Hematology 1 (Hps, Rbc, Ntrtn Anemia

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common lymphild progenitor (CLP) begets? (3)

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T-Cells, NK cells, B-Cells

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Common myeloid progenitor (CMP) begets? (4)

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Platelets, RBCs, Neutrophils, Monocytes

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Different sites of Hematopoiesis in the fetus (3)

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Yolk sac (0 -2 months) --> Liver and spleen (2 months - birth) --> bone marrow (5 months - birth)

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Hematopoiesis in yolk sac yields what kind of cells?

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Primitive erythropoiesis (EryP) --> mostly erythroid cells

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Hematopoiesis in bone marrow yields what kind of cells?

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definitive erythroiesus (EryD) --> myeloid and lymphoid cells

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Where are hematopoietic stem cells found? (3) What are their properties (4)

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Sites: Bone marriow, Peripheral blood, Cord blood. Properties: Regenreate, proliferate, Differentiate, Capable of establishing full range of hematopoiesis.

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What is the usefulness of CD markers?

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Useful for identifiying the cell and determining where it is in the differentiation pathway (since different CD markers appear at different stages of hematopoiesis)

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CD 34. Site (2) and function

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On stem cells and endothelial cells. On endothelial cells, adhesive molecule that bind L-selection. On stem cell, function is uncertain (maybe homing)

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CD 117. Site and function

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Stem cell epitope (it’s a tyrosine kinase domain). Receptor for the stem cell factor (SCF), also known as cKIT.

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CD 113. Site and function

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Ubiquitous. Also known as nectin-3. Establishes and maintains plasma membrane protrusions. Found in cadherin based adhesion junctions. Mediates cell-cell adhesion

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CD 110. Site and function

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Stem cells. TPO-receptor (c-mpl). Binds thrombopoietin, a cytokine that potentiates platelet health and stimulation & survival of stem cells

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CDs that serve as markers for CLL and mantle cell lymphoma

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CD 19, CD 5/ CD 23

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Stages of erythropoeisis (6)

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Proerythroblast --> Basophilic normoblast --> polychromatic normoblast --> orthochromatic normoblast --> reticulocyte --> erythrocyte

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Production time for full erythropoiesis

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5 Days

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Changes in cell during erythropoeisis (4)

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Nucleus becomes smaller. Chromatin pattern becomes more aggregated. Cytoplasm changes from blue to orange. Decrease in RNA, increase in Hb.

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Stages of granulopoeisis (6)

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Myeloblast --> Promyelocyte --> Myelocyte --> Metamyelocyte --> Band --> Segement

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Function of EPO

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Expands the erythoid progenitors by acting through the erythropoietin receptor (EPO-R). Anti-apoptotic, therefore increases progenitor survival early in erythropoiesis

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Source of EPO (2)

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Endogenously produced in the kidneys (peritubular capillaries. Also syhtnesided pharmacologically (used to treat anemia of end stage renal disease).

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Differntial sensitivity of EPO at different stages of erythropoesis

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Early erythroid precursor (burst forming unit --> BFU-E) has some EPO-R. Later erythroid precursor (cloning forming unit --> CFU-E) has many EPO-R. RBC precursors have fewer EPO-R. And finally, the mature RBC has no EPO-R

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Role of JG cells in regulation of erythropoietin

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JG cells sense oxygen using the Hif1 alpha factor. When O2 levels rise, Hifl alpha gets destroyed; when O2 levels drop, Hif1 alpha is retained. It complexes with Hif1 beta and this complex goes to the nucleus to singal EPO synthesis.

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Role of VHL in regulation of erythropoietin

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CHL protein complex is responsible for destroying Hif1 alpha. A mutation in vHL will lead to increased Hif1 alpha and hence, over signaling of EPO

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G-CSF and GM-CSF (site of synthesis and function (3))

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Are produced in the Bone marrow. They mobilized BM and peripheral blood pluripotent stem cells and HSCs. They increase granulocyte and moncyte counts in vivo. They improve mature neutrophil and macrophage function in vivo (GM-CSF)

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Pharmacological application of G-CSF and GM-CSF

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Congenital neutropenia, HIV, BM and stem cell transplantation, Stem cell harvest, Recovery post transplant, Cancer chemotherapy.

