We will discuss a few things like the components of blood, erythrocytes (shape, metabolism), the ABO and rhesus systems of blood grouping, erythropoiesis and its control, anaemias...
The components of blood:
- Healthy adult male blood c8% body weight (c5litres)
55% volume - plasma
- Fluid medium (what is serum?) - 92% water, salts, etc. +8% plasma proteins
45% volume - cells
- Leukocytes (white cells) c5-10000mm^-3
- Platelets c300000mm^-3
- Erythrocytes (red cells) c5x10^6 mm^-3
Leukocytes
- Polymorphonuclear granulocytes 50-70+% (eosino(1-4%)-, baso (0.1%)- or neutrophils)
- Monocytes 2-8%
- Lymphocytes 20-40%
Blood cell functions
- Neutrophils - phagocytosis and release of mediators for inflammation
- Basophils - release histamine (mast cells)
- Eosinophils - destroy multicellular parasites. Immediate hypersensitivity
- Monocytes (macrophages) - phagocytosis, etc.
- Lymphocytes some secrete antibodies (B) some are involved in cell mediated immune responses (T) - complex immunological roles (cell mediated immunity)
- Platelets - involved in haemostasis
- Red cells - O2 transport
Plasma Proteins
- 7-8% of plasma weight - say 7.3g/100ml
- Albumins 4.2g/100ml
- Globulins 2.8g/100ml
- Fibrinogen 0.3g/100ml
Functions
- Store of protein - decrease in plasma albumin during severe starvation
- Transport of insoluble substances like vitamins, hormones, metals. e.g. retinol binding protein, transferring for iron, transcortin for cortisol
- Increase blood viscosity
- Act as buffers
- Gamma globulins - antibodies
- Fibrinogen - blood clotting
- Exert a colloid osmotic pressure of c25mm/Hg
Oedema
Excess tissue fluid -> swelling
Arteriole capillaries venule
high ----> low pressure
Outward pressure = hydrostatic pressure in capillary
Inward pressure = hydrostatic pressure interstitial fluid + osmotic pressure due to plasma proteins
Red cells - advantages of shape
Biconcave disks:
- Large surface area
- no point is far from surface
- distansible
Speeds gas exchange and allows to squeeze through small capillaries
There is no nucleus, mitochondria, ribosomes 85% dry weight is Hb. No aerobic metabolism, no protein synthesis and only live for 120 days.
Metabolic needs from glycolysis (needs only a little ATP, mainly for ion pumps). Produces 2,3 DPG unique to red cells. A mutase converts 1,3,DPG to 2,3 DPG (diphosphoglycerate/-ceric acid)
- Yellow tinge to tissues and skin due to excess bilirubin
- Normal plasma bilirubin 5mg/L but can rise to 40mg/L
Causes
- Increased red cell destruction.
- Haemolytic jaundice. Quite common and harmless in newborn babies
- Obstruction of the bile ducts e.g. by gallstones
Liver damage or disease prevents normal conjugation and excretion
Rhesus system
- 85% of population have antigen D on red cells: Rh+
- 15% no antigen D: Rh- Neither group normally has anti D. But Rh- person exposed to Rh+ blood develops anti D (e.g. as a result of transfusion or childbirth). Anti D persists to 2nd exposure - agglutination. Anti D can cross the placent and destroy RBCs of Rh+ baby. Prevention for this is to give 'Rh- mother' anti D antibodies.
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| Erythropoiesis |
Erythropoietin
- Erythropoiesis is the process of red cell production from stem cells in the bone marrow.
- Reduced tissue oxygenation, increases RBC production e.g. anaemia after haemorrhage, high altitude, prolonged exercise
Circulatory diseases
- Hypertransfusion reduced RBC production
- Renal failure and kidney removal leads to severe anaemia
- Some renal tumours increase RBC count. Some renal extracts increase RBC count.
Kidney produces a hormone that control erythropoiesis. Erythropoietin is a glycoprotein of 165 amino acids and several sugar molecules. Some EP from liver (15%).
