OBJECTIVESBy the end of this lecture you will be able to know the followings:
-Definition and Etiology of Thalassemia, Sickle cell anemia, G6PD, and congenital spherocytosis.
-Diagnosis, and investigations of these types of anemias.
-Prevention and management of these diseases
In hemolytic anemia there is shortened life span of RBCs (normal= 120 days).
1.Increased breakdown of Hemoglobin leading to :A. Increased serum bilirubin (mainly indirect).
B. Increased urobilinogen in urine and stercobilinogen in faeces.
C. Increased serum iron and decrease in iron binding capacity.
2.Bone marrow compensatory reaction which lead to:A. Accelerated erythropoiesis (reticulocytosis more than 2%), reversed M/E ratio.
B. Expansion of bone configuration seen clinically and in X-ray especially in the skull (hair on end appearance).
Causes of Chronic Hemolytic Anemia:
A. Corpuscular causes :
1. Membrane defect :
A. Hereditary spherocytosis.
B. Hereditary elliptocytosis.
2. Enzyme defect :
A. G6PD. deficiency.
B. Pyruvate kinase deficiency.
3. Hemoglobinopathies :
A. Thalassaemia (quantitative β-chain defect).
B. Sickle cell anaemia (qualitative β-chain defect).
B- Extracorpuscular causes:1- Immune:-Iso-immune: Rh and ABO incompatibility. Auto-immune: (e.g SLE).
2- Non- immune:-
-Paroxysmal nocturnal hemoglobinuria
-Infections (Malaria, toxoplasmosis, septicemia).
-Toxic: snake venom.
It is a chronic haemolytic anaemia transmitted as autosomal dominant trait due to dysfunction of a cell membrane protein “spectrin” making the cell more permeable to Na+ influx result in increase intracellular water → swelling & spherocytosis.
The spherocyte is relatively rigid and passes with difficulty through the minute apertures between splenic cords and sinuses and thus becomes easily destroyed.
After splenectomy the haemolysis improves, although the biochemical and morphological abnormalities are not corrected.
Clinical Picture:-Onset in infancy and may be a cause of neonatal jaundice.
-General feature of anemia, jaundice, splenomegaly, aplastic crisis and gall stone formation.
-Folate deficiency, and hemosiderosis.
Laboratory Finding:-Anemia: normocytic normochromic.
-Reticulocytosis (count from 5 up to 20%).
-Spherocytes in peripheral film.
-Increase osmotic fragility: spherocytes are destroyed in higher concentration of saline than normal RBCs.
-Bone marrow: erythroid hyperplasia .
Differential diagnosis:--From other congenital hemolytic anemias.
-Autoimmune hemolytic anemia: comb's test is positive.
Treatment:1- Supportive: packed red cell transfusion for severe anemia. Folic acid supplementation.
2- Splenectomy invariably produces a clinical cure.
Splenectomy in early childhood may causes increased susceptibity to infection, the operation should be delayed if possible, until 5-6 years old.
3- Splenectomized children should receive:
pneumococcal and hemophilus influenzae b vaccines.
Prophylactic long acting penicillin.
Glucose-6-phosphate dehydrogenase deficiency(Favism, Drug induced Hemolytic Anemia)
X-linked recessive disorder. Males more than females.
Age : may present in the neonatal period.
-More than 200 variant of the enzyme could be recognized in different localities in the world.
A. G6PD.(A):- Common among American, enzyme activity in 5-15% of normal.
B. G6PD.(B):- Common in Mediterranean area, where enzyme activity is less than 5% and lead to haemolytic attack.
C. G6PD. (C):- Common in Chineese.
Pathogenesis:-G6PD is Responsible for Production of NADPH and renewal of reduced glutathione (GSH) in the red cell membrane.
-GSH protects red cells from oxidants by reducing them.
-G6PD deficiency → ↓NADPH →↓ GSH →↓ protection of RBCs from oxidants.
-Exposure of G6PD deficient RBC to an oxidant → impaired elimination of oxidant → oxidation of Hb → oxidized Hb is denaturated and deposited as Heinz inclusion bodies in RBCs lead to ↓ red cell integrity → hemolysis.
Examples of oxidant agents :-Fava beans (Contains L-Dopa)
-Infections: Due to release of oxidants from active phagocytes . -Viruses; Respiratory, hepatitis, infectious mononucleosis -Bacterial pneumonias.
-Metabolic: Diabetic Ketoacidosis.
-Drugs:- -Antipyretics: Aspirin, phenacetin
-Sulfonamides. – Antimalarials. -Nitrofurans
-Antibiotics: chloramphenicol – Para-aminosalicylic acid, -synthetic vitamin k, Naphthalene - Methylene blue.
