Hydroxyurea efficacy in sickle cell anemia patients in low-income middle country in Cote d’Ivoire

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Very few studies have been set in Subsaharan Africa according to hydroxyurea effacy and safety. We aimed to evaluate Hydroxyurea efficacy and safety and its benefits in low-resource settings. Methods We conducted a prospective comparative study of SCA patients. 128 patients was enrolled and divided in two groups. 68 patients treated by hydroxyurea at doses 10-20mg/kg/day and 62 patients control groups without hydroxyurea. The end points assessed was feasibility, safety, and benefits (laboratory variables, sickle cell–related events, transfusions). Results : The patients assigned to hydroxyurea treatment had lower annual rate of crises than the control group (median, 2.9 vs. 5.3 crises per year, P=0.001), fewer annual rate of hospitalizations (median 2.2 vs. 4.7, P=0.002), and fewer annual rate of transfusion (median 1.3 vs.5.1, P=0.001). We observed a significant increase in Hb F level from 11.77% to 14.6% (p=0.001) in patient treated by hydroxyurea. We also observed a significant increase in the mean of Hb level from 7.3 g/dl to 9.2 g/dl for patients treated by hydroxyurea (p=0.004). Patients treated by hydroxyurea also have a beneficial effect on WBC and platelet levels by reduction in leukocytosis and thrombocytosis. the occurrence of annual number of infectious complications was significantly lower in the group of patients with hydroxyurea. Conclusion : Hydroxyurea has a key clinical benefits by reducing the incidence of vaso-occlusive events, infections, transfusions, which translates into fewer hospitalizations. The main problem is the fact that, it’s not accessible for most of our patients who live in poor socio-economical condition. Introduction Sickle cell disease is the most common genetic haemoglobin disorder and most commonly affects individuals of African descent. Ivory Coast is one of the fifteen most affected countries in the world [ 1 ]. Sickle cell disease or sickle cell anaemia is an autosomal recessive genetic disease involving the inheritance of abnormal haemoglobin. It is a point mutation of haemoglobin which results from a single β-globin gene mutation, leading to an amino-acid substitution (Glu→Val, βA→βS) and formation of the abnormal HbS tetramer. Under deoxygenated states, HbS undergoes rapid intracellular polymerization, which damages the erythrocyte membrane and significantly alters both its shape and its flexibility while carrying oxygen to the body. These stiff and ‘sickled’ red blood cells have a decreased lifespan, and result in both acute and chronic hemolysis. They also undergo a complex process known as vaso-occlusion, in which sickled erythrocytes and other circulating cells adhere to the vascular endothelium, aggregate together to disrupt blood flow especially in the small blood vessels, and cause hypoxia to tissues and vital organs [ 2 ]. According to the World Health Organization, on a global scale, the incidence of sickle hemoglobinopathies is greatest in sub-Saharan Africa, with more than 300,000 babies with sickle cell disease born annually, representing approximately 1% of births in the region. Côte d’Ivoire is one of the fifteen most affected countries in the world [ 3 ] where the sickle cell burden is greatest, early diagnostic capacities are lacking and childhood mortality is high [ 4 ]. As recently as the 1980s, the only available disease-modifying therapy for SCA was intermittent red blood cell transfusions, which were commonly reserved for acute, life-threatening complications. In the 1990s, hydroxyurea emerged as a promising pharmacologic therapy for SCA, due primarily to its ability to induce HbF [ 5 ], and over the past 30 years has become the primary disease modifying treatment modality [ 6 ]. In multiple prospective research studies, hydroxyurea has consistently demonstrated improvement in the abnormal laboratory parameters of SCA, while also reducing the acute clinical complications such as painful vaso-occlusive events and acute chest syndrome, as well as the need for blood transfusions and hospitalization [ 5 – 6 ]. More recently, hydroxyurea has been associated with improved survival for both adults and children with SCA [ 7 ]. In Côte d’Ivoire, the use of hydroxyurea remains limited beacause of the low income of the population, its non-availability on a large scale but also because of the initial reluctance of practitioners to use it. We therefore propose to carry out this work whose general objective was to evaluate the effectiveness of hydroxyurea in sickle cell patients in Ivory Cost in terms of its impact on clinical and biological manifestations. Material and Methods Patients and inclusion criteria The clinical hematology department of the University Hospital Center of Yopougon (CHUY) in Abidjan, is the referral center for the management of hematology disorders in Cote d’Ivoire. We performed a prospective comparative study of hydroxyurea on patients with sickle cell anemia. All patients treated for sickle cell anemia at CHUY have been registered in our database. The study cohort included sickle cell anemia with documented by electrophoresis hemoglobin tests, treated by hydroxyurea or not. A total of 128 patients was enrolled in the study divide in two groupes of patients. Groupe 1 with 66 patients treated by hydroxyurea and groupe 2 with 62 patients without hydroxyurea call as a control group. The study duration was from april 2019 to May 2023. Demographics, clinical and laboratory information and data were collected at the time of diagnosis. All the Patients routinely received folic acid, sulfadoxine pyrimethamine for malaria prophylaxis, and penicillin as prophylaxis for bacterial infections. Infants received pneumococcal conjugate vaccine in the first year of life per national expanded program on immunization. Treatment with hydroxyurea The patients were treated with hydroxyurea according to protocols approved by the institutional review board and informed consent for the treatment was obtained in accordance with the declaration of Helsinki. hydroxyurea at 10–20 mg/kg/day was prescribed to SCA patients with severe or recurrent sickle-related clinical complications such as painful vaso-occlusive crises, blood transfusions, hospitalization for sepsis or malaria, as well as high-risk designation based on prior cerebrovascular accident, acute chest syndrome, or other life-threatening event. Patients initiating hydroxyurea were recommended to have a full blood count after 4–6 weeks of commencing hydroxyurea to monitor for myelosuppression whenever possible. Clinical data collection All Patients were followed with routine examination every 3 months and more frequently as clinically indicated. Routinely collected data included the occurrence of SCD related acute clinical crises, blood transfusions, hospitalizations, and infection. Every 6 months, routine laboratory testing was performed including full blood count, serum chemistries including renal function and liver function, and urinalysis. Patient information was recorded on paper case report forms and stored in individual patient files. Key clinical variables were abstracted from paper forms at the time of analysis and linked with an electronic database of laboratory results. Statistical analysis Data entry and analysis was done using the following software: Epi info 7.2.5.0 for data collection, IBM SPSS software version 25.0 was used for statistical analysis. The qualitative variables were expressed as numbers and percentage and the quantitative variables were expressed as a mean with a standard deviation. The statistical test applied for this study is the Student test on paired series. Differences in means for which the p value is less than 5% (p value < 0.05) were considered significant. Human Ethics and Consent to Participate Written informed consent for participation in the study was obtained from adult’s patients or children’s parents, in accordance with the Declaration of Helsinki. Approval was granted by National Research Ethic Committee of Côte d’Ivoire. As sentiment was required from young children (10–17 years) in addition to their parent’s or guardian consent. Results Patient Population. The study included 128 patients divided into two groups of patients. 