Case Study 1 MICR 410 - Hematology Spring, 2011 Note: Embedded in your PowerPoint, you must address all questions in the case! HIBA ALLO CHRISTINA CASTRO CLAIRE ENDO ADRIAN VALONES

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 What is the significance if any of knowing the patient’s background? http://www.inmagine.com/unx202/u14837207-photo

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

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) α-Thalassemia has a 40% incidence in the Greek population

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)

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 Nondeletional Hb H disease include Hb H disease with Constant Spring. The abnormal α-globin genes is result of a point mutation affecting the termination codon of the α2 gene on another chromosome.

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 Lecture material/ text book information/review article/WEB information etc http://bloodjournal.hematologylibrary.org/content/105/2.cover-expansion

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 http://bloodjournal.hematologylibrary.org/content/105/2.cover-expansion Zhou S et al. J. Biol. Chem. 2006;281:32611-32618 http://www.med.cmu.ac.th/dept/pediatrics/06-interest-cases/ic-52/case52-page-1.HTM High performance liquid chromatography is a newborn screening test required by California state law. Newborns with abnormal hemoglobin such as Bart’s hemoglobin indicate alpha thalassemia.

Therapy and Prognosis for Hb H Disease 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 Hb H Disease is primarily preventive and supportive in nature. Patients with nondeletional Hb H disease have more severe clinical and hematologic features including: Younger age at diagnosis, higher proportion of patients requiring transfusion, large liver and spleen sizes, higher requirement for splenectomy, higher percentage of growth deficiencies and more are symptomatic at presentation

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

Take Home Message Treatment 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

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