Association of Clinical and Hematological variables with the disease severity in Indian Sickle cell anemia patients
1Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur, India.
2Department of Biotechnology and Bioinformatics, Sambalpur University, India.
*Corresponding Author E-mail: lvksbhaskar@gmail.com
Sickle cell anemia (SCA) is the most common genetic disorder that is caused due to mutation of the β globin gene. Although SCA is a monogenic disorder, the clinical presentation varies greatly among patients. The present study was designed to be a cross sectional study, aimed at analysing the SCA severity and its association with different clinical, biochemical and hematological variables in SCA patients of Indian origin. About 190 random homozygous SCA patients confirmed by hemoglobin electrophoresis were used in the study. Routine biochemical laboratory (liver function test and Renal function test) and hematologic tests (Total hemoglobin, fetal hemoglobin, hematocrit, MCV and MCH) were done. Values pertaining to complete blood count (CBC), Hb-HPLC and clinical investigations were collected from patient’s records. The mean age of patients with severe disease was significantly lesser than the moderate and mild disease patients. The body mass index (BMI) was also significantly lower in severe disease patients compared to the moderate and mild disease. The patients with severe disease had low levels of red blood cells, total hemoglobin (tHb) and fetal hemoglobin (HbF) compared to the other groups. There is no significant difference in the kidney and liver function among various degrees of disease severity. In summary, this study demonstrates that the tHb and HbF and total leucocyte count (TLC) are major prognostic factors for several clinical complications in SCA. Baseline measurement of these important variables is paramount in predicting important aspects of clinical course and improves the quality lives of these children.
KEYWORDS: Sickle cell anemia, Clinical complications, Hematological variables, Severity scores.
Sickle cell anemia (SCA) is the most common genetic disorder that is caused due to mutation of the β globin gene1. Hypoxemia in these individuals leads to hemoglobin polymerization, formation of sickled red blood cells (RBCs) and many of the hallmark events in SCA2. RBCs of SCA patients are prone to endogenous free radical mediated oxidant damage3. Further, vaso- occlusion or disruption of microvasculature by sickled erythrocyte produces distinctive signs and symptoms of the disease and makes them susceptible to a number of serious complications4.
Painful crises are the most common external manifestation of vascular occlusion and are the main reason for hospitalization and medical costs5. Other vaso-occlusive events included splenic sequestration and priapism. Recurrence of vaso-occlusion causes progressive organ damage, leading to kidney failure, heart failure, stroke, avascular necrosis, gallstone formation, cognitive impairment, predisposition to infections and other complications6,7.
Although SCA is a monogenic disorder, the clinical presentation varies greatly among patients. Further, the complication associated with SCA begins in the first year of life and varies with age8. In addition, the severity of a particular clinical feature found to vary in different individuals9,10.
Several studies have proposed methods for estimating severity scores, none satisfying to capture the general severity of the disease due to its unusual clinical heterogeneity11,12. Several lines of evidence demonstrated that fetal hemoglobin (HbF) was the most efficient variable to modulate the clinical and hematologic features of SCA13-15. Total hemoglobin (tHb) concentration and hematocrit are inversely associated with the degree of hemolysis in SCA patients. Therefore, it can be presumed that the severity of the disease is the measure of clinical and laboratory findings16. In addition, the interactions of geographical, socio-economic, genetic and environmental factors should be taken into consideration for assessing the disease severity17.
Sickle cell anemia is prevalent in tribal and non-tribal populations of Chhattisgrah18. Some populations still use phytomedicines for effective management of SCA19,20. The present non-experimental study is a humble effort in the direction of accomplishing to analyse the SCA severity and its association with different clinical, biochemical and hematological variables in SCA patients of Indian origin.
This study was designed to be a cross sectional study, in which data were collected prospectively. This was an observational study, with no interventions performed on any subject. The Institutional Ethics Committee of Sickle cell institute Chhattisgarh, Raipur, has approved the study protocol. The present study included 190 random homozygous SCA patients after obtaining the informed written consent. The study subjects are mainly from the outpatient clinic of the Sickle Cell Institute Chhattisgarh. For all patients, solubility test, Hb electrophoresis, HPLC and other Clinical investigations were performed. Routine biochemical laboratory (LFT and RFT) and hematologic tests (Hb, HbF, HCT, MCV and MCH) were done. Values pertaining to CBC and HPLC were collected from patient’s records. Patients receiving interferon treatment and/or hydroxyurea treatment were excluded. All the patients were evaluated for clinical phenotypes such as pain, anemia, jaundice, pneumonia, stroke, and osteonecrosis. Severity scores were determined using the combination of anemia, complications, TLC and transfusion scores. A complete overview of the criteria used for assessing the severity score was given elsewhere21.
