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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 1  |  Page : 22-27

Relationship between genotype variants and the age of first acute splenic sequestration in patients with sickle cell disease in a tertiary center of Saudi Arabia: A retrospective study


1 Department of Pediatric Hematology/Oncology, Pediatrics Hospital, King Saud Medical City, Riyadh, Saudi Arabia
2 Head, Research Support, Research and Innovation Center Data Manager, Trauma Registry Department, King Saud Medical City, Ministry of Health, Riyadh, Saudi Arabia

Date of Submission22-Dec-2020
Date of Decision06-Oct-2021
Date of Acceptance06-Oct-2021
Date of Web Publication28-Apr-2022

Correspondence Address:
Dr. Lobna Abdulaziz Baitalmal
Department of Pediatrics Hematology Oncology, King Saud Medical City, Riyadh
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_244_20

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  Abstract 


BACKGROUND: Acute splenic sequestration crisis (ASSC) is one of the earliest life-threatening complications of sickle cell disease (SCD). Here, we aimed to identify the relation between the age of the first splenic sequestration episode and SCD variants. Episodes of acute splenic sequestration before 1 year of age are associated with a higher risk of recurrence.
METHODS: We carried out a retrospective chart review study from the medical charts of SCD patients ≤12 years admitted to the Department of Pediatric Hematology King Saud Medical City, Riyadh with the first episode of ASSC and no other complications from January 2014 to December 2019.
RESULTS: We included 47 patients (46.8% males, 53.2% females) diagnosed with SCD and having experienced their first ASSC in this review. The mean age of the patients at which the first episode of splenic sequestration happened was 3.26 years. The genotype distribution in the population was 74.5% HBSS, 21.3% HBS β0 thalassemia, and 4.3% HBSβ+ thalassemia. The crisis precipitated with fever in 74.5% of patients. Treatment included programmed blood transfusion (46.2%), splenectomy (29.8%). The recurrence rate after the first episode of ASSC was 59.6%. The high rate of recurrence was mainly due to the early age of presentation and poor compliance with suggested treatment. The use of hydroxyurea in 19.1% of patients showed a decrease of recurrence of ASSSC by 66.6% of patients.
CONCLUSION: The study concluded that the HBSS variant of SCD had the earliest presentation with the first episode of ASSC but the differences were numerical without any statistical difference. Earlier age of presentation is associated with a higher rate of recurrence, but the difference was numerical not statistically significant. Our study shows hydroxyurea decreased recurrent splenic sequestrations; further research would help in establishing its role

Keywords: HbSS, retrospective, sickle cell disease, splenic sequestration


How to cite this article:
Baitalmal LA, Al Kasim FA, Ghareeb EF, Azmet FR, Jaganathan PP. Relationship between genotype variants and the age of first acute splenic sequestration in patients with sickle cell disease in a tertiary center of Saudi Arabia: A retrospective study. J Appl Hematol 2022;13:22-7

How to cite this URL:
Baitalmal LA, Al Kasim FA, Ghareeb EF, Azmet FR, Jaganathan PP. Relationship between genotype variants and the age of first acute splenic sequestration in patients with sickle cell disease in a tertiary center of Saudi Arabia: A retrospective study. J Appl Hematol [serial online] 2022 [cited 2022 May 17];13:22-7. Available from: https://www.jahjournal.org/text.asp?2022/13/1/22/344262




  Introduction Top


Sickle cell disease (SCD) is an autosomal recessive disorder resulting from a mutation of the β-globin gene (Glu6Val). SCD is characterized by the production of abnormal hemoglobin (Hb) S and is associated with high morbidity and mortality. The prevalence of SCD in Saudi Arabia varies significantly in different parts of the country, most Prevalent, is in the Eastern province then, followed by the southwestern provinces. The reported prevalence is 2%–27% for sickle-cell trait and up to 2.6% for SCD. There are different variants of SCD genotypes include HbSS disease, HbS/β0 thalassemia, HbSC, HbS/β+ thalassemia, HbS/HPFH, Alfa deletions HbS, and HbS/HbE syndrome.[1],[2],[3] Acute splenic sequestration crisis (ASSC) is characterized by rapid splenic enlargement ≥ 2 cm, a fall in Hb level >2 g/dL from the patient's baseline level, and markedly elevated reticulocyte count.[4] It represents an uncommon but one of the earliest life-threatening complications seen in SCD patients.[5],[6] It usually occurs in children between 3 months to 6 years of age.[7] Patients at a very early age with homozygote sickle cell variant (HbSS), producing sickled erythrocytes without splenic infarctions and organ involution, have the highest risk of developing ASSC. The implications of ASSC are severe anemia, hypovolemic shock, and in some cases death.[8] The clinical manifestations of ASSC are weakness, pallor, dyspnea, tachycardia, faintness, and abdominal distention. There are major and minor attacks. The minor attacks are characterized by a moderate increase in splenic size associated with a decrease in Hb level of 2–3 g/dl with transient thrombocytopenia, while major attacks are associated with features of hypovolemia and sudden drop in Hb level, sometimes decreasing to 1–3 g/dl. In major attacks, hypovolemic shock and death can occur.[9],[10]

