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Table of Contents
DIAGNOSTICS IN CLINICAL SETTING
Year : 2018  |  Volume : 4  |  Issue : 2  |  Page : 67-71

Sickle cell anemia: An update on diagnosis, management and prevention strategies


1 Senior Resident, Department of Pathology & Laboratory Medicine, All India Institute of Medical Sciences, Bhubaneswar, India
2 Assistant Professor, Department of Pathology & Laboratory Medicine, All India Institute of Medical Sciences, Bhubaneswar, India

Date of Submission11-Dec-2018
Date of Acceptance26-Dec-2018
Date of Web Publication4-Feb-2019

Correspondence Address:
Gaurav Chhabra
Assistant Professor, Pathology & Lab Medicine, AIIMS, Bhubaneswar
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-2113.251444

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  Abstract 


Sickle cell anemia is the most common disease entity of all the monogenic disorders. This is an autosomal recessive disorder. HbS polymerization, vaso-occlusion, and hemolytic anemia are central to the pathophysiology of sickle cell disease, they precipitate a cascade of pathologic events, which in turn lead to a wide range of complications. The disease is particularly more prevalent in certain regions of the country like Odisha, Madhya Pradesh, Tamilnadu and has a significant impact on morbidity. Community based approach by providing availability of screening tests, & pre-marital and pre-pregnancy counselling should be initiated to reduce the disease burden in the society.

Keywords: Sickle cell anemia, Sickle cell disease, Sickle cell anemia diagnosis, sickle cell anemia management.


How to cite this article:
Mishra S, Chhabra G. Sickle cell anemia: An update on diagnosis, management and prevention strategies. Indian J Community Fam Med 2018;4:67-71

How to cite this URL:
Mishra S, Chhabra G. Sickle cell anemia: An update on diagnosis, management and prevention strategies. Indian J Community Fam Med [serial online] 2018 [cited 2019 Aug 20];4:67-71. Available from: http://www.ijcfm.org/text.asp?2018/4/2/67/251444




  Introduction Top


Sickle cell anemia is the most common disease entity of all the monogenic disorders. This is an autosomal recessive disorder. The prevalence is estimated to be increasing worldwide.[1],[2] Latest reports say that around 300,000 infants are born each year with Homozygous Sickle cell anemia. This disease is specifically prevalent in sub-Saharan African countries, the Mediterranean basin, the Middle Eastern countries, and the Indian subcontinent.[3],[4] The prevalence of Sickle cell anemia is at par with that of Malaria. It is postulated that the disease is still there in the population as it protects against life-threatening malarial diseases. The famous “malaria hypothesis” was formulated by Haldane in 1949 and by Allison in 1954. This disease is a prototype example of natural selection and balanced polymorphism, a process that is ongoing. Although, this hypothesis is highly debatable. The fact remains that the disease load is nowhere near eradication. So, the need of the hour is a better diagnostic facility, reduction of the disease load by providing pre-marital counselling and pre-pregnancy work-up. The disease has many modifying many modifying factors, some of which are still under investigation.[5],[6]

Prevalence in India

In 1952, in the Nilgiri hills of northern Tamil Nadu sickle cell disease was first described. After the first discovery, it has been found widespread in all the regions of the country.[7] The Anthropological Survey of India has conducted extensive studies on sickle cell distribution and have found that in some communities the prevalence is as high as 35%.[8]

Prevalence in Odisha

According to a statement released by the State health department in 2015 Odisha has 5.35 lakh of the population affected by the disease, among them 5 lakh people could be found in 13 western Orissa districts.[9]


  Pathophysiology Top


Hemoglobin is a tetrameric protein. Each unit of hemoglobin comprises two pairs of globin chains with each group having one haem molecule. Thus, each molecule of hemoglobin had four haem molecules, and in turn, these can carry four oxygen molecules. Globin chains are derived from Chromosome 11 and Chromosome 16, which codes for beta (β) chains and alpha (α) chains respectively. There are four genes coding for alpha chains and 2 for beta chains. Sickle cell disease is caused by a point mutation in the sixth codon of β-globin that leads to the replacement of a glutamate residue with a valine residue. Due to the point mutation in sickle cell anemia, hemoglobin undergoes a conformational change during oxygenation and de-oxygenation and the globin molecule becomes “sticky” or unstable leading to polymerization and precipitation. This happens in the deoxygenated state. As the hemoglobin precipitates, it makes the RBCs sickle-shaped. These RBCs again gain their original structure on oxygenation. But repeated episodes of sickling leads to membrane damage and severe dehydration of the cells, thus rendering them rigid and non-pliable. This results in its reduced lifespan.

