Blood (II)

Below I have added some quotes from the chapters of the book I did not cover in my first post, as well as some supplementary links.

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“Haemoglobin is of crucial biological importance; it is also easy to obtain safely in large quantities from donated blood. These properties have resulted in its becoming the most studied protein in human history. Haemoglobin played a key role in the history of our understanding of all proteins, and indeed the science of biochemistry itself. […] Oxygen transport defines the primary biological function of blood. […] Oxygen gas consists of two atoms of oxygen bound together to form a symmetrical molecule. However, oxygen cannot be transported in the plasma alone. This is because water is very poor at dissolving oxygen. Haemoglobin’s primary function is to increase this solubility; it does this by binding the oxygen gas on to the iron in its haem group. Every haem can bind one oxygen molecule, increasing the amount of oxygen able to dissolve in the blood.”

“An iron atom can exist in a number of different forms depending on how many electrons it has in its atomic orbitals. In its ferrous (iron II) state iron can bind oxygen readily. The haemoglobin protein has therefore evolved to stabilize its haem iron cofactor in this ferrous state. The result is that over fifty times as much oxygen is stored inside the confines of the red blood cell compared to outside in the watery plasma. However, using iron to bind oxygen comes at a cost. Iron (II) can readily lose one of its electrons to the bound oxygen, a process called ‘oxidation’. So the same form of iron that can bind oxygen avidly (ferrous) also readily reacts with that same oxygen forming an unreactive iron III state, called ‘ferric’. […] The complex structure of the protein haemoglobin is required to protect the ferrous iron from oxidizing. The haem iron is held in a precise configuration within the protein. Specific amino acids are ideally positioned to stabilize the iron–oxygen bond and prevent it from oxidizing. […] the iron stays ferrous despite the presence of the nearby oxygen. Having evolved over many hundreds of millions of years, this stability is very difficult for chemists to mimic in the laboratory. This is one reason why, desirable as it might be in terms of cost and convenience, it is not currently possible to replace blood transfusions with a simple small chemical iron oxygen carrier.”

“Given the success of the haem iron and globin combination in haemoglobin, it is no surprise that organisms have used this basic biochemical architecture for a variety of purposes throughout evolution, not just oxygen transport in blood. One example is the protein myoglobin. This protein resides inside animal cells; in the human it is found in the heart and skeletal muscle. […] Myoglobin has multiple functions. Its primary role is as an aid to oxygen diffusion. Whereas haemoglobin transports oxygen from the lung to the cell, myoglobin transports it once it is inside the cell. As oxygen is so poorly soluble in water, having a chain of molecules inside the cell that can bind and release oxygen rapidly significantly decreases the time it takes the gas to get from the blood capillary to the part of the cell—the mitochondria—where it is needed. […] Myoglobin can also act as an emergency oxygen backup store. In humans this is trivial and of questionable importance. Not so in diving mammals such as whales and dolphins that have as much as thirty times the myoglobin content of the terrestrial equivalent; indeed those mammals that dive for the longest duration have the most myoglobin. […] The third known function of myoglobin is to protect the muscle cells from damage by nitric oxide gas.”

“The heart is the organ that pumps blood around the body. If the heart stops functioning, blood does not flow. The driving force for this flow is the pressure difference between the arterial blood leaving the heart and the returning venous blood. The decreasing pressure in the venous side explains the need for unidirectional valves within veins to prevent the blood flowing in the wrong direction. Without them the return of the blood through the veins to the heart would be too slow, especially when standing up, when the venous pressure struggles to overcome gravity. […] normal [blood pressure] ranges rise slowly with age. […] high resistance in the arterial circulation at higher blood pressures [places] additional strain on the left ventricle. If the heart is weak, it may fail to achieve the extra force required to pump against this resistance, resulting in heart failure. […] in everyday life, a low blood pressure is rarely of concern. Indeed, it can be a sign of fitness as elite athletes have a much lower resting blood pressure than the rest of the population. […] the effect of exercise training is to thicken the muscles in the walls of the heart and enlarge the chambers. This enables more blood to be pumped per beat during intense exercise. The consequence of this extra efficiency is that when an athlete is resting—and therefore needs no more oxygen than a more sedentary person—the heart rate and blood pressure are lower than average. Most people’s experience of hypotension will be reflected by dizzy spells and lack of balance, especially when moving quickly to an upright position. This is because more blood pools in the legs when you stand up, meaning there is less blood for the heart to pump. The immediate effect should be for the heart to beat faster to restore the pressure. If there is a delay, the decrease in pressure can decrease the blood flow to the brain and cause dizziness; in extreme cases this can lead to fainting.”

