SICKLE CELL DISEASE

SICKLE CELL DISEASE

preliminary
Anemia is generally defined as a reduction in erythrocyte volume or hemoglobin concentration or hematocrit levels below normal values ​​for age so that the ability of the blood to provide oxygen to the tissues is reduced. Anemia is not a specific condition, but can be caused by various pathological reactions. Based on the etiology, it can be classified into anemia due to impaired formation of red blood cells, anemia due to blood loss and the last is anemia due to excessive destruction of red blood cells. 1.2

Based on the classification of anemia above, sickle cell anemia is included in the third type of anemia, namely anemia caused by excessive destruction of red blood cells due to defects in constitutional factors in red blood cells, in this case a defect in hemoglobin, which is referred to as hemoglobinopathy. Sickle Cell Disease is a hemoglobinopathy due to a mutation in one of the globin genes due to changes in amino acids so that its structure is different from normal Hb, and without a reduction in globin chain synthesis. 1,2,3,4

Pathophysiologically, the amino acid change from glutamic acid to valine in the -globin chain causes red blood cells to become sickle-shaped when deoxygenated, but can still return to their normal shape when oxygenated. When the red blood cell membrane has undergone a change, the polymerization of the red blood cell has become irreversible. Treatment according to the clinical picture that appears. Treatment can be done with blood transfusions, bone marrow transplantation, administration of anti-sickling drugs, and administration of drugs to trigger HbF synthesis. 5,6,7

Definition
Sickle cell anemia is a blood disorder caused by a change in the 6th amino acid in the -globin protein chain which causes a change in the shape of red blood cells to be similar to sickle called HbS. This disease can be passed from parents to sons or daughters. Inheritance of one of the sickle cell genes does not suffer from sickle cell anemia but is only carriers. If two carriers mate, they will have children with a probability of having sickle cell anemia 2,5,8

Figure 2. Mutations in the 6th amino acid sequence of the -globin chain Quoted from literature 5

Figure 2. Mutations in the 6th amino acid sequence of the -globin chain
Quoted from literature 5

Normal red blood cells are circular, flattened in the middle, allowing them to pass through the blood vessels easily and supply oxygen to all parts of the body. It is difficult for sickle-shaped red blood cells to pass through blood vessels, especially in narrowed areas of blood vessels or at blood vessel junctions. This is due to its shape like a crescent moon that can get stuck in blood vessels, so that it can clog blood vessels, besides that sickle cells can also cause serious infections, and damage organs, and even cause death. 1,2,3,4

Figure 1.a Normal erythrocytes

Figure 1.a Normal erythrocytes

Prevalence and distribution
Of the total number of sickle cell disease sufferers, the highest prevalence is in tropical Africa, India, and Central Asia. Nearly three-quarters of these cycle cell cases occur in Africa. WHO reports about 2% of newborns suffer from sickle cell and carriers around 2-40%. In the United States, it is reported that about 1 in 625 babies are born with SCD. In Central Asia about 6000 children are born with SCD and about 50% are in Saudi Arabia. And in India the prevalence ranges from 0.4-22%, especially in endemic areas1,3

 

Pathophysiology
The current understanding of sickle cell disease is closely related to its pathophysiological basis. It is a complex mechanism by which abnormal hemoglobin produces severe systemic effects. Such as sickling process, polymerization, structural changes, dehydrated red blood cells, impaired coagulation, and abnormal activation of vascular endothelial cells. Basically, there are multisystemic complications in Sickle cell disease so that the pathophysiology is grouped either molecularly, biochemically, cellularly, or vascularly. 3,5,6,7,9,10

1. Molecular
Molecularly, sickle cell disease is caused by a single base mutation, resulting in the substitution of a single amino acid at position 6, i.e. valine, with glutamic acid (Glu6Val) which results in a Hb (a2/βS2) tetramer which is poor when deoxygenated, forming HbS. This HbS causes changes in the physical and chemical structure of erythrocytes where there is a tendency for polymerization.

Figure 3 polymerization process Quoted from the library

Figure 3 polymerization process
Quoted from the library

 

2. Biochemistry
Biochemically, sickle cell disease involves detoxification, GSH, oxidative stress and inflammation. In sickle cell disease there is an increase in oxidation reactions. HbS is less stable than HbA, which acts to increase free radicals, and reduces glutathione (GSH) production. This reduction in glutathione stimulates K+ in the cells to leave the cells so that the red blood cells are dehydrated. Increased oxidative stress in HbS cells leads to impaired membrane permeability, cells become stiff and dehydrated. It has a strong role in causing hemolysis and vasoocclusion. Inflammation is characterized by vascular changes, including vasodilation, increased permeability and slowing of blood flow caused by the release of inflammatory mediators. This causes leukocytes to move to the endothelium as a defense mechanism to prevent entry into the tissue.

