Chapter 18: The Circulatory System: Blood
Study Table 18.1; relate each function to the elements or properties of the blood
For example: Transporting heat depends on the ability of water to carry heat, and the circulation of the blood from the body’s core to the surface, where heat radiates and warm water evaporates from sweat.
Plasma (55% by volume)
RBCs (45% – this is the hematocrit)
WBCs and platelets (<1%)
Properties: Memorize the normal values, specific as stated for male and female, in Table 18.2 . Distinguish by whole blood, plasma, or serum (plasma minus clotting factors). Viscosity of whole blood is 4.5 -5, but of plasma is 2.
Review colloids, p. 65, osmosis, p. 107; relate to importance of osmolarity, colloid osmotic pressure, and the problems of hypoproteinemia and ascites.
From Table 18.3, learn the normal percents for 3 categories of plasma proteins, and the normal range for glucose, sodium, calcium, and potassium.
Plasma is 92% water – what blood functions are related to the properties, quantity, and movement of water?
Plasma proteins: Review protein structure in chapter 2, especially concerning active sites for ligands.
As all plasma proteins are colloidal, there are certain properties they share: they are all negatively charged on their surfaces, although each type has specific active sites to bind particular ligands. Positively-charged ions in the plasma can reversibly bind to plasma proteins. Collectively, the plasma proteins create the colloid osmotic pressure (COP) of the blood and are the major contributors to plasma viscosity.
Except for most of the hormones, some of the enzymes, and the gamma globulins, plasma proteins are made by the liver. There is an amazingly high turnover rate, as these proteins only last about 2 hours before being recycled; the liver produces about 4 g of new plasma proteins per hour. How does this relate to malnutrition, liver disease, and ascites? Why would someone with end-stage liver disease look a lot like a child with kwashiorkor?
Since the smallest plasma proteins, the albumins, comprise about 60% of the total, any major change in their abundance has more impact than any other single category of plasma proteins. In addition to contributing to COP and plasma viscosity, albumins reversibly bind Hydrogen ions (H+), making them important plasma buffers, along with calcium ions (Ca2+), creating a calcium reservoir in the plasma, and bilirubin, a waste product being transported to the liver to be excreted in the bile.
The globulins don’t form a coherent functional group; they are just classed together because of similar size, and then subdivided from smallest to largest. Alpha and beta globulins are formed by the liver; they transport substances in the plasma that don’t travel in water well, including lipids (such as steroid and thyroid hormones) and heavy metals (such as iron and copper). The gamma globulins are totally different from the alpha and beta globulins; gamma globulins are antibodies, formed by the plasma cells of the immune system, scattered throughout the body but mostly in the spleen.
Antibodies (gamma globulins) are an important component of the immune system and will be studied in more detail later. Antibodies are formed after exposure to some antigen. Antigens include surface molecules on cells, and different antigens can be inherited. Because of similarities in their chemical nature, some bacterial antigens cross-react with human immune systems to produce antibodies to certain blood cell surface antigens. Antibodies to different blood types cause complications with blood transfusions.
Clotting factors will be studied later – but keep in mind that almost all are made by the liver. Most types are proenzymes in the clotting cascade, but the most abundant clotting factor is fibrinogen, the inactive precursor of fibrin, the protein that forms the strands within a clot.
Not all hormones are proteins, but certainly some of them are, along with prohormones, and they have to be included as plasma proteins – even though they’re just ‘along for the ride.’
Review the endocrine system! The liver is not a major endocrine organ, but that doesn’t make its secretions unimportant. Review somatomedin (insulin-like growth factor, or IGF – see p. 643, also Table 17.5 for a more complete list of liver hormones).
There are enzymes and inactive enzyme precursors (proenzymes) in the plasma. While they make up a very small percentage of the total, they have important regulatory functions. Many are made by the liver (especially the proenzymes, and at least one prohormone), some of the enzymes have escaped from dying cells. These can often be useful diagnostically, as some are characteristic of a particular organ. So, a simple blood test can often reveal liver damage, or heart attack.
Aside from water and proteins, everything else in the plasma is a solute – it dissolves in the water of the plasma. Functional categories that are useful are: organic versus inorganic, gases versus solids, or nutrients versus wastes. Because of the abundance of nitrogen in proteins, and the ability to detect nitrogen easily in chemical tests, an entire category of wastes, the nonprotein nitrogenous wastes (NPN), is used to diagnose disease, usually kidney disease (if NPNs are high). Chief among these is urea, a waste compound made by the liver from ammonia and carbon dioxide. Its value, blood urea nitrogen (BUN) can detect liver disease as well. Notice, in Table 18.3, how low the nitrogenous waste values are compared to the nutrients, such as glucose and amino acids. Notice, also, how high urea concentration is compared to other NPNs.
Electrolytes have a major impact on two vital areas: fluid balance and pH balance. While these will be studied in more detail in a later chapter, we’ll be working on them with each system. Remember the normal pH range in human blood, and review the hormones that regulate ions (aldosterone, and the calcium-regulating hormones).
Review the nature of cations and anions, and the definitions of pH, acid, base, and salt (ch. 2). Then, review the sodium-potassium pumps of cells (ch. 3) – which ion is pumped which way, and how much?
Carbon dioxide, being carried from cells (where it is generated) to the lungs (where it is excreted) has a major impact on blood pH, because it interacts with water (most significantly in the presence of the enzyme carbonic anhydrase, found in RBCs) to form carbonic acid. So, fluids with high CO2 concentration have a lower pH. See p. 80 for the reactions.