68 patients treated by hydroxyurea ans 62 patients without hydroxyurea. Patient baseline characteristics are presented in Table 1. Patients were homogeneously distributed between the two groups. Indeed, there were no significant differences between the two groups of patients with respect to age, sex, number of annual vasculo oclusif crisis (VOC), number of annual hospitalisation, phenotype profil and blood counts in the two groups before treatment was begun. Results According to clinical manifestations The ranks of the crisis rates significantly differed in the two groups (Table 2), with median rates of 2.9 crises per year in the hydroxyurea group and 5.3 crises per year in the control group (P 0.001). The median annual hospitalizations rate was significantly lower (2.2 vs.4.7) in patient treated by hydroxyurea than in the patient without hydroxyurea (p=0.002). Median annual Transfusion rate requirements also decreased significantly (p = 0.001) in the hydroxyurea going from more than 3.4 to 1.3 transfusions per year after treatment follow up. Regarding the complications profile, we observed 10% of anemic complications, including 3.9% which persisted despite treatment and 0.8% occurring under treatment with hydroxyurea. These complications included cholelithiasis, splenic sequestration and a leg ulcer that appeared after 9 months of treatment. But the occurrence of anemique complications wasn’t significantly different in the group without hydroxyurea (p=0.48). There is no difference in the occurrence of ischemique complication in the two groups. Ischemic complications persisted in 8 patients, mainly retinopathy and osteonecrosis. Two episodes of stroke and priapism occurred in 3 patients who did not have these complications before treatment. Although, the occurrence of annual number of infectious complications is significantly lower in the group of patient with hydroxyurea (16 cases) versus (30 cases) of patients without hydroxyurea (p=0.008). Infectious complications, including osteomyelitis and pulmonary infection. Results According to biological manifestations On the biological features, the wall patients presented homozygote severe form ( SS) with 68% cases, and 32% of SFA2 phenotype. We observed in table 3 a significant increase in Hb F level from 11.77% to 14.6% (p=0.001) in patient treated by hydroxyurea. In SS phenotype patients, the percentage of Hb F increased by 3.43%, while in SFA2 phenotype patients it increased by 1.19%, with a value of p=0.0023. We also observed a significant increase in the mean of Hb level from 7.3 g/dl to 9.2 g/dl for patient treated by hydroxyurea (p=0.004). Patients treated by hydroxyurea also have a beneficial effect on WBC and platelet levels by reduction in leukocytosis and thrombocytosis usually observed in sickle cell disease. Discussion Hydroxyurea has key clinical benefits, including reducing the frequency of transfusions and the number and intensity of vaso-occlusive crises, which translates into fewer hospitalizations. Indeed, we observed a significant reduction in the number of vaso-occlusive crises. The average number of annual vaso-occlusive crises decreased from 5.2 to 2.9, with a statistically significant difference (p = 0.001) with the patient treated by hydroxyurea as previously reported by Mellouli and Bejaoui [ 8 ]. These results are also supported by Tshilolo et al in 2018 [ 9 ], who demonstrated that hydroxyurea is a safe daily medication in children with sickle cell disease in Africa, reducing the number of vaso-occlusive crises, infections, transfusions and deaths. Thomas et al [ 10 ] as well as Brun M et al in 2001 [ 11 ] also explained that hydroxyurea contributes to stopping the inflammatory processes involved in vaso-occlusive events. The median Transfusion requirements rate also decreased significantly (p = 0.001) in our study, going from more than 3.4 transfusions per year to 1.3 transfusions at the end of the study. These results agree with those of Wang et al. [ 12 ] in a pediatric study which reported the absence of transfusion after 12 months of treatment, compared to more than three transfusions per year before hydroxyurea. In the previously mentioned pediatric studies, the number of hospital days decreased significantly during treatment with hydroxyurea. In our study, the median annual hospitalizations rate decreased significantly, from 3.8 to 2.2. Similar results are reported by Oliveri and Vichinsky[ 13 ]. Wang et al report that the use of hydroxyurea treatment is associated with substantial savings in medical costs due to its reported benefits over long-term treatment [ 12 ]. Indeed, these significant reductions in hospitalization days provide real savings on hospital costs and improve the psychological well-being of patients. Thus, the treatment becomes mainly outpatient and can be administered at home. The clinical benefits observed are distributed similarly across the entire population of our study. Indeed, hydroxyurea reduces the number of vaso-occlusive crises (VOC) and annual transfusions, both in patients with homozygous sickle cell disease (SSFA2) and in those with heterozygous sickle cell disease (SFA2), without significant difference. Regarding the complications profile , there was no significant difference with the two groups of patients regarding to anemic and ischemic complications. we observed 10% of anemic complications, including 3.9% which persisted despite treatment and 0.8% occurring under treatment with hydroxyurea. These complications included cholelithiasis, splenic sequestration and a leg ulcer that appeared after 9 months of treatment. Ischemic complications persisted in 8 patients, mainly retinopathy and osteonecrosis. Two episodes of stroke and priapism occurred in 3 patients who did not have these complications before treatment. However the infectious complications was significantly lower (16 cases) in the groups of hydroxyurea than the groups without hydroxyurea (30 cases) mainly due to osteomyelitis and pulmonary infection. These observations are also reported in Western literature. Although hydroxyurea has been recognized as effective in reducing vaso-occlusive crises in adults and children, uncertainties persist regarding its action on certain organs. It is unknown whether hydroxyurea can prevent or correct chronic damage to all organs [ 14 , 15 , 16 ] opinions remain controversial. A few complications with hydroxyurea have been reported by Claster et al. such as a fatal splenic sequestration and a stroke [ 16 ]. Jayabose et al. [ 17 ] observed the appearance of osteonecrosis of the femoral head despite HU treatment in one patient. A study by Koren et al. [ 18 ] described the occurrence of aseptic necrosis of the hip during treatment with hydroxyurea in two patients. Vichinsky and Lubin [ 19 ] reported a fatal cerebrovascular accident in a patient treated with HU. The appearance of these known complications of sickle cell disease under treatment suggests that hydroxyurea cannot prevent all the vaso-occlusive phenomena of this disease. On the biologicals aspects, our patients mainly presented homozygote severe form ( SS) with 68% cases, followed by subjects presenting the SFA2 phenotype (32%). Studies conducted by Wang et al. [ 12 ] and Mellouli et al. [ 8 ] also reported similar results, with 96.43% and 57.45% of patients presenting the severe SSFA2 form, respectively. Several arguments suggest that Hb F has an attenuating effect on the severity of sickle cell disease. Individuals with sickle cell disease with hereditary persistence of Hb F, as well as patients from certain regions such as Saudi Arabia and India, with high levels of Hb F, have less severe crises. The occurrence specific complications such as hand-foot syndrome, acute chest syndrome or vaso-occlusive crises are proportional to the decrease in Hb F level during the first months of life [ 20 ]. The observation that the severity of sickle cell anemia was inversely related to the level of Hb F led to attempts to reactivate the synthesis of Hb F. Hydroxyurea, being the reactivator molecule of the synthesis of The best tolerated Hb F [ 20 ], has been studied in several studies around the world. For example, the study conducted by Mellouli et al. [ 8 ] in Tunisia in 2007 showed a significant increase in Hb F level from 3–30% after 6 years and 9 months of treatment with hydroxyurea. Likewise, the study by Tshilolo et al. [ 9 ] revealed a significant increase in hemoglobin and fetal hemoglobin levels, from 11.8 to 13.1%. In our study, we observed a significant increase in Hb F level from 11.70–14.6% (p = 0.001). In SSFA2 sickle cell patients, the percentage of Hb F increased by 3.43%, while in SFA2 patients it increased by 1.19%, with a value of p = 0.0023. Thus, hydroxyurea contributes to a greater increase in the percentage of Hb F in SSFA2 patients than in SFA2 patients. These results are in agreement with those of the study conducted by Davies et al. [ 21 ], who also reported a less significant increase in Hb F in patients with SFA2 patients, but who were better relieved at pain level. The beneficial effect of hydroxyurea is not only attributed to the reactivation of Hb F synthesis, as at the beginning of its use in sickle cell patients, but it is also linked to multiple other processes [ 5 ]. Some patients experienced an improvement in their clinical condition without a significant increase in their Hb F levels while on treatment. It is suggested that several mechanisms of action of hydroxyurea may benefit sickle cell patients. We also observed anemia with a significant increase in the mean Hb level from 7.3 g/dl to 9.2 g/dl (p = 0.004). Patients also experienced leukocytosis, but statistically significantly (p = 0.001) the white blood cell count normalized. These results are consistent with those of Ware et al. [ 15 ]. Jayabose et al; demonstrated in his study a drop in all leukocyte subpopulations which was more marked with neutrophils. The decrease in neutrophils levels could play an important role CVO where these cells can participate in the genesis of vaso-occlusions and the inflammatory pathways [ 17 ]. Like many authors, we noted the beneficial effect of HU on WBC and platelet levels in the sense of a reduction in leukocytosis and thrombocytosis usually observed in sickle cell disease. This reduction is beneficial for blood rheology. However, the risk of cytopenia justified close and regular monitoring of the blood counts of patients receiving HU. It is important to emphasize the clinical benefits of high adherence to hydroxyurea, especially in young patients with sickle cell disease major. Recent studies carried out in the United States have shown the good tolerance of hydroxyurea in toddlers, which prompts some to recommend its use from the first year of life. However, the main problem linked to hydroxyurea is the variability of its effectiveness from one patient to another. Indeed, clinical improvement is not always directly linked to the increase in Hb F levels. This suggests that, although the reactivation of Hb F synthesis plays an important role in the action of hydroxyurea, the improvement in general condition is also linked to other factors. This “paradox” can be explained by other