Controversies in the pathophysiology of leg ulcers in sickle cell disease.
chronic wounds
leg ulcers
pathophysiology
sickle cell disease
treatment
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
12 Jun 2024
12 Jun 2024
Historique:
received:
22
12
2023
accepted:
27
05
2024
medline:
13
6
2024
pubmed:
13
6
2024
entrez:
13
6
2024
Statut:
aheadofprint
Résumé
Patients with sickle cell disease (SCD) often experience painful vaso-occlusive crises and chronic haemolytic anaemia, as well as various acute and chronic complications, such as leg ulcers. Leg ulcers are characterized by their unpredictability, debilitating pain and prolonged healing process. The pathophysiology of SCD leg ulcers is not well defined. Known risk factors include male gender, poor social conditions, malnutrition and a lack of compression therapy when oedema occurs. Leg ulcers typically start with spontaneous pain, followed by induration, hyperpigmentation, blister formation and destruction of the epidermis. SCD is characterized by chronic haemolysis, increased oxidative stress and decreased nitric oxide bioavailability, which promote ischaemia and inflammation and consequently impair vascular function in the skin. This cutaneous vasculopathy, coupled with venostasis around the ankle, creates an ideal environment for local vaso-occlusive crises, which can result in the development of leg ulcers that resemble arterial ulcers. Following the development of the ulcer, healing is hindered as a result of factors commonly observed in venous ulceration, including venous insufficiency, oedema and impaired angiogenesis. All of these factors are modulated by genetic factors. However, our current understanding of these genetic factors remains limited and does not yet enable us to accurately predict ulceration susceptibility.
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
Références
Rees DC, Williams TN, Gladwin MT. Sickle‐cell disease. Lancet. 2010;376(9757):2018–2031.
Therrell BL, Lloyd‐Puryear MA, Eckman JR, Mann MY. Newborn screening for sickle cell diseases in the United States: a review of data spanning 2 decades. Semin Perinatol. 2015;39(3):238–251.
Pauling L, Itano HA. Sickle cell anemia a molecular disease. Science. 1949;110(2865):543–548.
Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene‐Frempong K, Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4(1):1–22.
Serjeant GR. Leg ulceration in sickle cell anemia. Arch Intern Med. 1974;133(4):690–694.
Alleyne SI, Wint E, Serjeant GR. Psychosocial aspects of sickle cell disease. Health Soc Work. 1976;1(4):104–119.
Alleyne SI, Wint E, Serjeant GR. Social effects of leg ulceration in sickle cell anemia. South Med J. 1977;70(2):213–214.
Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Outcome of sickle cell anemia: a 4‐decade observational study of 1056 patients. Medicine (Baltimore). 2005;84(6):363–376.
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. Br J Haematol. 2008;142(1):119–125.
Olatunya OS, Albuquerque DM, Adekile AD, Costa FF. Evaluation of sociodemographic, clinical, and laboratory markers of sickle leg ulcers among young Nigerians at a tertiary health institution. Niger J Clin Pract. 2018;21(7):882–887.
Antwi‐Boasiako C, Andemariam B, Colombatti R, Asare EV, Strunk C, Piccone CM, et al. A study of the geographic distribution and associated risk factors of leg ulcers within an international cohort of sickle cell disease patients: the CASiRe group analysis. Ann Hematol. 2020;99(9):2073–2079.
Spira JAO, Borges EL, Guedes ACM, Andrade PGR, Lima VL. Prevalence of people with sickle cell disease and leg ulcers in Brazil: socioeconomic and clinical overview. PLoS One. 2022;17(9):e0274254.
Madu A, Madu K, Anigbogu I, Ugwu AO, Okwulehie VA, Ololo U, et al. Phenotypic characterisation and associations of leg ulcers in adult sickle cell patients. Wound Repair Regen. 2022;30(1):126–131.
Eckman JR. Leg ulcers in sickle cell disease. Hematol Oncol Clin North Am. 1996;10(6):1333–1344.
