Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Dec 8;2014(12):CD008394.
doi: 10.1002/14651858.CD008394.pub3.

Interventions for treating leg ulcers in people with sickle cell disease

Arturo J Martí-Carvajal  1 , Jennifer M Knight-Madden, Maria José Martinez-Zapata
Affiliations

Interventions for treating leg ulcers in people with sickle cell disease

Arturo J Martí-Carvajal et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: The frequency of skin ulceration makes it an important contributor to the morbidity burden in people with sickle cell disease. Many treatment options are available to the healthcare professional, although it is uncertain which treatments have been assessed for effectiveness in people with sickle cell disease.

Objectives: To assess the clinical effectiveness and safety of interventions for treating leg ulcers in people with sickle cell disease.

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register.We searched LILACS (1982 to August 2012), the African Index Medicus (up to August 2012), ISI Web of Knowledge (1985 to August 2012), and the Clinical Trials Search Portal of the World Health Organization (August 2012). We checked the reference lists of all the trials identified. We also contacted those groups or individuals who may have completed relevant randomised trials in this area.Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 21 July 2014; date of the last search of the Cochrane Wounds Group Trials Register: 18 September 2014.

Selection criteria: Randomised controlled trials of interventions for treating leg ulcers in people with sickle cell disease compared to placebo or an alternative treatment.

Data collection and analysis: Two authors independently selected studies for inclusion. All three authors independently assessed the risk of bias of the included studies and extracted data.

Main results: Six studies met the inclusion criteria (198 participants with 250 ulcers). Each trial investigated a different intervention and within this review we have grouped these as systemic pharmaceutical interventions (L-cartinine, arginine butyrate, isoxsuprine) and topical pharmaceutical interventions (Solcoseryl(®) cream, RGD peptide dressing, topical antibiotics). Three interventions reported on the change in ulcer size (arginine butyrate, RGD peptide, L-cartinine). Of these, RGD peptide matrix significantly reduced ulcer size compared with a control group, mean reduction 6.60cm(2) (95% CI 5.51 to 7.69; very low quality of evidence). Three trials reported on the incidence of complete closure (isoxsuprine, arginine butyrate, RGD peptide matrix; ranging between low and very low quality of evidence). None reported a significant effect. No trial reported on: the time to complete ulcer healing; ulcer-free survival following treatment for sickle cell leg ulcers; quality of life measures; or incidence of amputation. There was no reported information on the safety of these interventions.

Authors' conclusions: There is evidence that a topical intervention (RGD peptide matrix) reduced ulcer size in treated participants compared to controls. This evidence of efficacy is limited by the generally high risk of bias associated with these reports.We planned to analyse results according to general groups: pharmaceutical interventions (systemic and topical); and non-pharmaceutical interventions (surgical and non-surgical). However, we were unable to pool findings due to the heterogeneity in outcome definitions, and inconsistency between the unit of randomisation and the unit of analysis. This heterogeneity, along with a paucity of identified trials, prevented us performing any meta-analyses.This Cochrane review provides some evidence for the effectiveness of one topical intervention - RGD peptide matrix. However, this intervention was assessed as having a high risk of bias due to inadequacies in the single trial report. Other included studies were also assessed as having a high risk of bias. We recommend that readers interpret the trial results with caution. The safety profile of the all interventions was inconclusive.

PubMed Disclaimer

Conflict of interest statement

In 2004 Arturo Martí‐Carvajal was employed by Eli Lilly to run a four‐hour workshop on 'How to critically appraise clinical trials on osteoporosis and how to teach this'. This activity was not related to his work with The Cochrane Collaboration or any Cochrane Review.

In 2007 Arturo Martí‐Carvajal was employed by Merck to run a four‐hour workshop 'How to critically appraise clinical trials and how to teach this'. This activity was not related to his work with The Cochrane Collaboration or any Cochrane Review.

Jennifer Knight‐Madden and María José Martínez‐Zapata: none known.