beneficial effects of HU, such as the reduction of leukocytes, the reduction of platelet, reticulocytes and the increase of Hb and MCV [ 15 , 17 , 21 ]. Over the years, other mechanisms of action have been suggested: reduction of excessive adhesion of sickle cell reticulocytes to the endothelium, modulation of inflammatory processes, cellular effects (reduction of dense cells), induction of NO [ 11 ]. Safety Our patients tolerated a mean dose of HU of 17.1 ± 3.4 mg/kg/day. This suggests that the maximum tolerated dose is not necessary to achieve a therapeutic effect. The average dose of HU used in the study by Tshilolo et al. in 606 children was 17.5 ± 1.8 mg/kg/day [ 8 ]. Therefore, the dose must be adjust on a case-by-case basis to reduce toxicity. The initial dose is 10 to 15 mg/kg/day in one dose, up to a maximum of 30 mg/kg/day [ 8 ].. We observed 2 cases of rash and 2 cases of hyperpigmentation. The most common short-term toxicity includes mild and reversible cytopenias. In general, toxic events occurred in 5.1% of participants, which was below the protocol-specified safety threshold during treatment. [ 17 ]. Although all cell lines can be affected, the most commonly encountered hematologic toxicity includes mild to moderate neutropenia followed by reticulocytopenia and thrombocytopenia [ 8 , 17 ]. This risk of cytopenia justifies regular hematological monitoring in patients receiving HU. In our study as well as in previous work, no mortality or carcinogenic effects were observed [ 15 , 17 , 22 ]. Ware et al [ 18 ] also showed the safety of HU in infants. However, the absence of malignant process during our study does not guarantee the reliability of the long-term safety of this treatment. Conclusion Our Study confirms the key clinical benefits of hydroxyurea, including reducing the frequency of transfusions and the number and intensity of vaso-occlusive crises, which translates into fewer hospitalizations. Hydroxyurea treatment in low-income country such sub-Saharan Africa was feasible and safe for children with sickle cell anemia. The benefits observed constitute a reason for prescription. However, hydroxyurea does not seem to completely prevent or correct all the chronic complications observed during sickle cell disease. Its toxicity is modest in the short and medium term while that in the long term remains uncertain, which justifies regular clinical and biological controls and the need for long-term studies. Declarations Data Availability Data available on request due to privacy / ethical restrictions. Conflicts of Interest The authors declare that they are no conflicts of interest Authors’s contributions KG Koffi and Dieket R conceived and designed the study. Dieket R, E N’Dhatz, Silué, I Kamara, and Abenan N collected and processed data from patients. KG Koffi and Dieket R wrote the manuscript. E N’Dhatz made critical revisions to the manuscript. AD Silue performed the data analysis. All the authors have reviewed the final manuscript and have agreed to its submission Acknowledgments The authors are grateful to the patients who volunteered for this study. The authors also thank all the administrative, medical staff, coordinators and research assistant of the University Hospital Center of Yopougon (CHUY) who helped with the recruitment of patients and foster an environment conducive to this study. Funding This study did not receive any funding References Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet 2017;390:311 23. [PubMed: 28159390] Bunn HF.Pathogenesis and treatment of sickle cell disease. N Eng J Med 1997; 337 :762 World Health Organisation, “Sickle cell anaemia. Agenda item 11.4,” in 59thWorldHealthAssembly,27May2006,WorldHealth Organisation, Geneva, Switzerland, 2006 Piel FB, Patil AP, Howes RE, et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet 2013;381:142–51. [PubMed: 23103089] 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. N Engl J Med. 1995 May 18;332 (20):1317-22. Charache S, Terrin ML, Moore RD et alEffect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. New England Journal of Medicine. 1995; 332:1317–22. Steinberg MH, Barton F, Castro O et al Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment.JAMA. 2003 Apr 2;289 (13):1645-51. Mellouli F, Bejaoui M. The use of Hydroxyurea in severe forms of sickle cell disease : A study of 47 case in tunisian pediatric cases. Arch Pédiatrie 2008;15:24–8. Tshilolo L, Tomlinson G, Williams TN et al ; Hydroxyurea for Children with Sickle Cell Anemia in Sub-Saharan Africa.New England Journal of Medicine. 2018: 11. Thomas R, Dulman R, Lewis A et al.Longitudinal prospective survey of sickle cell infants treated by hydroxyurea. Sang et Cancer Pédiatriques. 2019 : e27816. Brun M, Bourdoulous S, Couraud PO, et al.Effect of hydroxyurea on endothelial cells in culture. 25th Annual Meeting of the National Sickle Cell Program.New York City. April 14th-17th 2001 Wang WC, Oyeku SO, Luo Z, Boulet SL, Miller ST, Casella JF, et al. Hydroxyurea Is Associated With Lower Costs of Care of Young Children With Sickle Cell Anemia. Pediatrics. 2013 Oct;132(4):677–83. Olivieri NF, Vichinsky EP et al. Hydroxyurea in children with sickle cell disease: impact on splenic function and compliance with therapy. J Pediatr Hematol Oncol 1998;20:26–31. Charache S . Experimental therapy for sickle cell disease : Use of hydroxyurea . Am J Pediatr Hematol Oncol 1994 ; 16 : 62-6. Ware R, Steinberg MH , Kinney TR . Hydroxyurea : An alternative to transfusion therapy for stroke in sickle cell anaemia . Am J of Hematol 1995 ; 50 : 140-3. Claster S ,Vichinsky E . First report of reversal of organ dysfunction in sickle cell anaemia by the use of hydroxyurea : splenic regeneration Blood 1996 ; 88 : 1951- 3 Jayabose S , Tugal O, Sandoval C et al . Clinical and hematologic effects of hydroxyurea in children with sickle cell anaemia . J Pediatr 1996 ; 129 : 559-65 . Koren A, Dora Segal-Kupershmit , Zalaman L et al . Effect of hydroxyurea in sickle cell anaemia : A clinical trial in children and teenagers with severe sickle cell anaemia and sickle cell bêtathalassemia Pediatr Hematol and Oncol 1999 ; 16 : 221-32. Vichinsky EP and Lubin BM . A cautionary note regarding hydroxyurea in sickle cell disease . Blood 1994 ; 83 : 1124-8 Charache S. Fetal hemoglobin, sickling, and sickle cell disease. Adv Pediatr 1990;37:1-31. Davies SC, Gilmore A. The role of hydroxyurea in the management of sickle cell disease. Blood Rev. 2003; 17:99–109 De Montalembert M, Davies SC. Is hydroxyurea leukemogenic in children with sickle cell disease Blood. 2001;98:2878–9 Tables Table1. Characteristics of the Patients at Base Line, According to Treatment Group. Caracteristics Hydroxyurea n=66 No Hydroxyurea n=62 Age. Mean Years 10.5±7 11.2±6 Gender n° Male Female 41 25 42 20 N°. VOC/years 3-5 6-8 > 8 Mean value±e.t 27 24 15 5.2 ±1.1 27 23 12 5.7 ±1.2 N°.hospitalisation/ years 3-5 6-8 >8 Mean value±e.t 35 29 2 3.8 ±1.4 33 26 3 3.5 ±1.8 Transfusion / Years 3-5 ≥ 6 Mean Value 50 16 3.4 ±1.2 48 14 3.7 ±1.3 Hemoglobine g/dL ( mean ± e.t ) 7.3 ±1.05 7.6±1.1 Hématocrite % ( mean ± e.t ) 22.3±3.7 23.1±2.6 Leukocyte count (G/L) ( mean ± e.t ) 12.278±4104 11.394±5231 Platelet count (G/L) ( mean ± e.t ) 358.665±142.588 311.435±123.167 Electropheretic profil Sickle cell Anemia (SS) Sickle β 0 Thalassemia (SFA2) 45 21 43 19 % Hb F 11.7 ±7.7 12.2 ±2 % Hb S 86 ±7.8 82 ±4.5 Table 2. Impact of hydroxyurea on clinical manifestations Parameters Patient with hydroxyurea Patient without hydroxyurea P value Median VOC rate/years 2.9 ± 0.7 5.3 ± 1.1 0.001 S Median hospitalisation rate / years 2.2 ± 0.5 4.7 ± 1.4 0.002 S Median Transfusion rate / Years 1.3 ± 0.7 5.1 ± 1.5 0.001 S Anemic Complications 8 ± 0.2 10 ± 0.3 0.48 NS Ischemic Complications 18 ± 0.3 17 ± 0.5 0.74 NS Infectious Complications 16 ± 0.3 30 ± 0.4 0.008 S Table 3. Influence of hydroxyurea on biologicals parameters Parameters Patient With hydroxyurea Patient Without hydroxyurea P value Hemoglobine g/dL ( mean ± e.t ) 9.2 ± 1.1 7.2 ± 1.1 0.004 S Hematocrite % ( mean ± e.t ) 28.3 ± 18.7 22.3 ± 3.7 0.001 S Leukocyte count (G/L) ( mean ± e.t ) 9.5 ± 4.8 12.6 ± 3.1 0.001 S Platelet count (G/L) ( mean ± e.t ) 316.4 ± 130.1 358.6 ± 142.6 0.005 S % Hb F 14.6 ± 7.2 12 ± 7.8 0.001 S % Hb S 84.3 ± 11.9 86.2 ± 7.9 0.001 S Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5375843","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":381918354,"identity":"635cb971-ec70-4a4d-872e-5f43f7d7c1dd","order_by":0,"name":"KOUASSI GUSTAVE KOFFI","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYHACZgYGGwk5BgYeEEeOWC1pFsZQLcZEa6lIbCBai3xE+mODDwkS6RuOnz344AODQT5BLYY3cowTZyRI5G44k5dsOIPBwLKBoJYZOcyHeX8AtRzIMZPmYfhjQNiWGemPD/MAHWZw/g1IiwFhLfISCcbJQC0JBjdyiNRiwPPG2BDoF8OZN0AMA2JsaU9/LPEhoU6e73yO4YMPFcTYcgDKUAAzCGsA2tKAzhgFo2AUjIJRgA4AH+Y4DWuGqf0AAAAASUVORK5CYII=","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"KOUASSI","middleName":"GUSTAVE","lastName":"KOFFI","suffix":""},{"id":381918355,"identity":"6c42164e-a66c-4817-bd55-fa1be47ba857","order_by":1,"name":"Ruth Dieket","email":"","orcid":"","institution":"Hematology teaching hospital of Yopougon Abidjan","correspondingAuthor":false,"prefix":"","firstName":"Ruth","middleName":"","lastName":"Dieket","suffix":""},{"id":381918356,"identity":"7a4d6338-03b5-4981-8ff5-9adf19618f5b","order_by":2,"name":"Emeraude N’dhatz","email":"","orcid":"","institution":"Hematology teaching hospital of Yopougon Abidjan","correspondingAuthor":false,"prefix":"","firstName":"Emeraude","middleName":"","lastName":"N’dhatz","suffix":""},{"id":381918357,"identity":"93d44148-b705-4197-bca9-862c74e126a9","order_by":3,"name":"Nelly Eloise Abenan","email":"","orcid":"","institution":"Hematology teaching hospital of Yopougon