1. Dr. Shumaila Asim Lecture #6
Hemoglobinopathies
Dr. Shumaila Asim
Lecture #6

2. Hemoglobinopathies Disorders of hemoglobin caused by:
Synthesis of structurally abnormal Hb
Synthesis of insufficient quantities of normal Hb
Combination of both
Usually inherited
Range in severity from asymptomatic laboratory abnormalities to death in utero.
Different hemoglobins are produced during embryonic, fetal, and adult life.

3. Properties of the Human Hemoglobins
HbA1(α2 β2)‐ major adult
HbA2(α2δ2)‐minor
HbF(α2γ2)
hemoglobin tetramer‐highly soluble but individual globin chains are insoluble.
Unpaired globin precipitates, forming inclusions that damage the cell.

4. Function of Hemoglobin
oxygen transport
Bind O2 efficiently & retain at high O2 tension (alveolus).
Release at low O2 tension(tissue).
cooperativity or heme‐heme interaction
Bohr effect (ability of hemoglobin to deliver more oxygen to tissues at low pH)

5. Hemoglobin‐oxygen dissociation curve

6. Classification of Hemoglobinopathies
Structural hemoglobinopathies—hemoglobins with altered amino acid sequences eg HbS
Thalassemias—defective biosynthesis of globin chains
Thalassemic hemoglobin variants—structurally abnormal Hb associated with co‐inherited thalassemic phenotype HbE, Hb Constant Spring,Hb Lepore
Hereditary persistence of fetal hemoglobin
Acquired hemoglobinopathies
Methemoglobin
Sulfhemoglobin
Carboxyhemoglobin
HbH in erythroleukemia

7. STRUCTURAL HEMOGLOBINOPATHIES
Sickle cell anemia (Hb S)
Hemoglobin C disease (Hb C)
Hemoglobin SC disease (Hb S+ Hb C)
Thalasemia

8. Hemoglobinopathies Sickle cell (HbS) disease
Caused by a single mutation in beta-globin gene
Glutamic acid at position 6 in HbA is replaced by valine
The shape of RBCs become sickled
Causes sickle cell anemia

10. HbS polymerises reversibly when deoxygenated, to form a gelatinous network of fibrous polymer that stiffens the erythrocyte membrane, ↑viscosity. These changes produce characteristic sickle shape‐ prone to hemolysis
Classification
Homozygous SS sickle cell anaemia
Heterozygous AS sickle cell trait (generally asymtomatic – protects against falciparum malaria)

11. Pathophysiology Slow blood circulation sicklling viscocity
promote further
sicklling
Lower PH & Decrease
O2 tension &
increase sicklling
hypoxia

12. Sickle shape erythrocytes
vulnerable to lysis
HbS, when deoxygenated, is less soluble
it forms long, filamentous polymers that readily precipitate
characteristic sickle shape

13. In homozygous individual (HbS/HbS)
the complex process of polymerization occurs readily
In heterozygous individual (HbA/HbS) sickle cell trait
asymptomatic

14. Sickled erythrocytes block blood flow especially in the spleeen & joints
cells lose water, become fragile, have shorter life span
hemolysis & anemia

15. All of this leads to hypoxia, painful crises, and infarction
of the organs.
It should be noted that the presence of HbA and HbF
modify the degree, or the severity of sickling.

16. Clinical Picture
Symptoms of sickle cell anaemia are seldom manifested before the age of 6 months when the level of circulating Hb F falls to the adult level. Usually the condition is characterized by a chronic haemolytic state with jaundice and relatively constant haemoglobin level of 7-8 g/dl.

17. Clinical Picture Patients with sickle cell anaemia usually
manifest the following symptoms:
Stomach, arm, legs, and joint pain.
Tired, tense, and nervous.
Short trunk, ulcers in legs, thin arms and tower-shaped head.
Enlarged liver and heart.