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Thrombopoietin (site of synthesis and function(2))

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synthesized in the liver and binds to the c-mpl receptor to: stimulate and support survival of HSCs, regulate negakaryocyte proliferation, differentiation and platelet production.

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Lecture 3

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RBC: Structure and function

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Functions of the RBC (3)

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To allow for exchange of O2 and CO2. Metabolize glucose to generate ATP. Become senescent whe metabolic activity slows

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Advantage fo RBC denucleation (2)

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Obviates the cardiac work of moving 1000 tons of inert nuclei (at the expense of losing 5% of hemoglobin). Transforms cell from rigid spere to supple biconcave disk

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Why a biconcave disk (2)

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Allows RBC to traverse capillaries that are 0.25 the diameter of erythrocte. Deformable RBC exchanges gas better than cynlindrical shape.

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Cell membrane structure of RBC (3)

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Lipid Bilayer, Transmembrane proteins, cytoskeleton

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Band 3

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A transmembrane protein that serves as the anion channel fo the cell membrane

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glycophorins

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These are transmembrane proteins that accoung for the red cell charge (negatively charged sialic acid) and blood group antigen. The negatively charged sialic acid prevents agglutination

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Key component of cytoskeleton of RBC (3)

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Ankyrin, spectrin and protein 4.1

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Function of cytoskeletion of RBC

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Deternines cell size and shape.

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spectirn binding

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Binds to actin. This binding is stabilized by protein 4.1. Ankyrin anchors the latice network (spectrin-actin complex) to the lipid bilayer. Characterisitics of this lattice network give shape to RBC and confers deformability

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Rouleux formation in RBCs

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These are stacks of RBCs that’s stick to each other (fibrinogen coats the sialic acid residues). This stack of RBCs have an increased mass with allows for them to move centrally in the blood vessel. Once in capillaries, Rouleux disintegrates and RBCs deform.

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Hereditary Sphereocytosis

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RBCs are spherical and not biconcave. Caused by deficiency in structural proteins (deficiency of ankryn or spectrin, protein 4.1 deficency, point mutation of Band 3)

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Blood smear of hereditary spherocytosis

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No central pallor, suggesting spherical RBCs. Some RBCs will show central pallor.

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Consequence of Spherocytosis

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These RBCs are not deformable and so they hemolyze in the spleen (hemolytic anemia)

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Hereditary Elliptocytosis

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RBCs are elliptical. Caused by spectrin dimer and tetramer abnormalities.

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Consequences of Elliptocytosis

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Generally, this is less of a problem than Sphereocytosis. Most patients are asymptomatic

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Life span of Red cells

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agerage lifespan is 120 days

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Destruction of RBC (sites(2))

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Spleen is the major site. Liver is an auxilliary site

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How are RBCs destroyed

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At 100 days, there is a slowdown of glycolysis and a decline in ATP and loss of membrane lipids. There is a stiffening of Hb-spectirn crosslinks. Naturally occuring IgG antibodies to neoantigens in response to aggregation of band 3 molecules. Removal from blood by splenic macrophages.

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Lecture 4

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Nutritional anemias

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Causes of Hypoproliferative anemia (failure of RBC production) (3)

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Insufficient stimulus to proliferate (Epo problems). Inablitiy to proliferate (B12, folate availability, cytokine therapy). Inability to synthesize adequate amounts of hemoglobin.

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Sources of Iron, B12 and folic acid (3)

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Liver, Red meat , fresh vegetables

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Who needs the most iron in their diet?

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Pre-menopausal women (about 18 micrograms)

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Who needs the most vitamin B 12

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Pregnant women and Breastfeeding women

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Who needs the most Folic acid

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Pregnant women and Breastfeeding women

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Four causes of microcytic hypochrmic anemias

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Fe Deficiency Anemia and Anemia of Chronic inflammation (Due to deficiency of iron). Sideroblastic Anemia (due to deficiency of protoporphyin). Thalasemia (due to mutation in globin

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Sources of Fe for plasma pool of Fe-transferrin (2)

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RBC destruction by the RE system. Iron absorption fro diet (1- 2 mg daily)

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Iron losses from plasma pool (4)

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RBC production in the bone marrow. Excreted iron (1-2 mg daily). Iron stored as Ferritin and Hemosiderin. Myoglobin and Respiratory Enzymes.

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Tranferrin

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An iron transfer protein that binds to receptors on cell membranes. Contains two atoms of Fe.