Membrane damage leads to exposing of phosphatidylserine on the outer leaflet of the membrane. This helps in easy removal of these cells by macrophages, thus resulting in extravascular hemolysis. Excessive sickling can lead to the stacking of these sickle cells and occlusion of micro-vessels. Vaso-occlusion is one of the most frequent complications in these patients.

Vaso-occlusion affects various organs and can present in varied forms like acute chest syndrome, acute abdominal pain due to mesenteric vaso-occlusion, acute Ischemic stroke, and avascular necrosis of bones and renal impairment. Auto-splenectomy is a characteristic feature of homozygous sickle cell anemia.[10],[11]

Although HbS polymerization, vaso-occlusion, and hemolytic anemia are central to the pathophysiology of sickle cell disease, they precipitate a cascade of pathologic events, which in turn lead to a wide range of complications. These processes include vascular-endothelial dysfunction, functional nitric oxide deficiency, inflammation, oxidative stress, and reperfusion injury, hypercoagulability, increased neutrophil adhesiveness, and platelet activation.[10],[11]

The interaction of HbS with other globin chains affects its polymerization properties. HbA and HbF prevents polymerization. Coexisting alpha thalassemia and iron deficiency enhances the severity of the disease. Non-genetic factors precipitating sickling are infection, inflammation, dehydration, humidity, high altitude, smoking, and air pollution.[10],[11]

Crisis in Sickle cell disease

A crisis arises because of rapid hemolysis or non-production of RBCs. Increased hemolysis can be seen in infections, inflammatory conditions or sudden changes in weather. Reduced production can be due to megaloblastic precipitation leading to ineffective erythropoiesis, i.e., destruction of RBCs within the marrow. Aplastic crisis can be precipitated by Parvovirus B19, which results in erythroid maturation arrest in pro-normoblast stage and erythroid destruction.

A patient of sickle cell anemia can also present with pancytopenia. That can be either due to hypersplenism or due to marrow infarction (vaso-occlusion of marrow). Prompt action is therefore required in such conditions.


  Laboratory diagnosis Top


Complete Blood counts

In heterozygous sickle cell anemia, the numbers and RBC indices are all normal. Lower MCV and MCH may be seen in patients with co-existing alpha thalassemia. In people with homozygous sickle cell anemia, the presentation is uncommon in the first year of life attributed to the presence of fetal hemoglobin. After one year of age, following the switchover, the HbF is entirely replaced by HbS, the patient develops chronic anemia and reticulocytosis.

Peripheral smear

In heterozygous sickle cell anemia, the blood picture is predominantly normocytic normochromic with target cells and sickle cells are usually not seen while in homozygous condition, sickle cells will be more easily found. [Figure 1]
Figure 1: Peripheral blood showing Sickle cells: A-X400, B- X1000 (Leishman).

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Other investigations

Sickling test

This is an easy and reproducible method to screen both heterozygous and homozygous conditions. Here blood is incubated at 37 C with 2% sodium metabisulphite or sodium dithionite. Wet-mounts are prepared and examined to detect sickling changes in the red corpuscles. [Figure 2]
Figure 2: Sickling test (2% Sodium metabisulphite)

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Hemoglobin Electrophoresis

Electrophoresis can be done in cellulose acetate at acidic or alkaline pH. Alkaline pH separates HbS from other hemoglobins such as Hb D and Hb G, which co-elutes with Hb S at acidic pH.