It is a medical emergency that requires immediate restoration of blood volume by fluids and, blood transfusion. Blood transfusion usually releases the trapped RBC resulting in higher transfusion yields than expected, warranting caution on the amount of blood transfused to avoid a posttrans fusional hematocrit above 35%. Management of acute splenic sequestration also includes treating an associated infectious cause. A major concern following a first episode is preventing the risk of recurrence. Parental education about the importance of fever, spleen palpation, acute pallor, and referral to the hospital is pivotal.[11]

Although most genotype variants of SCD report ASSC episodes, it is important to understand the relation between the type of variants and the age of onset of the first episode of ASSC for better management of the complication. Very few studies have identified the relationship between the age of the first episode of splenic sequestration and SCD variants. Based on medical chart review and analysis, we performed a retrospective study in the Department of Pediatric Hematology, King Saud Medical City, Riyadh to identify the relationship between the age of the first splenic sequestration episode and SCD variants. In addition, we also reviewed the types of treatment proposed and their results; the use of hydroxyurea and estimated the recurrence rate of ASSC.


  Methods Top


We performed a retrospective chart review study in the Department of Pediatric Hematology, King Saud Medical City, Riyadh. We reviewed records of all the SCD patients admitted from January 2014 to December 2019. Inclusion criteria include patients ≤12 years of age with SCD and the first episode of acute splenic sequestration that is defined as an acute splenic enlargement ≥ 2 cm, a fall in Hb level >2 g/dL from the patient's baseline level and normal or increased basal reticulocyte count. Exclusion criteria included patients with SCD admitted with complications other than acute splenic sequestration or with age ≥12 years.

Data collection

We formulated a data collection sheet, and it included the variables, namely, patient demographic data, the first episode of splenic sequestration, frequency, risk factors (age, infection, SCD variants), response to treatment (blood transfusion, splenectomy), use of hydroxyurea, outcome after therapy by clinical and laboratory parameters. We collected the data from patient files as well as from the electronic medical record system. The institutional review board approved the study with waiver of parental consent requirements looking into the retrospective nature of the study.

Statistical analysis

We used the Chi-squared test along with Fisher's exact test to find the relationship between dependent variables, bivariate analysis of the continuous data using Student's t-test for parametric distributions, and relevant nonparametric tests for nonnormal continuous data. We represented the data as number and percentage (%) for categorical variables or mean and standard deviation for continuous variables. The results were considered statistically significant if P < 0.05. Statistical analysis was performed using SPSS ver. 22.0 (IBM, Chicago, IL, USA).


  Results Top


In this study, we screened 400 SCD patients between January 2014 and December 2019. Out of the screened patients, we found 58 patients diagnosed with the first episode of acute splenic sequestration. We excluded 11 patients because of incomplete data availability. We reviewed the chart of 47 patients (46.8% males, 53.2% females), who met the inclusion and exclusion criteria. The different types of genotypes identified were HBSS (74.5%), HBS β+ thalassemia (21.3%), HBSβ+ thalassemia (4.3%), and Alfa -Deletions HBS (0%). We summarized the demographic characteristics of the study population in [Table 1].
Table 1: Demographic characteristics of the study sample