Figures

1
1
2
2
Flowchart of last search of the Group's Trials Register: 25 May 2012.
3
3
Risk of bias graph: review authors' judgements about each risk of bias domain presented as percentages across all included studies
4
4
Risk of bias summary: review authors' judgements about each risk of bias domain for each included study
1.1
1.1. Analysis
Comparison 1 L‐carnitine versus placebo, Outcome 1 Change in ulcer size (surface area or volume).
2.1
2.1. Analysis
Comparison 2 RGD peptide matrix versus placebo, Outcome 1 Incidence of complete closure.
2.2
2.2. Analysis
Comparison 2 RGD peptide matrix versus placebo, Outcome 2 Change in size of ulcers healed.
2.3
2.3. Analysis
Comparison 2 RGD peptide matrix versus placebo, Outcome 3 Adverse events.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Baum 1987 {published data only}
    1. Baum KF, MacFarlane DE, Maude GH, Serjeant GR. Topical antibiotics in chronic sickle cell leg ulcers. Transactions of the Royal Society of Tropical Medicine and Hygiene 1987;81(5):847‐9. [PUBMED: 2835836] - PubMed
    1. Macfarlane DE, Baum KF, Maude GH, Serjeant GR. Topical antibiotics in chronic sickle‐cell leg ulcers. West Indian Medical Journal 1986;35 Suppl:46‐7.
La Grenade 1993 {published data only}
    1. Grenade L, Thomas PW, Serjeant GR. A randomized controlled trial of solcoseryl and duoderm in chronic sickle‐cell ulcers. West Indian Medical Journal 1993; Vol. 42, issue 3:121‐3. [PUBMED: 8273321] - PubMed
McMahon 2010 {published data only}
    1. Koshy M, Askin M, McMahon L, Adams‐Graves P, Halloway L, Faller DV, et al. Arginine butyrate in sickle cell leg ulcers: interim findings of a phase II trial [abstract]. The National Sickle Cell Disease Program Annual Meeting Conference Proceedings. 2000:175a.
    1. Koshy M, Askin M, McMahon L, Adams‐Graves P, Halloway L, Faller DV, et al. Arginine butyrate in sickle cell leg ulcers: interim findings of a randomized phase II trial [abstract]. The National Sickle Cell Disease Program Annual Meeting Conference Proceedings. 2001:Abstract no: 124.
    1. Koshy M, Edinburgh L, McMahon L, Adams‐Graves P, Halloway L, Faller DV, et al. Arginine butyrate in sickle cell leg ulcers: interim findings of a phase II trial [abstract]. Blood 1999;Suppl:417a.
    1. McMahon L, Tamary H, Askin M, Adams‐Graves P, Eberhardt RT, Sutton M, et al. A randomized phase II trial of Arginine Butyrate with standard local therapy in refractory sickle cell leg ulcers. British Journal of Haematology 2010;151(5):516‐24. [PUBMED: 20955402] - PubMed
    1. McMahon LC, Askin M, Koshy M, Tamary H, Atweh GF, Adam‐Graves P, et al. A phase II trial of arginine butyrate in refractory sickle cell leg ulcers [abstract]. Blood 2002;100 (11 Pt 1 of 2):10a‐1a.
Serjeant 1977 {published data only}
    1. Serjeant GR, Howard C. Isoxsuprine hydrochloride in the therapy of sickle cell leg ulceration. West Indian Medical Journal 1977;26(3):164‐6. [PUBMED: 333769] - PubMed
Serjeant 1997 {published data only}
    1. Serjeant BE, Harris J, Thomas P, Serjeant GR. Propionyl‐L‐carnitine in chronic leg ulcers of homozygous sickle cell disease: a pilot study. Journal of the American Academy of Dermatology 1997;37(3 Pt 1):491‐3. [PUBMED: 9308570] - PubMed
Wethers 1994 {published data only}
    1. Ramirez GM, Wethers DL, Koshy M, Steinberg MH, Phillips G Jr, Siegel RS, et al. Accelerated healing of chronic sickle cell leg ulcers treated with a RGD matrix. The National Sickle Cell Disease Program Annual Meeting Conference Proceedings. 1994. - PubMed
    1. Wethers DL, Ramirez GM, Koshy M, Steinberg MH, Phillips G Jr, Siegel RS, et al. Accelerated healing of chronic sickle‐cell leg ulcers treated with RGD peptide matrix. RGD Study Group. Blood 1994;84(6):1775‐9. [PUBMED: 8080985 ] - PubMed