Minniti CP, Delaney KMH, Gorbach AM, Xu D, Lee CCR, Malik N, et al. Vasculopathy, inflammation, and blood flow in leg ulcers of patients with sickle cell anemia. Am J Hematol. 2014;89(1):1–6.
Durosinmi MA, Gevao SM, Esan GJ. Chronic leg ulcers in sickle cell disease: experience in Ibadan. Nigeria Afr J Med Sci. 1991;20(1):11–14.
Delaney KMH, Axelrod KC, Buscetta A, Hassell KL, Adams‐Graves PE, Seamon C, et al. Leg ulcers in sickle cell disease: current pattern and practices. Hemoglobin. 2013;37(4):325–332.
Reis de Souza V, Kelly S, Cerdeira Sabino E, Mendes de Oliveira F, Silva T, Miranda Teixeira C, et al. Factors associated with leg ulcers in adults with sickle cell disease in Brazil. Adv Skin Wound Care. 2023;36(2):98–105.
Minniti CP, Taylor JG, Hildesheim M, O'Neal P, Wilson J, Castro O, et al. Laboratory and echocardiography markers in sickle cell patients with leg ulcers. Am J Hematol. 2011;86(8):705–708.
Shi C, Dumville JC, Cullum N, Connaughton E, Norman G. Compression bandages or stockings versus no compression for treating venous leg ulcers. Cochrane Database Syst Rev. 2021;7(7):CD013397.
Zhang H, Yang Z. Research on dynamic comfort maintenance by measuring lower limb oedema and seat pressure during simulated seated sleep in flight. Int J Occup Saf Ergon. 2024;30(1):72–83.
Molnar JA, Underdown MJ, Clark WA. Nutrition and chronic wounds. Adv Wound Care (New Rochelle). 2014;3(11):663–681.
Stechmiller JK. Understanding the role of nutrition and wound healing. Nutr Clin Pract. 2010;25(1):61–68.
Ataga KI, Saraf SL, Derebail VK. The nephropathy of sickle cell trait and sickle cell disease. Nat Rev Nephrol. 2022;18(6):361–377.
Kato GJ, Steinberg MH, Gladwin MT. Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest. 2017;127(3):750–760.
Serjeant GR, Serjeant BE, Mohan JS, Clare A. Leg ulceration in sickle cell disease: medieval medicine in a modern world. Hematol Oncol Clin North Am. 2005;19(5):943–956.
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(4):1403–1408.
Gniadecka M, Gniadecki R, Serup J, Søndergaard J. Microvascular reactions to postural changes in patients with sickle cell anaemia. Acta Derm Venereol. 1994;74(3):191–193.
Oguanobi N, Onwubere B, Anisiuba B, Ike S, Ejim E, Ibegbulam O. Clinical findings associated with cardiovascular autonomic dysfunction in adult sickle cell anaemia patients. Acta Cardiol. 2012;67:169–175.
Hassan A, Gayus GL, Abdulrasheed I, Umar MA, Ismail DL, Babadoko AA. Chronic leg ulcers in sickle cell disease patients in Zaria. Nigeria Arch Int Surg. 2014;4(3):141–145.
Gabuzda TG. Sickle cell leg ulcers: current pathophysiologic concepts. Int J Dermatol. 1975;14(5):322–325.
Mohan JS, Marshall JM, Reid HL, Thomas PW, Serjeant GR. Postural vasoconstriction and leg ulceration in homozygous sickle cell disease. Clin Sci (Lond). 1997;92(2):153–158.
Ayoola OO, Bolarinwa RA, Onakpoya UU, Adedeji TA, Onwuka CC, Idowu BM. Intima‐media thickness of the common femoral artery as a marker of leg ulceration in sickle cell disease patients. Blood Adv. 2018;2(22):3112–3117.