“If hypertension is persistent, patients are most likely to be treated with drugs that target specific pathways that the body uses to control blood pressure. For example angiotensin is a protein that can trigger secretion of the hormone aldosterone from the adrenal gland. In its active form angiotensin can directly constrict blood vessels, while aldosterone enhances salt and water retention, so raising blood volume. Both these effects increase blood pressure. Angiotensin is converted into its active form by an enzyme called ‘Angiotensin Converting Enzyme’ (ACE). An ACE inhibitor drug prevents this activity, keeping angiotensin in its inactive form; this will therefore drop the patient’s blood pressure. […] The metal calcium controls many processes in the body. Its entry into muscle cells triggers muscle contraction. Preventing this entry can therefore reduce the force of contraction of the heart and the ability of arteries to constrict. Both of these will have the effect of decreasing blood pressure. Calcium enters muscle cells via specific protein-based channels. Drugs that block these channels (calcium channel blockers) are therefore highly effective at treating hypertension.”

“Autoregulation is a homeostatic process designed to ensure that blood flow remains constant [in settings where constancy is desirable]. However, there are many occasions when an organism actively requires a change in blood flow. It is relatively easy to imagine what these are. In the short term, blood supplies oxygen and nutrients. When these are used up rapidly, or their supply becomes limited, the response will be to increase blood flow. The most obvious example is the twenty-fold increase in oxygen and glucose consumption that occurs in skeletal muscle during exercise when compared to rest. If there were no accompanying increase in blood flow to the muscle the oxygen supply would soon run out. […] There are hundreds of molecules known that have the ability to increase or decrease blood flow […] The surface of all blood vessels is lined by a thin layer of cells, the ‘endothelium’. Endothelial cells form a barrier between the blood and the surrounding tissue, controlling access of materials into and out of the blood. For example white blood cells can enter or leave the circulation via interacting with the endothelium; this is the route by which neutrophils migrate from the blood to the site of tissue damage or bacterial/viral attack as part of the innate immune response. However, the endothelium is not just a selective barrier. It also plays an active role in blood physiology and biochemistry.”

“Two major issues [related to blood transfusions] remained at the end of the 19th century: the problem of clotting, which all were aware of; and the problem of blood group incompatbility, which no one had the slightest idea even existed. […] For blood transfusions to ever make a recovery the key issues of blood clotting and adverse side effects needed to be resolved. In 1875 the Swedish biochemist Olof Hammarsten showed that adding calcium accelerated the rate of blood clotting (we now know the mechanism for this is that key enzymes in blood platelets that catalyse fibrin formation require calcium for their function). It therefore made sense to use chemicals that bind calcium to try to prevent clotting. Calcium ions are positively charged; adding negatively charged ions such as oxalate and citrate neutralized the calcium, preventing its clot-promoting action. […] At the same time as anticoagulants were being discovered, the reason why some blood transfusions failed even when there were no clots was becoming clear. It had been shown that animal blood given to humans tended to clump together or agglutinate, eventually bursting and releasing free haemoglobin and causing kidney damage. In the early 1900s, working in Vienna, Karl Landsteiner showed the same effect could occur with human-to-human transfusion. The trick was the ability to separate blood cells from serum. This enabled mixing blood cells from a variety of donors with plasma from a variety of participants. Using his laboratory staff as subjects, Landsteiner showed that only some combinations caused the agglutination reaction. Some donor cells (now known as type O) never clumped. Others clumped depending on the nature of the plasma in a reproducible manner. A careful study of Landsteiner’s results revealed the ABO blood type distinctions […]. Versions of these agglutination tests still form the basis of checking transfused blood today.”