References to studies excluded from this review

Afifi 1979 {published data only}
    1. Afifi AM, Adnan M, Taha M, Amasha ME. Xanthinol nicotinate in the management of leg ulcers associated with haemoglobinopathies. Current Medical Research and Opinion 1979, issue 5:309‐13. [PUBMED: 80156092] - PubMed
Cacciola 1990b {published data only}
    1. Cacciola E, Giustolisi R, Musso R, Longo A, Cacciola E. Antithrombin III concentrate for treatment of chronic leg ulcers in sickle cell‐beta thalassemia: a pilot study. Annals of Internal Medicine 1990;111(6):534‐6. [PUBMED: 2774375] - PubMed
Lucena 2007 {published data only}
    1. Lucena A, Souza K, Anselmo C, Nascimento A, Araújo A. InGaP (670nm) laser use in the leg ulcer healing in patients with sickle cell anemia [O uso do laser de ingap (670nm) na cicatrização de úlceras de perna em pacientes com anemia falciforme]. Anais da Faculdade de Medicina da Universidade Federal de Pernambuco 2007;52(1):45‐50. [LILACS ID: 495328]
Neves 2010 {published data only}
    1. Neves AF, Martins A, Queiroz AMM, Thomé ED, Queiroz APA, Lobo CLC. Evaluation of the topical application of opioid analgesia for a leg ulcer of a sickle cell disease patient [Avaliação da analgesia de opioide tópico em úlcera de perna de paciente falcêmico]. Revista Brasileira de Hematologia e Hemoterapia 2010;32(2):123‐5. [LILACS ID: lil‐553486]
Okany 2004 {published data only}
    1. Okany CC, Atimomo CE, Akinyanju OO. Efficacy of natural honey in the healing of leg ulcers in sickle cell anaemia. The Nigerian Postgraduate Medical Journal 2004;11(3):179‐81. [PUBMED: 15505645] - PubMed
Paggiaro 2010 {published data only}
    1. Paggiaro AO, Carvalho VF, Fonseca GHH, Doi A, Ferreira MC. Negative pressure therapy for complex wounds in patients with sickle‐cell disease: a case study. Ostomy Wound Management 2010;56(8):62‐7. [IDS Number: 644CO ] - PubMed
Sawyer 1979 {published data only}
    1. Sawyer PN, Haque S, Reddy K, Sophie Z, Feller J. Wound healing effects of debrisan on varicose, postoperative, decubitus, and sickle‐cell ulcers in man. Vascular Surgery 1979; Vol. 13, issue 4:251‐6.
Serjeant 1970 {published data only}
    1. Serjeant GR, Galloway RE, Gueri MC. Oral zinc sulphate in sickle‐cell ulcers. Lancet 1970; Vol. 2, issue 7679:891‐2. [PUBMED: 4097279] - PubMed