Abidjan","correspondingAuthor":false,"prefix":"","firstName":"Nelly","middleName":"Eloise","lastName":"Abenan","suffix":""},{"id":381918358,"identity":"570f9a72-0787-4240-bcdf-fb5914944e82","order_by":4,"name":"Alexis Dohoma Silué","email":"","orcid":"","institution":"Hematology teaching hospital of Yopougon Abidjan","correspondingAuthor":false,"prefix":"","firstName":"Alexis","middleName":"Dohoma","lastName":"Silué","suffix":""},{"id":381918359,"identity":"afb2260d-fd05-4a61-9a14-4dde64e6b74a","order_by":5,"name":"Ismael Kamara","email":"","orcid":"","institution":"Hematology teaching hospital of Yopougon Abidjan","correspondingAuthor":false,"prefix":"","firstName":"Ismael","middleName":"","lastName":"Kamara","suffix":""},{"id":381918360,"identity":"521fc614-ead2-4101-9b35-10b27b61db90","order_by":6,"name":"Boidy Kouakou","email":"","orcid":"","institution":"Hematology teaching hospital of Yopougon Abidjan","correspondingAuthor":false,"prefix":"","firstName":"Boidy","middleName":"","lastName":"Kouakou","suffix":""},{"id":381918361,"identity":"86fef23a-be3e-477b-8d6f-9775956c0aef","order_by":7,"name":"Danho Clotaire Nanho","email":"","orcid":"","institution":"Hematology teaching hospital of Yopougon Abidjan","correspondingAuthor":false,"prefix":"","firstName":"Danho","middleName":"Clotaire","lastName":"Nanho","suffix":""}],"badges":[],"createdAt":"2024-11-02 00:38:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5375843/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5375843/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":70299667,"identity":"2ee14ca4-e1da-4a90-9ef5-00ed911ba6aa","added_by":"auto","created_at":"2024-12-02 01:47:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":524673,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5375843/v1/59e44448-7f9d-4915-9e73-dca777c4f4bb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Hydroxyurea efficacy in sickle cell anemia patients in low-income middle country in Cote d’Ivoire","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSickle cell disease is the most common genetic haemoglobin disorder and most commonly affects individuals of African descent. Ivory Coast is one of the fifteen most affected countries in the world [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Sickle cell disease or sickle cell anaemia is an autosomal recessive genetic disease involving the inheritance of abnormal haemoglobin. It is a point mutation of haemoglobin which results from a single β-globin gene mutation, leading to an amino-acid substitution (Glu\u0026rarr;Val, βA\u0026rarr;βS) and formation of the abnormal HbS tetramer. Under deoxygenated states, HbS undergoes rapid intracellular polymerization, which damages the erythrocyte membrane and significantly alters both its shape and its flexibility while carrying oxygen to the body. These stiff and \u0026lsquo;sickled\u0026rsquo; red blood cells have a decreased lifespan, and result in both acute and chronic hemolysis. They also undergo a complex process known as vaso-occlusion, in which sickled erythrocytes and other circulating cells adhere to the vascular endothelium, aggregate together to disrupt blood flow especially in the small blood vessels, and cause hypoxia to tissues and vital organs [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAccording to the World Health Organization, on a global scale, the incidence of sickle hemoglobinopathies is greatest in sub-Saharan Africa, with more than 300,000 babies with sickle cell disease born annually, representing approximately 1% of births in the region. C\u0026ocirc;te d\u0026rsquo;Ivoire is one of the fifteen most affected countries in the world [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] where the sickle cell burden is greatest, early diagnostic capacities are lacking and childhood mortality is high [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. As recently as the 1980s, the only available disease-modifying therapy for SCA was intermittent red blood cell transfusions, which were commonly reserved for acute, life-threatening complications. In the 1990s, hydroxyurea emerged as a promising pharmacologic therapy for SCA, due primarily to its ability to induce HbF [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and over the past 30 years has become the primary disease modifying treatment modality [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In multiple prospective research studies, hydroxyurea has consistently demonstrated improvement in the abnormal laboratory parameters of SCA, while also reducing the acute clinical complications such as painful vaso-occlusive events and acute chest syndrome, as well as the need for blood transfusions and hospitalization [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. More recently, hydroxyurea has been associated with improved survival for both adults and children with SCA [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In C\u0026ocirc;te d\u0026rsquo;Ivoire, the use of hydroxyurea remains limited beacause of the low income of the population, its non-availability on a large scale but also because of the initial reluctance of practitioners to use it. We therefore propose to carry out this work whose general objective was to evaluate the effectiveness of hydroxyurea in sickle cell patients in Ivory Cost in terms of its impact on clinical and biological manifestations.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003ePatients and inclusion criteria\u003c/p\u003e \u003cp\u003eThe clinical hematology department of the University Hospital Center of Yopougon (CHUY) in Abidjan, is the referral center for the management of hematology disorders in Cote d\u0026rsquo;Ivoire. We performed a prospective comparative study of hydroxyurea on patients with sickle cell anemia. All patients treated for sickle cell anemia at CHUY have been registered in our database. The study cohort included sickle cell anemia with documented by electrophoresis hemoglobin tests, treated by hydroxyurea or not. A total of 128 patients was enrolled in the study divide in two groupes of patients. Groupe 1 with 66 patients treated by hydroxyurea and groupe 2 with 62 patients without hydroxyurea call as a control group. The study duration was from april 2019 to May 2023. Demographics, clinical and laboratory information and data were collected at the time of diagnosis. All the Patients routinely received folic acid, sulfadoxine pyrimethamine for malaria prophylaxis, and penicillin as prophylaxis for bacterial infections. Infants received pneumococcal conjugate vaccine in the first year of life per national expanded program on immunization.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTreatment with hydroxyurea\u003c/h2\u003e \u003cp\u003e The patients were treated with hydroxyurea according to protocols approved by the institutional review board and informed consent for the treatment was obtained in accordance with the declaration of Helsinki. hydroxyurea at 10\u0026ndash;20 mg/kg/day was prescribed to SCA patients with severe or recurrent sickle-related clinical complications such as painful vaso-occlusive crises, blood transfusions, hospitalization for sepsis or malaria, as well as high-risk designation based on prior cerebrovascular accident, acute chest syndrome, or other life-threatening event. Patients initiating hydroxyurea were recommended to have a full blood count after 4\u0026ndash;6 weeks of commencing hydroxyurea to monitor for myelosuppression whenever possible.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClinical data collection\u003c/h3\u003e\n\u003cp\u003eAll Patients were followed with routine examination every 3 months and more frequently as clinically indicated. Routinely collected data included the occurrence of SCD related acute clinical crises, blood transfusions, hospitalizations, and infection. Every 6 months, routine laboratory testing was performed including full blood count, serum chemistries including renal function and liver function, and urinalysis. Patient information was recorded on paper case report forms and stored in individual patient files. Key clinical variables were abstracted from paper forms at the time of analysis and linked with an electronic database of laboratory results.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData entry and analysis was done using the following software: Epi info 7.2.5.0 for data collection, IBM SPSS software version 25.0 was used for statistical analysis. The qualitative variables were expressed as numbers and percentage and the quantitative variables were expressed as a mean with a standard deviation. The statistical test applied for this study is the Student test on paired series. Differences in means for which the p value is less than 5% (p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05) were considered significant.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eHuman Ethics and Consent to Participate\u003c/h3\u003e\n\u003cp\u003e Written informed consent for participation in the study was obtained from adult\u0026rsquo;s patients or children\u0026rsquo;s parents, in accordance with the Declaration of Helsinki. Approval was granted by National Research Ethic Committee of C\u0026ocirc;te d\u0026rsquo;Ivoire. As sentiment was required from young children (10\u0026ndash;17 years) in addition to their parent\u0026rsquo;s or guardian consent.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient Population.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study included 128 patients divided into two groups of patients. 68 patients treated by hydroxyurea ans 62 patients without hydroxyurea. Patient baseline characteristics are presented in Table 1. Patients were homogeneously distributed between the two groups. Indeed, there were no significant differences between the two groups of patients with respect to age, sex, number of annual vasculo oclusif crisis (VOC), number of annual hospitalisation, phenotype profil and blood counts in the two groups before treatment was begun.