Blood

Blood

1. There is approximately 5 litres of blood in the body, 1 litre for every 13kg

2. 55% plasma

   • clear yellow fluid comprised of mainly water
   • plasma proteins
     • albumins
       • a group of transport proteins produced by the liver
       • carries steroid hormones and fatty acids
       • blood buffer
     • fibrinogens
       • blood clotting proteins produced by the liver
     • globulins
       • produced by B lymphocytes
         • some globulins are made in the liver
       • alpha and beta globulins transport fat-soluble vitamins, lipids and iron
       • gamma globulins contribute to the immunological response of the body
     • enzymes
       • blood plasma contains various enzymes and transports them to their site of action
     • hormones
       • peptide hormones
         • insulin
         • growth hormone
       • non-peptide hormones
         • cortisol
         • epinephrine
   • other plasma solutes
     • nutrients
       • products of digestion are absorbed into the bloodstream for distribution throughout the body
       • e.g. amino acids, monosaccharides, fatty acids, glycerol, vitamins and minerals
     • electrolytes
       • small, inorganic ions that help regulate and maintain osmotic pressure
     • dissolved gasses
       • small amounts of oxygen and carbon dioxide are carried in the blood plasma
     • organic waste products
       • waste products of metabolism are carried in the blood to the organ of excretion (kidney, skin, lungs, liver)
       • urea, creatinine, ammonia, uric acid and bilirubin

3. 45% blood cells and platelets

4. Haemostasis

   • vasoconstriction
     • initially slows blood flow to the area of injury
       • reduced blood allows contact activation of platelets and coagulation factors
         • von Willebrand factor mediates the adherence of platelets
           • adherent platelets release their granule contents and activates platelet prostaglandin synthesis
             • synthesis of prostaglandin leads to the formation of TXA2 (thromboxane A2) which stimulates the activation of new platelets as well as increases platelet aggregation
               • platelets are aggregated by cross-linking through active GPIIb/IIIa receptors with fibrinogen bridges
               • thromboxane A2 is also has a major positive feedback effect as it is important in the secondary amplification of platelet activation to form a stable platelet aggregate
                 • continuing platelet aggregation promotes the growth of the haemostatic plug
               • powerful vasoconstrictive activity
             • ADP is released from dense granules which has a major positive feedback role in promoting platelet activation
               • released ADP causes platelets to aggregate and swell and additional platelets are drawn to the area of injury
   • formation of platelet plug
   • blood clotting or coagulation
     • haemophilia is a disorder that impairs the body's ability to make blood clots
     • platelets alone are not enough to seal the damage in the vessel wall, a clot must form at the site of injury
       • the clotting cascade is a biological amplification system that occurs through two pathways that interact
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         • factors that are vitamin K dependant: - prothrombin - stable factor/proconvertin - anti haemophilic factor b/christmas factor - protein C - protein S - protein Z
         • intrinsic pathway
           • activated partial thromboplastin time assay (APTT) tests the intrinsic and common pathways - plasma is prepared by centrifugation the blood in the presence of a calcium chelator - the plasma obtained is a mixture of phospholipids/kaolin, solid particles with phospholipid anions which mimics the surface provided by provided by activated platelets - phospholipid/kaolin is a suspension of negatively changed phospholipids absorbed on particles of kaolin which is required to initiate the cascade in the lab as it mimics the acid phosphatase of activated platelets - plasma has no red blood cells so the clot formed from the APTT assay appears cloudy
           • HMWK and the conversion of prekallikrein to kallikrein activates factor XII
             • this with thrombin activates factor XI
               • factor XIa helps to activate factor IX
                 • activates factor IX to form IXa
         • extrinsic pathway
           • coagulation is initiated after vascular injury by the interaction of membrane bound tissue factor (factor III) with factor VII
             • forms complex: tissue factor - factor VIIa
               • • small amounts of thrombin generated allows factor VIII to convert to factor VIIIa and form a complex with factor IXa (factor IXa - factor VIIIa)
                   • activates more factor X (factor Xa) if sufficient calcium is also present
               • activates factor X to form Xa
                 • in the absence of its cofactor, factor Xa forms a small amount of thrombin (IIa) from prothrombin (factor II)
                   • small amounts of thrombin also activates factor V
                     • calcium, factor Va and factor Xa allows a large amount of thrombin to form from prothrombin
                       • thrombin (with calcium) hydrolyses fibrinogen (factor I), releasing fibrinopeptides A and B to form a fibrin monomer (factor Ia)
                         • fibrinogen consists of two identical subunits, each containing three polypeptide chains which are linked by disulphide bonds
                         • fibrin monomers link spontaneously by hydrogen bonds to form a loose insoluble fibrin polymer
                       • factor XIII is activated by thrombin and it stabilises the fibrin polymers with the formation of covalent bond cross-links
               • initiation is rapidly inactivated by tissue factor pathway inhibitor
                 • thrombin generation is now dependent on the intrinsic pathway
         • common pathway
     • coagulation is the conversion of liquid blood to a solid (the reaction is dependant on components of the plasma)
     • before a blood transfusion, the collected donation must not clot
       • citrate ions chelate the calcium ions required for the clotting cascade so citrate is added to the donation as it can also be metabolised easily when it enters the body
   • achieved when fibril formed by blood coagulation is added to the platelet mass and there is platelet-induced clot retraction/compaction

