Hematology Lecture (1) PDF

Hematology Lecture (1) Haemopoiesis, Erythropoiesis and the structure and function of the Erythrocytes  Blood ▪ It is a liquid connective tissue. ▪ It is composed of two parts: 1. Formed elements (blood cells). 2. Plasma. ...

Hematology Lecture (1) Haemopoiesis, Erythropoiesis and the structure and function of the Erythrocytes  Blood ▪ It is a liquid connective tissue. ▪ It is composed of two parts: 1. Formed elements (blood cells). 2. Plasma.  1. Formed elements (blood cells) ▪ These include 3 main types of cells: 1. Red blood cells (Erythrocytes). 2. White blood cells (Leukocytes). 3. Platelets (Thrombocytes).  2. Plasma ▪ Plasma is the liquid in which the formed elements are suspended. ▪ It is an aqueous solution composed of: 1. 90% of water. 2. 10% of solids (solutes). The plasma proteins account for 70% of the total solids (about 7% of the total plasma volume), the remainder consist of amino acids, lipoproteins, hormones …etc. The most abundant plasma protein is the albumin which maintains the osmotic pressure of the blood.  The hematocrit (PCV) ▪ It is an estimate of the volume of packed erythrocytes per unit volume of blood.  Plasma versus serum ▪ If blood is collected into a tube that contains NO anticoagulant it will clot. The blood sample will separate into a clot that contains the formed elements and a clear yellow liquid called serum (so basically, the serum is a plasma without clotting factors).  Plasma versus serum ▪ If blood is collected into a tube that contains an anticoagulant material it will not clot. ▪ If such blood is centrifuged it will separate into about 3 layers: 1. A lower layer, red in color which constitute about 40-45% composed of erythrocytes. 2. A middle thin layer not exceeding 1% and is white in color known as the buffy coat consisting of WBC and platelets. 3. An upper layer that is translucent and yellowish in color, formed by supernatant plasma.  Haemopoiesis ▪ It is the process of formation of new blood cells from the haemopoietic stem cells. ▪ Sites of haemopoiesis:- 1. In first trimester (i.e., early embryonic life), from the yolk sac. 2. In second trimester (i.e., mid pregnancy), mainly from the liver with the contribution of the spleen and lymph nodes. 3. In third trimester (from the last 3 months of pregnancy) and later on through life, from the bone marrow.  Sites of haemopoiesis 1st 2nd 3rd trimester trimester trimester  Stem cells ▪ These are the cells from which all haemopoietic cells originate. ▪ They are characterized by: 1. The ability of self-renewal (proliferation). 2. Differentiation. ▪ In order to proliferate and differentiate, stem cells require: 1. Regulatory factors (Hemopoietic Growth Factors). 2. Suitable microenvironment, provided by the marrow space.  Stem cells ▪ The earliest stem cell is known as pluripotent stem cell, that has the capacity to produce all types of cells. ▪ Under the influence of appropriate growth factors, those pluripotent stem cells will produce: 1. Myeloid multipotent stem cells. Myeloid stem cells Lymphoid stem cells 2. Lymphoid multipotent stem cells. ▪ Therefore, there is early separation between the myeloid and lymphoid lines.  Stem cells ▪ Under the influence of growth factors, both myeloid and lymphoid multipotent cells will differentiate into different lines to produce finally the mature end cells.  Stem cells ▪ During differentiation, the cells become more and more restricted (committed) so that at the end the precursor cells will produce only one type of mature cells. ▪ So the precursors don’t have self-renewal capacity and they are restricted to one line in differentiation. Capable of self-renewal Lost their self-renewal capability  Bone marrow ▪ Bone marrow is found in the medullary canals of long bones and in the cavities of cancellous bones. ▪ From the last three month of intrauterine life the BM becomes the main site for haemopoiesis. ▪ Under normal conditions, the production of blood cells by the bone marrow is adjusted to the body's needs, increasing its activity several-fold in a very short time.  Bone marrow with age ▪ In new-borns, all bone marrow (100%) is red and is therefore active in the production of blood cells. ▪ With age, the red bone marrow changes gradually into the yellow type so that in an old person (> 70 years old), the red marrow is only 20-25% of the whole marrow. ▪ Under certain conditions, such as severe bleeding or hypoxia, yellow bone marrow is replaced by red bone marrow.  Composition of red bone marrow 1. Stroma: meshwork of reticular cells and reticular fibers contains collagen types I and III, fibronectin, laminin, and proteoglycans. 2. Hematopoietic cords: containing hematopoietic cells and macrophages. 3. Sinusoidal capillaries: are formed by a discontinuous layer of endothelial cells, an external discontinuous layer of reticular cells and a loose net of reticular fibers reinforce the sinusoidal capillaries.  Erythrocytes ▪ They are biconcave disks without nuclei. ▪ Their shape provides a large surface-to-volume ratio, thus facilitating gas exchange. ▪ The normal RBC number: o 3.9–5.5 million/ul (females) o 4.1–6 million /ul (males). ▪ They are quite flexible and the fact that it has no nucleus permit them to adopt its shape to pass into the smallest pores of the capillaries.  The RBC membrane ▪ Composition: 1. 50% protein. 2. 40% lipid (e.g., phospholipids, cholesterol, and glycolipids). 3. 