Foetal haemoglobin (HbF) makes up about 0.5 – 0.8 % of total adult haemoglobin and consists of two α and two gamma (γ) globin chains.

It’s crucial that thrombin’s impact is restricted to the injured site. Tissue factor pathway inhibitor (TFPI), which is produced by endothelial cells and found in plasma and platelets, is the first inhibitor to function. It accumulates near the site of harm induced by local platelet activation. Xa and VIIa, as well as tissue factor, are inhibited by TFPI. Other circulating inhibitors, the most potent of which is antithrombin, can also inactivate thrombin and other protease factors directly. Coagulation cofactors V and VIII are inhibited by protein C and protein S. Tissue plasminogen activator (TPA) from endothelial cells facilitates fibrinolysis by promoting the conversion of plasminogen to plasmin.

For an action potential to occur, the membrane must become more permeable to Na+and the Na+influx must be greater than the K+efflux. An action potential occurs when depolarisation of the membrane reaches threshold potential. The membrane must be out of the absolute refractory period, however an action potential can still occur in a relative refractory period but only in response to a larger than normal stimulus.

Flow through a tube is dependent upon:
The pressure difference across the ends of the tube (P1– P2)
The resistance to flow provided by the tube (R)
This is Darcy’s law, which is analogous to Ohm’s law in electronics:
Flow = (P1– P2) / R
Resistance in the tube is defined by Poiseuille’s law, which is determined by the diameter of the tube and the viscosity of the fluid. Poiseuille’s law is as follows:
Resistance = (8VL) / (πR4)
Where:
V = The viscosity of the fluid
L = The length of the tube
R = The radius of the tube
Therefore, in simple terms, resistance is directly proportional to the viscosity of the fluid and the length of the tube and inversely proportional to the radius of the tube. Of these three factors, the most important quantitatively and physiologically is vessel radius.
It can be seen that small changes in the radius can have a dramatic effect on the flow of the fluid. For example, the constriction of an artery by 20% will decrease the flow by approximately 60%.
Another important and frequently quoted example of this inverse relationship is that of the radius of an intravenous cannula. Doubling the diameter of a cannula increases the flow rate by 16-fold (r4). This is the reason the diameter of an intravenous cannula in resuscitation scenarios is so important.
*Please note that knowledge of the detail of Poiseuille’s law is not a requirement of the RCEM Basic Sciences Curriculum.

The extrinsic pathway for initiating the formation of prothrombin activator begins with a traumatized vascular wall or traumatized extravascular tissues that come in contact with the blood. Exposed and activated by vascular injury, with plasma factor VII. The extrinsic tenase complex, factor VIIa-tissue factor complex, activates factor X to factor Xa.

Erythrocytes have a normal lifespan of about 120 days. Mature erythrocytes are biconcave discs with no nucleus, ribosomes or mitochondria but with the ability to generate energy as ATP by the anaerobic glycolytic pathway. The red cell membrane consists of a bipolar lipid layer with a membrane skeleton of penetrating and integral proteins anchoring carbohydrate surface antigens. The shape and flexibility of red cells allows them to deform easily and pass through capillaries.

Each muscle fibre is divided at regular intervals along its length into sarcomeres separated by Z-lines. The sarcomere is the functional unit of the muscle.

Each motor unit contracts in an all or nothing fashion, i.e. if a motor unit is excited, it will stimulate all of its muscle fibres to contract. The force of contraction of a muscle is controlled by varying the motor unit recruitment (spatial summation), and by varying the firing rate of the motor units (temporal summation). During a gradual increase in contraction of a muscle, the first units start to discharge and increase their firing rate, and, as the force needs to increase, new units are recruited and, in turn, also increase their firing rate. For most motor units, the firing rate for a steady contraction is between 5 and 8 Hz. Because the unitary firing rates for each motor unit are different and not synchronised, the overall effect is a smooth force profile from the muscle. Increasing the firing rate of motor units is temporal summation where the tension developed by the first action potential has not completely decayed when the second action potential and twitch is grafted onto the first and so on. If the muscle fibres are stimulated repeatedly at a faster frequency, a sustained contraction results where it is not possible to detect individual twitches. This is called tetanus.

Passive diffusion is a process that describes the movement down a concentration gradient. This process accounts for movement across small distances like within the cytosol or across membranes. Factors that affect the diffusion of a substance across a membrane are the permeability (p) of the membrane, a difference in concentration across the membrane and the membrane area over which diffusion occurs. The membrane thickness and composition, and the diffusion coefficient of the substance also affects the permeability. Fick’s law describes the rate of diffusion of a substance within a solution, which can be modified to describe the rate of diffusion across a membrane.

