Hemoglobinopathies

1. 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 • Usuallyinherited • Range in severity from asymptomatic laboratory abnormalities to death inutero. • Different hemoglobins are produced during embryonic, fetal, and adult life.

3. Properties of the HumanHemoglobins • HbA1(α2 β2)‐ majoradult • HbA2(α2δ2)‐minor • HbF(α2γ2) • hemoglobin tetramer‐highly soluble but individual globin chains areinsoluble. • Unpaired globin precipitates, forming inclusions that damage the cell.

4. Function ofHemoglobin • oxygentransport • Bind O2 efficiently & retain at high O2tension (alveolus). • Release at low O2tension(tissue). • cooperativity or heme‐hemeinteraction • Bohr effect (ability of hemoglobin to deliver more oxygen to tissues at lowpH)

5. Hemoglobin‐oxygendissociation curve

6. Classification of Hemoglobinopathies • Structural hemoglobinopathies—hemoglobins with altered amino acid sequencesegHbS • Thalassemias—defective biosynthesis of globinchains • Thalassemic hemoglobin variants—structurally abnormal Hb associated with co‐inherited thalassemic phenotype HbE, Hb Constant Spring,Hb Lepore • Hereditary persistence of fetalhemoglobin • Acquiredhemoglobinopathies • Methemoglobin • Sulfhemoglobin • Carboxyhemoglobin • HbH inerythroleukemia

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. HbSpolymerises reversibly when deoxygenated, to form a gelatinous network of fibrous polymer that stiffens the erythrocyte membrane, ↑viscosity. These changes produce characteristic sickle shape‐ prone tohemolysis • Classification • Homozygous SS sickle cellanaemia • Heterozygous AS sickle cell trait (generally asymtomatic – protects against falciparummalaria)

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 β16glu-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 Normochromicnormocyticanaemia 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 foetalhaemoglobin (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 ferriccan neither bind nor transport O2 • Inherited due to metHb reductase deficiency (autosomal recessive) • Acquired by ingestion of certain drugs (sulfonamides) chemicals • HbM: Histidine F8 tyrosine (congenital) • Fe+3makes 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.