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Red Blood Cells & Anemias Andrew D. Leavitt, MD Departments of Laboratory Medicine & Medicine March 26, 2012 RBC: ~5 x 10 6 /  l; Generate ~ 8,000,000,000/hour.

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Presentation on theme: "Red Blood Cells & Anemias Andrew D. Leavitt, MD Departments of Laboratory Medicine & Medicine March 26, 2012 RBC: ~5 x 10 6 /  l; Generate ~ 8,000,000,000/hour."— Presentation transcript:

1 Red Blood Cells & Anemias Andrew D. Leavitt, MD Departments of Laboratory Medicine & Medicine March 26, 2012 RBC: ~5 x 10 6 /  l; Generate ~ 8,000,000,000/hour

2 Outline – topics we will cover  Erythropoiesis – names, faces, & numbers (review)  RBC biology -Hemoglobin O 2 dissociation curves Hemoglobin – fetal, adult RBC membrane  Hemoglobin switching  Anemias: Production vs. destruction vs. loss Membrane or contents – Hgb, enzymes Immune mediated Physical destruction  Anemia of inflammation  Ribosomopathies

3 Erythropoiesis Abbott Labs, Morphology of Human Blood Cells Pro- Erythroblast Basophilic Erythroblast Polychromatic Erythroblast Orthochromatic Erythroblast Reticulocyte RBC CHROMATIN STRUCTURE NUCLEAR SIZE & COLOR CELL SIZE & CYTOPLASM COLOR 5 stages in the marrow

4 Red Blood Cell (RBC) Delivers O 2 from your lungs to all your tissues Takes CO 2 from your tissues to your lungs Also – binds NO (a vasodilator) Their size: 8  [capillaries have ~3  M diameter] Their life-span: 120 days Mature RBCs have no nucleus Too few RBCs = anemia

5 What tells your body to make RBCs? EPO: Is not stored, but expressed in response to the kidney sensing oxygen in the blood It - 1. Increases # of E-committed progenitors 2. Increase GATA1 and FOG expression 3. Enhances anti-apoptotic gene expression 4. Increases transferrin receptor expression

6 Hemoglobin Tetramer of two heterodimers (  &  ) Hemoglobin (Hgb) in the RBC carries O 2, which is poorly soluble in water, to tissues & CO 2 from tissues to lungs. ~640,000,000 Hemoglobin molecules/RBC Must coordinate: 1.heme and globin synthesis 2.  (Chromosome 11; 141 aa) &  (Chromnosome 16; 146) chains Colors of a bruise are globin breakdown products Heme Iron in a Porphyrin ring   Glu to Val Linus Pauling 1949 – molecular diagnosis 2012 – no therapy

7 Hemoglobin oxygen dissociation curve Arterial O 2 tension Mean Venous O 2 tension HbF ; CO 2

8 Erythropoiesis: Hemoglobin Switching (ALWAYS: 2 alpha & 2 “beta-like” [3 ‘  ’ options]) EmbryoFetusBirth Adult 6 mo. Globin chain synthesis (%) 0 50        HgF     (75) HgA     (25) HgA     (96-98) HgA 2     (2-3) HgF     (< 1) Hoffman et al. Hematology 2000 Alpha: Chromosome 16 Beta-like: Chromosome 11

9 * * *mutations lead to hereditary spherocytosis Schematic of red cell membrane depicting proteins crucial for normal membrane mechanical strength

10 Normal Values for Hematology Tests - UCSF

11 Thinking about anemia…a clinical perspective Framework: RBC size (MCV) & is the marrow responding (reticulocyte count) Etiology: Cell intrinsic: 1. Hgb – too little; abnormal type; unequal  and  synthesis 2. Enzyme 3. Membrane Cell extrinsic: Immune mediated Physical destruction Blood loss Marrow does not produce Primary – leukemia, myelodysplasia Secondary – vitamin deficiency

12 Reticulocyte Stain – detects the ribonucleoprotein in the young RBC Reticulocytes

13 #1.1 Too little Hgb: Iron Deficiency Anemia Small cells – microcytic (MCV < 80 fL) Young women – OK Older people – Worry about gastrointestinal blood loss Iron deficiency anemia, peripheral blood (40x) normal peripheral blood (40x) Lead poisoning can look like Fe deficiency – Lead blocks heme synthesis

14 Iron Deficiency Anemia peripheral blood, 100X Hypochromic RBCs Elliptocytes Iron stian of bone marrow – none found ~ 500 million people worldwide