Clinical picture: Favism: ingestion of fava beans → acute hemolytic anemia
Neonatal hyperbilirubinemia of unconjugated type: there is hemolysis plus immaturity of hepatic enzymes.
Signs and symptoms: Acute anemia (Marked pallor, irritability, etc.)
Nausea vomiting and epigastric pain
Hemoglobinuria (if hemolysis is severe) –Mild splenomegaly.
Jaundice with dark orange colored urine (urobilin) and dark stools
Death → may occur in cases of severe hemolysis
Course: spontaneous recovery from the attack is the rule.
Laboratory: Normochromic normocytic anaemia, Heinz bodies in blood smear. Diagnosis is confirmed by estimation of G.6.P.D activity in RBC, better around few weeks after the attack.
Treatment: -Avoid offending agents e.g infection.
-In severe cases, emergency packed RBC transfusion.
-Vitamin E (400-800 U/day) protect against hemolysis and antioxidant.
-In severe neonatal jaundice: exchange transfusion.
Hemoglobin is a tetramer formed of 4 polypeptide chain with a heme group attached to each chain.
Each chain is controlled by a special sequence gene which is activated and inactivated in a special sequence.
Types of Globin Chain (α. β. γ. δ): Each chain is controlled by 2 sets of gene
Types of Hb.:
HbF, (2α +2 γ).
HbA1 (2α + 2 β).
HbA2 (2α +2δ).
At birth After 6 months
HbF : 65%. HbF: 2%.
HbA1 : 34%. HbA1:95%.
HbA2: <1% HbA2: 3%
Sickle Cell Disease
It is transmitted as an incomplete autosomal dominant trait.
-Homozygotes (both parents are affected) →sickle cell anemia 85-95% HbS+ 5-15% HbF+ 2% HbA2.
-Heterozygotes (only one parent is affected) →sickle cell trait 55-60% HbA+ 25-45% HbS + 2-3% HbA2 .
This is a benign condition usually there is no anemia sickling does not occur except if patient is exposed to hypoxia.
-HbS is similar in structure to HbA except that at position 6 of the β-polypeptide chain, glutamic acid is replaced by Valine.
Clinical picture: Onset after 6 months and is expected only when patient is homozygous for sickle cell gene.
1- vaso-occlusive (thrombotic or painful) crisis: Vaso-occlusive is due to occlusion of small blood vessels → distal ischemia and infarction ,this is usually preceded by infection or spontaneously.
-Hand-foot syndrome (sickle dactylitis). -Bone crisis.
-Severe abdominal pain.
-Acute painful hepatomegaly + direct hyperbilirubinemia.
-Repeated painful splenic infarcts → autosplenectomy.
-Cerebral occlusion → strokes, acute hemiplegia.
-Acute episodes of painless hematuria.
-Acute chest syndrome.
-Acute episodes of painful priapism.
2. Aplastic Crisis :-Aplasia of the bone marrow during or following parvovirus 19 infection.
-Decrease in reticulocytic count.
-Lasts about 10-14 days and usually recovers spontaneously.
3-Sequestration crisis: Pooling of the blood become, for no obvious reasons sequestrated in spleen, leads to massive splenomegaly.
Shock collapse and may be dehydration.
In late childhood this splenomegaly diminish in size as result of the multiple infarcts this leads to hyposplenism considered as functional asplenia with liability of overwhelming infection caused by pneumococcal, H. influenza infection and salmonella osteomyelitis.
4-Hyperhemolytic crisis:May be precipitated by bacterial infection and presented by anemia, jaundice and fever.
Laboratory investigation:-Normocytic normochromic anemia -RBC show sickling under low O2 tension. -Hb electrophoresis studies:
*HbS (80-95%), HbA2 (2-3%) and HbA (5-15%) in sickle cell anemia.
* HbS (25-45%), HbA2 (2-3%) and HbA (55-60%) in sickle cell trait.
-Bone marrow aplasia during an aplastic crisis.
Treatment:◦ Treatment and prevention of infection by :
Prophylactice long acting penicillin.
Polyvalent, pneumococcal, and haemophilus infleunza b vaccine every 2 years.
◦ Blood transfusion correct anemia and prevent crisis.
◦ Vigorous treatment of crisis:
Painful crisis: give hydration, packed RBC, analgesic,vasodilator, (L carnitine, nitric oxide inhalation).
Aplastic crisis: give packed RBC.
Sequestration crisis, plasma expander, blood transfusion.
β – Thalassemia major (cooley's anemia):
β - Most common around meditranian sea. In β - thalassemia there is impaired production of β -chain due to mutation of one gene "heterozygous" or both genes homozygous".
According to degree of β – chain deficiency β thalassmia is divided into:
Βo no β-chain synthesis no HbA only HbF and HbA2.
β+ little β-chain synthesis, so HbA is scanty and more HbF and HbA2.