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults According to clinical manifestations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ranks of the crisis rates significantly differed in the two \u0026nbsp;groups (Table 2), with median rates of 2.9 \u0026nbsp;crises per year in the hydroxyurea group and 5.3\u0026nbsp;crises per year in the control group (P 0.001). \u0026nbsp;The median annual hospitalizations rate was significantly lower (2.2 vs.4.7) in patient \u0026nbsp; treated by hydroxyurea than in the patient without hydroxyurea (p=0.002). Median annual\u0026nbsp;Transfusion rate requirements also decreased significantly (p = 0.001) in the hydroxyurea going from more than 3.4 to 1.3 transfusions per year after treatment follow up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRegarding the complications profile, we observed 10% of anemic complications, including 3.9% which persisted despite treatment and 0.8% occurring under treatment with hydroxyurea. These complications included cholelithiasis, splenic sequestration and a leg ulcer that appeared after 9 months of treatment. \u0026nbsp;But the occurrence of \u0026nbsp;anemique complications wasn’t \u0026nbsp;significantly different \u0026nbsp;in the group without hydroxyurea (p=0.48). There is \u0026nbsp;no difference in the occurrence of ischemique complication in the two groups. Ischemic complications persisted in 8 patients, mainly retinopathy and osteonecrosis. Two episodes of stroke and priapism occurred in 3 patients who did not have these complications before treatment. Although, the occurrence of annual number of \u0026nbsp;infectious complications is significantly lower in the group of patient \u0026nbsp;with hydroxyurea (16 cases) versus (30 cases) of patients without hydroxyurea (p=0.008). Infectious complications, including osteomyelitis and pulmonary infection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults According to biological \u0026nbsp;manifestations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOn the biological features, the wall patients presented homozygote severe form ( SS) with \u0026nbsp;68% cases, and 32% \u0026nbsp;of \u0026nbsp;SFA2 phenotype. We observed in table 3 a significant increase in Hb F level from 11.77% to 14.6% (p=0.001) in patient treated by hydroxyurea. In SS phenotype patients, the percentage of Hb F increased by 3.43%, while in SFA2 phenotype patients it increased by 1.19%, with a value of p=0.0023. We also observed a significant increase in the mean of Hb level from 7.3 g/dl to 9.2 g/dl for patient treated by hydroxyurea (p=0.004). Patients treated by hydroxyurea also have a beneficial effect on WBC and platelet levels by reduction in leukocytosis and thrombocytosis usually observed in sickle cell disease. \u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHydroxyurea has key clinical benefits, including reducing the frequency of transfusions and the number and intensity of vaso-occlusive crises, which translates into fewer hospitalizations. Indeed, we observed a significant reduction in the number of vaso-occlusive crises. The average number of annual vaso-occlusive crises decreased from 5.2 to 2.9, with a statistically significant difference (p\u0026thinsp;=\u0026thinsp;0.001) with the patient treated by hydroxyurea as previously reported by Mellouli and Bejaoui [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These results are also supported by Tshilolo et al in 2018 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], who demonstrated that hydroxyurea is a safe daily medication in children with sickle cell disease in Africa, reducing the number of vaso-occlusive crises, infections, transfusions and deaths. Thomas et al [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] as well as Brun M et al in 2001 [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] also explained that hydroxyurea contributes to stopping the inflammatory processes involved in vaso-occlusive events.\u003c/p\u003e \u003cp\u003eThe median Transfusion requirements rate also decreased significantly (p\u0026thinsp;=\u0026thinsp;0.001) in our study, going from more than 3.4 transfusions per year to 1.3 transfusions at the end of the study. These results agree with those of Wang et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] in a pediatric study which reported the absence of transfusion after 12 months of treatment, compared to more than three transfusions per year before hydroxyurea.\u003c/p\u003e \u003cp\u003eIn the previously mentioned pediatric studies, the number of hospital days decreased significantly during treatment with hydroxyurea. In our study, the median annual hospitalizations rate decreased significantly, from 3.8 to 2.2. Similar results are reported by Oliveri and Vichinsky[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Wang et al report that the use of hydroxyurea treatment is associated with substantial savings in medical costs due to its reported benefits over long-term treatment [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Indeed, these significant reductions in hospitalization days provide real savings on hospital costs and improve the psychological well-being of patients.\u003c/p\u003e \u003cp\u003eThus, the treatment becomes mainly outpatient and can be administered at home.\u003c/p\u003e \u003cp\u003eThe clinical benefits observed are distributed similarly across the entire population of our study. Indeed, hydroxyurea reduces the number of vaso-occlusive crises (VOC) and annual transfusions, both in patients with homozygous sickle cell disease (SSFA2) and in those with heterozygous sickle cell disease (SFA2), without significant difference.\u003c/p\u003e \u003cp\u003e \u003cb\u003eRegarding the complications profile\u003c/b\u003e, there was no significant difference with the two groups of patients regarding to anemic and ischemic complications. we observed 10% of anemic complications, including 3.9% which persisted despite treatment and 0.8% occurring under treatment with hydroxyurea. These complications included cholelithiasis, splenic sequestration and a leg ulcer that appeared after 9 months of treatment. Ischemic complications persisted in 8 patients, mainly retinopathy and osteonecrosis. Two episodes of stroke and priapism occurred in 3 patients who did not have these complications before treatment. However the infectious complications was significantly lower (16 cases) in the groups of hydroxyurea than the groups without hydroxyurea (30 cases) mainly due to osteomyelitis and pulmonary infection.\u003c/p\u003e \u003cp\u003eThese observations are also reported in Western literature. Although hydroxyurea has been recognized as effective in reducing vaso-occlusive crises in adults and children, uncertainties persist regarding its action on certain organs. It is unknown whether hydroxyurea can prevent or correct chronic damage to all organs [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] opinions remain controversial. A few complications with hydroxyurea have been reported by Claster et al. such as a fatal splenic sequestration and a stroke [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Jayabose et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] observed the appearance of osteonecrosis of the femoral head despite HU treatment in one patient.\u003c/p\u003e \u003cp\u003eA study by Koren et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] described the occurrence of aseptic necrosis of the hip during treatment with hydroxyurea in two patients. Vichinsky and Lubin [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] reported a fatal cerebrovascular accident in a patient treated with HU.\u003c/p\u003e \u003cp\u003eThe appearance of these known complications of sickle cell disease under treatment suggests that hydroxyurea cannot prevent all the vaso-occlusive phenomena of this disease.\u003c/p\u003e \u003cp\u003eOn the biologicals aspects, our patients mainly presented homozygote severe form ( SS) with 68% cases, followed by subjects presenting the SFA2 phenotype (32%). Studies conducted by Wang et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and Mellouli et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] also reported similar results, with 96.43% and 57.45% of patients presenting the severe SSFA2 form, respectively. Several arguments suggest that Hb F has an attenuating effect on the severity of sickle cell disease. Individuals with sickle cell disease with hereditary persistence of Hb F, as well as patients from certain regions such as Saudi Arabia and India, with high levels of Hb F, have less severe crises. The occurrence specific complications such as hand-foot syndrome, acute chest syndrome or vaso-occlusive crises are proportional to the decrease in Hb F level during the first months of life [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe observation that the severity of sickle cell anemia was inversely related to the level of Hb F led to attempts to reactivate the synthesis of Hb F. Hydroxyurea, being the reactivator molecule of the synthesis of The best tolerated Hb F [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], has been studied in several studies around the world. For example, the study conducted by Mellouli et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] in Tunisia in 2007 showed a significant increase in Hb F level from 3\u0026ndash;30% after 6 years and 9 months of treatment with hydroxyurea. Likewise, the study by Tshilolo et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] revealed a significant increase in hemoglobin and fetal hemoglobin levels, from 11.8 to 13.1%.