Clinical use: in renal failure and blood doping of athletes
The anaemias
- Renal disease (erythropoietin)
- Blood loss (e.g. ulcer or gut tumour)
- Iron deficiency (microcytic)
- Lack of folic acid/B12 (macrocytic)
- Pernicious anaemia: loss of parietal cells (intrinsic factor) causes failure to absorb B12
- Thalassaemia: reduced production of α or β Hb chains.
- Sickle-cell: abnormal β chain.
- Aplastic anaemia: bone marrow failure
Iron deficiency
Adult male 4g iron in body 65% as Hb, 25% stored as ferritin. Hb molecule: 4 atoms of Fe. Lack of iron: microcytic (hypochromic) anaemia. 1% red cells replaced daily but most iron recycled (adult male loses 1mg/day) young women double+ ?! In the UK intake is 12-14mg/day
So why does anaemia occur?
Small variable proportion of dietary iron absorbed, depends upon:
- iron status
- physiological status (pregnancy)
- Form: Fe from haem best but less from vegetable sources.
- Promoters: vitamin C, alcohol (gastric acid), meat/fish
- Inhibitors: fibre, phytate, (unleavened bread), tannin (tea)
Vitamin B12
- Necessary for cell division (thymidine synthesis)
- Lack of B12 causes macrolytic (megaloblastic) anaemia; large unstable cells (also degeneration of the spinal cord)
- Daily requirement 1ug/day
- Healthy person can store it for 3 years therefore dietary deficiency is uncommon unless vegans, asian lactovegetarians
- Absorption need instinsic factor from parietal cells of the stomach
- Autoimmune disease attacks parietal cells -> no intrinsic factor-> pernicious anaemia, inject B12
(OMG I JUST NOTICED HOW OUTDATED THIS INFORMATION IS; AND THE LECTURER IS A NUTRITIONIST?!?!?!?!)
Folic acid
- Involved in cell division
- Deficiency more common: macrolytic anaemia
- sources: liver, green vegetables, wholemeal, some fruits.
- Anticonvulsants increase folic acid requirement
Thalsassaemia:
- Genetic disease, prevalent in those of Meditarranean origin (Cypriots in UK --- I AM A CYPRIOT IN UK o.O)
- Reduced synthesis of α or β haemoglobin chains
- Major (homozygous) or minor (heterozygous)
- Major α: non viable
- Major β: little functional Hb and severe haemolytic anaemia
- Repeated transfusions lead to iron overload
- Minor: few clinical symptoms under normal conditions
Sickle-cell anaemia
- Genetic disease that is common in Africa and India where malaria is common.
- Homozygous: sickle cell trait: mild; 10% of American Blacks and 30% in parts of Africa
- One amino acid change in β-chain
- Changes solubility of Hb. At low O2 tension tends to precipitate out and red cells become sickle-shaped. These sickle cells block small blood vessels -> cause multiple organ damage and severe anaemia.
- Homozygous: sickle cell disease; severe
- Heterozygous: sickle cell trait; mild but symptoms increased by hypoxia; e.g. altitude, anaesthesia
Aplastic anaemia
- Failure of erythropoiesis: lack of stem cells (usually also lack platelets - poor clotting and leukocytes -> prone to infections)
- Cytotoxic drugs used to treat cancer
- Other drugs (e.g. Chloramphenicol, phenylbutazone)
- Radiation
- Some chemicals (e.g. benzene, CCl4)
Treatment: transfusion + antibodies bone marrow transplants
Haemostasis
Process involved in prevention of blood loss after injury: vascular spasm, formation of a platelet plug, blood clotting.
Vascular spasm
- Damaged blood vessel responds to injury by constriction.
- More trauma (crush) more constriction - sharp cut more bleeding.
- In very small vessels endothelial surfaces may fuse.
