Haemoglobinopathies
at the end of this lecture you will learn:Definition of hemoglobinopathies. Structure of hemoglobin. Definition of thalassemia, main types and clinical classification. B- thalassemia major: definition, clinical features, hematological features, diagnosis and management. Sickle cell disease: definition, pathogenesis, clinical and hematological features and diagnosis.
A group of genetic disorders of Hb synthesis characterized by either a reduction of the rate of synthesis of globin chains ( Thalassaemias ) or the production of abnormal globin chains ( Hb-variants ).
Structure of Haemoglobin
Adult Hb (Hb-A) is a tetramer of 4 globin chains arranged in a helical form; there are 2 α and 2 β chains, (α 2 β 2) Other normal Hbs are :Fetal Hb ( Hb-F ), α 2γ2Hb-A2; α 2 δ2Normal adults have: about 98% Hb-A, 2% Hb-A2 and less than 1% Hb-FThalassemia syndromes
Thalassemias are a group of anemias that result from inherited defects in the production of hemoglobin. Thalassemia is characterized by reduction in the rate of synthesis(or total absence) of one or more of globin chains. Clinically the thalassemia syndromes are heterogenous due to many possible mutations affecting the human globin chain loci. Two main types of thalassemia Alpha thalassemia: genetic defects in synthesis of alpha globin chain . Beta thalassemia: genetic defects in synthesis of beta globin chain, it is the commonest type in iraq.Clinical Classification
Regardless of the underlying pathology, thalassaemias are classified into 3 types according to the clinical severity: Thalassaemia major: transfusion dependent, anaemia is severe ( Hb about 5 g/dl ), starts within the 1st year of life, rarely live beyound the 2nd decade of life. Thalassaemia intermedia: moderate anaemia ( Hb>7 g/dl), infrequent or no need for transfusions, late presentation and long survival. Thalassaemia minor: Mild or no anaemia, minimal red cell morphological changes, increased Hb-A2, also called thalassaemia trait or carrier.Beta thalassemia major
It is also known as cooleys anemia and homozygous β thalassemia.It result from point mutation in the B-globin gene: the final result is either reduction in the B-chain synthesis or total absence.Absence of B-globin is called beta-zero (B0 ) thalassemia.A reduced amount of B-globin is called beta-plus ( B+) thalassemia.Clinical features
Signs and symptoms appear within the first 6 months of life. Early symptoms in infants: irritability, pallor, failure to thrive. Splenomegaly, hepatomegaly Heart failure is common cause of death in untreated cases Bone marrow expantion to compensate condition: bossing of skull, facial deformities. Infection is common cause of death. During the 2nd decade organ failure develop due to iron over load & most die for this reason.
Lateral radiography of skull shows the typical hair-on-end appearance with thinning of cortical bone and widening of marrow cavity
Haematological features
Hypochromic microcytic anaemia with marked red cell distortion, target forms and normoblastaemia. Raised Hb-F level BM shows erythroid hyperplasia with increased marrow iron. Increased body iron contents Increased S.ferritin Increased transferrin saturation Increased marrow ironDiagnosis
Clinical features: Refractory anaemia with marked splenomegaly starting early in life Positive family history. Social history of Consanguineous marriage Haematological features: Typical red cell morphological changes. Raised Hb-F level on electrophoresis Increased serum iron parameters. Reduced B-chain synthesis rate Molecular techniques to demonstrate defective B- globin gene.Management
Most children with B-thalassemia … regular transfusion program till 2nd and 3rd decade. Iron chelating agents (desferal)Splenectomy performed after age of 5Y to reduce haemolysis and prolong red cell survival.B.M transplantation to provide patient with stem cells produce normal erythrocytes.Hb – Variants ; Sickle cell disease(SCD) SCD is the homozygous state of Hb-S, the disease is common in central Africa, middle east and in Black Americans of African origin. Molecular defect & pathogenesis SCD results from a point mutation in the B-globin gene that causes substitution of valine instead of glutamic acid at the 6th amino position of the globin chain, this markedly reduces Hb solubility which under reduced O2 tention forms crystals ( tactoids ) that gives a sickle form to the cells, these cells are rigid and will occlude microcirculations ( vas-occlusive phenomena ) leading to multiple infarcts in the spleen, bones and elsewhere. Sickle cells are abnormal that have a shortened life span and this lead to chronic haemolytic anaemia .
Clinical Features
The clinical featurs are those of chronic haemolytic anemia associated painful incidents ( Sickle Crises ) due to organ infarcts including: Painful abdominal crises due to splenic infarcts or mesenteric thrombosis. They loose their spleens by the age of 5 years ( autosplenectomy ) Painful dactylitis due to infarcts of small bones of the hand and feet ( hand and foot syndrome ) Painful chest crisis CVA These painful crises are associated with anaemia and jaundiceHaematological features.
Normochromic normocytic RBCs with frequent target forms and occasional sickle cells. Reticulocytosis Bone marrow Erythroid hyperplasia