Hemoglobin Disorders (Pediatrics)

Hemoglobin Disorders

• Hemoglobin disorders are qualitative defects resulting from single amino acid substitutions in the alpha or beta chains of adult hemoglobin, affecting the stability of the Hb molecule and its oxygen affinity.
• They are classified into two types: hemoglobinopathies and thalassemias.

Hemoglobinopathies

• Sickle Cell Hemoglobinopathy:
  • Characterized by a structural defect in the β chains of hemoglobin, where glutamic acid is replaced by valine.
  • Results in sickling of red blood cells, leading to hemolytic anemia.
  • HbS is less soluble than HbA, causing sickle cells to be prematurely destroyed.
  • Sickling can occur under physiological conditions, leading to increased blood viscosity, impaired blood flow, and thrombi formation.

Clinical Features of Sickle Cell Anemia

• Manifestations appear in the later part of the first year of life due to the presence of HbF in infant RBCs.
• Four types of crises can occur:
  • Vaso-occlusive or symptomatic crisis
  • Sequestration crisis
  • Aplastic crisis
  • Hyperhemolytic crisis

Vaso-occlusive or Symptomatic Crisis

• Most common problem, precipitated by infection, dehydration, hypoxia, or acidosis.
• Pain is due to disrupted blood flow in the microvasculature, leading to tissue ischemia.
• Manifestations include:
  • Acute abdominal pain
  • Hand-foot syndrome (sickle cell dactylitis)
  • Bone crises (osteonecrosis)
  • Central nervous system crises (hemiplegia, convulsion, blindness)
  • Pulmonary crises (dyspnea, severe hypoxemia, acute chest syndrome)
  • Renal disease (hematuria, papillary necrosis, renal infarction)
  • Splenic infarction (leading to autosplenectomy and functional hyposplenism)

Diagnosis

• Anemia (moderate to severe, normochromic, normocytic) with reticulocytosis
• Indirect evidence of hemolysis
• Blood smear: sickle cells, nucleated red cells
• ESR: low
• Hemoglobin electrophoresis: HbS migrates slower than HbA, giving the diagnostic SS pattern

Management

• Treatment of aplastic, sequestration, and hemolytic crises by blood transfusion
• Treatment of vaso-occlusive crisis by:
  • Analgesics for pain
  • Correction of dehydration and acidosis
  • Blood transfusion (indicated for severe pain or CNS involvement)
• Folic acid supplementation (1mg/day orally)
• Avoidance and correction of lung disease and hypoxemia
• Prophylaxis of infections (pneumococcal vaccine, H.influenzae vaccine, early diagnosis of infections)

Hydroxyurea Treatment

• Stimulates HbF synthesis (10-25%)
• Raises HbF and hemoglobin levels
• Decreases the rate of painful episodes
• Decreases the rate of ACS episodes and blood transfusions
• Safe and well-tolerated in children >5 years old
• Can preserve splenic function and improve growth when started in infancy

Bone Marrow Transplantation

• The only cure for the disease
• Limited by risk and morbidity
• Only applicable for children <16 years old with an HLA-matched sibling

Thalassemias

• Inherited disorders characterized by hypochromic anemia caused by deficient synthesis of one or more polypeptide chains of human Hb.
• Two hemoglobin gene clusters are involved in the production of Hb and are located on chromosomes 11 and 16.

β-Thalassemia

• Decreased formation of β chains (HbA) with the formation of γ chains (HbF) and δ chains (HbA2) to compensate for the deficiency of adult Hb.
• Four grades of β-thalassemia:
  • β-Thalassemia trait (asymptomatic, mild decrease in blood Hb)
  • β-Thalassemia intermedia (mild anemia, moderate degree of hepatosplenomegaly and skeletal deformities)
  • β-Thalassemia minor (mild form of β-thalassemia, requires transfusions in adolescence or adulthood)
  • β-Thalassemia major (homozygous β-thalassemia, the most severe form of thalassemia)

β-Thalassemia Trait

• Heterozygous thalassemia with no clinical abnormalities
• Mild decrease in blood Hb
• RBCs are microcytic hypochromic
• Serum iron is normal or slightly elevated
• Hemoglobin electrophoresis shows increased HbA2 (3.4-7%) and HbF (2-6%)

β-Thalassemia Intermedia

• Combination of β-thalassemia mutations leading to microcytic anemia with Hb around 7g/dL
• Do not require regular blood transfusions
• May develop moderate degrees of hepatosplenomegaly and skeletal deformities
• Splenectomy may be indicated with a rising transfusion requirement

β-Thalassemia Major

• Homozygous β-thalassemia with a profound or complete absence of β chain and Hb A
• Marked increase in HbF and HbA2
• Pathophysiology of the anemia of thalassemia:
  • α chain synthesis exceeds β chain synthesis
  • Free α chains form α-globin tetramers, leading to red cell damage and hemolysis
  • Red cell destruction occurs in the peripheral blood and within the bone marrow

Clinical Manifestation of β-Thalassemia Major

• Onset in the 2nd half of the first year
• General features of chronic hemolytic anemia
• Failure to thrive in early childhood
• Pallor, jaundice, and gallstones
• Hepatosplenomegaly and hypersplenism
• Abnormal facies
• Manifestations of hemosiderosis

Laboratory Data

• General laboratory data of chronic hemolytic anemia
• Hypochromic, microcytic anemia with reticulocytosis
• Leukopenia, thrombocytopenia
• Blood smear: target cells and nucleated cells, extreme anisocytosis
• Hb electrophoresis: HbF raised more than 90%, HbA2 increased, and no Hb A
• High serum ferritin

Treatment of β-Thalassemia Major

• Blood transfusions to maintain Hb above 9.5g/dL
• Immunization against H.influenzae, pneumococcal, and meningococcal infections
• Prophylactic penicillin therapy
• Bone marrow transplantation: curative, most successful in children <15 years old without iron overload and hepatomegaly who have an HLA-matched sibling

Prevention

• Prospective genetic counseling
• Prenatal diagnosis: chorionic villus biopsy between 11-13 weeks of gestation

Aplastic Anemia

• Marked decrease or absence of blood-forming elements in the bone marrow with peripheral pancytopenia
• Can be acquired or inherited
• Acquired aplastic anemia:
  • Idiopathic
  • Secondary (drugs, radiation, infection, immune disease)
  • Bone marrow replacement (tumor, fibrosis)
• Inherited aplastic anemia:
  • Fanconi anemia
  • Congenital aplastic anemia

Fanconi Anemia

• Pancytopenia
• Short stature
• Skin hyperpigmentation
• Skeletal abnormalities (absent radius and thumb)
• Renal anomalies
• Chromosomal abnormality with a high incidence of AML and carcinoma

Acquired Pancytopenia

• Clinical picture: manifestation of the cause, pallor, cardiac failure, fatigue, bleeding, and increased risk of infection
• Laboratory finding:
  • Blood picture: low Hb level, leukopenia, thrombocytopenia
  • Bone marrow examination: hypocellular