High Performance Liquid Chromatography (HPLC)

Hemoglobin HPLC or High-Performance Liquid Chromatography is the test of choice today to screen all hemoglobinopathies. It gives a correct estimate of HbA2 and HbF along with an HbS peak. The charge separates the hemoglobins. The stationary medium is negatively charged, and the mobile medium carries the hemolysate. Most positively charged hemoglobin is eluted last. The concentration of cations in the mobile phase gradually increases with an increase in pressure leading to elution of these positively charged hemoglobins. [Figure 3]A, [Figure 3]B
Figure 3: Chromatograms showing (A)Sickle cell trait (B) Homozygous Sickle cell anemia

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Molecular analysis

Reverse Dot-blot, Restricted fragment length polymorphism (RFLP), and gene sequencing are the methods used to confirm the diagnosis.


  Management Top


Science and treatment modalities are developing leaps and bounds. Within a few decades there has been an exponential change in patient management. But still we have not found a definite cure for sickle cell anemia.

There are four main treatment modalities available [12],[13]

  • Drug Treatment
  • Blood Transfusions,
  • Bone Marrow Stem Cell Transplantation
  • Gene Therapy


The first two are useful in acute crisis and prevent complications and the last two modalities hope to give a disease-free survival to the patients.


  Drug Treatment Top


Hydroxyurea which is a DNA-demethylating agent is the most effective drug found till now. Its mechanism of action pertains to induction of synthesis of HbF. 5-Azacytidine and decitabine were the first HbF-inducing agents to be tested as a therapeutic agent in patients with SCD.

People suffering from sickle cell disease undergo auto-splenectomy in the early years of their life. This is because of vaso-occlusion in the microvasculature of the spleen. Thus, they are susceptible to infection by capsulated organisms like pneumococcus. Specific prevention strategies are useful. Vaccinations are recommended for all infants and children. Painkillers and intravenous fluid are main pillars of management of pain crisis.

Blood transfusion

The indication is only during a painful crisis, not to correct anemia, but to relieve vaso-occlusion as during painful crisis, sickle cells causes vaso-occlusion resulting in tissue hypoxia. Transfusion helps by increasing functional red blood corpuscles and thus increase in oxygen carrying capacity of the blood. With supply of oxygen getting restored, pain subsides, thus, transfusions prevent strokes and hypersplenism. However, the hemoglobin should not be raised above 11 g%, as over-correction of anemia will lead to increased viscosity and sickling precipitation. Automated/Manual red cell exchange can be done before proceeding for surgeries in sickle patients, so as to maintain HbS < 30%

Hematopoietic Stem Cell Transplant

Hematopoietic stem cell transplant is the best treatment available which promises a disease-free survival once engraftment occurs. Basic idea is to replace the patient’s disease marrow by that of a normal marrow. Stem cells are collected from matched related or matched unrelated donors. The preferred method of stem cell is from peripheral blood by apheresis after adequate mobilization.

If the transplant is performed when the affected person is still young, then success rates can be as high as 90-95%. (Sickle Cell Society 2005).[13]

Gene Therapy

Gene therapy either addresses the defect and corrects it or silences the defective gene. This is still under evaluation and not readily available yet.

Caring for Patients with SCD in the Community Care Setting

“Prevention is better than cure”- This is the dictum of community-based approach. Our country has already initiated National Thalassemia Control Program. Indian patients predominantly have Arab Indian haplotype linked with their sickle gene which is associated with higher levels of fetal hemoglobin and mild clinical presentation. Therefore, there should be a better application of cheap tests like sickling and HPLC to screen the patients and carriers.[14],[15],[16],[17]

  1. The need of the hour is to increase awareness among the mass and to give proper health facilities to those already suffering from the disease.
  2. Each PHC, at least in high prevalence areas, should be equipped with these basic facilities for screening the patients.
  3. Pre-marital counselling, pre-pregnancy counselling, and proper ante-natal check-ups should be established.
  4. Workers trained for counselling can be provided in each state as per the requirement.
  5. The actual burden of the disease is still eluding as we are not aware of all the patients and carriers. So, a national registry can be initiated.
  6. General physicians heading the PHCs especially in the high-density areas like Western Odisha should be educated about the SCD and its varied presentations.
  7. Screening can be set-up at the community level in places like colleges before admission, offices before placement and screening in schools on a rotational basis.
  8. Blood banks should be established and be well equipped with red cell exchange facilities.
  9. Bone marrow transplant facilities should be improved.