3. Vascular
Every day about 1% of erythrocytes are destroyed, aging erythrocytes cause decreased glycolytic enzyme activity, which leads to decreased energy production and loss of membrane deformability and integrity. In sickle cell disease, extravascular hemolysis occurs. The vascular pathology of this disease is influenced by many factors, including increased adhesion between erythrocytes and leukocytes to the endothelium. Incidence of vascular occlusion in sickle cell disease is associated with the accumulation of granulocytes and increased production of the oxidative reaction, namely nitric oxide, which plays a role in vascular dysfunction.

4. Mobile
In sickle cell disease, hypercoagulable states often occur. Coagulation begins after vascular damage due to endothelial damage. This results in the release of phospholipid components, namely tissue factor and fibrinogen, increased thrombin and fibrin generation, as well as increased activity of procoagulant factors and platelet activation. Furthermore, thrombosis may contribute to some complications of Sickle cell disease, such as stroke due to obstruction of the great vessels due to thrombosis, also associated during pain crises. Involves both cellular components (platelets) and protein components. Coagulation begins after vascular damage due to endothelial damage. This results in the release of phospholipid components, namely tissue factor and fibrinogen.

Figure 7 General Pathophysiology of Sickle Cell Disease

Figure 7 General Pathophysiology of Sickle Cell Disease

Clinical Overview 2,3,5
Clinical picture in sickle cell anemia patients can be divided into 2 types, namely acute clinical picture and chronic clinical picture.

The following are some of the clinical features that are acute, namely:

1. Hemolysis crisis
Hemolysis crisis is caused by too short the age of red blood cells so that the faster the occurrence of hemolysis. This causes a decrease in hemoglobin and an increase in reticulocytes, which in turn leads to jaundice.

2. Blockage of blood vessels (vasoocclusive)
This blockage of blood vessels can be caused when the patient has a fever, dehydration, cold temperature, this blockage will be felt by the patient as pain. The pain can occur in various places, according to the location of the blockage, such as the chest, bones, stomach and brain. Blockages that occur in the brain can cause a stroke. Pain in the abdomen is generally caused by an infarction of the spleen. Pain in the chest is often accompanied by a bacterial infection which is then referred to as acute chest syndrome (ACS).

3. Hand-foot syndrome
This syndrome is characterized by swelling of the back of the hands and feet, and is very painful accompanied by fever and an increase in the number of leukocytes.

4. Aplastic crisis
This aplastic crisis is caused by a decrease in the formation of red blood cells accompanied by fever. Based on epidemiological studies, this was caused by a viral infection, namely human parvovirus B19.

The following are some clinical features that are chronic: 1) Inhibited growth and development; 2) Osteonecrosis; 3) Mental retardation; 4) Reduced visual-motor integration; 5) Reduced memory; 6) Reduced attention and concentration (attention and concentration); 7) Cardiomegaly; 8) Obstructive lung disease; 9) Kidney failure; and 10) Leg ulcers.

Diagnosis 2,3,4,11
After taking the history and physical examination, to find out the clinical picture of the patient, the next thing that can be done in establishing the diagnosis is to carry out supporting examinations. The simplest supporting examination is routine blood, anemia is found, with a hypochromic microcytic erythrocyte index, reticulocytosis, from the peripheral blood smear, sickle-like erythrocytes can be found, sometimes target cells are found. For simple screening, it can be done by giving blood an agent that can trigger deoxygenation, such as sodium dithionite. In blood containing HbS, thick blood will be found after the addition. However, this method can lead to both false positive and false negative results. Therefore, this method should not be used for the main examination in establishing the diagnosis.
The test used to detect HbS in the diagnosis of sickle cell anemia is HPLC (High-performance liquid chromatography), this method can distinguish between sickle cell disease and trait.

Figure 8 peripheral blood smear showing sickle cell erythrocytes

Figure 8 peripheral blood smear showing sickle cell erythrocytes

 

Sickle Cell Anemia                                                  Sickle Cell Trait

Hb S (α2s2)               : 75-85 %                              Hb S (α2s2)   : 40 %

Hb F (α2Ÿ2)                : 15-25 %                                        Hb F (α2Ÿ2)    : <2 %

HbA  (α2β2)             : 2 %                                    HbA  (α2β2)   : 60 %

Sickle Cell Disease Diagnostic Flow

Sickle Cell Disease Diagnostic Flow

Therapy 1,4,5
The goal of treating sickle cell anemia is to control symptoms by reducing pain, preventing infection, eye damage, stroke and preventing complications if they occur. The therapy that can be done for patients with sickle cell anemia are:

1. Blood transfusion
This transfusion therapy aims to increase the amount of normal hemoglobin in the blood so as to prevent the polymerization process. If the patient often experiences crises, especially vasoocclusion, this therapy needs to be carried out in the long term. However, it should also be noted that the side effects of this transfusion therapy, namely the occurrence of hyperviscosity, which is caused by the addition of hematocrit is directly proportional to blood viscosity, hypersplenism, iron poisoning, and the possibility of infection, which is caused by inaccurate blood screening.

