GROUP CASE STUDY Dr. Nancy McQueen MICR 410 - Hematology Spring, 2011 Ruby Khan Wilson Liu Baron Morano TO DO!!! Incorporate Ruby’s slides…send Wilson the answers to the case study form, print out forms, re-arrange order of presentation, edit content, practice

Case Summary 12-year-old male with right upper-quadrant pain and history of hemolytic and aplastic crises. Lab results: WBC: 8.0 x 109/L RBC: 4.0 x 1012 /L Hgb: 10.8 g/dL Hct: 0.29 L/L Platelets: 504 x 109 /L Erythrocyte indices: MCV = 72. 5 MCHC = 37.2 MCH = 27

Case Summary Based on the indices, the patient’s red blood cells are… Microcytic - Normochromic Osmotic fragility test: patient control Initial hemolysis 0.65% NaCl 0.45% NaCl Complete hemolysis 0.40% NaCl 0.30% NaCl Thermal Sensitivity Test: Erythrocytes fragmented at 46.0 Degrees Celcius

Key Diagnostic Information Age Right upper-quadrant pain Hemolytic anemia Aplastic Anemis Poikilocytosis Increased Osmotic fragility Abnormal red cell thermal sensitivity  Young!  Gallbladder – Cholecystitis  Premature RBC Death  Reticulocytopenia

Peripheral Blood smear Elliptocytes Spherocytes Teardrop cells Micro - Spherocytes

Our Diagnosis Patient suffers from… Acronym = H.P.P. HEREDITARY PYROPOIKILOCYTOSIS Hewlett Packard Pavilion Honda Power Port Hawaiian Paradise Park **Main Defect: Spectrin!!!

Pathophysiology of HPP HPP is an autosomal recessive disorder Patients with HPP are compound heterozygotes & exhibit 2 genetic defects: (1) A mutant α or β spectrin that causes severe impairment of spectrin dimer self-association (2) A partial spectrin deficiency, resulting from decreased synthesis of α spectrin, which causes Microspherocytosis Current understanding suggests HPP results when 1 parent has Hereditary Elliptocytosis (HE) & the other parent carries a gene that causes a spectrin deficiency HPP involves a spectrin dimer-dimer association problem Defective spectrin dimer self-association or protein 4.1 deficiency weakens the RBC skeleton, and under sheer stress in the circulation, the cells become distorted and lose their ability to regain their original disc shape  Resulting in Elliptocytes & Poikilocytes

Hemolysis can lead to rapid sequestration Pathophysiology of HPP In HPP, the clinical severity & morphology are thought to result from a combination of Horizontal & Vertical Defects Horizontal Defect – Spectrin self-association is severely impaired, which decreases the strength & stability of the skeleton, resulting in Poikilocytes & Fragmentation.  Vertical Defect - Spectrin deficiency impairs the vertical interaction of the skeleton with the lipid bilayer, which causes Microsphereocytes. HPP manifests as a severe hemolytic anemia with thermal instability of the RBCs. The severe anemia can result in growth retardation & early gallbladder disease (upper right quadrant pain). Hemolysis can lead to rapid sequestration & destruction of RBCs.

Testing for HPP KEY TESTS Peripheral Blood Smear RBC Indices Osmotic Fragility Thermal Sensitivity ADDITIONAL Coomb’s Test Vitamin B12 : Folate Bilirubin levels Ham’s Test Autohemolysis Test Acidified Glycerol Test FUTURE??? SDS-PAGE = Gel Electrophoresis Eosin-5-maleimide (EMA)-binding test

Therapy & Prognosis of HPP Treatment – Transfusion of packed red blood cells. Supportive Care – Intravenous fluids, Oxygen, & Monitoring HPP patient in an acute care setting as determined by the needs of the individual patient. Surgical Procedures – Splenectomy Treatment of Individual Symptoms No Specific Medications for HPP

Therapy & Prognosis of HPP Vitamins – Folic Acid often recommended due to Folate Deficiency that often occurs in patients with chronic hemolysis & increased erythropoiesis by the bone marrow.  Recommended Oral Dose of 1 mg/day Prognosis - Related to the number of transfusions needed to maintain adequate hemoglobin levels for a growing child & the ability to treat or to prevent life-threatening infections after splenectomy

Preventing HPP Since HPP is a genetic disease, there is not much that can be done to prevent it, aside from... Genetic Counseling From the Law for the Prevention of Progeny with Hereditary Diseases of 14 July 1933 Source : M. Burleigh & W. Wippermann, The Racial State. Germany, 1933-1945, (Cambridge, 1991), pp.136-138. Gene Therapy

Take Home Message The diagnosis: Hereditary Pyropoikilocytosis Typical symptoms Moderate to Severe Hemolytic Anemia Gallbladder Disease and Splenomegaly A Parent or Sibling With Hereditary Elliptocytosis The cause of the disease: Spectrin Defect Diagnostic tests include: CBC Peripheral Blood Smear Osmotic Fragility Test Thermal Sensitivity Test Treatment: Splenectomy Prognosis: Variable Prevention: Genetic Counseling Gene Therapy

References Textbook – Clinical Hematology and Fundamentals of Hemostasis (Fifth edition) Denise M. Harmening Medscape Online Reference - http://emedicine.medscape.com/article/205843-overview National Insitute of Health; Office of Rare Diseases Research - http://rarediseases.info.nih.gov/GARD/Disease.aspx?PageID=4&diseaseID=4619 Wikipedia: The Free Encyclopedia - http://en.wikipedia.org/wiki/Hereditary_elliptocytosis ; http://en.wikipedia.org/wiki/Pyropoikilocytosis Med India: Medical Lab Tests - http://en.wikipedia.org/wiki/Hereditary_elliptocytosis University of Virginia: School of Medicine - http://www.med-ed.virginia.edu/courses/path/innes/rcd/membrane.cfm eHow: Prevention of Hereditary Diseases - http://www.ehow.com/way_5188179_prevention-hereditary-diseases.html Farlex Free Dictionary - http://acronyms.thefreedictionary.com/Hereditary+pyropoikilocytosis History of The Holocaust.org - http://www.zupdom.com/icons-multimedia/ClientsArea/HoH/LIBARC/ARCHIVE/Chapters/Stabiliz/Racial/LawForPr.html BMJ - http://www.bmj.com/content/314/7079/0.8.full PubMed - http://www.ncbi.nlm.nih.gov/pubmed/12174674 ; http://www.ncbi.nlm.nih.gov/pubmed/21054813 PubMed Health - http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001597/ Check Orphan: Rare, Orphan, and Neglected Diseases - http://checkorphan.getreelhealth.com/index.php/research/view/pyropoikilocytosis/page/1 Inside Surgery - http://insidesurgery.com/tag/pyropoikilocytosis/