Haemoglobinopathies 1

Haemoglobinopathies

Normal haemoglobin is composed of two alpha and two non-alpha globin chains. Alpha globin chains are produced throughout life, including in the fetus, so severe mutations may cause intrauterine death.Production of non-alpha chains varies with age; fetal haemoglobin (HbF-αα/γγ) has two gamma chains, while the predominant adult haemoglobin (HbA-αα/ββ) has two beta chains. Thus, disordersaffecting the beta chains do not present until after 6 months ofage.

Defective haemoglobin(Qualitative)

Sickle cell anaemia It results from single base change in the DNA coding for the amino acid in the sixth position in the b-globin chain. Hemoglobin Beta Gene (HB-B) also known as Beta Globin is a protein that resides in the red blood cells. The HBB is 146 amino acids long and its molecular weight is 15,867 Daltons. The molecules of the hemoglobin are responsible to carry oxygen through the body. The HBB is found in part 15.5 of the chromosome 11. This leads to an amino acid the

Sickle cell anaemia

Hb S is insoluble and forms crystals when exposed to low oxygen tension.Deoxygenated sickle Hb polymerizes into long fibrils‘tactoids’. The abnormal haemoglobin C variant participates in polymerisation more readily than haemoglobin A, whereas haemoglobin F strongly inhibits polymerisationThe red cells sickle may block the different areas of the microcirculation or large vessels causing infarcts of various organs.

CLINICAL MANIFESTATION

1-Painful vaso-occlusive crisis. Plugging of small vessels inthe bone produces acute severe bone pain.This affects areas of active marrow: the hands and feet in children (so-called dactylitis) or the femora, humeri, ribs, pelvis and vertebrae in adults2-Stroke. silent stroke occurs in 10–15% of children with sickle-cell disease. Children at risk of stroke can be identified by screening with transcranial Doppler ultrasound, with fast flow associated with increased stroke risk. 3-Sickle chest syndrome. This may follow a vaso-occlusivecrisis and is the most common cause of death in adult sickle-cell disease. Bone marrow infarction results in fat emboli to the lungs, which cause further sickling and infarction, leading to ventilatory failure if not treated..

CLINICAL MANIFESTATION

4-Sequestration crisis. Thrombosis of the venous outflow from an organ causes loss of function and acute painful enlargement. In children, the spleen is the most common site. Massive splenic enlargement may result in severe anaemia, circulatory collapse and death. Recurrent sickling in the spleen in childhood results in infarction and adults may have no functional spleen. In adults, the liver may undergo sequestration with severe pain due to capsular stretching. Priapism is a complication seen in affected men. 5-Aplastic crisis. Infection of adult sicklers with human parvovirus B19 (erythrovirus) may result in a severe but self-limiting red cell aplasia

DIAGNOSIS

Peripheral blood smears : Patients with sickle-cell disease have a compensated anaemia,usually around 60–80 g/L. The blood film shows sickle cells,target cells and features of hyposplenism from a young age.A reticulocytosis is present.lls, target cells, Howell-Jolly bies,d opresence of HbS can be demonstrated by exposing red cells to a reducing agent such as sodium dithionite; HbA gives a clear solution,whereas HbS polymerises to produce a turbid solution.Haemoglobin ElectrophoresisDDD 9.7%, Hb-A2 = 3.3%)


Howell Jolly Body
Erythroblast

Haemoglobin Electrophoresis (alkaline pH )

Hb C
Hb S
Moves in same position as Hb A2
HbA
Anode
Haemolysate applied
Cathode

δ δ α α α s s α α γ γ α Hb S

Hb A2
Hb F
Genotype αααα βsβs δδ γγ Haemoglobins Produced :
Diagnosis: Hb SS Disease
Laboratory diagnosis of sickle cell anaemia made by presence of only Hb S, Hb A2, and Hb F on Hb electrophoresis with no Hb A, a positive sickling test and presence of sickle cells in blood film

Diagnosis of sickle cell anaemia Cont.

Haemoglobin Electrophoresis: Hb A 0 % Hb S 87.0 % Hb F 9.7 % Hb A2 3.3 % Both parents of the affected individual will have sickle-cell trait

TREATMENT

Painful vaso-occlusive crisis  1.hydration 2.precepitating factors  3.oxygen therapy 4.analgesic  5.exchange transfusion *Antisickling agent (Hydroxyurea) increase Hb F reduce sickling.  *Bone marrow transplantation(Allogeneic-BMT). * Gene therapy.

Treatment –cont. A regular transfusion programme to suppress HbS production and maintain the HbS level below 30% may be indicated in patients with recurrent severe complications, such as cerebrovascular accidents in children and chest syndrome in adult. Exchange transfusion,in which a patient is simultaneously venesected and transfused to replace HbS with HbA, may be used in life-threatening crises or to prepare patients for surgery.