Erythropoiesis is the process by which mature red blood cells red blood cells (erythrocytes) are made. This process is driven by the hormone EPO (erythropoetin) made by the kidneys (renal cortex – peritubular interstitial cells to be exact...) and liver (in children).
EPO production is driven by hypoxia. A chronic smoker, for example, will have increased EPO due to chronic state of hypoxia.
It stimulates erythrocyte precursors (pronormoblast) in the marrow to form mature erythrocytes (see above) by preventing their apoptosis (programmed cell death) via transcription factors like HIF-1 and GATA-1.
EPO has several indications.
- Treating anaemia in chronic kidney disease (CKD). In CKD, the diseased kidneys make less EPO; thus, by replacing EPO you can correct the anaemia.
- Doping involves EPO injection in athletes, resulting in more mature RBCs being made, therefore, a greater oxygen carrying capacity for endurance sports. It has made recent headlines in the cyclist Lance Armstrong's case.
Cell lineage (see above picture)
Here is the cell lineage for RBC: Haematopoetic stem cell → Myeloid stem cell → Pronormoblast → Normoblast → Reticulocyte → Erythrocyte
As a cell progresses from being a haematopoetic stem cell into an erythrocyte, the derived cells divide and become smaller.
One feature that distinguishes certain cells from others is the presence of nucleus and RNA. As a cell in the RBC lineage matures, it loses more and more of its nucleus and RNA until it eventually loses both and what you get is an erythrocyte. For example, nucleus is extruded from a normoblast to become a reticulocyte “retic”.
A reticulocyte is an immature RBC as it still has RNA so it spends about a day in the blood and loses its RNA to become a mature erythrocyte. See table below for a summary of the differences between them cells.
What makes erythrocyte special?
- It has a biconcave shape to allow maximal surface area for oxygen exchange
- It contains haemoglobin to carry the oxygen
- It lives for 120 days only
- The red cell membrane is held by structural proteins including ankyrin and spectrin
Normal haemoglobin concentration levels
- Male: 13.5 g/dl
- Non-pregnant female: 12.5 g/dl
- Pregnant female: 11.5 g/dl
Now, a bit about iron metabolism... (see picture below for guidance)
Iron is absorbed in the duodenum of the small intestine and is either stored as ferritin in the intestinal epithelium or is transported around the blood in receptors called transferrin to tissues that need iron the most e.g. bone marrow for erythropoesis. So iron is basically money and transferrin the wallet.
The more hungry the body is for iron (money), the more transferrin (wallet) is produced . In the case of iron deficiency, the body is hungry for iron so it makes more transferrin (wallet) in the hope that the receptors can find iron. But iron is deficient, therefore, the many transferrin receptors that are made remain unsaturated (i.e. many transferrin with no bound iron or many wallets with no money in it!)
Definition of Anaemia: Reduction in the haemoglobin concentration in the blood or red cell count. Basically, low EPO causes anaemia because less erythrocytes are made.
Anaemia is often seen in those with heart failure and kidney failure. One way of explaining this association is the CRAS syndrome (cardio-renal anaemia syndrome - see image below).
In anaemia, tissues are constantly hypoxic (low oxygen saturation). Therefore, vessels supplying this hypoxic tissue and systemic vessels vasodilate to get more blood to into them, resulting in a decrease in blood pressure. With the systemic drop in blood pressure, it causes renal failure due to hypoperfusion (→ decreased EPO production by the kidneys → anaemia).
To correct and increase the low blood pressure as a result of vasodilation, the RAAS (renin-angiotensin activating system) kicks in to increase water and sodium retention is activated.
The increased afterload as a result of RAAS activation causes heart failure, a condition where the heart is unable to pump enough blood to the body. If the kidneys do not receive much blood, then the renal cortex makes less EPO, therefore, the person becomes anaemic. If tissues do not receive much blood, it becomes hypoxic.
In summary, hypoxic tissues vasodilate, resulting in decreased blood pressure and the whole circle of CRAS repeats itself (low BP → RAAS activation which increases afterload → Heart failure → Tissue – Hypoxic and Kidneys – anaemic → Vasodilation → low BP → RAAS activation etc...)
Symptoms and Signs of Anaemia
- Shortness of breath
- Lethargy (fatigue)
- Palpitation (feeling of heart racing)
- Tachycardia (heart rate >100 beats per minute)
- Conjunctival pallor (pale white eyes)
- Jaundice (yellowing of the skin) in haemolytic anaemia
- Koilonychia (spoon-shaped nails) in iron deficiency anaemia
- Leg ulcers in sickle cell anaemia
You will commonly see doctors classifying anaemia descriptively and technically so here are some terms to keep in mind
- Hypo/micro: Small
- Normo: Normal
- Hyper/macro: Large
- -cytic: RBC size (used with micro/normo/macro- e.g. macrocytic)
- -chromic: RBC color, determined by the concentration of haemoglobin (used with hypo/normo/hyper- e.g. hypochromic)
- Anisocytosis: Varying RBC sizes
- Poikilocytosis: Varying RBC shapes (pencil-shape etc.)
