hemoglobinopathies

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Case discussion : 

Case discussion 50 days old female baby, FTND, 2nd degree consanguinous mrg c/o fever x 2 days CVS-soft systolic murmur Liver- 4cms below RCM Spleen 3 cms below LCM Hb-6.3 Retic count-0.8% Readmitted for c/o lack of activity c/o left inguinal swelling x 5 days Spleen- 5cms below RCM IMP: inguinal hernia PBS-nucleated RBCs Few retics Hb electrophoresis- beta thalassemia intermedia

Slide 2: 

Hemoglobinopathies Seminar by: Dr. Hariharan IInd yr MD Dept of Biochemistry 23.12.10 Moderator: Dr. Ramesh MD, DCH Professor and HOD Dept of Pediatrics

Approach to anemia : 

Approach to anemia Anemia Check MCV MCV < 80 MCV 80 - 100 MCV > 100 microcytic anemia normocytic anemia macrocytic anemia

Approach to normocytic anemia : 

Approach to normocytic anemia

Slide 5: 

Is anemia associated with other hematologic abnormalities? Reticulocytosis?  bilirubin/LDH no yes Aplastic anemia Leukemia Other bone marrow replacement disorders no yes bleeding or ongoing hemolysis PBS hemolysis Final diagnosis yes normal hypochromic

Final diagnosis : 

macrocytic? normocytic? microcytic? No above said PBS abnormalities defect in Hb synthesis Iron deficiency alpha or ß-Thalassemia trait Hb E disorders Lead poisons neutrophil hypersegmentation (megaloblastic changes)? no Folate , B12 Def, IEM Diamond-Blackfan anemia Congenital dyserythropoietic anemia Pearson syndrome Renal, thy, chr dis yes Final diagnosis

HEMOLYTIC ANEMIAS : 

HEMOLYTIC ANEMIAS normochromic, normocytic anemias (except for the thalassemias) in which the RBC survival time is decreased. The premature destruction may result from intrinsic abnormalities of the RBCs or abnormalities extrinsic to the RBC. Reticulocytosis is a constant feature.

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Hemogloinopathies - DEFINITION: Inherited abnormalities of hemoglobin synthesis characterised by structurally abnormal hemoglobin variants. Two main types of Mutations : Causing qualitative(Structural) abnormalities: Sickle Cell Anemia Causing quantitative(synthesis) abnormalities: Thalassemias, hereditary persistence of fetal hb

Prevalence of Hemogloinopathies : 

Prevalence of Hemogloinopathies

Slide 10: 

It is inherited as an autosomal recessive trait. Presents as sickle cell trait (heterozygous) and sickle cell disease(homozygous) It offers a protection against malaria for unknown reasons. Nearly 20 million people affected in India. Sickle cell anemia

Slide 11: 

Normal hemoglobin 2 alpha and 2 beta chains form a 4 chain tetramer HbS: Valine substituted for glutamic acid in both beta chains (HbSS). This occurs due to single point mutation at sixth position of beta globin chain which has thymine instead of adenine.

Pathophysiology : 

Pathophysiology  PO2- Hb is soluble Hb S polymerizes into insoluble aggregates leading to sickled cells  blood viscosity Capillaries gets clogged Upon reoxygenation, the RBC may return to its original shape But repeated sickling decreased circulation When PO2 , hypoxia and infarction of organs “sickle cell crisis”. damages the RBC membrane death the cells become irreversibly sickled hypoxia anemia

Slide 13: 

the cells become irreversibly sickled bLock in spleensplenic atrophy and necrosis these young patients are more prone to infections, especially from encapsulated microorganisms The liver and bone marrow then take over. removed by the spleen Hgb S has a decreased affinity for oxygen, leading to a shift to the right in the oxygen dissociation curve. This, however, creates more deoxyhemoglobin, and hence, more sickling

Clinical findings : 

Clinical findings 6 months of age - when hemoglobin F is replaced with hgb S rather than hgb A -functional asplenia, making bacterial sepsis the greatest risk for morbidity and mortality. 5 yr,-95% of children with sickle cell anemia will have functional asplenia. Acute sickle dactylitis, presenting as the hand-foot syndrome, painful, usually symmetric, swelling of the hands and feet. ischemic necrosis of the small bones, believed to be caused by a choking off of the blood supply as a result of the rapidly expanding bone marrow. In young children, pain inextremities; in older patients, pain in the head, chest, abdomen, and back Ischemia Acute pain episodes may progress to infarction of bone marrow or bone. Splenic infarcts are common and leads to"autosplenectomy." Pulmonary infarction, Strokes myocardium, liver, and kidneys do not live beyond middle age

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Priapism is a relatively frequent complication that results from the pooling of blood in the corpora cavernosa, causing obstruction of the venous outflow Chronic hemolytic anemia – Increased bilirubin turnover leads to gallstones Compensation mechanisms lead to cardiac hypertrophy and enlargement and eventual failure The hyperplastic bone marrow leads to thinning of the bones Hematologic complications-crises. Aplastic – usually associated with infection and results in temporary marrow aplasia due to overwork Hemolytic crisis – sudden acute anemia – in young children this may be due to splenic pooling Vaso-occlusive or painful – plugs of rigid sickle cells in the capillaries cause tissue damage and necrosis and lead to organ dysfunction. This is the “hallmark” of sickle cell disease.

