SI2101 Haematology Lecture 2: Haematopoiesis & Haemoglobin PDF

SI2101 Haematology Lecture 2: Haematopoiesis & Haemoglobin Dr. Louise Horrigan Physiology [email protected] University ofGalway.ie Learning To learn: The pathways...

SI2101 Haematology Lecture 2: Haematopoiesis & Haemoglobin Dr. Louise Horrigan Physiology [email protected] University ofGalway.ie Learning To learn: The pathways of haematopoiesis Objectives of Some disorders of haematopoiesis Today’s Lecture Erythropoiesis Haemoglobin re Cooperative Binding Anaemia (different types) Haemoglobin breakdown at end of life A Anaemia Haematopoiesis The Formation of New Blood Cells Erythropoiesis, leukopoiesis, thrombopoiesis In the foetus, haematopoiesis occurs in the liver, spleen, blood After birth, occurs mainly in red bone marrow Requires interaction with stromal cells of the bone marrow Development and differentiation is dependent on stimulation by specific growth factors and cytokines University ofGalway.ie Haematopoiesis occurs mainly in the bone marrow This image is licensed under the Creative Commons Attribution 3.0 Unported license. Obtained from Wikimedia Commons Author: Pbroks13 Haematopoietic stem cells are self-renewing multipotent stem cells Reside in bone marrow Respond to haematopoietic growth factors Erythropoietin, colony stimulating factors (eg. M-CSF or monocyte colony stimulating factor) and interleukins Capable of self-renewal as well as differentiation to “committed” progenitor cells Committed progenitors cells belong to either the myeloid lineage or the lymphoid lineage Lymphoid lineage gives rise to lymphocytes Myeloid lineage gives rise to all other leukocytes, erythrocytes and platelets University ofGalway.ie Erythropoiesis Erythrocytes have a lifespan of 120 days 2.5 million erythrocytes replaced every second! Erythropoiesis requires iron, vitamin B12, folic acid Stimulated by erythropoietin (EPO) Secreted mainly by the kidneys in response to need Circulates in plasma with a half-life of 7-8 hours Acts by binding to receptors on pronormoblasts in bone marrow University ofGalway.ie  Receptors for EPO Nucleus degenerates Image from Medical Physiology by Rhoades & Bell  Myeloid stem cell differentiates into a pronormoblast Early normoblasts produce huge numbers of ribosomes Haemoglobin synthesis and iron accumulation occur as the early normoblast differentiates further When the haemoglobin has accumulated, the cell ejects its organelles Nucleus degenerates and is pinched off Cell collapses inward to assume a biconcave shape Reticulocyte Process takes 15 days Reticulocyte enters bloodstream Within 2 days, ribosomes degraded by enzymes Mature erythrocyte University ofGalway.ie  The main stimulus for erythropoiesis is hypoxia HIF = Hypoxia- inducible factor Image from: Bunn, H. F. (2013). "Erythropoietin." Cold Spring Harbor perspectives in medicine 3(3): a011619.  Recombinant EPO (rhEPO) for medicinal uses? EPO abuse in sport? This image was obtained from Wikimedia Commons and is licensed under the Creative Commons Attribution-Share Alike 4.0 International license. Haemoglobin University ofGalway.ie Each haemoglobin molecule consists of 4 polypeptide chains, each bound to a ring-like haem group. An atom of iron (Fe ) sits at the 2+ centre of each haem. This image is licensed under the Creative Commons Attribution 3.0 Unported license. Source: Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013. Author: OpenStax College Haem attaches to the central Iron has 6 binding sites in iron atom in four positions. total: oxygen binds to the Image from Wikimedia Commons, licensed sixth site. under the Creative Commons Attribution- Share Alike 4.0 International license. Transport of O2 Each molecule of Hb can bind 4 molecules of O2 Oxyhaemoglobin vs deoxyhaemoglobin 1g of Hb can carry 1.34ml O2 O2 saturation is the amount of O2 bound to Hb relative to the amount that can bind At 100% saturation, the haem groups are fully occupied with O2 Normal arterial O2 saturation is 95 – 100% University ofGalway.ie Uptake & Release of O2 from Hb One molecule Oxyhaemoglobin of 02 binds Deoxyhaemoglobin Increasing affinity of Hb for 02 Uptake & release of O2 from Hb Co-operative binding Binding of one molecule of O2 causes a conformational change in the second polypeptide chain, increasing the affinity for the second O2 molecule Binding of the second 02 increases affinity for the third etc. The fourth O2 has 300 times greater affinity than the first Similarly, for oxyhaemoglobin, the first 02 is the most difficult to shed, the fourth is the easiest The cooperative binding of oxygen by haemoglobin enables it to deliver University far more oxygen than it would if the sites were independent. ofGalway.ie Normal haemoglobin levels The World Health Organization defines anaemia as blood haemoglobin values of less than 7.7 mmol/l (13 g/dl) in men and 7.4 mmol/l (12 g/dl) in women University ofGalway.ie Types of Hgb Haemoglobin A (HbA) constitutes 95 – 98% of Hb in the adult Two alpha and two beta polypeptide chains (a2b2) Haemoglobin A2 (HbA2) constitutes 1.5 – 3% of Hb in the adult Two alpha and two delta chains (a2d2) Foetal haemoglobin (a2g2) present at 0.5% in adult life