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The mean age at diagnosis of SCD was 3.22 years. The mean age of first splenic sequestration in the reviewed population was 3.26 years (0.4–10 years). ASSC presented earliest in the patients with HbSS genotype with a mean age of 2.92 years (0.4–10 years) at first presentation followed by HbSβ0 patients with a mean age of 3.94 years (2–7.3 years) then HbSβ+ patients with a mean of 4.91 years (2.5–7.5 years). We found that the differences in age of onset of splenic sequestration among the genotype variants were numerical without any significant statistical difference (P = 0.287) [Figure 1].
Figure 1: Box plot showing the impact of the type of sickle cell disease on age of first splenic sequestration

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The crisis was precipitated by fever in 74.5% of the patients. Spleen size at diagnosis ranged from 2.5–10 cm (mean 5.61 cm). Spleen size at discharge regressed in about 79% of patients ranged from 0 cm to 7 cm (mean 3.3 cm). The mean basal Hb was 8.5 g/dl (6–10.3 g/dl).

At admission, mean Hb was 4.72 g/dl ranging from 1 to 7 g/dl, which was a drop from baseline Hb level >2 g/dL. The reticulocyte count ranged from 0.05 to 35.76% because of associated aplastic crisis or hemolytic or splenic sequestration itself. Platelet count was on the lower side with a mean count of 128 × 109/L ranging from 42 to 358 × 109/L because of the disease process in most of the patients. Also observed high leukocyte count due to associated infection which mainly neutrophils predominate. Sixteen patients (34%) needed admission to high dependent areas due to hemodynamic instability and very low Hb [Table 2].
Table 2: Laboratory findings at admission

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Different types of treatment included programmed blood transfusion (46.8%), splenectomy (29.8%) The mean age of performing splenectomy was 4.79 years (3.28–6.88 years). Splenectomy was not conducted in 70.2% due to age, lack of eligibility, and refusal to give consent for the procedure from family members. We also noticed that the use of hydroxyurea in 19.1% decreased the recurrence of ASSC in 66.6% of patients. The recurrence rate of ASSC after the first episode was 59.6% with 53.6% of patients having three or more episodes of recurrence. HBSS had a numerically higher rate of recurrence compared to other variants, but the difference was not statistically significant (P = 0.605). The higher frequency of recurrence was associated with a numerically lower mean age of first splenic sequestration, but the difference was not statistically significant (P = 0.328) [Table 3].
Table 3: The relation between frequency of recurrence and age of first splenic sequestration

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The mean age for patients with recurrence was 2.76 years compared to nonrecurrence patients with a mean of 3.9 years. The HBSS which presents early had a higher rate of recurrence more than other variants [Table 4].
Table 4: The relation between type of sickle cell disease and frequency of recurrence

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  Discussion Top


This single-center record review study revealed that the HbSS variant of SCD had the earliest presentation numerically with ASSC among the three variants (HbSS, HbSβ0, HbSβ+) detected in the study. The recurrence rate in the study was 59.6% after the first episode, which was similar to other international data published earlier.

Al-Rimawi et al.'s study showed that the rate of ASSC in HbSβ0 patients was 32% and in HbSS patients were 25%. However, the mean age at the first episode was higher in HbSβ0 patients compared to HbSS patients. Most of the first episodes in HbSS patients occurred when the patient was under the age of 2 years, while in HbSβ0 patients, it was at the age ≥3.5 years.[10] A study by Brousse et al.[5] showed a very high recurrence rate of 67% after the first episode of ASSC. A study by Edmond et al.[7] reported that in a cohort of 308 children with HbSS, 89 experienced 132 clinically significant attacks of ASSC over 10-year period. The age at first attack ranged from 3 months to 6 years and the recurrence rate was only 49%.[7] This difference may be because of improvements in survival after the first ASSC, which has increased the number of children at risk. Age at the onset of the first episode was significantly associated with recurrence risk. Recurrences were significantly less frequent when the first episode occurred after 2 years of age than when it happened before 1 year of age. In our study, the high recurrence rate was attributed mainly to the early presentation and poor compliance with treatment. Clinically, this finding was important, as patients who experience their first splenic sequestration during infancy should be under closed monitoring.

