Case Study 1 MICR 410 - Hematology Spring, 2011

1. Case Study 1MICR 410 - HematologySpring, 2011 HIBA ALLO CHRISTINA CASTRO CLAIRE ENDO ADRIAN VALONES

2. Case Summary • John, a 4 year old boy, complains of weakness, fatigue, and dyspnea (labored breathing). • Parents encounter bouts of fatigue, but have never consulted a physician. • Parents are from Greece. • Significance: Greeks have a genetic predilection for certain diseases http://www.inmagine.com/unx202/u14837207-photo

3. Key Information Pointing to Diagnosis • Patient presents with anemia. Weakness, fatigue, and dyspnea are symptoms of anemia. • CBC • Low RBC, Hemoglobin, and HCT  Anemia • Hypochromic, Microcytic • Peripheral Blood Smear • Poikilocytosis, Polychromasia and Target Cells (dominant) • NOTE: Target Cells are also found in Hemoglobinopathies, Iron Deficiency Anemia, & Thalassemia http://www.med.cmu.ac.th/dept/pediatrics/06-interest-cases/ic-52/case52-page-1.HTM

4. KEY INFORMATION POINTING TO DIAGNOSIS • Additional lab test confirming the diagnosis: • Hemoglobin Electrophoresis & Iron Panel • Hemoglobin Electrophoresis Results Abnormal • HbA levels are low • 8% Hb Bart’s and 24% Hb H are abnormally present • Iron Studies are normal • α-Thalassemia is commonly found in Mediterranian people (Greeks and Sardinians)

5. The Diagnosis for Case 1 • R/O Iron Deficiency Anemia • Iron panel normal • R/O Hemoglobinopathies & β-Thalassemia • Alpha chains decreased: low Hgb A 66% (95-98%) • β and ϒ chains in excess: Hgb H 24%, Hgb Bart’s 8% • Hgb S, SC, C: No sickle cells or crystals present • Diagnosis: Hemoglobin H Disease (Alpha Thalassemia)

6. Pathophysiology of Hb H Disease • Patients with Deletional Hb H Disease lack 3 of the α-globin genes • Patients with Non-deletional Hb H Disease lack 2 of the α-globin genes and 1 of the present genes is abnormal • Gene deletion results in excess γ andβchains • Excess γ4 tetreamers form in the fetus • Excess β4 tetreamers form in adults • Hb H (β4) ranges from 5 to 30% of Hb in patients with the disease (24% in this case) • Hb H has a high affinity for oxygen resulting in a left shift of the O2 dissociation curve where less O2 is delivered to the tissues https://aspirusgmi.dnadirect.com/grc/patient-site/alpha-thalassemia-carrier-screening/genetics-of-alpha-thalassemia.html?w3bz10N81iH6NK6Ms-JpoqO Left Shift Abn Hb

7. Pathophysiology of Hb H Disease • Hb H forms an intracellular precipitate • As RBCs age they contain more precipitated Hb H due to attachment to the cell membrane • Precipitates make Hb H RBCs more rigid leading to culling in the spleen • Hb H Disease is mainly a hemolytic disorder • Precipitates may also cause ineffective erythropoiesis http://emedicine.medscape.com/article/958850-overview http://bloodjournal.hematologylibrary.org/content/105/2.cover-expansion

8. Diagnostic Tests for Hb H Disease • Hemoglobin electrophoresis is used to quantify and identify hemoglobin types • Iron Panel • Brilliant Cresyl Blue Stain can display Hb H inclusions • High Performance Liquid Chromatography can quickly separate different hemoglobins Zhou S et al. J. Biol. Chem. 2006;281:32611-32618 http://bloodjournal.hematologylibrary.org/content/105/2.cover-expansion http://www.med.cmu.ac.th/dept/pediatrics/06-interest-cases/ic-52/case52-page-1.HTM

9. Therapy and Prognosis for Hb H Disease • Therapy • For severe anemia: blood transfusions • Monitor for Hemochromatosis • Splenectomy • Hematopoietic Stem Cell Transplantation • Requires bone marrow transplant • Only used in severe cases • Avoid certain medications sulfa drugs, analgesics • Avoid mothballs and fava beans: causes severe anemia • Prognosis • Proper care reduces medical complications • Good prognosis with treatment • Nondeletional Hb H Disease has more severe complications than Deletional Hb H Disease

10. Prevention of Hb H Disease • Family history – genetic counseling • Likelihood of Hgb Bart’s (Hydrops Fetalis) • Prenatal Testing • Amniocentesis & Chorionic Villus Sampling • Ultrasound Monitoring of Hydrophobic Changes • Preimplantation Genetic Diagnosis (PGD) • Embryos grown in vitro • Increase chance of a healthy child

11. Take Home Message • The diagnosis is Hemoglobin H (alpha thalassemia) • Typical symptoms • Fatigue, weakness & dyspnea • The cause of the disease • 3 Alpha chain gene deletions • Diagnostic tests • CBC, Iron Panel & Hemoglobin electrophoresis • Treatment • Intermittent blood transfusions for severe anemia • Splenectomy then bone marrow transplant in severe cases • Dietary restriction & avoiding certain medications • Prognosis • Prognosis is good with proper medical care • Prevention is genetic counseling with family history, prenatal testing & PGD

12. References • Cheerva, A.C. and Coppes, M.J. (2011). Hemoglobin H Disease (Alpha Thalassemia). Retrieved from http://emedicine.medscape.com/article/955496-overview • Chui, D. H. K. et al. (2003). Hemoglobin H Disease: not necessarily a benign disorder. Blood, 101(3), 791-800. • Harmening, D. (2008). Clinical Hematology and Fundamentals of Hemostasis. (5th ed.). Baltimore, MD: F.A. Davis Company. • Knapp, A. et al. (2010). Evidence Review: Hemoglobin H Disease. Retrieved from http://www.hrsa.gov/heritabledisorderscommittee/reports/ hemogolbinh.pdf • London Fertility Centre. Information Sheet for Thalassemias and Preimplantation Genetic Diagnosis. Retrieved from http://www.fertilityplus.org.uk/data/documents/PGD-THALINFOSHEET74%20V4%2007%2010%2010.pdf