Additional references

Akinsheye 2010
    1. Akinsheye I, Klings ES. Sickle cell anemia and vascular dysfunction: the nitric oxide connection. Journal of Cellular Physiology 2010;224(3):620‐5. [PUBMED: 20578237] - PubMed
Akinyanju 1979
    1. Akinyanju O, Akinsete I. Leg ulceration in sickle cell disease in Nigeria. Tropical and Geographical Medicine 1979;31:87‐91. [PUBMED: 483376] - PubMed
al‐Momen 1991
    1. al‐Momen AK. Recombinant human erythropoietin induced rapid healing of a chronic leg ulcer in a patient with sickle cell disease. Acta Haematologica 1991;86:46‐8. [PUBMED: 1950363] - PubMed
Alexander 2004
    1. Alexander N, Higgs D, Dover G, Serjeant GR. Are there clinical phenotypes of homozygous sickle cell disease?. British Journal of Haematology 2004;126:606‐11. [PUBMED: 15287956] - PubMed
Alikhan 2004
    1. Alikhan MA, Carter G, Mehta P. Topical GM‐CSF hastens healing of leg ulcers in sickle cell disease. American Journal of Hematology 2004;76:192. [PUBMED: 15164391] - PubMed
Alleyne 1977
    1. Alleyne SI, Wint E, Serjeant GR. Social effects of leg ulceration in sickle cell anemia. Southern Medical Journal 1977;70:213‐4. [PUBMED: 841405] - PubMed
Amini‐Adle 2007
    1. Amini‐Adle M, Auxenfants C, Allombert‐Blaise C, Deroo‐Berger MC, Ly A, Jullien D, et al. Rapid healing of long‐lasting sickle cell leg ulcer treated with allogeneic keratinocytes. Journal of the European Academy of Dermatology and Venereology 2007;21:707‐8. [PUBMED: 17448004] - PubMed
Ankra‐Badu 1992
    1. Ankra‐Badu GA. Sickle cell leg ulcers in Ghana. East African Medical Journal 1992;69:366‐9. [PUBMED: 1396190] - PubMed
Anonymous 2012
    1. Anonymous. Methodological standards and patient‐centeredness in comparative effectiveness research: the PCORI perspective. JAMA 2012;307(15):1636‐40. [PUBMED: 22511692] - PubMed
Aslan 2007
    1. Aslan M, Freeman BA. Redox‐dependent impairment of vascular function in sickle cell disease. Free Radical Biology & Medicine 2007;43:1469‐83. [PUBMED: 17964418] - PMC - PubMed
Asnani 2009
    1. Asnani MR, Lipps GE, Reid ME. Utility of WHOQOL‐BREF in measuring quality of life in sickle cell disease. Health and Quality of Life Outcomes 2009;7:75. [PUBMED: 19664266] - PMC - PubMed
Ballas 2002
    1. Ballas SK. Treatment of painful sickle cell leg ulcers with topical opioids. Blood 2002;99:1096. [PUBMED: 11822360] - PubMed
Ballas 2010
    1. Ballas SK, Lieff S, Benjamin LJ, Dampier CD, Heeney MM, Hoppe C, et al. Definitions of the phenotypic manifestations of sickle cell disease. American Journal of Hematology 2010;85(1):6‐13. [PUBMED: 19902523] - PMC - PubMed
Balshem 2011
    1. Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology 2011;64(4):401‐6. [PUBMED: 21208779] - PubMed
Bardakdjian‐Michau 2009
    1. Bardakdjian‐Michau J, Bahuau M, Hurtrel D, Godart C, Riou J, Mathis M, et al. Neonatal screening for sickle cell disease in France. Journal of Clinical Pathology 2009;62:31‐3. [PUBMED: 19103855] - PubMed
Bender 2009
    1. Bender DA. A dictionary of food and nutrition. 3rd Edition. New York: Oxford University Press, 2009. [978‐0‐19‐923487‐5]
Bergin 2006
    1. Bergin SM, Wraight P. Silver based wound dressings and topical agents for treating diabetic foot ulcers. Cochrane Database of Systematic Reviews 2006, Issue 1. [DOI: 10.1002/14651858.CD005082.pub2] - DOI - PubMed
Cacciola 1989
    1. Cacciola E, Giustolisi R, Musso R, Longo A, Cacciola E. Antithrombin III concentrate for treatment of chronic leg ulcers in sickle cell‐beta thalassemia: a pilot study. Annals of Internal Medicine 1989;111:534‐6. [PUBMED: 2774375] - PubMed
Cacciola 1990a
    1. Cacciola E, Musso R, Giustolisi R, Cacciola E, Alessi M. Blood hypercoagulability as a risk factor for leg ulcers in sickle cell disease. Blood 1990;75(12):2467‐8. [PUBMED: 2350585] - PubMed
Chalchal 2001
    1. Chalchal H, Rodino W, Hussain S, Haq I, Panetta T, Solomon W, Gillette P, et al. Impaired venous hemodynamics in a minority of patients with chronic leg ulcers due to sickle cell anemia. VASA. Zeitschrift für Gefässkrankheiten. Journal for Vascular Diseases 2001;30:277‐9. [PUBMED: 11771212] - PubMed
Clare 2002
    1. Clare A, FitzHenley M, Harris J, Hambleton I, Serjeant GR. Chronic leg ulceration in homozygous sickle cell disease: the role of venous incompetence. British Journal of Haematology 2002;119:567‐71. [PUBMED: 12406102] - PubMed
Clarke 2007
    1. Clarke M. Standardising outcomes for clinical trials and systematic reviews. Trials 2007;8:39. [PUBMED: 18039365] - PMC - PubMed
Creary 2007