Connes P, Lamarre Y, Waltz X, Ballas SK, Lemonne N, Etienne‐Julan M, et al. Haemolysis and abnormal haemorheology in sickle cell anaemia. Br J Haematol. 2014;165(4):564–572.
Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev. 2007;21(1):37–47.
Nolan VG, Adewoye A, Baldwin C, Wang L, Ma Q, Wyszynski DF, et al. Sickle cell leg ulcers: associations with Haemolysis and SNPs in klotho, TEK and genes of the TGF‐β/BMP pathway. Br J Haematol. 2006;133(5):570–578.
Bartolucci P, Brugnara C, Teixeira‐Pinto A, Pissard S, Moradkhani K, Jouault H, et al. Erythrocyte density in sickle cell syndromes is associated with specific clinical manifestations and hemolysis. Blood. 2012;120(15):3136–3141.
Ranque B, Diaw M, Dembele AK, Lapoumeroulie C, Offredo L, Tessougue O, et al. Association of haemolysis markers, blood viscosity and microcirculation function with organ damage in sickle cell disease in sub‐Saharan Africa (the BIOCADRE study). Br J Haematol. 2023;203(2):319–326.
Minniti CP, Knight‐Madden J, Tonda M, Gray S, Lehrer‐Graiwer J, Biemond BJ. The impact of voxelotor treatment on leg ulcers in patients with sickle cell disease. Am J Hematol. 2021;96(4):E126–E128.
Vissa M, Vichinsky E. Voxelotor for the treatment of sickle cell disease. Expert Rev Hematol. 2021;14(3):253–262.
Chirico EN, Pialoux V. Role of oxidative stress in the pathogenesis of sickle cell disease. IUBMB Life. 2012;64(1):72–80.
Trent JT, Kirsner RS. Leg ulcers in sickle cell disease. Adv Skin Wound Care. 2004;17(8):146–410.
Landburg PP, Teerlink T, Biemond BJ, Brandjes DPM, Muskiet FAJ, Duits AJ, et al. Plasma asymmetric dimethylarginine concentrations in sickle cell disease are related to the hemolytic phenotype. Blood Cell Mol Dis. 2010;44(4):229–232.
Minniti CP, Gorbach AM, Xu D, Hon YY, Delaney KM, Seidel M, et al. Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose‐finding safety and tolerability trial. Lancet Haematol. 2014;1:e95–e103.
Riddell DR, Owen JS. Nitric oxide and platelet aggregation. Vitam Horm. 1997;57:25–48.
De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA, et al. Nitric oxide decreases cytokine‐induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995;96(1):60–68.
Francillon YJ, Jilly PN, Varricchio F, Castro O. Histochemical analysis of growth factor, fibronectin, and iron content of sickle cell leg ulcers. Wound Repair Regen. 1996;4(2):240–243.
Bowers AS, Reid HL, Greenidge A, Landis C, Reid M. Blood viscosity and the expression of inflammatory and adhesion markers in homozygous sickle cell disease subjects with chronic leg ulcers. PLoS One. 2013;8(7):e68929.
Domingos IF, Pereira‐Martins DA, Sobreira MJVC, Oliveira RTD, Alagbe AE, Lanaro C, et al. High levels of proinflammatory cytokines IL‐6 and IL‐8 are associated with a poor clinical outcome in sickle cell anemia. Ann Hematol. 2020;99(5):947–953.
Vicari P, Adegoke SA, Mazzotti DR, Cançado RD, Nogutti MAE, Figueiredo MS. Interleukin‐1β and interleukin‐6 gene polymorphisms are associated with manifestations of sickle cell anemia. Blood Cell Mol Dis. 2015;54(3):244–249.
Belisário AR, Mendes‐Oliveira F, de Souza VR, Bolina‐Santos E, Mendes FG, Moreno EC, et al. Association between inflammatory molecules, nitric oxide metabolites and leg ulcers in individuals with sickle cell anemia. Hematol Transfus Cell Ther. 2022;44(2):169–176.