Lab findings : 

Lab findings Normochromic, normocytic anemia 10-20% reticulocytes 6-10 g/dl hgb During crisis – marked anisoctyosis and poikilocytosis with target cells, fragmented cells,, and sickle cells Basophilic stippling, Howell Jolly bodies and siderocytes due to splenic hypofunction Bone marrow – normoblastic hyperplasia Diagnosis – by a peripheral smear, hgb electrophoresis, solubility tests, sodium metabisulfite will cause the cells to sickle by deoxygenating the blood (seen under the microscope) Basophilic stippling Howell Jolly bodies siderocytes hyperplasia nucleated RBCs

hemoglobin electrophoresis : 

hemoglobin electrophoresis Lane 2 is a normal adult. Lane 3 is a normal neonate. Lane 4 is a homozygous HbS individual. Lanes 6 and 8 are heterozygous sickle individuals. Lane 7 is a SC disease individual.

Treatment : 

Treatment prevention and treatment of complications immunize with the conjugate pneumococcal vaccine and all other routine vaccines At the age of 2 months all children should begin penicillin prophylaxis with 125 mg twice daily. 3 yr -250 mg bd Because of high red cell turnover, folate supplementation Pain- Opiate, NSAIDS Blood transfusions prevent most of the manifestations Hydroxyurea elevates fetal hemoglobin levels Bone marrow transplantation- <16 yr of age who have an HLA-matched sibling.

Sickle cell trait : 

Sickle cell trait – heterozygous for Hb S Usually the patient has no problems because >50% of their hemoglobin is Hb A There may be occasional problems upon exposure to severe hypoxia Diagnosis is by Hb electrophoresis or sodium metabisulfite

Thalassemia : 

Thalassemia The thalassemias are the most common genetic disorder on a worldwide basis

Alpha Thalassemia : 

Alpha Thalassemia Normal / Silent carrier - / Minor -/-, --/ Hb H disease --/- Barts hydrops fetalis --/-- Normal / Minor /0 , /+ Intermedia 0/+ Major 0/0 , +/+ Beta Thalassemia Classification & Terminology

Pathogenesis : 

 HbA2 In blood Overproduction of delta chain  alpha chain synthesis blocked b chain synthesis Survival of Hb F  HbF in blood Stimulates marrow-erythroid cells  erythropoietin prdn  Hb O2 affinity Many systems damaged skeletal changes, gout Precipitation of excess alpha chains Trapped in RES deformed Iron overload in bone marrow transfusion hypersplenism folate deficiency anemia ineffective erythropoiesis splenomegaly Pathogenesis Extramedullary hematopoiesis

Clinical features-Homozygous β0- Thalassemia (Thalassemia Major, Cooley's Anemia) : 

Clinical features-Homozygous β0- Thalassemia (Thalassemia Major, Cooley's Anemia) profound weakness and cardiac decompensation during the second 6 month of life Generally, fatigue, poor appetite, and lethargy are late findings of severe anemia thalassemic facies, pathologic fractures, hepatosplenomegaly, and cachexia Pallor, hemosiderosis, and jaundice may combine to produce a greenish brown complexion. Because of the anemia there is also an increase in iron absorption transfusional hemosiderosis iron overload: liver, fibrosis and cirrhosis; pancreas, diabetes mellitus; pituitary, testis, and ovaries, growth retardation, hypogonadism; parathyroid, hypocalcemia and osteoporosis;

Slide 24: 

Alpha untreated--/--: Prenatal or perinatal death --/- & --/cs: Normal life span with chronic hemolytic anemia B thalassemiaMajor: Death in first or second decade of life Intermedia: Usually normal life span Minor/Minima: Normal life span

Laboratory Findings : 

Laboratory Findings Eventually in β0-thalassemia there is severe anemia, few reticulocytes, numerous nucleated red cells, and microcytosis with almost no normal-appearing red cells on the smear The hemoglobin level falls progressively to lower than 5 g/dL The unconjugated serum bilirubin level is usually elevated iron accumulation with an elevated serum ferritin and saturation of the transferrin. Bone marrow hyperplasia can be seen on radiographs

Treatment : 

Treatment Blood Transfusion: A post-transfusion hemoglobin level of 9.5 g/dL is the goal. Transfusional hemosiderosis can be prevented by the use of deferoxamine chelator Splenectomy may be indicated for patients with thalassemia intermedia who have a falling steady-state hemoglobin and for transfused patients with a rising transfusion requirement. Bone marrow transplantation < than 15 yr of age without iron overload and hepatomegaly who have HLA-matched siblings.

Other Hemoglobinopathies : 

Other Hemoglobinopathies Hb D disease A glutamine replaces glutamic acid at position 121 on the  chain asymptomatic polymerization of deoxyhemoglobin leading to sickling and mild anemia. Hb E disease A glutamic acid replaces lysine at position 26 on the  chain leading to a slightly unstable hemoglobin with oxidant stress. mild microcytic anemia, target cells and increased osmotic fragility

Hemoglobin C disease : 

Hemoglobin C disease Lysine is substituted for glutamic acid at position 6 on the  chain. Hb C has decreased solubility and in the deoxyhemoglobin state, the RBCs form intracellular crystals leading to a rigid RBC with a decreased survival time (33-35 days). usually asymptomatic although patients may have joint or abdominal pain. Lab findings Slight reticulocytosis Hgb C crystals Target cells Microspherocytes Fragmented cells Diagnosis by Hb electrophoresis

HEMOGLOBINS WITH ALTERED AFFINITY FOR OXYGEN : 

HEMOGLOBINS WITH ALTERED AFFINITY FOR OXYGEN

Hemoglobinopathies-preventive approach : 

Hemoglobinopathies-preventive approach Screening strategies Prenatal diagnosis Hemoglobinopathy-antenatal diagnosis Test partners of heterozygous or affected individuals Antenatal diagnosis from DNA obtained by chorionic villus sampling, or by amniocentesis

References : 

References Nelson’s Textbook of Pediatrics Pubmed.com

Thank You : 

Thank You