    1. Creary M, Williamson D, Kulkarni R. Sickle cell disease: current activities, public health implications, and future directions. Journal of Women's Health 2007;16:575‐82. [PUBMED: 17627395] - PubMed
Cumming 2008
    1. Cumming V, King L, Fraser R, Serjeant G, Reid M. Venous incompetence, poverty and lactate dehydrogenase in Jamaica are important predictors of leg ulceration in sickle cell anaemia. British Journal of Haematology 2008;142:119‐25. [PUBMED: 18477043] - PubMed
Daudt 2007
    1. Daudt LE, Zechmaister D, Portal L, Neto EC, Silla LM, Giugliani R. Neonatal screening for hemoglobinopathies: a pilot study in Porto Alegre, Rio Grande do Sul, Brazil [Triagem neonatal para hemoglobinopatias: um estudo piloto em Porto Alegre, Rio Grande do Sul, Brasil]. Cadernos de Saúde Pública 2002;18:833‐41. [PUBMED: 12048609] - PubMed
Durosinmi 1991
    1. Durosinmi MA, Gevao SM, Esan GJ. Chronic leg ulcers in sickle cell disease: experience in Ibadan, Nigeria. African Journal of Medicine and Medical Sciencies 1991;20:11‐4. [PUBMED: 1905464] - PubMed
Eckman 1996
    1. Eckman JR. Leg ulcers in sickle cell disease. Hematology/Oncology Clinics of North America 1996;10:1333‐44. [PUBMED: 8956020] - PubMed
Edwards 2002
    1. Edwards J. Debridement of diabetic foot ulcers. Cochrane Database of Systematic Reviews 2002, Issue 4. [DOI: 10.1002/14651858.CD003556.pub2] - DOI - PubMed
Espinosa 1992
    1. Espinosa Martínez E, Villarreal Piloto C, Torres A, González A. Hyperbaric oxygen in the treatment of malleolar ulcer from sickle cell anemia [Oxigeno hiperbárico en el tratamiento de la úlcera maleolar de la anemia drepanocitica]. Revista Cubana de Hematología, Inmunología y Hemoterapia 1992;8:28‐36. [112188]
Frost 1990
    1. Frost ML, Treadwell P. Treatment of sickle cell leg ulcers with pentoxifylline. International Journal of Dermatology 1990;29:375‐6. [PUBMED: 2361798] - PubMed
Gabriel 2012
    1. Gabriel SE, Normand SL. Getting the Methods Right ‐ The Foundation of Patient‐Centered Outcomes Research. The New England Journal of Medicine 2012; Vol. Jul 25:Epub ahead of print. [PUBMED: 22830434] - PubMed
Gordon 2003
    1. Gordon S, Bui A. Human skin equivalent in the treatment of chronic leg ulcers in sickle cell disease patients. Journal of the American Podiatry Association 2003;93:240‐1. [PUBMED: 12756317] - PubMed
GRADEPro 2014 [Computer program]
    1. www.gradepro.org. GRADEpro. Version 20th October 2014. McMaster University, 2014.
Gulbis 2006
    1. Gulbis B, Ferster A, Cotton F, Lebouchard MP, Cochaux P, Vertongen F. Neonatal haemoglobinopathy screening: review of a 10‐year programme in Brussels. Journal of Medical Screening 2006;13:76‐8. [PUBMED: 16792829] - PubMed
Guyatt 2011
    1. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso‐Coello P, Rind D, et al. GRADE guidelines 6. Rating the quality of evidence‐‐imprecision. Journal of Clinical Epidemiology 2011;64(12):1283‐93. [PUBMED: 21839614] - PubMed
Guyatt 2011a
    1. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 7. Rating the quality of evidence‐‐inconsistency. Journal of Clinical Epidemiology 2011;64(12):1294‐302. [PUBMED: 21803546] - PubMed
Guyatt 2011b
    1. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J, et al. GRADE guidelines: 5. Rating the quality of evidence‐‐publication bias. Journal of Clinical Epidemiology 2011;64(12):1277‐82. [PUBMED: 21802904] - PubMed
Guyatt 2011c
    1. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 8. Rating the quality of evidence‐‐indirectness. Journal of Clinical Epidemiology 2011;64(12):1303‐10. [PUBMED: 21802903] - PubMed
Guyatt 2011d
    1. Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso‐Coello P, et al. GRADE guidelines: 9. Rating up the quality of evidence. Journal of Clinical Epidemiology 2011;64(12):1311‐6. [PUBMED: 21802902] - PubMed
Guyatt 2011e
    1. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso‐Coello P, et al. GRADE guidelines: 4. Rating the quality of evidence‐‐study limitations (risk of bias). Journal of Clinical Epidemiology 2011;64(4):407‐15. [PUBMED: 21247734] - PubMed
Guyatt 2011f
    1. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction‐GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 2011;64(4):383‐94. [PUBMED: 21195583] - PubMed
Guyatt 2011g
    1. Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. Journal of Clinical Epidemiology 2011;64(4):395‐400. [PUBMED: 21194891] - PubMed
Guyatt 2011h
    1. Guyatt GH, Oxman AD, Schunemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. Journal of Clinical Epidemiology 2011;64(4):380‐2. [PUBMED: 21185693] - PubMed
Guyatt 2012