- Normally short-lived
- Partly neurogenic and partly myogenic
Platelet plug
Platelets: small non-nucleated blood cells. Many vesicles and bind to collagen and elastin fibres. Vessel damage exposes collagen and elastin. Platelets bind to collagen and release contents of their granules. Chemicals from granules (e.g. ADP and 5HT) activate platelets. Activated platelets stick to each other and secrete thromboxane A2. Thromboxane A2 increases platelet aggregation and vasoconstriction. Undamaged endothelial cells secrete prostacyclin (PGI2) which inhibits platelet aggregation. PGI2 limits spread of plug. Endothelial cells also secrete nitric oxide which also inhibits aggregation and activation.
Blood clotting/coagulation
- Conversion of blood from a viscous liquid to a solid gel: clot/thrombus.
Two pathways for clotting:
a. Extrinsic pathway: damaged tissue -> extrinsic prothrombin activator
b. Intrinsic pathway: blood in contact with exposed collagen (or any wettable surface) -> intrinsic
Prothrombin: α-globulin produced in liver (vitamin K necessary) - activated to thrombin (Ca2+ needed)
Thrombin splits soluble fibrinogen to fibrin which polymerises to mesh of fibrin threads. These fibrin threads are the basis of clot - traps, cells, plasma, etc. Fibrin stabilizing factor + calcium - fibrin threads contract (exclude serum and bring cut surfaces together)
Clotting factors:
- Real process of clotting is a complex cascade of reactions. It involved many forms and if 1 is missing the process stops (e,g, haemophilia).
- Amplification through stages
- Extrinsic pathway generates small amount of thrombin quickly. Thrombin accelerates processes of intrinsic pathway. Extrinsic pathway primes intrinsic.
Factor:
I - fibrinogen (Ia)
II - prothrombin
III - tissue factor
IV - calcium
V, VII
VIII - antihaemophilic factor
IX - christmas factor
X,XI,XII (Hageman factor), XIII
''a'' indicates ''activated' factor
Intrinsic pathway
Contract with collagen (or glass) can activate factor XII to XIIa (in vivo?). Factor XIIa activates factor XI to XIa which activates factor IX to IXa. Factor IXa activates factor X to Xa (factor VIIIa and activated platelets necessary for this). Factor Xa is an enzyme that converts prothrombin to thrombin (in presence of Va)
Extrinsic pathway
Tissue factor on cell surfaces of non-endothelial cells exposed to plasma when vessel is damaged. Activates factor VII to VIIa. Directly activates factor X to Xa and also activates factor IX.
Note: Calcium is essential for clotting and vitamin K for synthesis of several clotting factors (prothrombin).
Prevention of clotting in vessels:
- Endothelium stops contact with tissue factor and collagen - inhibits platelet aggregation and activation (PGI2 and nitrix oxide).
- Tissue factor pathway inhibitor (TFPI) is present in plasma and secreted by endothelial cells. Inhibits actions of VIIa - limits intrinsic pathway
- Thrombin binds to endothelial protein thrombomodulin and inactivated. This activates plasma protein C which inactivates VIIIa and Va.
- Antithrombin III in plasma activated by heparin on endothelial cells - stops spread of clot.
- Plasminogen can be activated to plasmin which digests the clot.
Excessive bleeding
- Deficiency of vitamin K or liver disease decreases prothrombin etc. (malabsorption and newborn)
- Haemophilia - genetic lack of clotting factor usually factor VIII (sometimes IX or rarely another). Bleeding into joints, internal bleeding. Inject factor VIII.
- Thrombocytopenia - lack of platelets.
Bleeding time vs Clotting time
Thrombosis and anticoagulants:
- Abnormal clots may break away (embolism) and lodge in vessel that supplies heart, lungs or brain. Heparin activates antithrombin III. Small doses of aspirin inhibit thromboxane A2 production but not prostacyclin PGI2. Coumarin-type drugs (warfarin) act in vivo to reduce prothrombin, etc
In vitro:
- Heparin
- Remove Ca2+ with potassium citrate oxalate or EDTA
- Siliconize container
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