β++ more β chain synthesis → thalassemia intermediate.
β+++ normal in individual.
Thalassemias are hereditary chronic haemolytic anemias caused by impaired or absent synthesis of α or β globin chain.
Clinical picture: Age of presentation usually start at the age of 6-12 months.
Clinical evidence of haemolytic anemia, pallor, jaundice hepatosplenomegaly mongoloid facies (enlarged head, prominent malar bone, frontal bossing, depressed nasal bridge protrusion of maxilla ± exposure of upper teeth due to hyperplasia of B.M.)
◦ Haemolytic crisis precipitated by infection by parvovirus B19.
◦ Megaloblastic crisis due to folic acid deficiency
Cardiomegally and hemic murmur.
delayed puberty due to endocrinal disturbances.
Complication:- Increase susceptabilty to infection
Iron overload (haemochromatosis) due to increase iron absorption from gut and excess iron from repeated transfusion .iron accumulate in vital organ leads to heart failure, hepatomegally .D.M., bronze skin.
Anemic heart failure. -Hypersplenism. -Pathological fracture.
Complications of repeated blood transfusion: e.g. hepatitis C.
Diagnosis: Hypochromic microcytic anemia with anisocytosis, poikilocytosis, target cell.
Reticulocytic count: increased nucleated RBCs in peripheral blood.
Increase serum iron with decrease serum iron binding capacity.
Hb electrophoresis: (increase HbF).
B.M. examinations show erythroid hyperplasia.
X-ray bone of skull → hair on end apearance due to widening of diploid space. -Cardiomegaly may be present.
Evident diagnosis: Genotyping or P.C.R. (Polymerase Chain Reaction) to detect the mutation on chromosome 11.
-Weak mutation → thalassemia intermedia
Strong mutation → thalassemia major
TREATMENT1- Symptomatic treatment:
1- Packed RBC transfusion 10-15ml/kg/dose every 4-6wks.
Better to transfuse washed RBCS by saline.
Better to transfuse (neocyte) rich with hemoglobin
Better to transfuse from single donor.
Blood transfusion to keep Hb above 12gm/dl in order to:
a- Permit normal activity with comfort.
b- Improve crisis.
c- Minimize cardiac dilatation.
d- Prevent skull bone changes.
2- Iron chelation:
Desferroxamine (desferal) given S.C. by small iron infusion pump in dose 30-50mg/kg/dose 5 days/week. Vit C potentiate the action of desferal. -Recently oral chelating agent deferazirox (Exjade) 20-30mg/kg/dose.
3- Folate, 1mg Daily to compensate B.M. over activity.
4- Low iron diet with increase tea drinking (decreasing iron absorption)
5- Indications of splenectomy:
◦ Secondary hypersplenism.
◦ Huge spleen, cause dragging pain
-Splenectomy should be done after the age of 5 yr.
to guard against severe infection.
-Prophylactic pneumococcal and meningococcal vaccination should be given 2wk. before operation.
-long acting penicillin prophylactic 1,200,00 I Monthly.
6- New modalitiy: α chain stimulation by hydroxyurea, β hydroxybuterate to cause increase HbF that decrease ineffective erythropoiesis.
II. Curative therapy
B.M. transplantation from HLA identical of non affecting sibling
gene therapy by insertion of normal gene into B.M. stem cell
β Thalassemia minor (Heterozygous ) It may be asymptomatic or symptomatic:
-Mild anemia (Hb 9-11 g/dl) accentuated during infections.
-Anemia is microcytic hypochromic and does not respond to iron therapy.
-No jaundice or other signs of hemolysis.
-Hb electrophoresis: Hb A is predominant, Hb A2 is increase (<4%), Hb F may be slightly increase.
β Thalassemia intermedia :
Affects 2-10 % of homozygous patients and is characterized by:
Patients have higher ability to produce β –chain and high production of γ-chains.
Genetic, morphologic and biochemical features: like β-thalassemia major.
Anemia is milder (Hg level 7-10g/dl).
Pallor, jaundice, facial bony changes, splenomegaly and hepatomegaly are present.
No growth retardation and no hypogonadism.
Treatment: -Blood transfusion is usually not needed and given only when required.
-Decrease iron absorption from GIT (e.g. drink a cup of tea after each meal).
-Chelation therapy and folic acid supplementation.
α Thalassemia There is decrease synthesis of α chain and Hb A, F, A2 genetic deletion can affect one or more of the gene represent for α chain synthesis.
1- Deletion of one gene → silent carrier.
2- Deletion of two gene → α thalassemia trait.
3- Deletion of three gene → HbH.
4- Deletion of four gene → hydrops fetalis → miscarriage of non viable fetus,
COURTESY:DR. SHAHENAZ M. HUSSIEN
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