\u003c/p\u003e \u003cp\u003eIn our study, we observed a significant increase in Hb F level from 11.70\u0026ndash;14.6% (p\u0026thinsp;=\u0026thinsp;0.001). In SSFA2 sickle cell patients, the percentage of Hb F increased by 3.43%, while in SFA2 patients it increased by 1.19%, with a value of p\u0026thinsp;=\u0026thinsp;0.0023. Thus, hydroxyurea contributes to a greater increase in the percentage of Hb F in SSFA2 patients than in SFA2 patients. These results are in agreement with those of the study conducted by Davies et al. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], who also reported a less significant increase in Hb F in patients with SFA2 patients, but who were better relieved at pain level.\u003c/p\u003e \u003cp\u003eThe beneficial effect of hydroxyurea is not only attributed to the reactivation of Hb F synthesis, as at the beginning of its use in sickle cell patients, but it is also linked to multiple other processes [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Some patients experienced an improvement in their clinical condition without a significant increase in their Hb F levels while on treatment. It is suggested that several mechanisms of action of hydroxyurea may benefit sickle cell patients.\u003c/p\u003e \u003cp\u003eWe also observed anemia with a significant increase in the mean Hb level from 7.3 g/dl to 9.2 g/dl (p\u0026thinsp;=\u0026thinsp;0.004). Patients also experienced leukocytosis, but statistically significantly (p\u0026thinsp;=\u0026thinsp;0.001) the white blood cell count normalized. These results are consistent with those of Ware et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Jayabose et al; demonstrated in his study a drop in all leukocyte subpopulations which was more marked with neutrophils. The decrease in neutrophils levels could play an important role CVO where these cells can participate in the genesis of vaso-occlusions and the inflammatory pathways [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLike many authors, we noted the beneficial effect of HU on WBC and platelet levels in the sense of a reduction in leukocytosis and thrombocytosis usually observed in sickle cell disease. This reduction is beneficial for blood rheology. However, the risk of cytopenia justified close and regular monitoring of the blood counts of patients receiving HU.\u003c/p\u003e \u003cp\u003eIt is important to emphasize the clinical benefits of high adherence to hydroxyurea, especially in young patients with sickle cell disease major. Recent studies carried out in the United States have shown the good tolerance of hydroxyurea in toddlers, which prompts some to recommend its use from the first year of life. However, the main problem linked to hydroxyurea is the variability of its effectiveness from one patient to another. Indeed, clinical improvement is not always directly linked to the increase in Hb F levels. This suggests that, although the reactivation of Hb F synthesis plays an important role in the action of hydroxyurea, the improvement in general condition is also linked to other factors. This \u0026ldquo;paradox\u0026rdquo; can be explained by other beneficial effects of HU, such as the reduction of leukocytes, the reduction of platelet, reticulocytes and the increase of Hb and MCV [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOver the years, other mechanisms of action have been suggested: reduction of excessive adhesion of sickle cell reticulocytes to the endothelium, modulation of inflammatory processes, cellular effects (reduction of dense cells), induction of NO [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eOur patients tolerated a mean dose of HU of 17.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4 mg/kg/day. This suggests that the maximum tolerated dose is not necessary to achieve a therapeutic effect. The average dose of HU used in the study by Tshilolo et al. in 606 children was 17.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8 mg/kg/day [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Therefore, the dose must be adjust on a case-by-case basis to reduce toxicity. The initial dose is 10 to 15 mg/kg/day in one dose, up to a maximum of 30 mg/kg/day [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]..\u003c/p\u003e \u003cp\u003eWe observed 2 cases of rash and 2 cases of hyperpigmentation. The most common short-term toxicity includes mild and reversible cytopenias. In general, toxic events occurred in 5.1% of participants, which was below the protocol-specified safety threshold during treatment. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Although all cell lines can be affected, the most commonly encountered hematologic toxicity includes mild to moderate neutropenia followed by reticulocytopenia and thrombocytopenia [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This risk of cytopenia justifies regular hematological monitoring in patients receiving HU. In our study as well as in previous work, no mortality or carcinogenic effects were observed [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Ware et al [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] also showed the safety of HU in infants. However, the absence of malignant process during our study does not guarantee the reliability of the long-term safety of this treatment.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur Study confirms the key clinical benefits of hydroxyurea, including reducing the frequency of transfusions and the number and intensity of vaso-occlusive crises, which translates into fewer hospitalizations. Hydroxyurea treatment in low-income country such sub-Saharan Africa was feasible and safe for children with sickle cell anemia. The benefits observed constitute a reason for prescription. However, hydroxyurea does not seem to completely prevent or correct all the chronic complications observed during sickle cell disease. Its toxicity is modest in the short and medium term while that in the long term remains uncertain, which justifies regular clinical and biological controls and the need for long-term studies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData available on request due to privacy / ethical restrictions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they are no conflicts of interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’s contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKG Koffi and Dieket R conceived and designed the study. Dieket R, E N’Dhatz, Silué, I Kamara, \u0026nbsp; and Abenan N collected and processed data from patients. KG Koffi and Dieket R wrote the manuscript. E N’Dhatz \u0026nbsp; made critical revisions to the manuscript. AD Silue performed the data analysis. All the authors have reviewed the final manuscript and have agreed to its submission\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to the patients who volunteered for this study. The authors also thank all the administrative, medical staff, coordinators and research assistant of the University Hospital Center of Yopougon (CHUY) who helped with the recruitment of patients and foster an environment conducive to this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study did not receive any funding\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWare RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet 2017;390:311 23. [PubMed: 28159390]\u003c/li\u003e\n\u003cli\u003eBunn HF.Pathogenesis and treatment of sickle cell disease. N Eng J Med 1997; 337 :762\u003c/li\u003e\n\u003cli\u003eWorld Health Organisation, \u0026ldquo;Sickle cell anaemia. Agenda item 11.4,\u0026rdquo; in 59thWorldHealthAssembly,27May2006,WorldHealth Organisation, Geneva, Switzerland, 2006\u003c/li\u003e\n\u003cli\u003ePiel FB, Patil AP, Howes RE, et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet 2013;381:142\u0026ndash;51. [PubMed: 23103089]\u003c/li\u003e\n\u003cli\u003eCharache 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. N Engl J Med. 1995 May 18;332 (20):1317-22. \u003c/li\u003e\n\u003cli\u003eCharache S, Terrin ML, Moore RD et alEffect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. New England Journal of Medicine. 1995; 332:1317\u0026ndash;22.\u003c/li\u003e\n\u003cli\u003eSteinberg MH, Barton F, Castro O et al Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment.JAMA. 2003 Apr 2;289 (13):1645-51.\u003c/li\u003e\n\u003cli\u003eMellouli F, Bejaoui M. The use of Hydroxyurea in severe forms of sickle cell disease : A study of 47 case in tunisian pediatric cases. Arch P\u0026eacute;diatrie 2008;15:24\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eTshilolo L, Tomlinson G, Williams TN et al\u003cstrong\u003e; \u003c/strong\u003eHydroxyurea for Children with Sickle Cell Anemia in Sub-Saharan Africa.New England Journal of Medicine. 2018: 11.\u003c/li\u003e\n\u003cli\u003eThomas R, Dulman R, Lewis A et al.Longitudinal prospective survey of sickle cell infants treated by hydroxyurea. Sang et Cancer P\u0026eacute;diatriques. 2019 : e27816.\u003c/li\u003e\n\u003cli\u003eBrun M, Bourdoulous S, Couraud PO, et al.Effect of hydroxyurea on endothelial cells in culture. 25th Annual Meeting of the National Sickle Cell Program.New York City. April 14th-17th 2001\u003c/li\u003e\n\u003cli\u003eWang WC, Oyeku SO, Luo Z, Boulet SL, Miller ST, Casella JF, et al. Hydroxyurea Is Associated With Lower Costs of Care of Young Children With Sickle Cell Anemia. Pediatrics. 2013 Oct;132(4):677\u0026ndash;83. \u003c/li\u003e\n\u003cli\u003eOlivieri NF, Vichinsky EP et al. Hydroxyurea in children with sickle cell disease: impact on splenic function and compliance with therapy. J Pediatr Hematol Oncol 1998;20:26\u0026ndash;31.\u003c/li\u003e\n\u003cli\u003eCharache S\u003cstrong\u003e .