“No blood product can be made completely sterile, no matter how carefully it is processed. The best that can be done is to ensure that no new bacteria or viruses are added during the purification, storage, and transportation processes. Nothing can be done to inactivate any viruses that are already present in the donor’s blood, for the harsh treatments necessary to do this would inevitably damage the viability of the product or be prohibitively expensive to implement on the industrial scale that the blood market has become. […] In the 1980s over half the US haemophiliac population was HIV positive.”

“Three fundamentally different ways have been attempted to replace red blood cell transfusions. The first uses a completely chemical approach and makes use of perfluorocarbons, inert chemicals that, in liquid form, can dissolve gasses without reacting with them. […] Perfluorocarbons can dissolve oxygen much more effectively than water. […] The problem with their use as a blood substitute is that the amount of oxygen dissolved in these solutions is linear with increasing pressure. This means that the solution lacks the advantages of the sigmoidal binding curve of haemoglobin, which has evolved to maximize the amount of oxygen captured from the limited fraction found in air (20 per cent oxygen). However, to deliver the same amount of oxygen as haemoglobin, patients using the less efficient perfluorocarbons in their blood need to breathe gas that is almost 100 per cent pure oxygen […]; this restricts the use of these compounds. […] The second type of blood substitute makes use of haemoglobin biology. Initial attempts used purified haemoglobin itself. […] there is no haemoglobin-based blood substitute in general use today […] The problem for the lack of uptake is not that blood substitutes cannot replace red blood cell function. A variety of products have been shown to stay in the vasculature for several days, provide volume support, and deliver oxygen. However, they have suffered due to adverse side effects, most notably cardiac complications. […] In nature the plasma proteins haptoglobin and haemopexin bind and detoxify any free haemoglobin and haem released from red blood cells. The challenge for blood substitute research is to mimic these effects in a product that can still deliver oxygen. […] Despite ongoing research, these problems may prove to be insurmountable. There is therefore interest in a third approach. This is to grow artificial red blood cells using stem cell technology.”

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Links:

Porphyrin. Globin.
Felix Hoppe-Seyler. Jacques Monod. Jeffries Wyman. Jean-Pierre Changeux.
Allosteric regulation. Monod-Wyman-Changeux model.
Structural Biochemistry/Hemoglobin (wikibooks). (Many of the topics covered in this link – e.g. comments on affinity, T/R-states, oxygen binding curves, the Bohr effect, etc. – are also covered in the book, so although I do link to some of the other topics also covered in this link below it should be noted that I did in fact leave out quite a few potentially relevant links on account of those topics being covered in the above link).
1,3-Bisphosphoglycerate.
Erythrocruorin.
Haemerythrin.
Hemocyanin.
Cytoglobin.
Neuroglobin.
Sickle cell anemia. Thalassaemia. Hemoglobinopathy. Porphyria.
Pulse oximetry.
Daniel Bernoulli. Hydrodynamica. Stephen Hales. Karl von Vierordt.
Arterial line.
Sphygmomanometer. Korotkoff sounds. Systole. Diastole. Blood pressure. Mean arterial pressure. Hypertension. Antihypertensive drugs. Atherosclerosis Pathology. Beta blocker. Diuretic.
Autoregulation.
Guanylate cyclase. Glyceryl trinitrate.
Blood transfusion. Richard Lower. Jean-Baptiste Denys. James Blundell.
Parabiosis.
Penrose Inquiry.
ABLE (Age of Transfused Blood in Critically Ill Adults) trial.
RECESS trial.