10% carbohydrate. ▪ The membrane proteins arranged into: A. Integral proteins that span the whole width of the membrane. B. Peripheral proteins associated with the inner surface of the membrane serve as a membrane skeleton that determines the shape of the erythrocyte  The contents of the RBCs ▪ The cytoplasm of the RBC contains the following: a) A solution of hemoglobin, the O2-carrying protein that accounts for their acidophilia (pink color upon staining). Hemoglobin is the major protein present in the RBC and account for more than 95% of the cell dry weight. b) The enzymes of the glycolytic and hexose-monophosphate-shunt pathways of glucose metabolism. ▪ Keep in mind that RBC has no nucleus they cannot synthesize any more proteins or enzymes, they depend on the already present constituents during their maturation stages in the bone marrow.  RBC production (Erythropoiesis) ▪ RBC are produced from the pluripotent stem cells that will give rise to myeloid multipotent stem cell that in turn will pass into a series of stages to finally produce the mature RBC.  RBC production (Erythropoiesis) ▪ The pro-erythroblast is the earliest recognized precursor of the RBC (it can only produce RBC) they pass into many intermediate forms through the process of differentiation.  RBC production (Erythropoiesis) As the cell differentiates into many intermediate stages it will: 1. Accumulate more hemoglobin until it reaches maximum concentration of 34%. 2. The nucleus get smaller and smaller in size until it is finally extruded out of the cell. After extrusion of the nuclei the cells are known as “reticulocytes” they contain residual ribosomal RNA, they are released into the blood where they develop into mature erythrocyte within 1 to 2 days.  Reticulocytes number (retic count) ▪ Normally the percentage of reticulocytes in blood does not exceed 2.5%. ▪ The number of reticulocytes in the peripheral blood reflects the erythropoietic activity: A. Decreased reticulocytes number means decreased erythropoietic activity as in bone marrow failure. B. Increased reticulocytes number means increased erythropoietic activity as in acute and chronic hemorrhage, hemolytic anemia.  RBC function 1. Carry oxygen from lungs to the tissues. ▪ This function is carried out by the hemoglobin. ▪ Each gram of pure hemoglobin is capable of combining with 1.34 milliliters of oxygen. if hemoglobin was free in the cytoplasm it would be lost through the capillaries of the glomeruli therefore in order to stay inside the circulation it has to be contained inside the RBC.  RBC function 2. Transport of CO2 from the tissues to the lung ▪ CO2 is transported in the form of bicarbonate ion (HCO3-) from tissues to the lungs where it is reconverted to CO2 and expelled, this reaction catalyzed by carbonic anhydrase, an enzyme that catalyzes the reversible reaction between CO2 and water to form carbonic acid (H2CO3).  RBC function 3. Participation in acid-base balance ▪ The hemoglobin in the cells is an excellent acid-base buffer responsible for the buffering power of the blood.  Hemoglobin structure and function ▪ Normal hemoglobin concentration is about ✓ 13-17 g/dl in men. ✓ 12-15 g/dl in women. ▪ Hemoglobin production starts from the proerythroblast stage (the earliest recognized erythroid precursor in the bone marrow) and continue but in small amount in the reticulocyte stage and as the cell becomes mature the synthesis stops and the cell depends on the preformed hemoglobin in its function.  Hemoglobin structure and function ▪ A hemoglobin molecule consists of four heme groups each one is attached to a globin chain and each group consist of a protoporphyrin ring with an iron atom in the center. ▪ So there are 4 iron atoms capable of binding to 4 oxygen molecules (or 8 oxygen atoms) in each hemoglobin molecule. Globin chain  Types od hemoglobin ▪ Depending on the amino acid composition of the globin chain there are different forms of hemoglobin: 1. Embryonic hemoglobin that is present at embryonic stage. 2. Fetal hemoglobin (Hb F) present in fetal life up to 4-6 months of birth and present in adult life at very small amount. With 2α and 2γ chains 3. Adult hemoglobin (Hb A) present from 4-6 months of life with 2α and 2β chains and it is the major hemoglobin in our body. 4. Hemoglobin A2 this type is present normally at small amounts not exceeding 3.5%. With 2 α and 2 δ chains. The type of globin chain in the hemoglobin molecule determines the oxygen affinity of hemoglobin (for example Hb F has a higher affinity to oxygen than HbA).  Types od hemoglobin Type Globin chains Concentration in adult Embryonic Hb Absent Fatal Hb 2 α (alpha) 2 γ (gamma) Very little Adult hemoglobin (Hb A) 2 α (alpha) 2 β (beta) Very abundant Hemoglobin A2 2 α (alpha) 2 δ (delta) < 3.5%  Life span and destruction of RBC ▪ The life span of the RBC is about 120 days after which they are destroyed by the macrophages in the spleen , liver and bone marrow (reticuloendothelial system). ▪ As the cells have no nucleus, red cell metabolism gradually deteriorates as enzymes are degraded and not replaced and the cells become non-viable. ▪ When RBCs burst and release their content, the hemoglobin is phagocytized almost immediately by macrophages in many parts of the body, but especially by the liver, spleen and bone marrow.  Fate of Hb after RBC destruction ▪ The heme portion of Hb is degraded into: 1. The iron that is taken by plasma transferrin mainly to bone marrow to be reused for the synthesis of new RBC. (note: this is the major source of iron to the body because the body has a limited capacity to absorb iron). 2. The protoporphyrin ring is broken down to bilirubin. Bilirubin circulates to the liver where it is conjugated to glucuronides which are excreted into the duodenum via bile and converted to stercobilinogen and stercobilin (excreted in feces). Stercobilinogen and stercobilin are partly reabsorbed and excreted in urine as urobilinogen and urobilin. Note: in hemolytic anemia the indirect bilirubin is elevated and the patient suffers from jaundice due to excessive destruction of RBC.  Fate of Hb after RBC destruction ▪ The globin chains are broken down to amino acids which are reutilized for general protein synthesis in the body.