    1. Guyatt G, Oxman AD, Sultan S, Brozek J, Glasziou P, Alonso‐Coello P, et al. GRADE guidelines 11‐making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. Journal of Clinical Epidemiology 2012;Apr 27:Epub print. [PUBMED: 22542023] - PubMed
Hagar 2008
    1. Hagar W, Vichinsky E. Advances in clinical research in sickle cell disease. British Journal of Haematology 2008;141:346‐56. [PUBMED: 18341629] - PubMed
Halabi ‐Tawil 2008
    1. Halabi‐Tawil M, Lionnet F, Girot R, Bachmeyer C, Levy PP, Aractingi S. Sickle cell leg ulcers: a frequently disabling complication and a marker of severity. British Journal of Dermatology 2008;158:339‐44. [PUBMED: 18047512] - PubMed
Harrel 1990
    1. Harrell HL Jr. L‐carnitine for leg ulcers. Annals of Internal Medicine 1990;113:412. [PUBMED: 2382928] - PubMed
Henthorn 2004
    1. Henthorn JS, Almeida AM, Davies SC. Neonatal screening for sickle cell disorders. British Journal of Haematology 2004;124:259‐63. [PUBMED: 14717772] - PubMed
Higgins 2003
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327(7414):557‐60. [PUBMED: 12958120] - PMC - PubMed
Higgins 2011
    1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration. Available from www.cochrane‐handbook.org 2011; Vol. Version 5.1.0 [updated March 2011].
Higgins 2011a
    1. Higgins JPT, Altman DG (editors). Chapter 8: Assessing risk of bias in included studies. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Higgins 2011b
    1. Higgins JPT, Deeks JJ, Altman DG on behalf of the CSMG. Chapter 16: Special topics in statistics. In: Higgins JPT, Green S (editors). Cochrane Handbook of Systematic Reviews of Interventions. Version 5.1 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Hopewell 2010
    1. Hopewell S, Clarke M, Higgins JPT (editors). Core reporting of outcomes in effectiveness trials. Cochrane Methods. Cochrane DB Syst Rev 2010; Vol. Suppl 1:1‐29. [ISSN 2044‐4702]
Ioannidis 2004
    1. Ioannidis JP, Evans SJ, Gotzsche PC, O'Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Annals of Internal Medicine 2004;141(10):781‐8. [PUBMED: 15545678] - PubMed
Ioannidis 2010
    1. Ioannidis JP. Meta‐research: The art of getting it wrong. Research Synthesis Methods 2010;1(3‐4):169‐84. - PubMed
Kato 2007
    1. Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Reviews 2007;21:37‐47. [PUBMED: 17084951] - PMC - PubMed
Kato 2009
    1. Kato GJ, Hebbel RP, Steinberg MH, Gladwin MT. Vasculopathy in sickle cell disease: Biology, pathophysiology, genetics, translational medicine, and new research directions. American Journal of Hematology 2009;84:618‐25. [PUBMED: 19610078] - PMC - PubMed
Kirkham 2010
    1. Kirkham JJ, Dwan KM, Altman DG, Gamble C, Dodd S, Smyth R, et al. The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews. BMJ 2010;340:c365. [PUBMED: 20156912] - PubMed
Knox‐Macaulay 1983
    1. Knox‐Macaulay HH. Sickle cell disease in Sierra Leone: a clinical and haematological analysis in older children and adults. Annals of Tropical Medicine and Parasitology 1983;77:411‐9. [PUBMED: 6639186] - PubMed
Koshy 1989
    1. Koshy M, Entsuah R, Koranda A, Kraus AP, Johnson R, Bellvue R, et al. Leg ulcers in patients with sickle cell disease. Blood 1989;74:1403‐8. [PUBMED: 2475188] - PubMed
La Grenade 2003
    1. Grenade L, Thomas PW, Serjeant GR. A randomized controlled trial of solcoseryl and duoderm in chronic sickle‐cell ulcers. West Indian Medical Journal 1993;42:121‐3. [PUBMED: 8273321] - PubMed
Lionnet 2008
    1. Lionnet F, Bachmeyer C, Stankovic K, Tharaux PL, Girot R, Aractingi S. Efficacy of the endothelin receptor blocker bosentan for refractory sickle cell leg ulcers. British Journal of Haematology 2008;142:991‐2. [PUBMED: 18671710] - PubMed
MacFarlane 1986
    1. MacFarlane DE, Baum KF, Serjeant GR. Bacteriology of sickle cell leg ulcers. Transactions of the Royal Society of Tropical Medicine and Hygiene 1986;80:553‐6. [PUBMED: 3101240] - PubMed
Mack 2006
    1. Mack AK, Kato GJ. Sickle cell disease and nitric oxide: a paradigm shift?. The International Journal of Biochemistry & Cell Biology 2006;38:1237‐43. [PUBMED: 16517208 ] - PMC - PubMed
Makani 2007
    1. Makani J, Williams TN, Marsh K. Sickle cell disease in Africa: burden and research priorities. Annals of Tropical Medicine and Parasitology 2007;101:3‐14. [MEDLINE: ] - PMC - PubMed
Martin 2011
    1. Martin E. Concise Medical Dictionary. 8th Edition. New York: Oxford University Press, 2011.
Mañú 2009
    1. Mañú Pereira M, Corrons JL. Neonatal haemoglobinopathy screening in Spain. Journal of Clinical Pathology 2009;62:22‐5. [PUBMED: 19103853] - PubMed
Mery 2004
    1. Mery L, Girot R, Aractingi S. Topical effectiveness of molgramostim (GM‐CSF) in sickle cell leg ulcers. Dermatology 2004;208:135‐7. [PUBMED: 15057003] - PubMed