In the present study it is evident that the majority of the subjects had severe disease (51%), followed by moderate disease (35%) and mild disease (14%) (Figure 1). The distribution of age, body mass index, the number of hospitalizations and number of blood transfusions by disease severity among 190 patients is presented in Table
1. Comparison of age in different disease severity groups showed that the more severe disease is found in patients
with mean age of 13.8 years. Low BMI associated with severe disease among SCA patients is indicating growth retardation in these patients (Table 1). In addition to this, number of hospitalizations and blood transfusions are more in SCA patients with severe disease compared to the mild and moderate disease.
Figure 1: Presentation of different grades of severity in SCA patients.
The distribution of different clinical phenotypes among various grades of disease severity is shown in figure 2. Among the clinical phenotypes pallor, jaundice, hemolytic face, splenomegali, hepatomegali and renal failure are significantly higher in severe disease patients compared to the moderate and mild disease groups (Figure 2). Distribution of the hematological variables among sickle cell anemia patients with various degrees of severity is documented in Table 2.
Figure 2: Distribution of clinical complications in mild, moderate and severe SCA subjects.
Table 1: Basic information sickle cell anemia patients with different degrees of severity.
|
Variable |
Mild disease (n=27) |
Moderate Disease (n=67) |
Severe disease (n=96) |
P value |
|
Age |
18.9±8.3 |
19.2±10.9 |
13.8±6.3 |
<0.001 |
|
BMI |
18.2±5 |
16.4±3.2 |
15.2±2.3 |
<0.001 |
|
No. of Hospitalizations |
3.7±2.5 |
4.7±5 |
12.0±24.1 |
0.012 |
|
No. of Blood transfusions |
3.5±2.7 |
4.2±5.1 |
9.9±18.7 |
0.013 |
BMI: Body Mass Index
Table 2: Hematological variables among sickle cell anemia patients with various degree of severity
|
Variable |
Mild disease (n=27) |
Moderate disease (n=67) |
Severe disease (n=96) |
P value |
|
HbF (%) |
23.6±7.0 |
20.6±6.1 |
17.9±6.8 |
<0.001 |
|
Hb (g/dl) |
10.0±1.5 |
8.8±1.6 |
7.8±1.7 |
<0.001 |
|
Hematocrit (%) |
28.9±3.8 |
29.4±27.7 |
23.5±5.0 |
0.067 |
|
TLC (10ˆ9/L) |
6.5±1.7 |
8.3±2.8 |
14.5±5.8 |
<0.001 |
|
Platelets (10ˆ9/L) |
273.2±169 |
292.0±154 |
368.5±167 |
0.003 |
|
RBC (10ˆ12/L) |
3.5±0.7 |
3.5±2.6 |
2.7±0.6 |
0.005 |
|
MCV (fL) |
85.5±12.6 |
85.9±10.1 |
86.7±9.7 |
0.834 |
|
MCH (pg) |
29.4±4.4 |
28.6±3.7 |
29.3±4.0 |
0.477 |
|
RDW-CV (%) |
17.7±4.1 |
17.7±2.0 |
18.8±2.7 |
0.016 |
HbF: Fetal Hemoglobin; Hb: Hemoglobin; TLC: Total Leucocyte count; RBC: Red blood cells; MCV: Mean corpuscular volume; MCH: Mean corpuscular hemoglobin; RDW-CV: Red blood cell distribution width- coefficient variation
Table 3: Levels of serum bilirubin, serum transaminases, serum urea and creatinine among SCA subjects with various degrees of severity.
|
Variable |
Mild disease (n=27) |
Moderate disease (n=67) |
Severe disease (n=96) |
P value |
|
Total bilirubin (mg/dl) |
2.4±1.4 |
2.3±1.8 |
2.5±1.7 |
0.763 |
|
Direct bilirubin (mg/dl) |
0.6±1.1 |
0.4±0.5 |
0.4±0.3 |
0.198 |
|
SGPT (U/L) |
21.0±12.6 |
22.8±15.3 |
23.5±21.4 |
0.815 |
|
SGOT (U/L) |
41.9±37.5 |
47.3±28.3 |
50.6±26.4 |
0.361 |
|
Sr. Urea (mg/dl) |
15.6±5.5 |
16.9±10.0 |
17.7±11.8 |
0.664 |
|
Sr. Creatinine (mg/dl) |
0.7±0.2 |
0.6±0.2 |
0.6±0.2 |
0.201 |
SGPT: Serum glutamic pyruvic transaminase; SGOT: Serum glutamic oxaloacetic transaminase; Sr.: serum.