2. Induction of Hb F by using Hydroxyurea agent. The effects can be directly on erythrocytes or outside erythrocytes. In erythrocytes, hydroxyurea can cause inhibition of cation depletion and formation of cell density, reduce reticulocyte stress and the rate of hemolysis, inhibit adhesion of sickle cell endothelial cells to extracellular matrix components including fibronectin and thrombospondin and laminin. Meanwhile, outside of erythrocytes, hydroxyurea reduces the number of leukocytes both quantitatively and qualitatively, including reducing the production of free radicals and reducing the concentration of VCAM-1 which causes a decrease in endothelial activation.

3. If a crisis occurs, give a warm atmosphere, infusion of physiological saline 1½ times the need, treat infection with antibiotics, give adequate analgesics such as acetaminophen, NSAIDs or Narcotics such as morphine.
4. Aids erythropoiesis with folic acid and antioxidants

Prevention
1. Prenatal diagnosis, rapid and sensitive laboratory procedure
2. Screening for HbS at birth for control and initial treatment
3. Identify precipitating factors such as stress and cold weather, regular check-ups

Prognosis 12
In some mainland Africa, Sickle cell disease is still a deadly disease in children. This is because the handling has not been so optimal so that complications are easy to occur. In this disease, if the management is good, the prognosis is also good

Conclusion

1. Sickle Cell Disease is a hemoglobinopathy disease due to a mutation in one of the amino acids forming the globin chain which is inherited in an autosomal recessive manner.
2. Abnormal hemoglobin formation produces severe systemic effects such as sickling process, polymerization, coagulation disorders and abnormal activation of vascular endothelial cells.
3. The diagnosis of sickle cell disease is established based on history, physical examination, and investigations such as routine blood, reticulocytes, peripheral blood smear and HPLC.
4. The success of therapy both in terms of prevention and treatment greatly affects the prognosis

 

References

  1. Driscoll, C. Sickle Cell Disease. Pediatrics in Review. 2007
  2. http://ghr.nlm.nih.gov/condition : Sickle Cell disease. Genetics Home Reference of Sickle Cell Disease, 2009.
  3. B Schnog.A-J Duits, Muskiet. Sickle Cell Disease ; A general overview. Department Of Pediatrics . St.Elisabeth Hospital. Amsterdam . Netherlands the Journal of Medicine. 2009.
  4. L Wethers. M.D . Sickle Cell Disease in Childhood ; Laboratory Diagnosis,Pathophysiology and Health Maintenance.
  5. Frempong , Ohore. Pharmacologic Treatment of Sickle Cell Disease in Roland B. Scott Memmorial Symposium. Department Pediatrics. Pensylvania University, Sickle Cell Center. The Children’s Hospital of Philadelphia. 2009
  6. Oluwatogin, Pathological basis of symptoms and crises in Sickle cell Disorders : Implication for counseling and psychotherapy. Hematology reports . Reedemer’s University. 2010
  7. Marie-Helene, Emmanuelle. Pathophysiological insight in Sickle Cell disease. Indian Journal of Medical Research . 2011.
  8. Genetics behind Sickle Cell disease. Retrieved November 13th 2012 from http://ghr.nlm.nih.gov/Condition/Sickle Cell Disease.
  9. I.Ataga . S.Key Migel . Hypercoagubility in Sickle Cell Disease New Approaches to an old problem. Division of Hematology/Oncologi. University of North Carolina.
  10. Hillery Cheryl. MD. Thrombosis, Hemostasis and Vascular Biology in Sickle Cell Disease. Department of Pediatrics and Medicine. Medical College of Wisconsin. Blood Center of Wisconsin.
  11. http:Web/Med.MD.nih.ge Hemoglobin Electrophoresis
  12. Mortal, Sericant . G . Mortality from Sickle Cell Disease in Africa. British Medical Journal.

 By :

dr.Enda Yuliastini,SpA, DR.dr.Nadirah Rasyid Ridha,Mkes,SpA(K),Prof.DR.dr.Dassril Daud,SpA(K)

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