Haemoglobinopathies Ahmad Sh. Silmi Msc Haematology, FIBMS

Hemoglobinopathy definition An inherited mutation of the globin genes leading to a qualitative or quantitative abnormality of globin synthesis

Structural hemoglobinopathy Amino acid substitution in the globin chain e.g. sickle hemoglobin (HbS)

Sickle Cell Anaemia Sickle cell anaemia (SCA) is the homozygous form of the disease, in which the individuals inherits a double dose of the abnormal gene that encodes for haemoglobin S. Haemoglobin S is a tetramer composed of two α- chains and two β-chains. The β -chains, however, are abnormal, containing a valine instead of a glutamine at position 6. The structural formula for sickle cell anaemia (Hb SS) is α 2 β 2 6 glu-val. The formula alternatively may be written as α 2 β 2 s or α 2 β 2 6 val.

Sickle Cell Anemia – blood film Sickle Cells Erythroblasts Howell-Jolly Body

Pathophysiology Haemoglobin S is soluble and usually causes no problem when properly oxygenated. However, when the oxygen tension decreases, haemoglobin S polymerizes and forming fluid polymers. As these polymers realign, they cause the characteristic sickle shape into the red cells.

Sickle Cell Anemia – EM of red cell showing ‘tactoids’

Fibres of Sickle Hemoglobin

Fibres of Sickle Hemoglobin – cross section

Factors Affecting Sicklling process The degree of oxygenation PH Dehydration of the patient The concentration of other types of haemoglobins. (When these factors are decreases the sickling process is promoted.)

Pathophysiology sickllingviscocity Slow blood circulation hypoxia promote further sicklling Lower PH & Decrease O 2 tension & increase sicklling

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.

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.

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.

The Complication of Sickle Cell Disease Acute Chest Syndrome - A serious condition caused by infection or trapped red blood cells in the lungs. Anemia (low red blood cell count) Aplastic Crisis - Temporary lack of production of red blood cells. Bone Necrosis - Degradation of bone tissue which can lead to hip replacements and other complications.

The Complication of Sickle Cell Disease (cont. ’ ) Hand and Foot Syndrome - Painful swelling in the hands and feet. Severe Infections - Sepsis (blood stream infection), meningitis, and pneumonia. The risk of infection is increase because the spleen does not function properly. Splenic Sequestration Crisis - The spleen is the organ that filters blood. Rapid enlargement can result due to entrapment of sickled cells in the spleen. This condition can be life threatening. Stroke - Occurs when sickled cells create a blockage within the brain. Signs include seizure, weakness in the arms and legs, speech problems, and loss of consciousness.

Sickle cell trait Sickle cell trait is the heterozygous form of the disease, represents a combination of HbA and HbS. The structural formula is α 2 β 1 β 1 6 glu-val. Individuals with HbS trait are usually asymptomatic, but occasional haematuria occurs as a complication of the disorder.

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.

Laboratory Findings 1.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.

Screening Procedures Solubility Test-Special tubes that precipitate the abnormal haemoglobin S. Sodium metabisulfite- an old screening test, in which Na-metabisulfite induces sickling. It's important to remember that some rare abnormal Hb's also sickle, such as variants of HbC. 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 A 2 is slightly increased.

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.

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.