Rêgo MJBM, da Silva RR, Pereira MC, da Silva Araújo A, da Rocha Pitta MG, Falcão DA, et al. Evaluation of CD4+CD25+FoxP3+ T cell populations, IL‐10 production, and their correlation with clinical and biochemical parameters in sickle cell anemia patients with leg ulcers. Cytokine. 2015;75(2):310–315.
Ballas SK. Sickle cell anemia with few painful crises is characterized by decreased red cell deformability and increased number of dense cells. Am J Hematol. 1991;36(2):122–130.
Bowers AS, Duncan WW, Pepple DJ. Red blood cell deformability is reduced in homozygous sickle cell disease patients with leg ulcers. Clin Hemorheol Microcirc. 2016;5(2):199–204.
Connes P, Lamarre Y, Hardy‐Dessources MD, Lemonne N, Waltz X, Mougenel D, et al. Decreased hematocrit‐to‐viscosity ratio and increased lactate dehydrogenase level in patients with sickle cell anemia and recurrent leg ulcers. PLoS One. 2013;8(11):e79680.
Akinsheye I, Alsultan A, Solovieff N, Ngo D, Baldwin CT, Sebastiani P, et al. Fetal hemoglobin in sickle cell anemia. Blood. 2011;118(1):19–27.
Hutz MH, Salzano FM, Adams J, Opitz JM. Hb F levels, longevity of homozygotes and clinical course of sickle cell anemia in Brazil. Am J Med Genet. 1983;14(4):669–676.
Adedeji MO, Ukoli FA. Haematological factors associated with leg ulcer in sickle cell disease. Trop Geogr Med. 1987;39(4):354–356.
Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia. N Engl J Med. 1995;332(20):1317–1322.
Dissemond J, Hoeft D, Knab J, Franckson T, Kroger K, Goos M. Leg ulcer in a patient associated with hydroxyurea therapy. Int J Dermatol. 2006;45(2):158–160.
Hwang SW, Hong SK, Kim SH, Seo JK, Lee D, Sung HS. A hydroxyurea‐induced leg ulcer. Ann Dermatol. 2009;21(1):39–41.
Best PJ, Daoud MS, Pittelkow MR, Petitt RM. Hydroxyurea‐induced leg ulceration in 14 patients. Ann Intern Med. 1998;128(1):29–32.
Salmon‐Ehr V, Leborgne G, Vilque JP, Potron G, Bernard P. Effets secondaires cutanés de l'hydroxyurée: étude prospective de 26 patients consultant dans un service de dermatologie. Rev Med Interne. 2000;21(1):30–34.
Soya E, Makowski C, Blaise S. Leg ulcer induced by hydroxycarbamide in sickle cell disease: what is the therapeutic impact? Int Wound J. 2019;16(4):897–902.
Tolu SS, Crouch A, Choi J, Gao Q, Reyes‐Gil M, Ogu UO, et al. Hydroxyurea and fetal hemoglobin effect on leg ulcers in patients with sickle cell disease. Ann Hematol. 2022;101(3):541–548.
de Montalembert M, Voskaridou E, Oevermann L, Cannas G, Habibi A, Loko G, et al. Real‐life experience with hydroxyurea in patients with sickle cell disease: results from the prospective ESCORT‐HU cohort study. Am J Hematol. 2021;96(10):1223–1231.
Alexander N, Higgs D, Dover G, Serjeant GR. Are there clinical phenotypes of homozygous sickle cell disease? Br J Haematol. 2004;126(4):606–611.
Serarslan G, Akgül F, Babayigit C. High prevalence of pulmonary hypertension in homozygous sickle cell patients with leg ulceration. Clin Exp Hypertens. 2009;31(1):44–48.
De Castro LM, Jonassaint JC, Graham FL, Ashley‐Koch A, Telen MJ. Pulmonary hypertension associated with sickle cell disease: clinical and laboratory endpoints and disease outcomes. Am J Hematol. 2008;83(1):19–25.