15 Daily absorption: Duodenum ~ 1 mg Daily loss: urine, feces, skin, hair ~ 1 mg Transferrin Plasma (4 mg) Circulating RBCs (1.7 – 2.4 gm) Menstrual loss/hemorrhage Macrophage (0.5 – 1.5 gm) Ineffective erythropoiesis Bone Marrow Erythroblasts ( ~ 150 mg) The Iron Circuit – mostly a game of recycling

16 Weiss & Goodnough NEJM 2005 Iron Circuit in Disease Infection/inflammation/malignancy IL-6/LPS hepcidin (25aa protein) absorption macrophage Fe storage Impairs Erythropoiesis: Decrease EPO Directly suppresses marrow Interferon –  TNF –  IL-1, IL-10

17 Storage iron (blue) Iron deficienyc anemia - iron stain Anemia of inflammation – iron stain Iron stain of bone marrow aspirates

18 #1.2 Abnormal Hgb: Sickle cell disease Multi-system disease Cardiovascular/strokes Kidneys Skin Lungs Immune system Treatment: Supportive care Transfusions Demethylating agents Stem cell transplants

19 #1.3 Abnormal  /  Globin ratio: Thalassemia Small cells – microcytic (MCV < 80 fL) Imbalance between  and  chains Name based on which chain is deficient [  or  thal] Make lots of RBCs, just unstable and lyse, so increased retics Alpha Thal: silent carrier  trait  or  Hgb H  Hydrops fetalis  Beta Thal: Minor Intermedia Major

20 Erythropoiesis: Hemoglobin Switching (ALWAYS: 2 alpha & 2 “beta-like” [3 ‘  ’ options]) EmbryoFetusBirth Adult 6 mo. Globin chain synthesis (%) 0 50        HgF     (75) HgA     (25) HgA     (96-98) HgA 2     (2-3) HgF     (< 1) Hoffman et al. Hematology 2000 Alpha: Chromosome 16 Beta-like: Chromosome 11

21 Beta-thalassemia major Nucleated RBC Target cells Alpha thal trait Normal peripheral smear Hemoglobin H, -- / -A Target cells Retics

22 Severe thalassemia Beta-thalassemia major Nucleated RBC Target cells Beta-thalassemia major (transfused) Nucleated RBC Normal RBCs (transfused)

23 Bite cells #2 Enzyme: G-6-PD deficiency (Heinz body hemolytic anemia) Arrows show Heinz bodies Sulfa drugs, fava beans, antimalarials..… Reduced glutathione (GSH) is critical for RBCs to counter oxidative stress.

24 * * *mutations lead to hereditary spherocytosis #3: Membrane: red cell membrane depicting proteins crucial for normal membrane mechanical strength

25 Hereditary spherocytosis (HS) spherocytes Reticulocytes

26 Thinking about anemia…a clinical perspective Framework: RBC size (MCV) & is the marrow responding (reticulocyte count) Etiology: Cell intrinsic: 1. Hgb – too little; abnormal type; unequal  and  synthesis 2. Enzyme 3. Membrane Cell extrinsic: Immune mediated Physical destruction Blood loss Marrow does not produce Primary – leukemia, myelodysplasia Secondary – vitamin deficiency

27 Autoimmune hemolytic anemia spherocytes Reticulocytes

28 Testing for anti-RBC antibodies: attached or in circulation Hemolytic disease of the newborn

29 RBC destruction - extrinsic Hemolytic uremic syndrome (HUS) Retics schistocytes (RBC fragments) Thrombotic thrombocytopenic purpura (TTP) schistocytes (RBC fragments) Erythroid Hyperplasia, TTP, bone marrow aspirate (100x)

30 Megaloblastic anemia (MCV > 100) B12 deficiency Folate deficiency Affects DNA synthesis

31 Megaloblastic anemia (MCV > 100) Anemia yet hypercellular marrow – ineffective erythropoiesis

32 Narla & Ebert 2010 Ribosomopathies and hematopoietic disorders Our findings indicate that the erythroid lineage has a low threshold for the induction of p53, providing a basis for the failure of erythro- poiesis in the 5q- syndrome, DBA, and perhaps other bone marrow failure syn- dromes.

33 Thanks for your attention!

34 Take home message…… Blood is good…everyone should have some! Share it…become a blood donor if you can UCSF Blood donor center: Millberry Union next to Subway sandwich shop The best donor center nurses in town


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