  Conclusion Top


Sickle cell anemia poses to be a major problem in India, particularly in Odisha. Adequate knowledge of pathophysiology and clinical symptom is important for the diagnosis and better management of the patients. Community based screening programs, pre-marital and pre-pregnancy counselling should be made an integral part of antenatal check-ups particularly in the regions with high prevalence of the disease.



 
  References Top

1.
Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN. Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions. PLoS Med. 2013;10(7):e1001484  Back to cited text no. 1
    
2.
Williams TN, Weatherall DJ. World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harb Perspect Med. 2012 Sep1;2(9):a011692.  Back to cited text no. 2
    
3.
Baruah MK, Saikia M, Baruah A. Pattern of hemoglobinopathies and thalassemias in upper Assam region of North Eastern India: high performance liquid chromatography studies in 9000 patients. Indian J Pathol Microbiol. 2014 Apr-Jun;57(2):236-43.  Back to cited text no. 3
    
4.
Nagar R, Sinha S, Raman R. Haemoglobinopathies in eastern Indian states: a demographic evaluation. J Community Genet. 2015 Jan;6(1):1-8.  Back to cited text no. 4
    
5.
Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Williams TN, et al. Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. Nat Commun. 2010 Nov 2;1:104.  Back to cited text no. 5
    
6.
Sinha S, Black ML, Agarwal S, Das R, Bittles AH, Bellgard M. ThalInd. A β-thalassemia and hemoglobinopathies database for India: defining a model country-specific and disease-centric bioinformatics resource. Hum Mutat. 2011 Aug;32(8):887-93.  Back to cited text no. 6
    
7.
Collah, R, Khushnooma, I, Gorakshakar, A. Burden of thalassemia in India: The  Back to cited text no. 7
    
8.
Roadmap for control. PediatricHematology Oncology Journal.2017;2(4): 79-84.  Back to cited text no. 8
    
9.
Rao VR. Genetics and epidemiology of sickle cell anemia in India. Indian J MedSci. 1988 Sep;42(9):218-22.  Back to cited text no. 9
    
10.
Balgir RS. The spectrum of haemoglobin variants in two scheduled tribes of Sundargarh district in north-western Orissa, India. Ann Hum Biol. 2005 Sep-Oct;32(5):560-73.  Back to cited text no. 10
    
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Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010 Dec 11;376(9757):2018-31.  Back to cited text no. 11
    
12.
Piel FB, Steinberg MH, Rees DC. Sickle Cell Disease. N Engl J Med. 2017 Apr; 20;376(16):1561-73.  Back to cited text no. 12
    
13.
Anand Kumar K, Radhakrishna N, Sachdeva A. Management of thalassemia in Indian perspective. In: Sachdeva A, editor. Thalassemia: National Guidelines for management of transfusion-dependent thalassemia and non-transfusion dependent thalassemia; 2014. 296-302.  Back to cited text no. 13
    
14.
Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA.2014 Sep; 10;312(10):1033-48.  Back to cited text no. 14
    
15.
Collah R, Mehta P, Mukherjee MB. Newborn Screening for Sickle Cell Disease: Indian Experience. Int. J. Neonatal Screen. 2018; 4(4): 31.  Back to cited text no. 15
    
16.
Chatterjee T, Chakravarty A, Chakravarty S. Population Screening and Prevention Strategies for Thalassemias and other Hemoglobinopathies of Eastern India: Experience of 18,166 cases. Hemoglobin. 2015;39(6):384-8.  Back to cited text no. 16
    
17.
National Health Mission Guidelines on Hemoglobinopathies in India Prevention and control of hemoglobinopathies in India-Thalassemia, Sickle cell disease and other variant hemoglobins. Ministry of Health and Family Welfare, Govt of India; 2016.  Back to cited text no. 17
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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  In this article
Abstract
Introduction
Pathophysiology
Laboratory diagnosis
Management
Drug Treatment
Conclusion
References
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