Hemoglobin

Hemoglobin Molecule

1

The Globin Chain Cluster on Chromosomes 16 and 11

2

Synthesis of Individual Globin Chains in Prenatal and Postnatal Life

3

The Expression of Human Globin Gene

4

Synthesis of Hemoglobin

5

Hemoglobin Abnormalities •Reduced rate of synthesis of normal α - or β - globin chains: thalassemia •Synthesis of an abnormal hemoglobin: hemoglobinopathy

6

The Clinical Syndromes Caused by Hemoglobin Abnormalities

Syndrome Thalassemia Hemoglobinopathy

Abnormality Reduced globin chain synthesis (α - or β -thalassemia) Abnormal Hb

Hemolysis

Crystalline hemoglobins (Hb S,C, D, E) or unstable hemoglobins

Familial polycythemia

Altered oxygen affinity

Methemoglobinemia

Failure of reduction (HbM)

7

The Geographical Distribution of Thalassemias and Hemoglobin Abnormalities

8

Thalassemias

9

Pathophysiology of β -Thalassemia (1)

10

Pathophysiology of β -Thalassemia (2)

11

12

Examples of Mutations Which Produce β -Thalassemia

•FS frame shifts •NS non-sense •SPL splicing 13

14

15

Thalassemia Major: Appearance and Skull X-ray

16

17

Peripheral Blood of Thalassemia Major

18

β -Thalassemia Major: Biopsy of Liver Before and After Iron Chelation

19

The Genetics of α -Thalassemia

20

α -Thalassemia Blood Film

21

Hb H Inclusion Bodies

22

α - Thalassemia : Hydrops Fetalis Deletion of All Four α - Globin Genes

23

Clinical Classification of Thalassemia •Hydrops fetalis

Four gene deletion of α -thalassemia

•Thalassemia major

Transfusion-dependent homozygous β -thalassemia or other

combinations

•Thalassemia intermedia Moderate severity caused by variety of genetic defects •Thalassemia minor

-thalassemia trait α -thalassemia trait β

24

Diagnosis of Thalassemia Type α -Thalassemia

Heterozygotes

Homozygotes

MCV,* MCH** low MCV, MCH low, moderate anemia, HbH

β 0-Thalassemia

MCV, MCH low, HbA2>3.5%

Thalassemia major (No HbA)

β +-Thalassemia

MCV, MCH low, HbA2>3.5%

Thalassemia intermedia (10-20% HbA)

*MCV<78 fl **MCH<26 pg

25

Treatment of Thalassemia • Thalassemia minor needs no treatment or follow up except for genetic counseling and monitoring during pregnancy. Iron deficiency should be excluded • Thalassemia major patients need life long blood transfusions, iron chelation, hormone replacement, osteoporosis prevention. Curative treatment: stem cell transplantation 26

Comparison of Currently Available Iron Chelators

Property Usual dose (mg/kg/d) Route Half-life Excretion Status

Desferrioxamine

Deferiprone

Deferasirox

25-60

75

20-30

SC, IV (8-12 hr, 5 d/wk)

Oral (3 times daily)

Oral (Once daily)

20-30 min

3-4 hr

12-16 hr

Urinary, faecal

Urinary

Faecal

Licensed

Licensed outside Approved in US, US/Canada Switzerland, and (approved in 46 30 countries countries)

Effects of Iron Chelators on Ferritin Desferrioxamine, deferiprone, and deferasirox all decrease ferritin

Mean Change in Serum Ferritin (µg/L)

Deferasirox shown to maintain and reduce serum ferritin levels in phase 2/3 clinical trials in adult and paediatric patients (12-month efficacy—serum ferritin) 2500

β-thalassaemia

SCD

β-thalassaemia, MDS, other rare anaemias

2000 1500 1000 500 0 -500 -1000 -1500

Deferasirox

5

10 Doses (mg/kg/day)

MDS: myelodysplastic syndrome; SCD: sickle cell disease.

20

30

Hemoglobinopathies

29

Molecular Pathology of Sickle Cell Anemia

30

The Oxygenated and Deoxygenated Hemoglobin Molecule

31

Pathophysiology of Sickle Cell Disease

32

Polymerization of Deoxygenated Sickle Hemoglobin in Various Tissues and Depolymerization of Reoxygenated Hemoglobin in the Lungs

33

Induction of Red-Cell Sickling by Polymerization of Deoxyhemoglobin S

34

Principal Interactions Responsible for the Adhesion of a Sickle Red Cell to the Microvascular Endothelium

35

The Process of Vaso-Occlusion in Patients with Sickle Cell Disease

Hebbel, R. P. N Engl J Med 2000;342:1910-1912

36

Clinical Features of Sickle Cell Anemia       

The clinical expression is very variable Severe hemolytic anemia Painful vaso-occlusive crises Visceral sequestration crises Aplastic crises Hemolytic crises Infections are a major problem: S. pneumoniae, H. influenzae, Salmonella  Lower leg ulcers, proliferative retinopathy, gallstones 37

Peripheral Blood of Sickle Cell Anemia

38

Scanning EM of a Sickle Cell

39

Sickle cell

Normal erythrocyte

40

Leg Ulcer in Sickle Cell Anemia

41

Toes in Sickle Cell Anemia

42

Pulmonary Infiltrates in Sickle Cell Anemia

43

Treatment of Sickle Cell Anemia  General health care maintenance: immunizations, prophylactic penicillin, folic acid, adequate hydration  Prompt treatment of infections (particularly children with high fever)  Transfusion therapy to maintain Hb~10g/dl  Adequate pain control: analgesics, inhaled NO  Hydroxyurea  Bone marrow transplantation 45

Mechanisms of Action of Hydroxyurea in Sickle Cell Disease

46

47

Mechanism of the Beneficial Effects of Hydroxyurea Therapy

48

‫תלסמיה בישראל‬

‫• ביתא תלסמיה נפוצה בין יהודים ממוצא מזרחי וערבים‬ ‫• נשאים ניתנים לגילוי ע"י ספירת דם ע"י אינדקסים של‬ ‫הכדוריות אדומות ואלקטרופורזיס של המוגלובין )‪(↑Hb A2‬‬

‫• יעוץ גנטי נדרש באם האם נשאית‬ ‫• אלפא תלסמיה פחות שכיחה מביתא תלסמיה‪ .‬נפוצה באותן‬ ‫עדות‪.‬‬ ‫• נשאים מאובחנים ע"י שלילת מצבים אחרים הגורמים לשינויים‬ ‫באינדקסים של הכדוריות אדומות אך אבחנה מלאה דורשת‬ ‫בדיקת ד‪.‬נ‪.‬א‬ ‫‪49‬‬

‫אנמיה חרמשית בישראל‬

‫•‬

‫•‬ ‫•‬ ‫•‬ ‫•‬

‫•‬

‫אנמיה חרמשית לא קיימת ביהודים‪ .‬נפוצה רק בין ערבים בדואים‬ ‫שמוצאם מאפריקה וכן בין עובדים זרים ממוצא אפריקני‪.‬‬ ‫שכיחה בעיקר בגליל בישובים עם אוכלוסיה בדואית‬ ‫בצפון הארץ קיימת תכנית גילוי נשאים הכוללת ספירת דם‬ ‫)גילוי נשאי תלסמיה( ו ‪) HPLC‬גילוי ‪(HbS, HbC, HbD‬‬ ‫באם האם מתגלה כנשאית נבדק האב ובהמשך נעשה אבחון טרום‬ ‫לידתי‬ ‫תכנית הגלוי הורידה את מספר לידות החולים‬ ‫‪50‬‬