Minniti 2010
    1. Minniti CP, Eckman J, Sebastiani P, Steinberg MH, Ballas SK. Leg ulcers in sickle cell disease. American Journal of Hematology 2010;85(10):831‐3. [MEDLINE: ] - PMC - PubMed
Modell 2008
    1. Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bulletin of the World Health Organization 2008;86:480‐7. [PUBMED: 18568278] - PMC - PubMed
Mohan 1997
    1. Mohan JS, Marshall JM, Reid HL, Thomas PW, Serjeant GR. Postural vasoconstriction and leg ulceration in homozygous sickle cell disease. Clinical Science 1997;92:153‐8. [PUBMED: 9059316] - PubMed
Mohan 2000
    1. Mohan JS, Vigilance JE, Marshall JM, Hambleton IR, Reid HL, Serjeant GR. Abnormal venous function in patients with homozygous sickle cell (SS) disease and chronic leg ulcers. Clinical Science 2000;98:667‐72. [PUBMED: 10814603] - PubMed
Moher 2010
    1. Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c869. [MEDLINE: ] - PMC - PubMed
Moore 2005
    1. Moore ZEH, Cowman S. Wound cleansing for pressure ulcers. Cochrane Database of Systematic Reviews 2005, Issue 4. [DOI: 10.1002/14651858.CD004983.pub2] - DOI - PubMed
Morgan 1981
    1. Morgan AG, Venner AM. Immunity and leg ulcers in homozygous sickle cell disease. Journal of Clinical & Laboratory Immunology 1981;6:51‐5. [PUBMED: 7265175] - PubMed
Morris 2008
    1. Morris CR. Mechanisms of vasculopathy in sickle cell disease and thalassemia. Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program 2008; Vol. 2008, issue 1:177‐85. [PUBMED: 19074078] - PubMed
Mousa 2010
    1. Mousa SA, Qari MH. Diagnosis and management of sickle cell disorders. Methods in Molecular Biology 2010;663:291‐307. [PUBMED: 20617425] - PubMed
Nebeker 2004
    1. Nebeker JR, Barach P, Samore MH. Clarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting. Annals of Internal Medicine 2004;140(10):795‐801. [PUBMED: 15148066] - PubMed
Nelson 2000
    1. Nelson EA, Bell‐Syer SEM, Cullum NA. Compression for preventing recurrence of venous ulcers. Cochrane Database of Systematic Reviews 2000, Issue 4. [DOI: 10.1002/14651858.CD002303] - DOI - PubMed
Nolan 2006
    1. Nolan VG, Baldwin C, Wang L, Ma Q, Wyszynski DF, Farrell JJ, Sebastiani P, et al. Sickle Cell Leg Ulcers: Associations with Haemolysis and SNPs in Klotho, TEK and Genes of the TGF‐beta/BMP Pathway. British Journal of Haematology 2006;133(5):570‐8. [PUBMED: 16681647] - PMC - PubMed
O'Meara 2000
    1. O'Meara S, Cullum N, Majid M, Sheldon T. Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration. Health Technology Assessment 2000;4(21):1‐237. [PUBMED: 11074391] - PubMed
O'Meara 2009
    1. O'Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: 10.1002/14651858.CD000265.pub2] - DOI - PubMed
O'Meara 2010
    1. O'Meara S, Al‐Kurdi D, Ovington LG. Antibiotics and antiseptics for venous leg ulcers. Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/14651858.CD003557.pub3] - DOI - PubMed
Ofosu 1987
    1. Ofosu MD, Castro O, Alarif L. Sickle cell leg ulcers are associated with HLA‐B35 and Cw4. Archives of Dermatology 1987;123(4):482‐4. [PUBMED: 3493733] - PubMed
Orkin 2010
    1. Orkin SH, Higgs DR. Medicine. Sickle cell disease at 100 years. Science (New York, N.Y.) 2010;329(5989):291‐2. [PUBMED: 20647458] - PubMed
Paladino 2007
    1. Paladino SF. Leg ulcers in sickle cell disease. Revista Brasileira de Hematologia e Hemoterapia 2007;29:288‐90. [470902]
Palfreyman 2006
    1. Palfreyman SSJ, Nelson EA, Lochiel R, Michaels JA. Dressings for healing venous leg ulcers. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI: 10.1002/14651858.CD001103.pub2] - DOI - PubMed
Pieters 1995
    1. Pieters RC, Rojer RA, Saleh AW, Saleh AE, Duits AJ. Molgramostim to treat SS‐sickle cell leg ulcers. Lancet 1995;345:528. [PUBMED: 7861910] - PubMed
Porta 2008
    1. Porta M (ed). Dictionary of Epidemiology. 5th Edition. New York: Oford University Press, 2008. [ISBN 978‐0‐19‐531449‐6]
Prabhakar 2010
    1. Prabhakar H, Haywood C Jr, Molokie R. Sickle cell disease in the United States: looking back and forward at 100 years of progress in management and survival. American Journal of Hematology 2010;85(5):346‐53. [PUBMED: 20425797] - PubMed
Ramalho 1985
    1. Ramalho AS, Velloso LA, Diniz M. Sickle cell syndromes and ulcer of inferior extremities [Síndromes falcêmicas e úlceras de membros inferiores]. Anais Brasileiros de Dermatologia 1985;60:307‐10. [29971]
Rees 2010
    1. Rees DC, Williams TN, Gladwin MT. Sickle‐cell disease. Lancet 2010;376(9757):2018‐31. [PUBMED: 21131035] - PubMed
Reindorf 1989