5. Erythropoiesis

   • occurs in a erythroid niche in which about 30 erythroid cells, at various stages, surround a central macrophage
   • regulated by erythropoietin
     • expressed in the kidneys and works with other factors such as IL-3 and IL-6
     • thrombopoietin is largely made in the liver and is important for the regulation of platelet generation
     • prevents apoptosis of RBC progenitors in bone marrow
     • heavily glycosylated polypeptide hormone
       • can increase the number of progenitor cells committed to erythropoiesis
   • pronormoblasts are the first recognisable erythrocyte precursors in the bone marrow

6. Red blood cells

   • asphyxiation occurs when blood contains excess substances like carbon dioxide and carbon monoxide with which haemoglobin forms semi-permanat or permanent compounds instead of reversible bonds that haemoglobin forms with oxygen
   • flat, round, biconcave discs with depressed centres
   • flexible and have a collapsible cytoskeleton
   • lack a nucleus and mitochondria
     • very low metabolism
   • blood type due to different surface antigens
   • growth factors are important for the generation and differentiation of red blood cells
     • Il-3, GM-CSF and vitamin B12

7. Oxygen

   • 1 litre of blood contains 3ml of oxygen that is physically dissolved (1.5%) and 197ml of oxygen that is bound to haemoglobin (98.5%)
     • each haemoglobin is made up of 4 subunits bound together
       • each subunit consists of a molecular haem group and a polypeptide attached to the haem group
         • the four polypeptides of haemoglobin are collectively called globin
         • each of the four haem groups contains one iron atom (Fe3+), to which molecular oxygen binds
           • cooperativity
             • the oxygen-haemoglobin dissociation curve shows the increasing partial pressure of oxygen increases the combination of oxygen with haemoglobin
               • the curve shows a drop in PO2 from 100 to 60 mmHg has minimal effect on Hb saturation
                 • below 60 mmHg there is progressive hyperventilation
                   • hypoxic responses originate in the carotid and aortic bodies and do not do much in the moment-to-moment control of breathing
               • curve shows that a large amount of oxygen can be released from haemoglobin with only a small change in PO2, facilitating release into tissue
               • increase in pH causes curve to shift to the left
               • increase in temperature causes the curve to shift to the right
               • oxygen saturation (SaO2)
                 • refers to the amount of oxygen bound to haemoglobin relative to the maximal amount that can bind
                 • pulse oximeters are used in clinics to measure O2 sats
                   • they measure the ratio of absorption of red and infrared light by oxyHb and deoxyHb
               • 1g of Hb binds to 1.39ml of oxygen
                 • normal blood has ~150g of haemoglobin for every litre of blood
                   • oxygen capacity = 150 x 1.39 = 208 ml per L of blood
                     • remember to add the dissolved oxygen component which is 3ml/L if blood
           • there is around 280 million Hb molecules per red blood cell
   • the amount of oxygen dissolved in blood is proportional to the partial pressure of oxygen

8. Carbon dioxide

   • blood carries more dissolved carbon dioxide than dissolved oxygen
     • only 7% of CO2 entering the blood dissolves in the plasma and erythrocytes
   • another 23% of the carbon dioxide molecules entering the blood reacts reversibly with the amino groups of haemoglobin to form carbaminohaemoglobin
     • deoxyhaemoglobin a greater affinity for carbon dioxide than oxyhaemoglobin
   • the remaining 70% of CO2 is converted to bicarbonate
     • first reaction that produces carbonic acid is catalysed by carbonic anhydrase
       • the formation of bicarbonate is rapid and does not require any enzyme and once formed, the bicarbonate ion moves out of the erythrocyte into the plasma
         • the reaction moves towards the right in systemic capillaries and to the left in pulmonary capillaries
         • the CO2 and HCO3- pathway plays a critical role in the regulation go H+ ions and in maintaining acid-base balance in the body
         • acidity can be regulated by using ventilation to adjust the partial pressure of carbon dioxide or by using the kidneys to regulate the bicarbonate concentration Henderson Hasselback equation
   • normally 200ml of CO2 is produced per minute
     • 80 molecules of CO2 is expired by the lungs for every 100 O2 molecules entering the lungs
       • ratio 0.8
   • very small changes in the partial pressure of carbon dioxide has large effects on ventilation

9. Buffers

   • pH of blood plasma is controlled at 7.4 in order to maintain homeostasis
   • carbonic acid-bicarbonate buffer is the most important buffer for maintaining acid-base balance in the blood
   • an increase in alveolar ventilation (controlled by chemoreceptors in the medulla oblongata) can lower PCO2 levels in necessary
     • the chemoreceptors respond to a decrease in the cerebral interstitial pH by increasing ventilation
   • the kidneys have a large role in regulating the systemic bicarbonate
     • kidneys resorbs a lot of the filtered bicarbonate and produces new bicarbonate, to replace those consumed, by acid secretion
       • proximal tubule reabsorbs at least 70-80% of the filtered bicarbonate
       • net acid secretion = titratable acids + ammonium - urinary bicarbonate
   • proteins are also important buffers in the body
     • they are mainly intracellular and include haemoglobin
   • phosphate buffer is mainly intracellular and is an important urinary buffer but also plays a minor role in the blood

10. Platelets

    • thrombocytes
      • small acellular particles budded from special cells

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