disease show enhanced adhesion to vascular endothelium and increased expression of CD 64. Blood 1998;91:266–274.
11.
Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR: Pain in sickle cell disease. Rates and risk factors. N Engl J Med 1991;325:11–16.35.
12.
Kasschau MR, Barabino GA, Bridges KR, Golan DE: Adhesion of sickle neutrophils and erythrocytes to fibronectin. Blood 1996;87:771–780.
13.
Wautier JL, Pintigny D, Wautier MP, Paton RC, Galacteros F, Passa P, Caen JP: Fibrinogen, a modulator of erythrocyte adhesion to vascular endothelium. J Lab Clin Med 1983;101:911–918.
14.
Wick TM, Moake JL, Udden MM, McIntire LV: Unusually large von Willebrand factor multimers preferentially promote young sickle and nonsickle erythrocyte adhesion to endothelial cells. Am J Hematol 1993;42:284–292.
15.
Brittain HA, Eckman JR, Swerlick RA, Howard RJ, Wick TM: Thrombospondin from activated platelets promotes sickle erythrocyte adherence to human microvascular endothelium under physiologic flow: A potential role for platelet activation in sickle cell vaso-occlusion. Blood 1993;81:2137–2143.
16.
Natarajan M, McIntire LV, Udden M, Moake J: Adhesion of sickle cells and damage to IL-1 stimulated endothelial cells under flow conditions in vitro (abstract). Ann Biomed Eng 1994;22:26a.
17.
Oppenheim JJ, Zachariae COC, Mukaida N, Matsushima K: Properties of the novel proinflammatory supergene ‘intercrine’ cytokine family. Annu Rev Immunol 1991;9:617–648.
18.
Darbonne WC, Rice GC, Mohler MA, Apple T, Hebert CA, Valente AJ, Baker JB: Red blood cells are a sink for interleukin-8, a leucocyte chemotaxin. J Clin Invest 1991;88:1362.
19.
Solovey A, Yi Lin BS, Browne P, Choong S, Wayner E, Hebbel RP: Circulating activated endothelial cells in sickle cell anemia. N Engl J Med 1997;337:1584–1590.
20.
Duits AJ, Pieters RC, Saleh AW, van Rosmalen E, Katerberg H, Berend K, Rojer RA: Enhanced levels of soluble VCAM-1 in sickle cell patients and their specific increment during vaso-occlusive crisis. Clin Immunol Immunopathol 1996;81:96–98.
21.
Ballas SK, Dover GJ, Charache S: Effect of hydroxyurea on the rheological properties of sickle erythrocytes in vivo. Am J Hematol 1989;32:104–111.
22.
Styles LA, Lubin B, Vichinsky E, Lawrence S, Hua M, Test S, Kuypers F: Decrease of very late activation antigen-4 and CD36 on reticulocytes in sickle cell patients treated with hydroxyurea. Blood 1997;89:2554–2559.
23.
Bisse E, Wieland H: High performance liquid chromatographic separation of human haemoglobins: Simultaneous quantitation of foetal and glycated haemoglobins. J Chromatogr 1988;434:95–110.
24.
Saleh AW, Duits AJ, Gerbers A, de Vries C, Hillen HFP: Cytokines and soluble adhesion molecules in sickle cell anemia patients during hydroxyurea therapy. Acta Haematol 1998;100:26–31.
25.
Berliner N, Hsing A, Graubert T, Sigurdsson F, Zain M, Bruno E, Hoffman R: Granulocyte colony-stimulating factor induction of normal human bone marrow progenitors results in neutrophil-specific gene expression. Blood 1995;85:799–803.
26.
Harlan JM, Schwartz BR, Reidy MA, Schwartz SM, Ochs HD, Harker LA: Activated neutrophils disrupt endothelial monolayer integrity by an oxygen radical-independent mechanism. Lab Invest 1985;52:141–150.
27.
Schnog JJ, Lard LR, Rojer RA, van der Dijs FP, Muskiet FA, Duits AJ: New concepts in assessing sickle cell disease severity. Am J Hematol 1998;58:61–66.
1999
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.