Al-Rimawi et al. study also concluded that the recurrence risk was about 70% in those who survived their first ASSC episode, and these episodes were closely related with subsequent hypersplenism. The most important predicting factors for ASSC in SCD patients were the presence of splenomegaly of more than 5 cm below the costal margin, history of ASSC in siblings, and high HbF. It was suggested that any child with a history of major episodes of ASSC needed a long term transfusion therapy if under 5 years age and prompt splenectomy if >5 years age or where there was a minor episode that was followed by the development of chronic hypersplenism.[10]

Khaled et al. showed that age of onset of symptoms <24 months was an independent predictor of ASSC occurrence and recurrence in patients with SCD. In patients with the HbSS genotype, the risk of sequestration increases significantly if the symptoms appear before the age of 17 months. Based on the first ASSC characteristics, the risk of recurrence was 3.37 higher in patients who presented their first episode between the age of 2 and 5 years.[12]

Brousse et al., Two-thirds of the patients had a fever or infection at the time of the first ASSC. Increased inflammation during a febrile condition or vaso-occlusive crisis may promote the trapping of blood within the spleen by increasing blood cellularity, blood viscosity, and erythrocyte rigidity (Krishnan et al., 2010). Parental education is crucial. In particular, parents must be aware of the need to seek immediate medical advice in the event of a fever, how to palpate the spleen, and know the baseline level for their child.[5] Our study found a similar result where most of our patient's crises were preceded by fever and some cases associated with vasocculosive, aplastic, and hemolytic crisis. In our study, patients need programmed blood transfusion in 46.8% and sometimes admission has another reason for blood transfusion like (stroke, hemolytic, and aplastic crisis). The study by Daak et al. in Western Sudan, The median age of sequestration crises was 1.4 years, with 75% of episodes occurring before 2 years of age. Recurrence rates are higher among those who have their first event before 1 year of age.[13]

The mainstay of long-term management of ASSC in SCD globally is splenectomy and blood transfusion. Splenectomy, if complete, will prevent future sequestration episodes, and if partial, may reduce ASSC recurrence. However, there is a lack of evidence from trials showing that splenectomy improves survival and decreases morbidity in people with SCD. There is a need for a well-designed, adequately powered, randomized controlled trial to assess the benefits and risks of splenectomy compared to transfusion programs, as a means of survival improvement from acute splenic sequestration in people with SCD.[14]

The median age of children with sequestration crises is 1.4 years, with 75% of episodes occurring before 2 years of age. Due to the variation in mutations among children with SCD within a particular geographic region, prevalence estimates are difficult to quantify, but reports are between 7% and 30%. Recurrence rates among children with one sequestration crisis are 50%–78% and are higher among those who have their first event before 1 year of age.[15]

Splenectomy is one of the most common procedures required for patients with SCD. In a study, Ghmaird et al. 100% of the patients underwent complete splenectomy. Splenectomy in young children with ASSC can be safe and effective when performed with penicillin prophylaxis and improved vaccination strategies.[16],[17]

Vietck et al. found that partial splenectomy decreased the risk of subsequent episodes of splenic sequestration in SCD and reduced the need for transfusions. Infectious complications did not appear to be increased. Consideration for this procedure should be given to those patients who have more than one ASSC and/or long-term transfusion requirements.[16]

In a study by Rezende et al. 89 patients had 173 episodes of ASSC with 75% of the first episodes occurring before 2 years of age. The estimated probability of occurrence of the first episode of ASSC during the study period was 40% while recurrence was detected in 57.3%. Splenectomy was indicated in only 12.4% of the cases after the first episode and in 60.4% of the cases after the second episode. There was a median time of 2 months between the indication for splenectomy and the actual surgical procedure. During the intervening period, 37.2% of the children suffered a new episode of ASS and one child died. The case-fatality rate was 1.1% for the first episode and 7.8% for the subsequent episodes. Among 255 children, 19 died: 36.8% due to infections and 26.3% after ASSC.[18]

In our study, we performed splenectomy in 29.8% after complete vaccination.