    1. Reindorf CA, Walker‐Jones D, Adekile AD, Lawal O, Oluwole SF. Rapid healing of sickle cell leg ulcers treated with collagen dressing. Journal of the National Medical Association 1989;81:866‐8. [PUBMED: 2769790] - PMC - PubMed
Rice 1953
    1. Rice SM. Healing of chronic sicklemia leg ulcers healed by cortisone. A.M.A. Archives of Dermatology and Syphilology 1953;68:576‐9. [PUBMED: 13091419] - PubMed
Santen 2004
    1. Santen SA. Transfusion therapy. In: Tintinalli JE, Kellen GD, Stapczynski JS editor(s). Emergency Medicine: A comprehensive study guide. 6th Edition. New York: McGraw Hill, 2004:1348‐53. [0‐07138875‐3]
Schleucher 2007
    1. Schleucher R, Gaessler M, Knobloch J. Rapid healing of a late diagnosed sickle cell leg ulcer using a new combination of treatment methods. Journal of Wound Care 2007;16(5):197‐8. [PUBMED: 17552401] - PubMed
Sehgal 1992
    1. Sehgal SC, Arunkumar BK. Microbial flora and its significance in pathology of sickle cell disease leg ulcers. Infection 1992;20(2):86‐8. [PUBMED: 1582689] - PubMed
Serarslan 2009
    1. Serarslan G, Akgül F, Babayigit C. High prevalence of pulmonary hypertension in homozygous sickle cell patients with leg ulceration. Clinical and Experimental Hypertension 2009;31(1):44‐8. [PUBMED: 19172458] - PubMed
Serjeant 2005
    1. Serjeant GR, Serjeant BE, Mohan JS, Clare A. Leg ulceration in sickle cell disease: medieval medicine in a modern world. Hematology/Oncology Clinics of North America 2005;19(5):943‐56. [PUBMED: 16214654] - PubMed
Serjeant 2010
    1. Serjeant GR. One hundred years of sickle cell disease. British Journal of Haematology 2010;151(5):425‐9. [PUBMED: 20955412] - PubMed
Sher 1994
    1. Sher GD, Olivieri NF. Rapid healing of chronic leg ulcers during arginine butyrate therapy in patients with sickle cell disease and thalassemia. Blood 1994;84(7):2378‐80. [PUBMED: 7919358] - PubMed
Smith 2011
    1. Smith F, Dryburgh N, Donaldson J, Mitchell M. Debridement for surgical wounds. Cochrane Database of Systematic Reviews 2011, Issue 5. [DOI: 10.1002/14651858.CD006214.pub3] - DOI - PubMed
Spence 1985
    1. Spence RJ. The use of a free flap in homozygous sickle cell disease. Plastic and Reconstructive Surgery 1985;76(4):616‐9. [MEDLINE: ] - PubMed
Steinberg 2009
    1. Steinberg MH. Genetic etiologies for phenotypic diversity in sickle cell anemia. Scientific World Journal 2009;9:46‐67. [PUBMED: 19151898] - PMC - PubMed
Taylor 2008
    1. Taylor JG 6th, Nolan VG, Mendelsohn L, Kato GJ, Gladwing MT, Steinberg MH. Chronic hyper‐hemolysis in sickle cell anemia: association of vascular complications and mortality with less frequent vasooclussive pain. PloSOne 2008;3:e2095. [PUBMED: 18461136] - PMC - PubMed
Trent 2004
    1. Trent JT, Kirsner RS. Leg ulcers in sickle cell disease. Advances in Skin & Wound Care 2004;17(8):410‐6. [PUBMED: 15492676] - PubMed
Tshilolo 2008
    1. Tshilolo L, Kafando E, Sawadogo M, Cotton F, Vertongen F, Ferster A, et al. Neonatal screening and clinical care programmes for sickle cell disorders in sub‐Saharan Africa: lessons from pilot studies. Public Health 2008;122(9):933‐41. [PUBMED: 18555498] - PubMed
Vermeulen 2004
    1. Vermeulen H, Ubbink DT, Goossens A, Vos R, Legemate DA. Dressings and topical agents for surgical wounds healing by secondary intention. Cochrane Database of Systematic Reviews 2004, Issue 1. [DOI: 10.1002/14651858.CD003554.pub2] - DOI - PMC - PubMed
Wasiak 2008
    1. Wasiak J, Cleland H, Campbell F. Dressings for superficial and partial thickness burns. Cochrane Database of Systematic Reviews 2008, Issue 4. [DOI: 10.1002/14651858.CD002106.pub3] - DOI - PubMed
Weatherall 2006
    1. Weatherall D, Akinyanju O, Fucharoen S, Olivieri N, Musgrove P. Inherited Disorders of Hemoglobin. Disease Control Priorities in Developing Countries. 2nd Edition. Washington DC: The World Bank and Oxford University Press, 2006.
Wilkinson 1998
    1. Wilkinson EAJ, Hawke CC. Oral zinc for arterial and venous leg ulcers. Cochrane Database of Systematic Reviews 1998, Issue 4. [DOI: 10.1002/14651858.CD001273] - DOI - PubMed
Wood 2008
    1. Wood KC, Hsu LL, Gladwin MT. Sickle cell disease vasculopathy: a state of nitric oxide resistance. Free Radical Biology and Medicine 2008;44(8):1506‐28. [PUBMED: 18261470] - PubMed

References to other published versions of this review

Martí‐Carvajal 2012
    1. Martí‐Carvajal AJ, Knight‐Madden JM, Martinez‐Zapata MJ. Interventions for treating leg ulcers in people with sickle cell disease. Cochrane Database of Systematic Reviews 2012, Issue 11. [DOI: 10.1002/14651858.CD008394.pub2] - DOI - PubMed

Publication types

MeSH terms

LinkOut - more resources