In order for primary active transport to pump ions against their electrochemical gradient, chemical energy is used in the form of ATP. This is facilitated by the Na+/K+-ATPase antiporter pump, which uses metabolic energy to move 3 Na+ions out of the cell for every 2 K+ions that come in, against their respective electrochemical gradients. As a result, the cell the maintains a high intracellular concentration of K+ions and a low concentration of Na+ions.

The electron transfer system is responsible for most of the energy produced during respiration. The is a system of hydrogen carriers located in the inner mitochondrial membrane. Hydrogen is transferred to the electron transfer system via the NADH2 molecules produced during glycolysis and the Krebs cycle. As a result, a H+ion gradient is generated across the inner membrane which drives ATP synthase. The final hydrogen acceptor is oxygen and the H+ions and O2 combine to form water.

Fibrinolysis is a normal haemostatic response to vascular injury. Plasminogen, a proenzyme in blood and tissue fluid, is converted to plasmin by activators either from the vessel wall (intrinsic activation) or from the tissues (extrinsic activation). The most important route follows the release of tissue plasminogen activator (TPA) from endothelial cells.

Action potentials are initiated in nerves by activation of ligand-gated Na+channels by neurotransmitters. Opening of these Na+channels results in a small influx of sodium and depolarisation of the negative resting membrane potential (-70 mV). If the stimulus is sufficiently strong, the resting membrane depolarises enough to reach threshold potential (generally around -55 mV), at which point an action potential can occur. Voltage-gated Na+channels open, causing further depolarisation and activating more voltage-gated Na+channels and there is a sudden and massive sodium influx, driving the cell membrane potential to about +40 mV.

Mitochondria are membrane-bound organelles that are responsible for the production of the cell’s supply of chemical energy. This is achieved by using molecular oxygen to utilise sugar and small fatty acid molecules to generate adenosine triphosphate (ATP). This process is known as oxidative phosphorylation and requires an enzyme called ATP synthase. ATP acts as an energy-carrying molecule and releases the energy in situations when it is required to fuel cellular processes. Mitochondria are also involved in other cellular processes, including Ca2+homeostasis and signalling. Mitochondria contain a small amount of maternal DNA.
Mitochondria have two phospholipid bilayers, an outer membrane and an inner membrane. The inner membrane is intricately folded inwards to form numerous layers called cristae. The cristae contain specialised membrane proteins that enable the mitochondria to synthesise ATP. Between the two membranes lies the intermembrane space, which stores large proteins that are required for cellular respiration. Within the inner membrane is the perimitochondrial space, which contains a jelly-like matrix. This matrix contains a large quantity of ATP synthase.
Mitochondrial disease, or mitochondrial disorder, refers to a group of disorders that affect the mitochondria. When the number or function of mitochondria in the cell are disrupted, less energy is produced and organ dysfunction results.

Haemoglobin is composed of four polypeptide globin chains each with its own iron containing haem molecule. Haem synthesis occurs largely in the mitochondria by a series of biochemical reactions commencing with the condensation of glycine and succinyl coenzyme A under the action of the key rate-limiting enzyme delta-aminolevulinic acid (ALA) synthase. The globin chains are synthesised by ribosomes in the cytosol. Haemoglobin synthesis only occurs in immature red blood cells.
There are three types of haemoglobin in normal adult blood: haemoglobin A, A2 and F:
– Normal adult haemoglobin (HbA) makes up about 96 – 98 % of total adult haemoglobin, and consists of two alpha (α) and two beta (β) globin chains. 
– Haemoglobin A2 (HbA2), a normal variant of adult haemoglobin, makes up about 1.5 – 3.5 % of total adult haemoglobin and consists of two α and two delta (δ) globin chains.
– Foetal haemoglobin is the main Hb in the later two-thirds of foetal life and in the newborn until approximately 12 weeks of age. Foetal haemoglobin has a higher affinity for oxygen than adult haemoglobin. 
Red cells are destroyed by macrophages in the liver and spleen after , 120 days. The haem group is split from the haemoglobin and converted to biliverdin and then bilirubin. The iron is conserved and recycled to plasma via transferrin or stored in macrophages as ferritin and haemosiderin. An increased rate of haemoglobin breakdown results in excess bilirubin and jaundice.

The resting potential in most neurons has a value of approximately -70 mV.
The threshold potential is generally around -55 mV.
Initial depolarisation when there is Na+influx through ligand-gated Na+channels.
Action potential is an all or nothing response. The size of the action potential is constant and so, the intensity of the stimulus is coded by the frequency of firing of a neuron.
K+efflux is responsible for repolarisation.

A membrane potential is a property of all cell membranes, but the ability to generate an action potential is only a property of excitable tissues. The resting membrane is more permeable to K+and Cl-than to other ions (and relatively impermeable to Na+); therefore the resting membrane potential is primarily determined by the K+equilibrium potential. At rest the inside of the cell is negative relative to the outside. In most neurones the resting potential has a value of approximately -70 mV.