Parent F, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med. 2011;365(1):44–53.
Nolan VG, Baldwin C, Ma Q, Wyszynski DF, Amirault Y, Farell JJ, et al. Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia. Br J Haematol. 2004;128:266–272.
Powars D, Chan LS, Schroeder WA. The variable expression of sickle cell disease is genetically determined. Semin Hematol. 1990;27(4):360–376.
Flint J, Harding RM, Boyce AJ, Clegg JB. The population genetics of the haemoglobinopathies. Baillieres Clin Haematol. 1998;11(1):1–51.
Higgs DR, Aldridge BE, Lamb J, Clegg JB, Weatherall DJ, Hayes RJ, et al. The interaction of alpha‐thalassemia and homozygous sickle‐cell disease. N Engl J Med. 1982;306(24):1441–1446.
Steinberg MH. Predicting clinical severity in sickle cell anaemia. Br J Haematol. 2005;129(4):465–481.
Ofosu MD, Castro O, Alarif L. Sickle cell leg ulcers are associated with HLA‐B35 and Cw4. Arch Dermatol. 1987;123(4):482–484.
Salazar G, Colombo G, Lenna S, Antonioli R, Beretta L, Santaniello A, et al. HLA‐B35 influences the apoptosis rate in human peripheral blood mononucleated cells and HLA‐transfected cells. Hum Immunol. 2007;68(3):181–191.
Santaniello A, Salazar G, Lenna S, Antonioli R, Colombo G, Beretta L, et al. HLA‐B35 upregulates the production of endothelin‐1 in HLA‐transfected cells: a possible pathogenetic role in pulmonary hypertension. Tissue Antigens. 2006;68(3):239–244.
Nebor D, Durpes MC, Mougenel D, Mukisi‐Mukaza M, Elion J, Hardy‐Dessources MD, et al. Association between Duffy antigen receptor for chemokines expression and levels of inflammation markers in sickle cell anemia patients. Clin Immunol. 2010;136(1):116–122.
Afenyi‐Annan A, Kail M, Combs MR, Orringer EP, Ashley‐Koch A, Telen MJ. Lack of Duffy antigen expression is associated with organ damage in patients with sickle cell disease. Transfusion. 2008;48(5):917–924.
Drasar ER, Menzel S, Fulford T, Thein SL. The effect of Duffy antigen receptor for chemokines on severity in sickle cell disease. Haematologica. 2013;98(8):e87–e89.
Lee RC, Feinbaum RL, Ambros V. The C. Elegans heterochronic gene lin‐4 encodes small RNAs with antisense complementarity to lin‐14. Cell. 1993;75(5):843–854.
Kim VN, Han J, Siomi MC. Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol. 2009;10(2):126–139.
Santos ED, Melo GI, Santana PV, Quadros IG, Yahouédéhou SC, Guarda CC, et al. A description of the hemolytic component in sickle leg ulcer: the role of circulating miR‐199a‐5p, miR‐144, and miR‐126. Biomol Ther. 2022;12(2):317.
Le NT, Abe JI. MicroRNA 199a and the eNOS (endothelial NO synthase)/NO pathway. Arterioscler Thromb Vasc Biol. 2018;38(10):2278–2280.
Li B, Zhu X, Ward CM, Starlard‐Davenport A, Takezaki M, Berry A, et al. MIR‐144‐mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell disease. Exp Hematol. 2019;70:85–96.
Zhang H, Li S, Zhou Q, Sun Q, Shen S, Zhou Y, et al. Qiliqiangxin attenuates phenylephrine‐induced cardiac hypertrophy through downregulation of MiR‐199a‐5p. Cell Physiol Biochem. 2016;38(5):1743–1751.
Hua Q, Jin M, Mi B, Xu F, Li T, Zhao L, et al. LINC01123, a c‐Myc‐activated long non‐coding RNA, promotes proliferation and aerobic glycolysis of non‐small cell lung cancer through miR‐199a‐5p/c‐Myc axis. J Hematol Oncol. 2019;12(1):91.