- MCV (mean corpuscular volume): mean SIZE of RBC [Normal 80-100 fL] [-cytic anaemias (e.g. microcytic vs normocytic)]
- MCH (mean cell haemoglobin): mean haemoglobin WEIGHT of RBC [Normal 30±3pg]
- MCHC (mean cell haemoglobin concentration): mean haemoglobin CONCENTRATION of RBC [Normal 33±3g/dl] [-chromic anaemias (e.g. hypochromic vs normochromic)]
- RDW (red cell distribution width): deviation of RBC size [if increased, it indicates large varying sizes of RBC (i.e. anisocytosis)]
- Serum iron [Normal - 50-180 μg/dL]
- Serum ferritin: Ferritin is the storage form of iron, found in reticuloendothelial stores
- Serum transferrin: Receptors to carry iron. (Imagine iron being money and transferrin being the wallet)
- TIBC (total iron binding capacity): Equates to the number of unsaturated transferrin (empty wallets). In the case of iron-deficiency, TIBC is high because there is low iron/money and many transferrin/wallet, thus, many empty wallets.
- Reticulocyte%: Percentage of reticulocyte in peripheral smear [Normal <2%]
Because this is a pathology article, I will not delve too much into the different types of anaemia but here is a quick glance at the most common ones, sorted according to mean corpuscular volume (RBC cell size)
Note that ACD can present as both micro- and normocytic anaemia.
Iron deficiency anaemia
- Cause: Blood loss e.g. GI bleed
- Hypochromic (less haemoglobin so less colour)
- Increased anisocytosis (as iron reserves fall, so does the size of RBC as they get progressively smaller, hence the variation in its size) and poikilocytosis
- Lab values
- Reduced MCV, Serum iron, ferritin, reticulocyte (you need raw materials like iron to make retics!)
- Increased Transferrin, TIBC (there is few iron/money, so even though there is increased transferrin/wallet, they remain unoccupied – many empty wallets!)
- Treatment: Give oral iron and treat the cause of blood loss
Anaemia of chronic disease
- Cause: Malignancy and chronic inflammation
- Lab values
- Increased Ferritin (increased in inflammation. Malignancy is associated with inflammation!)
- Reduced MCV (though rarely <75fL, or normal MCV), Serum iron, Transferrin (even though there is low serum iron, the body falsely sees the high ferritin as high iron storage, so it doesn't make much transferrin), TIBC (few iron with even fewer transferrin, so most of the very few wallets there are have money i.e. they are saturated... TIBC looks at unsaturation so TIBC is LOW!)
- Treatment: Treat the underlying cause
Folate/B12 deficiency (Megaloblastic anaemia)
- Cause: Folate/B12 deficiency
- Drugs: Metformin (used to treat diabetics), Methotrexate (used to treat patients with rheumatoid arthritis)
- Abstinence from meat products (rich source of Vitamin B12)
- B12 deficiency
- Gastric malabsorption: Gastrectomy, pernicious anaemia (antibodies attack parietal cells, intrinsic factor, or receptors for IF on ileum)
- Intestinal malabsorption: Inflammatory bowel disease, ileal resection
- Folate deficiency
- Increased requirement: Pregnancy
- Intestinal malabsorption
- Inflammatory bowel disease
- Jejunal resection
- Lab Values
- Reduced Serum Folate/B12,
- Increased MCV, presence of hypersegmented neutrophils (>5 lobes)
- Treatment: Treat the cause
- α thalassemia: Decreased amount of α chain
- β thalassemia: Decreased amount of β chain
- Lab Values
- Reduced MCV and MCH
- Increased Abnormal haemoglobin electrophoresis
- Treatment: Only treat if severe anaemia
- Membrane: Hereditary spherocytosis (defect in the structural protein e.g. spectrin, ankyrin which holds the RBC membrane in place)
- Metabolism: G6PD deficiency (deficient in the enzyme G6PD [Glucose-6-phosphate dehydrogenase] results in less NADP being made and NADP is needed to protect the RBC from oxidative attack. Therefore, the RBC haemoglobin undergoes more oxidative attack.)
- Autoimmune haemolytic anaemia (AIHA): Auto-antibodies (IgG for warm AIHA, IgM for cold AIHA ) against RBC. Macrophages ingest the antibody-coated RBCs. It may occur alone or may be associated with autoimmune conditions (eg. SLE systemic lupus erythematosus). infections (e.g. infectious mononucleosis) and drug-induced (e.g. methyldopa used in treating high blood pressure)
- Lab Values
- Hereditary spherocytosis: Osmotic fragility
- G6PD deficiency: Enzyme assay, 'bite cells' on blood film which have had Heinz bodies (oxidized and denatured haemoglobin, removed by the spleen)
- AIHA: Direct antiglobulin test (DAT - see image below) / Coombs test positive result
- Hereditary spherocytosis: Splenectomy
- G6PD deficiency: Avoid the food/drug causing the oxidative attack (e.g. fava beans)
- AIHA: Steroids to reduce the inflammation and treat the underlying cause e.g. drug-induced
Images courtesy of Wikipedia, Cornell University, BMJ and Robbins' Basic Pathology
- Hoffbrand A.V. et al (2006).Essential Haematology. 5th Edition .London: Blackwell Publishing. p1-12
- Meer V.D. and Veldhuisen D.J. (2009).Heart failure: Anaemia and renal dysfunction in chronic heart failure . Heart. 95(21), p1808-1812.
- Uthman E (2012). Pathophysiologic Consequences, Classification, and Clinical Investigation. Available:http://web2.airmail.net/uthman/anemia/anemia.html. Last Accessed Date:2012.
- Harper J L et al (2012). Iron Deficiency Anemia. Available:http://emedicine.medscape.com/article/202333-overview. Last Accessed Date:2012.
- Ebert BL, Bunn HF (1999) Regulation of the erythropoietin gene. Blood 94: 1864-1877