Hemoglobinopathies / Sickle-cell anemia

Introduction.
Overview of structural hemoglobinopathies.
Clinical features of Sickle cell anemia.
Laboratory findings and diagnosis.
Hemoglobin S beta thalasemia.
Conclusion.
References.

Introduction:

Hemoglobin diseases or abnormalities can be either a defect in the rate of synthesis OR in the synthesis of abnormal hemoglobin which is the topic of this essay.  This essay will outline the structural defects of hemoglobin S, hemoglobin C and hemoglobin E, the laboratory diagnosis and clinical aspects of the sickle cell disease will be mentioned as well.  Finally, blood findings in sickle beta thalasemia combination will be described.

Overview of structural hemoglobinopathies:

The structural defects of hemoglobin (HbS, HbC, and HbE) are usually due to point mutation in the beta globin gene.

*In HbE, there is a point mutation in the beta chain in position 26 of HbA that changes the sequence coding for glutamic amino acid to a sequence coding for the amino acid lysine.

*In HbC the genetic point mutation occurs in beta chain in position 6 of HbA leading to exchange of the amino acid glutamine to the  amino acid lysine.

*The third type of haemoglobin structural defects, which will be described  in more detail, is HbS.  It occurs due to point mutation in beta chain of HbA in position 6 resulting in changing the sequence conding for  glutamic acid to another coding for valine.  Glutamic acid  is an acidic amino acid, while valine is hydrophobic, this tells us that the new formed hemoglobin (HbS) is less soluble in cellular fluid than HbA (normal hemoglobin).  As a result, HbS is going to precipitate leading to the formation of crystals giving the diseased  red blood cells a sickle shape.  Finally, cells become fragile and then lysis ensues. (1)

Clinical Features of Sickle Cell Anaemia:

Sickle cell disease is an autosomal recessive i.e. subject can be trait (heterozygous) HbA/S and shows no clinical features. On the other hand,  in homozygous individuals, several clinical features will appear.  The degree of appearance of clinical features varies among different people.  The most common clinical feature of sickle cell anemia is sickle cell crises: (2) (3)

1. Vaso-occlusive crises:
 Several factors contribute to the vaso-occlusive crises, such as, infections, acidosis, dehydration or deoxygenation.  Infarcts may occur in the lungs and the spleen.  Moreover, crises of the brain and spinal cord are very serious.  In addition, obstruction of the micro-circulation by intravascular sickling may happen.

2. Hand & foot syndrome:

Seen in children in which 2 to 4 extremities are affected.  Dorsa of the hands and feet are swollen and painful.  Beside that, fever and leukocytosis may occur.

3. Visceral -sequestration crises:
 Including hepatic and splenic sequestration

4. Abdominal crises:
 Due to infarction of the mesentry and abdominal viscera.  Causing severe abdominal pain and signs of peritoneal irritation.

5. Bones & joints:
 Infarction in bones, such as, hips, shoulders, spine, extremities and rib cage may lead to bone and joint crises.  There is also swelling of elbows and knees.

6. Hemolytic crises:
 Represented by an increased rate of hemolysis, a fall in hemoglobin and reticulocytosis.

7. Infection crises:
During the first 5 years of life, Strep. pnuemonia is not only the major offending organism, but  also result in more than 70% of meningitis in children with sickle cell anemia.  However, after 5 years of age, gram negative bacteria replace Strep. pnuemonia as the major offenders.

Toxemia and heart failure occur more frequently in sicklers than in the general population (3)

Other clinical features:

  Ulcers of the lower legs due to local ischemia.
  Splenomegaly in infancy and early childhood
  Chronic liver damage due to micro infarcts.
  Renal failure : infarcts of the medulla with papillary necrosis causing inability of the kidneys to concentrate urine which in turn increase possibility for dehydration and crises.(2)

Laboratory findings and diagnosis:

(I)  Lab. findings:

_Hemoglobin concentration is 6-9 g/dl, the average is 7.5 g/dl.

_Blood smear:

  Sickle cells
  Target cells
  Polichromatophilia
  Extreme poikilocytosis/ Anisocytosis.
  Howell-jolly bodies

_Mean reticulocyte count:  8-12%
_White Blood Cells count: increased due to the process of shifting of granulocytes from the margenated  to the circulating   region.
_Platelets: increased, but decreased during vaso-occlusive crises.
_Factor VIII activity, fibrinogen and fibrinolytic activity increased due to endothelial damage resulting from sickling process.
_Lactate dehydrogenase (LDH) increase due to hemolysis.
_Alkaline Phosphatase elevated during symptomatic crises.
 

(B) Diagnosis:

1. .Electrophoretic separation of hemoglobin.  HbS is more predominant, while HbF found in varying concentrations.  On the other hand, HbA2 concentration is normal, but there is no HbA.

2. Maneuvers.  In this test hemoglobin is exposed to deoxygenated medium in which the HbS will change itís shape, while normal Hb will maintain itís structure.

3. Solubility test is the last test mentioned in this essay for the diagnosis of sickle cell disease.  It is done as follows:  blood is added to a buffered solution of a reducing agent.  HbS precipitates making the solution looks turbid,  where as blood free of HbS will show a clear solution.

Hemoglobin S beta thalasemia:

RBCs show the morphological features of both HbS and thalasemia i.e. there are both sickle forms and red cells microcytosis, hypochromia, target cells and basophilic stippling.

Conclusion

To sum up, hemoglobinopathies can either be due to a defect in the function or the structure of hemoglobin.  HbS,  HbC and HbE are examples of structural defects of hemoglobin.  Hemoglobin crises, such as, vaso-occlusive, hand & foot syndrome in children, abdominal crises, bone and joint crises and many other clinical features in addition to infections are some of the clinical problems that patients homozygous for the HbS gene may face.  Moreover,  the laboratory diagnosis of HbS disease can be done by electrophoresis,  solubility test and deoxygenation test.  Finally, a combination between HbS and beta thalasemia can exist in which the red blood cells show the morphological features of both HbS & thalasemia.

References:

(1) licture by Dr. Gillite on molecular aspects of hemoglobinopathies.
(2) Hoffbrand & Pettit,  Essential Haematology. 3rd ed. John st. London, Blackwell science, 1997. PP 111-114.
(3)  Wintrobe, Richard Lee, etal.  Clinical hematology  8th ed.  Phildelphia, LEA & FEBIGER 1981, PP 841-843.  P848.  PP850-851.
(4)  hematology practical.