The patients with severe disease had low levels of red blood cells, tHb and HbF compared to the other groups. In contrast to this, total leucocyte count (TLC) and platelets are significantly higher in severe disease groups than the mild and moderate disease groups. The red blood cell distribution width (RDW-CV) was also increased in patients with severe disease (Table 2). Levels of total bilirubin, direct bilirubin, SGOT, SGPT, urea and creatinine in serum did not differ significantly among SCA subjects with various degrees of severity (Table 3).
Analysis of disease severity scores in 190 sickle cell anemia patients showed that the severe disease incidence is more compared to the moderate and mild disease. The mean age of patients with severe disease was significantly lesser than the moderate and mild disease patients. The BMI was also significantly lower in severe disease patients compared to the moderate and mild disease. The patients with severe disease had low levels of red blood cells, tHb and HbF compared to the other groups. There is no significant difference in the kidney and liver function among various degrees of disease severity.
Introduction of several disease modifying therapies increased the life span of SCD patients compared to their historical peers22. Comparison of vaso-occlusive events in SCA patients over 40 years of age with patients under 30 years of age, showed lower numbers of vaso- occlusive events in the older patients23. Subsequent studies found that SCA patients above 40 years had a mild clinical picture and 72% of patients in this age group did not exhibit a painful crisis in the past two years24. In consensus with these reports, younger patients with a mean age of 13.8 years exhibited severe disease compared to the older patients. However, the elderly patient may also appear to develop other age-related complications that interact and add to the disease morbidity. Blood transfusions are used to treat the patients admitted in critical care setting with life- threatening anemia or with serious complications25. Analysis of transfusion frequencies and complications related to SCA of 3,208 patients showed that transfusion frequency was less in patients transitioning to adult care compared to pediatric patients who suffer from more complications26. Our study also showed more hospitalizations and higher frequency of transfusions in the younger patients.
Several studies have demonstrated the link between HbF levels and sickle cell complications. Initial studies reported that the patients with leg ulcer had lower tHb and HbF levels than controls27. Subsequent studies demonstrated the association between increased HbF levels and reduced risk for early onset of sickle cell complications28. However, the levels of HbF are significantly associated with the common SNPs at the BCL11A, HBS1L-MYB, and HBB genes29. In the present study we found significantly lower levels of tHb and HbF in patients with the severe disease. Analysis of platelets and leucocyte in SCA children showed increased platelets and WBC counts associated with bacterial infection, acute chest syndrome and with vaso- occlusive crisis30-34. Comparison of SCA and other anemias suggested that the RDW was significantly higher in SCA patients while no difference in tHb or MCV was observed35. Further, elevated RDW correlated significantly with the degree of anemia and reticulocytosis in SCA patients36,37.
Compared to the normal and homozygous sickle cell patients, carriers of sickle cell trait showed increased serum transaminases38. Although elevation of bilirubin, alkaline phosphatase with mild transaminitis was found in some SCA patients, these abnormalities are not specific to SCA patients39. In majority of the SCA patients, serum creatinine levels are slightly lower than the normal due to high glomerular filtration rate (GFR) in SCA patients40,41. Comparison of urea and creatinine levels in Iraqi children with SCA showed that these two were considerably lower in the SCA patients42. In our sample the serum urea and creatinine levels were not significantly different among various degrees of severity. The main limitation of the present study is that it used data from only one medical centre. However, this study demonstrates that the tHb and HbF and TLC are major prognostic factors for several clinical complications in SCA. Baseline measurement of these important variables is paramount in predicting important aspects of a clinical course. Therefore, it is important to evaluate these variables in all children with SCA to provide appropriate treatment and improve the quality lives of these children
This work was supported by Chhattisgarh Council of Science & Technology (CCOST) project (No.2740/ CCOST/ MRP/2015).
Authors declare that there is no conflict of interest.
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Received on 08.11.2020 Modified on 20.12.2020
Accepted on 15.01.2021 © RJPT All right reserved
Research J. Pharm. and Tech. 2021; 14(10):5254-5257.
DOI: 10.52711/0974-360X.2021.00915