At birth – 80% HbF, 20% HbA Greater affinity for O2 than HbA, facilitating movement of O2 from maternal to foetal circulation g chains have higher affinity for O2 than b chains Embryonic haemoglobins produced by embryonic yolk sac z2e2 (Gower 1) or a2e2 (Gower 2) University ofGalway.ie  Normal developmental profile of haemoglobins Data from Huehns and Shooter (1965) and from Kleihauer (1970) as rendered by Bunn and Forget (1986). The names of the normal embryonic haemoglobins are Gower-1 (ζ2ɛ2), Gower-2 (α2ɛ2), and Portland-1 (ζ2γ2). Hb Portland-2 (ζ2β2) is not usually found. Image taken from Manning et. al. (Protein Sci. 2007) where it was reprinted from Bunn and Forget 1986 by Manning et al. with permission from Elsevier ©1986.) Anaemia Anaemia is a condition in which either the number of erythrocytes or the haemoglobin within them is lower than normal Iron-deficiency anaemia Pernicious anaemia Haemorrhagic anaemias Due to either sudden or persistent blood loss Haemolytic anaemias Erythrocytes rupture prematurely Haemoglobin abnormalities, transfusion mismatch, infections Aplastic anaemia Destruction or inhibition of bone marrow University Chemicals, ionising radiation, viruses ofGalway.ie Sickle Cell anaemia (Haemoglobin S) Iron Essential for haemoglobin synthesis and function Absorbed from diet in small intestine Of the required 15mg/day, only 1mg is absorbed to replace lost iron Remainder recycled from dead red blood cells 65% of body’s iron is in haemoglobin Remainder in liver, spleen, bone marrow Stored as ferritin (complex of protein and Fe2+) Free iron is transported in blood as Fe 3+ bound to transferrin University ofGalway.ie Iron-deficiency anaemia The most common type of anaemia Findings: Low ferritin level is the most sensitive index of early iron deficiency as iron stores are depleted before serum iron falls Possible low red blood cell count Low haemoglobin Low haematocrit Erythrocytes may be microcytic Low Mean Corpuscular Volume (MCV) Image obtained from Erythrocytes may be hypochromic University of Minnesota Low Mean Corpuscular Haemoglobin (MCH) and Mean Hematography® Corpuscular Haemoglobin Concentration (MCHC) http://www1.umn.edu/hema/ pages/casestudiesreal.html May see target cells and pencil cells Deficiency of Folic Acid & Vitamin B12 Both required for DNA synthesis Deficiency impairs DNA synthesis which is needed for nuclear division Causes normoblast apoptosis Deficient normoblasts that survive to the late stages produce fewer but larger reticulocytes – macrocytic erythrocytes (megaloblastic anaemia) Asynchronous maturation between cytoplasm and nucleus Vitamin B12 from food binds to intrinsic factor in the stomach which allows it to be absorbed in the ileum Up to 15% of older adults in developed countries are deficient due to age-related problems with absorption Other causes of deficiency Strict vegan diet University ofGalway.ie Pernicious anaemia: autoimmune disease where intrinsic factor is not produced Abnormalities of haemoglobin production: haemoglobinopathies Approximately 5% of the world’s population has a globin variant Inherited disorders Types: 1. Chains produced in decreased amounts or absent a or b thalassemia 2. Abnormal polypeptide chains produced Haemoglobin C, E, I, J, S etc. University ofGalway.ie Haemoglobin S Normal a chains but abnormal b chains Single amino acid substitution (valine for glutamic acid) At low O2 concentrations, Hb changes into a gelatinous material that distorts the biconcave shape Cells cause obstruction Membranes are fragile ‘Sickling’ can cause Intense pain Serious anaemia Sickle cell trait can confer resistance against malaria Image from Professor Bain’s teaching images, Imperial College London Haemoglobin breakdown at end of RBC lifespan Old or damaged erythrocytes are consumed by macrophages in the spleen Haemoglobin broken down to haeme and globin Globin is re-used or broken down to amino acids Iron is re-used for new haemoglobin formation Haeme is converted first to biliverdin and then to bilirubin, a yellow pigment, and carried by albumin to the liver, where it is metabolised and secreted in bile A buildup of bilirubin causes jaundice – yellowing of the skin and sclera of they eyes Jaundice is a complication of haemolysis (due for example, an incorrect blood transfusion) University ofGalway.ie  Jaundice Image attribution: James Heilman MD via Wikipedia https://creativecommons.org/li censes/by/3.0 Image from BioNinja https://ib.bioninja.com.au/options/option-d-human- University ofGalway.ie physiology/d3-functions-of-the-liver/erythrocyte-recycling.html Summary of main points: All blood cells derived from haematopoietic stem cells in bone marrow Myeloid and lymphoid lineages Erythropoiesis, leukopoiesis, thrombopoiesis Rate of cell production equals rate of destruction Erythropoiesis is stimulated by EPO, which is released in response to hypoxia Haemoglobin is the oxygen-carrying pigment of erthyrocytes Cooperative binding is essential for the loading and unloading of oxygen Anaemia occurs either when there is a low number of RBCs or when the amount of Hb within the cells is lower than normal Haemoglobin is recycled following RBC death University ofGalway.ie