\u003c/strong\u003eExperimental therapy for sickle cell disease : Use of hydroxyurea . Am J Pediatr Hematol Oncol 1994 ; 16 : 62-6.\u003c/li\u003e\n\u003cli\u003eWare R, Steinberg MH , Kinney TR . Hydroxyurea : An alternative to transfusion therapy for stroke in sickle cell anaemia . Am J of Hematol 1995 ; 50 : 140-3.\u003c/li\u003e\n\u003cli\u003eClaster S ,Vichinsky E . First report of reversal of organ dysfunction in sickle cell anaemia by the use of hydroxyurea : splenic regeneration Blood 1996 ; 88 : 1951- 3 \u003c/li\u003e\n\u003cli\u003eJayabose S , Tugal O, Sandoval C et al . Clinical and hematologic effects of hydroxyurea in children with sickle cell anaemia . J Pediatr 1996 ; 129 : 559-65 .\u003c/li\u003e\n\u003cli\u003eKoren A, Dora Segal-Kupershmit , Zalaman L et al\u003cstrong\u003e .\u003c/strong\u003eEffect of hydroxyurea in sickle cell anaemia : A clinical trial in children and teenagers with severe sickle cell anaemia and sickle cell b\u0026ecirc;tathalassemia Pediatr Hematol and Oncol 1999 ; 16 : 221-32.\u003c/li\u003e\n\u003cli\u003eVichinsky EP and Lubin BM . A cautionary note regarding hydroxyurea in sickle cell disease . Blood 1994 ; 83 : 1124-8\u003c/li\u003e\n\u003cli\u003eCharache S. Fetal hemoglobin, sickling, and sickle cell disease. Adv Pediatr 1990;37:1-31.\u003c/li\u003e\n\u003cli\u003eDavies SC, Gilmore A. The role of hydroxyurea in the management of sickle cell disease. Blood Rev. 2003; 17:99\u0026ndash;109\u003c/li\u003e\n\u003cli\u003eDe Montalembert M, Davies SC. Is hydroxyurea leukemogenic in children with sickle cell disease Blood. 2001;98:2878\u0026ndash;9\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable1. Characteristics of the Patients at Base Line, According to Treatment Group.\u003c/p\u003e\n\u003ctable style=\"width: 655px;border-collapse: collapse;border: none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.35pt;border: 1pt solid windowtext;padding: 0in 5.4pt;height: 34.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003eCaracteristics\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 34.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Hydroxyurea n=66\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 193.95pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 34.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003eNo Hydroxyurea n=62\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003eAge. Mean Years\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e10.5\u0026plusmn;7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 193.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e11.2\u0026plusmn;6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003eGender n\u0026deg;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003e\u0026nbsp;Male\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003e\u0026nbsp;Female\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e41\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e25\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 193.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e42\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e20\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 62.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eN\u0026deg;. VOC/years\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 3-5\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 6-8\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026gt; 8 \u0026nbsp; \u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eMean value\u0026plusmn;e.t\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 62.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e27\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e24\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e15\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e5.2\u003c/span\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026plusmn;1.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 193.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 62.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e27\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e23\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e5.7\u003c/span\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026plusmn;1.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 90.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eN\u0026deg;.hospitalisation/ years\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 3-5\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 6-8\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026gt;8\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/span\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eMean value\u0026plusmn;e.t\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 90.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e35\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e29\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e2\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\";'\u003e3.8\u003c/span\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026plusmn;1.4\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 193.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 90.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e33\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e26\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e3\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e3.5\u003c/span\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026plusmn;1.8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style='font-family: \"Times New Roman\";'\u003eTransfusion\u0026nbsp;/ Years\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style='font-family: \"Times New Roman\";color:black;'\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; 3-5\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026ge; 6\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003eMean Value\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e50\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e16\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e3.4\u003c/span\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026plusmn;1.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 193.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e48\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e14\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e3.7\u003c/span\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026plusmn;1.3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:12.0pt;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:150%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eHemoglobine\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:justify;line-height: 115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eg/dL ( mean \u0026plusmn; e.t )\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e7.3\u003c/span\u003e\u003cspan style=\"font-family: Calibri;color:black;\"\u003e\u0026plusmn;1.05\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 193.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e7.6\u0026plusmn;1.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:12.0pt;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:150%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eH\u0026eacute;matocrite % ( mean \u0026plusmn; e.t )\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e22.3\u0026plusmn;3.7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 193.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e23.1\u0026plusmn;2.6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:12.0pt;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:150%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eLeukocyte count (G/L) ( mean \u0026plusmn; e.t )\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e12.278\u0026plusmn;4104\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 193.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e11.394\u0026plusmn;5231\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:12.0pt;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:150%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ePlatelet count (G/L) ( mean \u0026plusmn; e.t )\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e358.665\u0026plusmn;142.588\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 193.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e311.435\u0026plusmn;123.167\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:12.0pt;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:150%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eElectropheretic profil \u0026nbsp;Sickle cell Anemia\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:12.0pt;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:150%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e(SS)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:12.0pt;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:150%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eSickle \u0026beta;\u003csup\u003e0\u003c/sup\u003e Thalassemia\u003csup\u003e\u0026nbsp;\u0026nbsp;\u003c/sup\u003e(SFA2)\u003csup\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e45\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e21\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 193.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e43\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e19\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:12.0pt;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:150%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e% Hb F\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e11.7\u0026nbsp;\u003c/span\u003e\u003cspan style='font-family: \"Arial\",sans-serif;'\u003e\u0026plusmn;7.7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 193.