18. Sickle cell trait
Sickle cell trait is the heterozygous form of the disease, represents a combination of HbA and HbS. The structural formula is α2β1 β16 glu-val.
Individuals with HbS trait are usually asymptomatic, but occasional haematuria occurs as a complication of the disorder.

19. Sickle Cell Trait
The peripheral blood smear is usually normal, with the exception of target cells. Solubility screening tests are positive. Haemoglobin electrophoresis shows:
Hb A = 60%, Hb S = 40%, Hb A2 usually elevated.
Sickle cells usually are not seen in peripheral blood smear except during crises.

20. Factors promote sickling
The drastic lowering PH
Reduction in oxygen tension
These conditions are caused in:
Sever respiratory infections.
Air travel in unpressurized aircraft
Anesthesia
Congestive heart failure.
Excessive exercise which leads to accumulation of lactic acid.

21. Laboratory Findings Sickle cell anaemia
Normochromic normocytic anaemia with haemoglobin level ranging between 6 and 8 g/dl. The peripheral blood can be striking with:
Numerous target cells
Fragmented red cells
Polychromasia and nucleated red cells
Sickle cells ( common)
Reticulocyte average count 5-20% but will reduce during the aplastic crises.
Leukocytosis and thrombocytosis is common.
The bone marrow reflects a marked erythroid hyperplasia, except during aplastic crises.

22. Screening Procedures
The definitive test is haemoglobin electrophoresis; the patient with sickle cell anaemia produces no beta chain. Thus, the result is:
Hb S = 80% and Hb F ranges from 1-20%. Increasing haemoglobin F value is lowering the severity of the disease. This is seen in newborns and in combination of HbS with hereditary persistence of foetal haemoglobin (HPFH). Haemoglobin A2 is slightly increased.

23. Treatment
One of the most important measures in treating sickle cell is to minimize the number of crises by educating sufferers and their families about circumstances, which may trigger sickling crises. They should be advised to avoid sudden cold, dehydration, hypoxic conditions, and infections.
Hypertransfusion or even exchange transfusion with normal blood can lower the proportion of haemoglobin S sufficiently to reduce greatly the incidence of sickling crises. This is most useful as a short-term measure, for example in pregnancy or before and during major surgery.

24. Hemoglobinopathies Hemoglobin C disease:
Caused by a single mutation in β-globin gene
Glutamic acid at position 6 in HbA is replaced by lysine
Causes a mild form of hemolytic anemia

25. HbSC disease HbC copolymerize (interact) with HbS
when both are present, causing a sickling disorder resembling homozygous HbS disease
HbA ,F and most Hb variants do not copolymerize with HbS they prevent severe sickling disorders when they are present with HbS

26. Hemoglobinopathies Methemoglobinemia:
Caused by oxidation of Hb to ferric (Fe3+) state
Methemoglobin cannot bind oxygen
Caused by certain drugs, reactive oxygen species and NADH-cytochrome b5 reductase deficiency
Chocolate cyanosis: brownish-blue color of the skin and blood

27. Met Hbemia (Hb M)
Heme iron is ferric can neither bind nor transport O2
Inherited due to metHb reductase deficiency (autosomal recessive)
Acquired by ingestion of certain drugs (sulfonamides) chemicals
HbM: Histidine F tyrosine (congenital)
Fe+3 makes a tight ionic complex with phenolate anion of tyrosine

28. Infants are particulary vulnerable to methemoglobinemia because HbF is more sensitive to oxidants compared to Hb A
>%10 of Hb is in metHb cyanosis
Diagnosis:electrophoresis ,characteristic absorption spectrum of metHb

29. Hemoglobinopathies Thalassemia:
Genetic blood disorder resulting in a mutation or deletion of the genes that control globin production.
Normal hemoglobin is composed of 2 alpha and 2 beta globins
Mutations in a given globin gene can cause a decrease in production of that globin, resulting in deficiency
aggregates become oxidized  damage the cell membrane, leading either to hemolysis, ineffective erythropoiesis, or both.
2 types of thalassemia: alpha and beta.