Mitochondria are membrane-bound organelles that are responsible for the production of the cell’s supply of chemical energy. This is achieved by using molecular oxygen to utilise sugar and small fatty acid molecules to generate adenosine triphosphate (ATP). This process is known as oxidative phosphorylation and requires an enzyme called ATP synthase. ATP acts as an energy-carrying molecule and releases the energy in situations when it is required to fuel cellular processes. Mitochondria are also involved in other cellular processes, including Ca2+homeostasis and signalling. Mitochondria contain a small amount of maternal DNA.
Mitochondria have two phospholipid bilayers, an outer membrane and an inner membrane. The inner membrane is intricately folded inwards to form numerous layers called cristae. The cristae contain specialised membrane proteins that enable the mitochondria to synthesise ATP. Between the two membranes lies the intermembrane space, which stores large proteins that are required for cellular respiration. Within the inner membrane is the perimitochondrial space, which contains a jelly-like matrix. This matrix contains a large quantity of ATP synthase.
Mitochondrial disease, or mitochondrial disorder, refers to a group of disorders that affect the mitochondria. When the number or function of mitochondria in the cell are disrupted, less energy is produced and organ dysfunction results.

Negative feedback loops, also known as inhibitory loops, play a crucial role in controlling human health. It is a self-regulating mechanism of some sort.

A negative feedback system is made up of three main components: a detector (often neural receptor cells) that measures the variable in question and provides input to the comparator; a comparator (usually a neural assembly in the central nervous system) that receives input from the detector, compares the variable to the variable set point, and determines whether or not a response is required.

The comparator activates an effector (typically muscular or glandular tissue) to conduct the appropriate reaction to return the variable to its set point.

Synthesis of platelets occurs in the bone marrow by fragmentation of megakaryocytes cytoplasm, derived from the common myeloid progenitor cell. The average time for differentiation of the human stem cell to the production of platelets is about 10 days. The major regulator of platelet formation is thrombopoietin and 95% of this is produced by the liver. Normal platelet count is 150 – 450 x 109/L and the normal lifespan of a platelet is about 10 days. Usually about one-third of the marrow output of platelets may be trapped at any one time in the normal spleen.

Frictional forces at the sides of a vessel cause a drag force on the fluid touching them in laminar blood flow, which creates a velocity gradient where the flow is greatest at the centre. Laminar blood flow may become disrupted and flow may become turbulent at high velocities, especially in large arteries or where the velocity increases sharply at points of sudden narrowing in the vessels, or across valves. There is increased tendency for thrombi formation when there is turbulent blood flow. Clinically, turbulence may be heard as a murmur or a bruit. As a result of elevated cardiac output, there may be turbulent blood flow, even when the cardiac valves are anatomically normal, and as a result, a physiological murmur can be heard. One such example is pregnancy.

Haemoglobin is a 64.4 kd tetramer consisting of two pairs of globin polypeptide chains: one pair of alpha-like chains, and one pair of non-alpha chains. The chains are designated by Greek letters, which are used to describe the particular haemoglobin (e.g., Hb A is alpha2/beta2).

Two copies of the alpha-globin gene (HBA2, HBA1) are located on chromosome 16 along with the embryonic zeta genes (HBZ). There is no substitute for alpha globin in the formation of any of the normal haemoglobins (Hb) following birth (e.g., Hb A, Hb A2, and Hb F). Thus, absence any alpha globin, as seen when all 4 alpha-globin genes are inactive or deleted is incompatible with extrauterine life, except when extraordinary measures are taken.

A homotetramer of only alpha-globin chains is not thought to occur, but in the absence of alpha chains, beta and gamma homotetramers (HbH and Bart’s haemoglobin, respectively) can be found, although they lack cooperativity and function poorly in oxygen transport. The single beta-globin gene (HBB) resides on chromosome 11, within a gene cluster consisting of an embryonic beta-like gene, the epsilon gene (HBE1), the duplicated and nearly identical fetal, or gamma globin genes (HBG2, HBG1), and the poorly expressed delta-globin gene (HBD). A heme group, consisting of a single molecule of protoporphyrin IX co-ordinately bound to a single ferrous (Fe2+) ion, is linked covalently at a specific site to each globin chain. If the iron is oxidized to the ferric state (Fe3+), the protein is called methaemoglobin.

Alpha globin chains contain 141 amino acids (residues) while the beta-like chains contain 146 amino acids. Approximately 75 percent of haemoglobin is in the form of an alpha helix. The non helical stretches permit folding of the polypeptide upon itself. Individual residues can be assigned to one of eight helices (A-H) or to adjacent non helical stretches.