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e12.2\u003c/span\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026plusmn;2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:12.0pt;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:150%;'\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e% Hb S\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170.1pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e86\u003c/span\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026plusmn;7.8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 193.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style=\"font-family:Calibri;color:black;\"\u003e82\u003c/span\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026plusmn;4.5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 2. Impact of hydroxyurea on clinical manifestations\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"633\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.0126%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.5877%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient with hydroxyurea\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.2733%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient without hydroxyurea\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.2749%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.8515%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.0126%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian VOC rate/years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.5877%;\"\u003e\n \u003cp\u003e2.9 \u0026plusmn; 0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.2733%;\"\u003e\n \u003cp\u003e5.3 \u0026plusmn; 1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.2749%;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.8515%;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.0126%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Median hospitalisation rate / years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.5877%;\"\u003e\n \u003cp\u003e2.2 \u0026plusmn; 0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.2733%;\"\u003e\n \u003cp\u003e4.7 \u0026plusmn; 1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.2749%;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.8515%;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.0126%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian Transfusion rate\u0026nbsp;/ Years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.5877%;\"\u003e\n \u003cp\u003e1.3 \u0026plusmn; 0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.2733%;\"\u003e\n \u003cp\u003e5.1 \u0026plusmn; 1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.2749%;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.8515%;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.0126%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnemic Complications\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.5877%;\"\u003e\n \u003cp\u003e8 \u0026plusmn; 0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.2733%;\"\u003e\n \u003cp\u003e10 \u0026plusmn; 0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.2749%;\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.8515%;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.0126%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIschemic Complications\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.5877%;\"\u003e\n \u003cp\u003e18 \u0026plusmn; 0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.2733%;\"\u003e\n \u003cp\u003e17 \u0026plusmn; 0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.2749%;\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.8515%;\"\u003e\n \u003cp\u003eNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.0126%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInfectious Complications\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.5877%;\"\u003e\n \u003cp\u003e16 \u0026plusmn; 0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.2733%;\"\u003e\n \u003cp\u003e30\u0026nbsp;\u0026plusmn; 0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.2749%;\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.8515%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Table 3. Influence of hydroxyurea on biologicals parameters\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.6559%;\"\u003e\n \u003cp\u003eParameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003ePatient With \u0026nbsp;hydroxyurea\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003ePatient Without hydroxyurea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.0568%;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8249%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.6559%;\"\u003e\n \u003cp\u003eHemoglobine\u003c/p\u003e\n \u003cp\u003eg/dL ( mean \u0026plusmn; e.t )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003e9.2\u0026nbsp;\u0026plusmn; 1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003e7.2 \u0026plusmn; 1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.0568%;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8249%;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.6559%;\"\u003e\n \u003cp\u003eHematocrite % ( mean \u0026plusmn; e.t )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003e28.3 \u0026plusmn; 18.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003e22.3 \u0026plusmn; 3.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.0568%;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8249%;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.6559%;\"\u003e\n \u003cp\u003eLeukocyte count (G/L) ( mean \u0026plusmn; e.t )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003e9.5 \u0026plusmn; 4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003e12.6 \u0026plusmn; 3.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.0568%;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8249%;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.6559%;\"\u003e\n \u003cp\u003ePlatelet count (G/L) ( mean \u0026plusmn; e.t )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003e316.4 \u0026plusmn; 130.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003e358.6 \u0026plusmn; 142.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.0568%;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8249%;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.6559%;\"\u003e\n \u003cp\u003e% Hb F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003e14.6 \u0026plusmn; 7.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003e12 \u0026plusmn; 7.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.0568%;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8249%;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 23.6559%;\"\u003e\n \u003cp\u003e% Hb S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003e84.3 \u0026plusmn; 11.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.7312%;\"\u003e\n \u003cp\u003e86.2 \u0026plusmn; 7.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.0568%;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8249%;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5375843/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5375843/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e. Very few studies have been set in Subsaharan Africa according to hydroxyurea effacy and safety. We aimed to evaluate Hydroxyurea efficacy and safety and its benefits in low-resource settings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e We conducted a prospective comparative study of SCA patients. \u0026nbsp;128 patients was enrolled and divided in two groups. 68 patients treated by hydroxyurea at doses 10-20mg/kg/day and 62 patients control groups without \u0026nbsp;hydroxyurea. The end points assessed was feasibility, safety, and benefits (laboratory variables, sickle cell–related events, transfusions).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults : \u003c/strong\u003eThe patients assigned to hydroxyurea treatment had lower annual rate of crises than the control group (median, 2.9 vs. 5.3 crises per year, P=0.001), fewer annual rate of hospitalizations (median 2.2 vs. 4.7, P=0.002), and fewer annual rate of transfusion (median 1.3 vs.5.1, \u0026nbsp;P=0.001). We observed a significant increase in Hb F level from 11.77% to 14.6% (p=0.001) in patient treated by hydroxyurea. We also observed a significant increase in the mean of Hb level from 7.3 g/dl to 9.2 g/dl for patients treated by hydroxyurea (p=0.004). Patients treated by hydroxyurea also have a beneficial effect on WBC and platelet levels by reduction in leukocytosis and thrombocytosis. the occurrence of annual number of infectious complications was significantly lower in the group of patients with hydroxyurea.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Hydroxyurea has a key \u0026nbsp;clinical benefits by \u0026nbsp;reducing the incidence of vaso-occlusive events, infections, transfusions, which translates into fewer hospitalizations. The main problem is the fact that, it’s not accessible for most of our patients who live in poor socio-economical condition.\u003c/p\u003e","manuscriptTitle":"Hydroxyurea efficacy in sickle cell anemia patients in low-income middle country in Cote d’Ivoire","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-28 11:58:43","doi":"10.21203/rs.3.rs-5375843/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c8f98dbd-b748-4ae9-8897-c28c78bcbae9","owner":[],"postedDate":"November 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-02T01:38:47+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-28 11:58:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5375843","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5375843","identity":"rs-5375843","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}