1. Thalassemias Troy Phillips DO Assistant Professor VCOM Carolinas & Spartanburg Family Medicine Residency tphillips@srhs.com

2. Objectives Review pathophysiology, screening, clinical manifestations and treatment of alpha and beta thalassemias. Review COMLEX I level questions related to the above. Do this without losing the attention of the vast majority of the class

3. Definitions Anemia – Reduction below normal limits of circulating red cell mass (normal value depends on age) Alpha Thalassemia – hemoglobin abnormality in which there is decreased/absent  -chain production relative to β-chain production Beta Thalassemia - hemoglobin abnormality in which there is decreased β-chain production relative to  -chain production

4. Normal Structure of Hemoglobin Adult Hemoglobin (HgA) – normally makes up %97 of adult hemoglobin – is made up of 4 subunits 2  2  Each has heme ring with a central Fe molecule

5. Hemoglobin Production Changes with Development Fetal hemoglobin (HbF) – composed of 2  - & 2 γ- globin chains HbA 2 – minor hemoglobin of adults – Contains 2  - & 2 δ-globin chains. – Normally 2 to 3% of all Hb – 4- 6% in most carriers of β- thalassemia (because you lack B chains)

6. Alpha Thalassemia Disease States Alpha chain is expressed from 2 separate genes on chromosome 16 Silent Carrier – asymptomatic – Only one alpha mutation α thalassemia trait – mild microcytosis, hypochromatic, asymptomatic – Two alpha mutations Hb H Disease – severe anemia, microcytosis, hypochromatic, symptomatic – 3 alpha mutations (maybe 4? He says this later…that you can have all beta and have HbH…watch out for that) Hydrops Fetalis – lethal in utero- Barts Hb – Total absence of α-globin synthesis- no useable hemoglobin before birth – No physiologically useful hemoglobin is produced, only γ-globin (high O2 affinity and can’t deliver O2 to tissues)

8. Beta Thalassemia Disease States β thalassemia minor (trait) – Heterozygous – Asymptomatic but will have a mild microcytic, hypochromic anemia One bad beta chain, one good beta chain β thalassemia intermedia – homozygous but milder phenotype β thalassemia major (Cooley Anemia) – homozygous and unable to produce any viable HgA – Severe microcytic, hypochromic anemia, symptomatic No good beta chains, all alpha

10. Skeletal Changes Due to expansion and invasion of erythroid bone marrow, which widens the marrow space, thinning the cortex and leading to osteoporosis Can also cause marked changes in facial structure “chipmunk facies.”

11. Diagnosis Peripheral blood smear – Ordered when microcytic (low MCV), hypochromic (low MCH) anemia detected on CBC – Will show dacrocytes (teardrops), codocytes (target), Heinz bodies – Won’t tell you what predominant hemoglobin is present Hemoglobin Electrophoresis (confirmation) – Shows which types of hemoglobin are absent or present

12. Treatment Alpha Thalassemia – Silent Carrier and Trait are asymptomatic, no treatment required – Hb H may require periodic transfusions and monitoring for iron overload – Hydrops fetalis is lethal in utero

13. Treatment Beta Thalassemia – Minor asymptomatic and no treatment required – Intermedia Transfusions eventually required- later on in life Closely monitor iron stores Consider splenectomy in severe cases – Major Hypertransfusion (1-3 units pRBCs every 3-5 weeks to keep hemoglobin >9) Splenectomy Iron chelation therapy (prevent iron overload)

14. Why splenectomy? Often massive splenomegaly present. An intact spleen also causes shortened survival of transfused red cells and progressive worsening of anemia. What vaccine needs to be given prior to splenectomy and why? Strep Pneumonia can happen bc it’s encapsulated….and no more spleen so give  Pneumococcal vaccine

15. Practice Questions A 14 year old girl is brought to the emergency department by a camp counselor for severe leg pain. She knows she has a “chronic disease” but isn’t sure what it is. Physical exam shows a 2cm ulcer which on culture, grows out Salmonella. A peripheral smear shows Howell-Jolly bodies. Which of the following is the most likely condition? A. Alpha thalassemia B. Beta thalassemia C. G6PD deficiency D. Hereditary spherocytosis E. Sickle cell anemia

16. Practice Questions The anemia associated with beta thalassemia minor is A.Mild, microcytic, hypochromic, asymptomatic B.Severe, microcytic, hyperchromic, symptomatic C.Mild, macrocytic, hyperchromic, asymptomatic D.Mild, normocytic, normochromic, asymptomatic E.lethal

17. Test questions….

18. References UpToDate - Clinical manifestations and diagnosis of the thalassemias, Pathophysiology of alpha and beta thalassemia Harrison’s Principles of Internal Medicine, Thalassemia Syndromes Kaplan Medical COMLEX Level 1 Pathology Review, RBC Pathology