Heme iron is linked covalently to a histidine at the eighth residue of the F helix (His F8), at residue 87 of the alpha chain and residue 92 of the beta chain. Residues that have charged side groups, such as lysine, arginine, and glutamic acid, lie on the surface of the molecule in contact with the surrounding water solvent. Exposure of the hydrophilic (charged) amino acids to the aqueous milieu is an important determinant of the solubility of haemoglobin within the red blood cell and of the prevention of precipitation.

The haemoglobin tetramer is a globular molecule (5.0 x 5.4 x 6.4 nm) with a single axis of symmetry. The polypeptide chains are folded such that the four heme groups lie in clefts on the surface of the molecule equidistant from one another.

Parasympathetic preganglionic neurones originate in the brainstem from which they run in cranial nerves III, VII, IX and X and also from the second and third sacral segments of the spinal cord. Parasympathetic preganglionic neurones release acetylcholine into the synapse, which acts on cholinergic nicotinic receptors on the postganglionic fibre. Parasympathetic peripheral ganglia are generally found close to or within their target, whereas sympathetic peripheral ganglia are located largely in two sympathetic chains on either side of the vertebral column (paravertebral ganglia), or in diffuse prevertebral ganglia of the visceral plexuses of the abdomen and pelvis. Parasympathetic postganglionic neurones release acetylcholine, which acts on cholinergic muscarinic receptors.

At the neuromuscular junction, acetylcholine is released from the prejunctional membrane which acts on cholinergic nicotinic receptors on the postjunctional membrane.

Darcy’s law states that flow through a tube is dependent on the pressure differences across the ends of the tube (P1 – P2) and the resistance to flow provided by the tube (R). Resistance is due to frictional forces and is determined by the length of the tube (L), the radius of the tube (r) and the viscosity of the fluid flowing down that tube (V). The radius of the tube has the largest effect on resistance and therefore flow – this explains why smaller gauge cannulas with larger diameters have a faster rate of flow. Increased viscosity, as seen in polycythemia, will slow the rate of blood flow through a vessel.

There are three types of storage granules contained in platelets. These are dense granules which contain the following:
-ATP
-ADP
-serotonin and calcium alpha granules containing clotting factors
-von Willebrand factor (VWF)
-platelet-derived growth factor (PDGF)
– other proteins lysosomes containing hydrolytic enzymes.

Diffusion is the passive movement of ions across a cell membrane down their electrochemical or concentration gradient through ion channels. Ion channels can be voltage-gated (regulated according to the potential difference across the cell membrane) or ligand-gated (regulated by the presence of a specific signal molecule). Facilitated diffusion is the process of spontaneous passive transport of molecules or ions down their concentration gradient across a cell membrane via specific transmembrane transporter (carrier) proteins. The energy required for conformational changes in the transporter protein is provided by the concentration gradient rather than by metabolic activity. In secondary active transport there is no direct coupling of ATP but the initial Na+ electrochemical gradient that drives the secondary active transport is set up by a process that requires metabolic energy. Examples include the sodium/calcium exchanger, or the sodium/glucose symporter.

Haemoglobin is composed of four polypeptide globin chains each with its own iron containing haem molecule. Haem synthesis occurs largely in the mitochondria by a series of biochemical reactions commencing with the condensation of glycine and succinyl coenzyme A under the action of the key rate-limiting enzyme delta-aminolevulinic acid (ALA) synthase. The globin chains are synthesised by ribosomes in the cytosol. Haemoglobin synthesis only occurs in immature red blood cells.
There are three types of haemoglobin in normal adult blood: haemoglobin A, A2 and F:
– Normal adult haemoglobin (HbA) makes up about 96 – 98 % of total adult haemoglobin, and consists of two alpha (α) and two beta (β) globin chains. 
– Haemoglobin A2 (HbA2), a normal variant of adult haemoglobin, makes up about 1.5 – 3.5 % of total adult haemoglobin and consists of two α and two delta (δ) globin chains.
– Foetal haemoglobin is the main Hb in the later two-thirds of foetal life and in the newborn until approximately 12 weeks of age. Foetal haemoglobin has a higher affinity for oxygen than adult haemoglobin. 
Red cells are destroyed by macrophages in the liver and spleen after , 120 days. The haem group is split from the haemoglobin and converted to biliverdin and then bilirubin. The iron is conserved and recycled to plasma via transferrin or stored in macrophages as ferritin and haemosiderin. An increased rate of haemoglobin breakdown results in excess bilirubin and jaundice.

Protein and phosphate are the primary intracellular anions, while chloride (Cl-) and bicarbonate are the predominant extracellular anions (HCO3-).

Total adult haemoglobin comprises about 96 – 98 % of normal adult haemoglobin (HbA). It consists of two alpha (α) and two beta (β) globin chains.