Nevitt et al. published a systematic review in Cochrane Database of Systematic Reviews that included 17 studies exploring the role of hydroxyurea for SCD. The review revealed that hydroxyurea was effective in the short term at decreasing the frequency of painful episodes and raising fetal Hb levels in the blood in adults and children with SCD. Hydroxyurea was also efficacious in first stroke prevention in patients with an increased risk of stroke without an increase in any side effects (including serious and life-threatening side effects). There is currently a lack of research on the long-term beneficial effects of hydroxyurea, the right dose to be used, and any long-term or any serious side effects associated with the drug. There is a need for well-designed studies to address these questions in the future.[19]

The study by Brousse et al., in three of the patients, the first ASSC episode occurred shortly after hydroxyurea therapy initiation, in keeping with reports of splenic regeneration in patients treated with hydroxyurea (Claster and Vichinsky, 1996; de Montalembert et al., 2006). Studies of the splenic uptake of Tc99 m sulfur colloid in SCD infants showed a lower proportion of asplenia in the hydroxycarbamide-treated group (43%) than in an untreated age-matched group (94%) (Hankins et al., 2005). These data suggest that hydroxyurea may prevent or delay the development of functional asplenia, thereby increasing the risk of ASSC by lengthening the at-risk period. This hypothesis leads us to believe that parents of young children (under 5 years of age) treated with hydroxyurea should be taught to be particularly cautious regarding the risk of ASSC, particularly if the child has splenomegaly and even more so if he or she has a history of ASSC.[5]

A multicenter randomized trial by Wang et al. Three recent systematic reviews of the use of hydroxyurea for SCD have been published. BABY HUG is the first randomized trial of hydroxyurea in children with SCA. No previous systematic reviews or meta-analyses of the effects of hydroxyurea on splenic or renal function in SCA have been published. In these literature reviews, we found two retrospective studies that showed modestly preservation of splenic uptake in older children and a small prospective study that showed no effect.[20] So our findings suggest the usage of Hydroxyurea decrease the splenic sequestration crisis as opposed to previous literature, it could be explained that the drug started late after 1–2 years of last episode or patient presents with the first sequestration at age of 4–5 years, it needs more studies to evaluate this part and determine the effect of hydroxyurea on splenic sequestration occurrence, it needs more studies to evaluate this part and determine the effect of hydroxyurea on splenic sequestration occurrence.

Brousse et al. showed that temporary blood transfusion programmed was used in 29% patients. Ten of these patients had another reason for receiving blood transfusions (abnormal transcranial Doppler velocity, acute chest syndrome, or systemic inflammatory disease). We hypothesize that recurrent ASSC is more likely to result in autosplenectomy through recurrent infarction, whereas hypersplenism is probably a more chronic state that may, be prolonged by blood transfusions.[5] We Started programmed blood transfusion in 46.8% of patients if they developed one major crisis or 2 minor crises or associated with other complications like (stroke, aplastic, VOC, and hemolytic crisis).

As mentioned, ASSC is a serious life-threatening complication of SCD. If not appropriately managed, ASSC can progress to coma and death from hypovolemia.[6] In one of the earliest case report series, Jenkins et al. described 10 cases of sudden death in children with SCD. Out of the 10 cases, 5 had ASSC as the first manifestation of the disease.[21] The Jamaican cohort of children with SCD provided the most reliable data on the topic. The prospective follow-up of patients diagnosed from cord blood samples showed ASSC and infection as the primary causes of death in the first 3 years of life, with ASSC accounting for eight of the 18 deaths in 53 patients followed from diagnosis.[22] A follow-up published by Topley et al.[4] showed 10 of 25 deaths due to ASSC. Seventy-one episodes of ASSC occurred in 52 of the 216 children with SCD with a first episode mortality rate of 12%. Fourteen of the 46 survivors of the first episode had at least one recurrence with an increase in mortality (20%). The report of Emond et al.[7] is the most recent experience with ASSC from the Jamaican cohort with thirteen patient deaths related to it with 11 during the first episode itself. Early detection and parental education on the occurrence of ASSC had a sharp positive impact on the related mortality.[23] We concluded that the HBSS variant presents earlier with First acute splenic sequestration and higher recurrence rate than the other variants. Earlier age of presentation is associated with a higher rate of recurrence. We should enhance parental education about spleen measurement. Our study show hydroxyurea decreased recurrent splenic sequestrations, further research would help in establishing its role.


  Conclusion Top


HBSS variant presents earlier with First acute splenic sequestration and higher recurrence rate than the other variants. Earlier age of presentation is associated with a higher recurrence rate, but these differences were numerical without any statistical difference. Close monitoring of the HBSS pattern is important as it has an influence on the severity of the course of ASSC and we should enhance parenteral education about spleen measurement. The use of hydroxyurea is also found to decrease recurrent splenic sequestrations but more studies about their effects on ASSC are needed for a conclusion

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.



 
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