Balasubramaniyan N, Devereaux M, Orlicky D, Sokol R, Suchy F. miR‐199a‐5p inhibits the expression of ABCB11 in obstructive cholestasis. J Biol Chem. 2021;297(6):101400. https://pubmed.ncbi.nlm.nih.gov/34774795/
Kooshkaki O, Rezaei Z, Rahmati M, Vahedi P, Derakhshani A, Brunetti O, et al. MiR‐144: a new possible therapeutic target and diagnostic/prognostic tool in cancers. Int J Mol Sci. 2020;21(7):2578.
Rodrigo‐Muñoz JM, Gil‐Martínez M, Lorente‐Sorolla C, García‐Latorre R, Valverde‐Monge M, Quirce S, et al. miR‐144‐3p is a biomarker related to severe corticosteroid‐dependent asthma. Front Immunol. 2022;13:858722.
Jansen F, Yang X, Hoelscher M, Cattelan A, Schmitz T, Proebsting S, et al. Endothelial microparticle–mediated transfer of microRNA‐126 promotes vascular endothelial cell repair via SPRED1 and is abrogated in glucose‐damaged endothelial microparticles. Circulation. 2013;128(18):2026–2038.
Ma Y, Liu H, Wang Y, Xuan J, Gao X, Ding H, et al. Roles of physical exercise‐induced MiR‐126 in cardiovascular health of type 2 diabetes. Diabetol Metab Syndr. 2022;4(1):169.
Leisegang MS, Schröder K, Brandes RP. Redox regulation and noncoding RNAs. Antioxid Redox Signal. 2018;29(9):793–812.
Silva DG, Junior EB, de Souza Torres L, Júnior OR, de Castro Lobo C, Bonini‐Domingos CR, et al. Relationship between oxidative stress, glutathione S‐transferase polymorphisms and hydroxyurea treatment in sickle cell anemia. Blood Cell Mol Dis. 2011;47(1):23–28.
de Oliveira Filho RA, Silva GJ, de Farias Domingos I, Domingues Hatzlhofer BL, da Silva AA, de Lima Filho JL, et al. Association between the genetic polymorphisms of glutathione S‐transferase (GSTM1 and GSTT1) and the clinical manifestations in sickle cell anemia|Elsevier enhanced reader. Blood Cell Mol Dis. 2013;51:76–79.
Serjeant BE, Harris J, Thomas P, Serjeant GR. Propionyl‐L‐carnitine in chronic leg ulcers of homozygous sickle cell disease: a pilot study. J Am Acad Dermatol. 1997;37(3 Pt 1):491–493.
Serjeant GR, Galloway RE, Gueri MC. Oral zinc sulphate in sickle‐cell ulcers. Lancet. 1970;2(7679):891–892.
Martí‐Carvajal AJ, Knight‐Madden JM, Martinez‐Zapata MJ. Interventions for treating leg ulcers in people with sickle cell disease. Cochrane Database Syst Rev. 2021;1(1):CD008394.
Miranda CT, Vermeulen‐Serpa KM, Pedro AC, Brandão‐Neto J, de Lima Vale SH, Figueiredo MS. Zinc in sickle cell disease: a narrative review. J Trace Elem Med Biol. 2022;72:126980.
Attisano L, Wrana JL. Signal transduction by the TGF‐beta superfamily. Science. 2002;296(5573):1646–1647.
Pastar I, Khan AA, Stojadinovic O, Lebrun EA, Medina MC, Brem H, et al. Induction of specific MicroRNAs inhibits cutaneous wound healing. J Biol Chem. 2012;287(35):29324–29335.
