Q6 Answers

Q6 (a) - 2-Year-Old Child with Frontal Bossing, Chipmunk Face, Jaundice, Failure to Thrive

i. Most Likely Diagnosis (1 mark)

ii. Pathophysiology in Brief (2 marks)

1. Absent/deficient beta-globin chains → excess free alpha-globin chains accumulate
2. Free alpha chains are unstable and precipitate inside RBC precursors → cause oxidative membrane damage and intramedullary destruction (ineffective erythropoiesis - up to 70-80% of RBC precursors destroyed in marrow)
3. Those RBCs that do reach circulation are short-lived → hemolytic anemia
4. Severe anemia stimulates massive erythropoietin release → extreme erythroid hyperplasia
5. Marrow expansion erodes cortical bone → frontal bossing, maxillary enlargement ("chipmunk face"), hair-on-end appearance on skull X-ray
6. Extramedullary hematopoiesis occurs in liver and spleen → hepatosplenomegaly + jaundice (from hemolysis)
7. Chronic hemolysis + iron overload (from transfusions and increased GI absorption) → multi-organ damage over time

iii. Laboratory Investigations + Confirmatory Test (3 marks)

• CBC: severe anemia (Hb ~4 g/dL), microcytosis (MCV <70 fL), hypochromia (MCH <20 pg)
• Peripheral blood smear: target cells, nucleated RBCs (normoblasts), fragmented RBCs, hypochromic microcytes, poikilocytosis
• Reticulocyte count: low-normal (ineffective erythropoiesis means reticulocytosis is not as prominent as expected)
• Serum bilirubin: elevated (indirect) - due to hemolysis
• Serum iron: elevated
• Serum ferritin: markedly elevated
• TIBC: reduced
• LDH: elevated (marker of hemolysis/ineffective erythropoiesis)
• Liver function tests: may show hyperbilirubinemia
• Skull X-ray: "hair-on-end" appearance (if done)

• Beta-thalassemia major shows: HbF markedly elevated (>90%), HbA absent or severely reduced, HbA2 may be elevated
• This is the gold standard confirmatory test
• DNA analysis/molecular testing for beta-globin gene mutations can further confirm and identify specific mutations (important for family screening and prenatal diagnosis)

Q6 (b) - 5-Year-Old Boy with Bleeding, Joint Swelling, Prolonged APTT

i. Working Diagnosis (1 mark)

• Male child (X-linked recessive)
• Prolonged bleeding from immunization site, easy bruising
• Recurrent hemarthrosis (knee joint swelling twice in 3 years) - pathognomonic of hemophilia
• Limping gait
• Markedly prolonged APTT with normal BT, near-normal PT, and normal platelet count
• Isolated intrinsic pathway defect = Factor VIII or IX deficiency

ii. Other Laboratory Investigations (3 marks)

1. Mixing study (APTT correction test):
   • Mix patient plasma 1:1 with normal pooled plasma
   • If APTT corrects → factor deficiency (vs. inhibitor, where it does not correct)
   • Incubate for 1-2 hours to check for inhibitors
2. Factor VIII activity assay:
   • Measures plasma Factor VIII coagulant activity (%)
   • Severe hemophilia A: <1% | Moderate: 1-5% | Mild: 5-40%
   • This is the most important next test
3. Factor IX activity assay:
   • To distinguish Hemophilia A from Hemophilia B (Christmas disease)
   • Factor IX will be normal in Hemophilia A
4. von Willebrand Factor (vWF) antigen and activity:
   • To rule out von Willebrand disease (vWD type 3 can also have low Factor VIII)
5. Inhibitor screen / Bethesda assay:
   • To check for Factor VIII inhibitors (especially relevant before starting treatment)
6. Genetic/molecular testing:
   • Inversion of intron 22 of F8 gene is the most common mutation in severe Hemophilia A

iii. Confirmatory Test (1 mark)

iv. Blood Component for Therapeutic Transfusion (1 mark)

• Recombinant Factor VIII concentrate - first choice (avoids infection risk)
• Plasma-derived Factor VIII concentrate - acceptable alternative
• Cryoprecipitate - contains Factor VIII, fibrinogen, vWF, Factor XIII; used when Factor VIII concentrates are unavailable (each unit of cryoprecipitate from 1 unit of blood contains ~80-100 IU Factor VIII)
• DDAVP (desmopressin) - can be used in mild Hemophilia A to stimulate endogenous Factor VIII release (not applicable in severe disease)