Cells of the blood

• 91.5% of blood is plasma, with the rest being solutes.

  7% of plasma are proteins, including albumin, globulins and fibrinogen.

  1.5% are electrolytes, nutrients, gases and waste products
• Haematopoeisis describes the production of cells that circulate in the bloodstream. Specifically, erythropoiesis is the process by which red blood cells (erythrocytes) are produced
• The production of all blood cells begins with the haemocytoblast, a multipotent haematopoietic stem cell. Haemocytoblasts have the greatest powers of self-renewal of any adult cell. They are found in the bone marrow and can be mobilised into the circulating blood when needed.

  Some haemocytoblasts differentiate into common myeloid progenitor cells, which go on to produce erythrocytes, as well as mast cells, megakaryocytes and myeloblasts.
• 2.5 billion red cells/kg/day produced
• Rate of production tightly regulated to ensure adequate but not excessive numbers of red blood cells.
• The site of erythropoiesis changes throughout life. In the very early foetus, it occurs in the yolk sac. From 2 – 5 months gestation, it occurs in the liver and spleen before finally establishing in the bone marrow from about 5 months gestation.

  In children, erythropoiesis can occur in the bone marrow of most bones. However, in adults, it only occurs in the bone marrow of the vertebrae, ribs, sternum, sacrum, pelvis and proximal femur.

  When erythropoiesis is inadequate in the bone marrow, this can trigger extramedullary haematopoiesis – i.e. haematopoiesis occurring outside the marrow.
• he process by which common myeloid progenitor cells become fully mature red blood cells involves several stages. First, they become normoblasts (aka erythroblasts), which are normally present in the bone marrow only.

  Then, they lose their nucleus as they mature into reticulocytes, which can be thought of as immature red blood cells. Some of these are released into the peripheral circulation.

  Finally, reticulocytes lose their remaining organelles as they mature into erythrocytes-which are fully mature red blood cells. the average lifespan of a red blood cell is approximately 120 days.
• Erythropoiesis is driven by erythropoietin, a glycoprotein cytokine.

  EPO is secreted by the kidneys. It is constantly secreted at a low level, sufficient for the normal regulation of erythropoiesis. If erythrocyte level drops, the blood becomes relatively hypoxic. Reduced partial pressure of oxygen (pO2) in the kidney is detected by the renal interstitial peritubular cells. In response, there is a surge in EPO production, which acts on the bone marrow to stimulate increased red blood cell production. This causes haemoglobin levels to increase causing the pO2 to rise and EPO levels to fall.
• Thrombocytes: platelets that help with clotting, aggregate on exposure to von Willebrand factor
• Erythrocyte: carry oxygen
• Mast cell: key in allergic reactions and releasing histamine
• Basophil: Intensify inflammatory reaction in allergies
• Neutrophil: destroy bacteria (most abundant)
• Eosinophil: some allergic reactions and parasitic worm. Key in asthma
• Macrophage: phagocytose pathogens, called monocytes in the blood
• NK cells: innate immune cell, help in viral infections
• T-cell: turns into CD4 or CD8 depending on pathogen
• B-cell: forms plasma cells therefore antibodies
• Myeloid Lineage: innate immune cells

  Lymphoid Lineage: adaptive immune cells + NK cells (innate)
• Proerythroblast develops from myeloid progenitor cell in the bone marrowAs it develops it will eventually eject it’s nucleus and enter the blood as a Reticulocyte. After 1-2 days of development the reticulocyte will develop into a mature Erythrocyte or RBC.
• Erythrocytes (red blood cells): contain haemoglobin, biconcave discs, anucleate, lifespan 120 days. Removed from the circulation by phagocytic macrophage in the spleen and liver.
• HbA1c is used to monitor diabetes every 120 days once diagnosed
• Red blood cells are destroyed in the spleen
• Sickle cell disease - a genetic disorder that causes red blood cells to become misshapen and unable to carry oxygen
• Thalassaemia - a group of inherited blood disorders caused by a defect in the production of haemoglobin
• Chronic kidney disease often causes anaemia. In the damaged kidney, there is a reduced basal level EPO production and a reduced response to hypoxia leading to anaemia. To counteract this, patients can be given EPO injections as required
• Exogenous EPO can be used as a performance-enhancing drug among athletes. By stimulating increased red blood cell production, it increases the amount of haemoglobin available for oxygen binding, thus improving the oxygen supply to muscles. However, studies have disagreed over whether this translates to enhanced athletic performance.
• The underproduction of red blood cells results in anaemia. Anaemia is defined as a low haemoglobin concentration, but the absolute values differ between women and men. In broad terms, anaemia can be caused by decreased red cell production, or increased red cell removal.

  Reduced red cell production may be due to 3 main things:

  • Lack of ‘building blocks’ for production, e.g. iron, folate or B12 deficiency.
  • Failure of the stimulus – i.e. EPO deficiency secondary to chronic kidney disease.
  • Bone marrow failure, such as aplastic anaemia
• Overproduction of red blood cells can occur in conditions such as polycythaemia rubra vera. This is a myeloproliferative disease which results from dysregulation at the level of the haematopoietic stem cell.

  Even though EPO production is switched off, excess red blood cells are continually produced. Over 95% of patients with polycythaemia are positive for the JAK-2 mutation, and it usually affects patients over the age of 60. Patients are usually well with the disease for years but it can cause increased risk of thrombosis, and around 3% of cases transform into acute leukaemia.
• Bone marrow is the primary site of haematopoeisis after birth. Two types - red and yellow bone marrow. Red marrow is replaced by yellow marrow as we age due to fat infiltration. It may convert back to red marrow e.g. after severe bleeding
• Neutrophils account for 40-70% of all white blood cells. They are first to sight of infection, have single lobed nucleus and are phagocytes.
• Basophils have bilobed nucleus, are involved in allergy and also combat multicellular parasites.
• Eosinophils are involved in allergy, are binucleated and also combat multicellular parasites.
• Monocytes have large kidney-shaped nucleus and turn into macrophages.
• Macrophages play major role in antigen presentation and are major phagocytes.
• Lymphocytes are divided into B cells and T-cells. B-cells become plasma cells. T-cells are either helper (CD4+) or cytotoxic (CD8+). They are 6-9 micrometres (small)
• Haemoglobin normal range: 130-180 x 10^9/L. Low in anaemia
• White Blood Count normal range 3.8-10.6 x10^9/L. Raised in infection, inflammation, leukaemia. Low in chemotherapy.
• Neutrophils normal range 1.8-6.5 x 10^9/L. Raised in bacterial infection
• Lymphocytes normal range 1.1-3.5 x10^9/L. Raised in viral infection