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Ferritin

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Water soluble protein-iron complex composed of an outer protein shell and iron-phosphage -dydroxide core. Can bind 4000-5000 atoms of iron

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Hemosiderin

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Insoluble protein-iron comlex; partially digested aggregates of ferritin

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Hepcidin

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Polypeptide synthesized in the liver. Acute phase reactant amd major regulator of iron homeiostatis, inhibiting iron release from cells

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Characteristic history and Physical for Pt with Iron deficiency anemia

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Blood Loss, Pica, Pallor, Koilonychia (indentation of fingernails

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Sources of chronic blood loss

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Mensturation. Pregnancy. GI bleed. GU bleed. Loss of urione hemsidering in intravascular hemolysis. Pulmonary hemosiderosis.

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Diagnostic tests for Fe deficiency (4)

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Bone Marrow Aspirate with Iron stain (the gold standard because a bone marrow biopsy will understimate the amount of iron present). Serum Ferritin (<10 - 20). Serum Fe/TIBC and % Saturation. Serum transferrin Receptor/

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Serum Fe, TIBC (transferrin * 1.25) and Serum Ferritin in Iron deficiency

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decreased Fe, increased TIBC, decreased Ferritin

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Serum Fe, TIBC (transferrin * 1.25) and Serum Ferritin in ACI

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Decreased Fe, decreased TIBC, increased Ferritin

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Serum Fe, TIBC (tarnsferrin * 1.25) and Derum Ferritin in Sideroblastic Anemia

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Increased Fe. Normal TIBC, normal to increased Serum ferritin

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Treatment of iron deficiency anemia

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Identify and stop abnormal blood loss, and replace iron

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Iron replacement therapies (4)

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Ferrous sulfate, ferrous Gluconate. Ferrous Fumarate, Iron-Polysaccharide

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Things to note in anemia correction

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Anemia should be half corrected in one month and fully corrected in two months with TID iron replacement

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characteristics of Anemia of chronic inflammation (2)

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normocytic or slightly microcytic anemia. May or may not have an identifiable chronic disease associated with it. Elevated ESR and C-reactive protein.

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Mechanism of causation of ACI (3)

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cytokine suppresion of erthropoiesis. Poor iron mobilization, presumanly due to increased hepcidin. Blunted erythrpoietin response.

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Causes of Megaloblasatic Anemias (macrocytic anemia) (2)

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Deficiency of Vitamin B 12 and Deficiency of Folic Acid.

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Mechanism of causing megaloblastic anemia

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Folate and B 12 are necessary for DNA replication which is essential for cell division during maturation and differentiation.

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Peripheral smear of megaloblastic anemia (3)

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Macroovalocytes, hypersegmented PMNs, Schistocytes.

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Bone marrow in patient with megaloblastic anemia (3)

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Hypercellular, Megaloblasti RBC precursors, Giant Bands and metamyelocytes

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Evidence of Hemolysis in Megaloblastic anemia (3)

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Increased LDH, Increased indirect bilirubin, Decreased haptoglobin

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Physical exam (2)

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Neurological abnormalities in B 12 are due to defects in myelin sheath production leading to: peripheral sensory nerve problems, Posterior and lateral columns

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Diagnostic tests for B12 and Folate deficiency (2)

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check serum levels. If normal, check Homocysteine and methyl malonic acid to detect tissue deficiencies.

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B 12 deficiency ( HC and MMA)

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HC is elevated, MMA is elevated

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Folate deficiency (HC vs MMA)

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HC is elevated, MMA is normal

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Cobalmin (B 12) dependent reactions

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Homocysteine --> methionine, and Methyl malonyl CoA --> Succinyl CoA

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Sources of B 12 deficiency (as many as possible)

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vegan, malabsorption, pernicious anemia, gastrectomy, pancreatic insufficiency, terminal ileum resection, terminal ileitis, fish tapeworm, bacterial overgrowth

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Soureces of Folic Acid deficiency (as many as possible)

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Decreased absorption (dietary, intestinal malabsorption, anticonvulsants), altered metabolism (ETOH and drugs), Increased utilization (pregnancy, hemolyitic anemia, malignancy)

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Treatment of megaloblastic anemia

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If folate deficient: folic acid (1-5 mg/ day). If B12 deficient: replace B 12 (different regiments)