Batista THC, Santana RM, Sobreira MJ, Arcanjo GS, Domingos IF, Pereira‐Martins DA, et al. Up‐regulation of miR‐130a is related to leg ulcers in sickle cell anaemia. Br J Haematol. 2022;197(1):e16–e18.
de Carvalho‐Siqueira GQ, Ananina G, de Souza BB, Borges MG, Ito MT, da Silva‐Costa SM, et al. Highlight article: whole‐exome sequencing indicates FLG2 variant associated with leg ulcers in Brazilian sickle cell anemia patients. Exp Biol Med (Maywood). 2019;244(11):932–939.
Senet P, Blas‐Chatelain C, Levy P, Manea EM, Peschanski M, Mirault T, et al. Factors predictive of leg‐ulcer healing in sickle cell disease: a multicentre, prospective cohort study. Br J Dermatol. 2017;177(1):206–211.
Tan J, Smith A, Abisi S, Eastham D, Burnand KG. Tissue and urinary haemosiderin in chronic leg ulcers. Eur J Vasc Endovasc Surg. 2007;34(3):355–360.
Saad STO, Zago MA. Leg ulceration and abnormalities of calf blood flow in sickle‐cell anemia. Eur J Haematol. 1991;46(3):188–190.
Billet HH, Patel Y, Rivers SP. Venous insufficiency is not the cause of leg ulcers in sickle cell disease. Am J Hematol. 1991;37(2):133–134.
Clare A, FitzHenley M, Harris J, Hambleton I, Serjeant GR. Chronic leg ulceration in homozygous sickle cell disease: the role of venous incompetence. Br J Haematol. 2002;119(2):567–571.
Minniti CP, Kato GJ. Critical reviews: how we treat sickle cell patients with leg ulcers. Am J Hematol. 2016;91(1):22–30.
Babalola OA, Ogunkeyede A, Odetunde AB, Fasola F, Oni AA, Babalola CP, et al. Haematological indices of sickle cell patients with chronic leg ulcers on compression therapy. Afr J Lab Med. 2020;9(1):8.
MacFarlane DE, Baum KF, Serjeant GR. Bacteriology of sickle cell leg ulcers. Trans R Soc Trop Med Hyg. 1986;80(4):553–556.
Ademiluyi SA, Rotimi VO, Coker AO, Banjo TO, Akinyanju O. The anaerobic and aerobic bacterial flora of leg ulcers in patients with sickle‐cell disease. J Infect. 1988;17(2):115–120.
Sehgal SC, Arunkumar BK. Microbial flora and its significance in pathology of sickle cell disease leg ulcers. Infection. 1992;20(2):86–88.
Byeon J, Blizinsky KD, Persaud A, Findley K, Lee JJ, Buscetta AJ, et al. Insights into the skin microbiome of sickle cell disease leg ulcers. Wound Repair Regen. 2021;29(5):801–809.
Mohammedsaeed W, Cruickshank S, McBain AJ, O'Neill CA. Lactobacillus rhamnosus GG lysate increases Re‐epithelialization of keratinocyte scratch assays by promoting migration. Sci Rep. 2015;5:16147.
Nguyen VT, Nassar D, Batteux F, Raymond K, Tharaux PL, Aractingi S. Delayed healing of sickle cell ulcers is due to impaired angiogenesis and CXCL12 secretion in skin wounds. J Invest Dermatol. 2016;136(2):497–506.
Meneses JVL, Fortuna V, de Souza ES, Daltro GC, Meyer R, Minniti CP, et al. Autologous stem cell‐based therapy for sickle cell leg ulcer: a pilot study. Br J Haematol. 2016;175(5):949–955.
Lemonne N, Charlot K, Waltz X, Ballas SK, Lamarre Y, Lee K, et al. Hydroxyurea treatment does not increase blood viscosity and improves red blood cell rheology in sickle cell anemia. Haematologica. 2015;100(10):e383–e386.
Pule GD, Mowla S, Novitzky N, Wiysonge CS, Wonkam A. A systematic review of known mechanisms of hydroxyurea‐induced fetal hemoglobin for treatment of sickle cell disease. Expert Rev Hematol. 2015;8(5):669–679.