Carbonic acid can spontaneously dissociate to form ions; it is the free hydrogen ion that directly affects the pH:
Both of these reactions are freely reversible, depending chiefly on the concentration of carbon dioxide and hydrogen ions (or pH). So, which has a higher pH: blood coming into the lungs, or blood leaving the lungs?
Hemopoiesis is also called hematopoiesis. The rate of production of new cells in the red marrow is staggering; more than 2 million new RBCs are formed every second. If the RBC count remains stable, how many RBCs are destroyed every second?
As with any rapidly dividing cell, blood stem cells are vulnerable to mutation (review the cell cycle in ch. 3 to see why). Many drugs, as well as radiation and toxins, can suppress these cells, causing aplastic anemia. This is a common side effect of cancer treatment, and was a major problem after the Chernobyl incident. We worry about radiation’s affect on stem cells, so we always cover the body with a lead apron when someone needs radiography.
In embryonic life, the yolk sac produces the first blood cells, and forms the first blood vessels (see diagrams p. 1096.); otherwise, how would the cells move into the embryo proper? After the fetus’ liver and spleen are formed, hematopoeitic stem cells migrate to these organs and produce blood cells till at least birth. After ossification has begun, the red marrow forms as stem cells move in. The amount of red marrow increases with growth, but the extent of red marrow shrinks as the bones enlarge. In a small child, red marrow extends into the limbs, but in an adult, red marrow ends at the hip and shoulder joints – unless production must increase for some reason; then red marrow can expand back into the limb bones. What are the chances of radiating red marrow when taking ‘X-rays’ of an adult’s broken wrist?
Marrow for biopsies is easily removed with a sternal puncture. A greater volume of marrow, needed for a transplant, can be taken from a hip bone. Marrow cells can be given through a vein; they find their way from the circulating blood to the marrow. Why would marrow be removed prior to chemotherapy, and returned to the same patient after chemotherapy is over?
Hemopoiesis is shown in Fig. 18.4. One step is left out: the original hemocytoblast first differentiates into either a myeloid stem cell or a lymphoid stem cell. Lymphoid stem cells form the various lymphocytes; myeloid stem cells form everything else. To simplify the diagram, the amount of cell division is also not shown. Many of the stem cells, including the hemocytoblasts, have a very high rate of division. This calls for certain vitamins, including B12 and folic acid; a deficiency of these will impact particularly RBC production, since these are most abundant. (One proerytrhoblast forms 16 RBCs, due to cell division at several stages.)
Pernicious anemia is a deadly disorder caused by a
deficiency of vitamin B12. This vitamin is large and complex, and is digested
by stomach acid unless protected by a substance secreted by the stomach – this
substance is called intrinsic factor (the vitamin is the extrinsic
factor). As we age, production of intrinsic factor can decline, leading to
a B12 deficiency. Can you figure out why B12 has to be supplemented by
injection, not ingestion?
RBCs (red blood cells, or erythrocytes) are basically flexible bags of hemoglobin (Hb), with a few extra functions thrown in. Hemoglobin’s primary function is to carry oxygen, but it also has an essential role in carbon dioxide transport. The structure of Hb is a complex protein with four subunits, each with a protein unit called a globin and a cofactor called heme, made of a porphyrin ring with a central iron. There are several variants of globin molecues; the two most common are called alpha and beta, but there is also a fetal type. Be sure not to confuse globins with globulins!
Genetic mutations to the globin genes affecting Hb structure result in Hb that tends to clump rather than stay suspended in the RBC cytoplasm. Individuals with mutations on both chromosomes carrying the globin gene are afflicted with anemias, including sickle cell anemia and various thalassemias. In all of these, the RBC structure is more fragile, and hemolysis (rupture of cells) is common. Hemolytic anemia results as the RBC numbers drop faster than they can be replaced. On the other hand, carrying a single mutation makes the RBCs somehow more resistant to malaria; both sickle cell anemia and thalassemia originated in areas of the world where malaria is a major problem and used to cause many deaths. Can you see the advantage of having the mutation in such an area?
Porphyria is a group of disorders stemming from inability to form proper porphyrin rings. Some symptoms include craving to taste blood, and fear of strong light – thus the legend of vampires….other symptoms include strange behavior, and a peculiar blue color in the urine; King George III of England was said to suffer from porphyria, which may have led to the dissatisfaction of American colonists with English rule.
Because so many RBCs are produced – and needed – the process must be tightly regulated. There are at least three different regulatory loops involved: RBC production, RBC destruction, and iron absorption and storage.
RBC production is regulated by hypoxemia, an abnormally low level of oxygen in the blood. The oxygen content of the blood is monitored by at least 3 organs – the 2 kidneys, plus the liver – and if it falls too low, they secrete a hormone/growth factor, erythropoietin (EPO). EPO stimulates both cell division and differentiation in hemopoiesis, to increase the rate of erythropoiesis.
Anything that diminishes blood flow to the kidneys, which produce most of the EPO, can cause an excessive secretion of EPO, making the RBC production go too high – a condition called polycythemia. On the other hand, kidney disease often reduces EPO output, resulting in anemia. This is a common problem with dialysis patients and has been corrected with the availability of exogenous EPO. It's not uncommon that the first sign of kidney failure is the fatigue that signals anemia.
RBC production can only be maintained if required nutrients are available in sufficient amounts. This includes basics such as calories and protein, and the vitamins needed for rapid cell division (mostly B12 and folic acid), but also iron. (See fig. 18.6, p. 687). Iron is modified in the stomach, bound to a stomach factor, then absorbed into the blood through the small intestine – but only if the beta globulin that carries iron, transferrin, isn’t already saturated. If it is, the iron absorbed by the gut epithelium is simply sloughed off when the cells die. Iron that is picked up by transferrin can be carried to the liver for storage as ferritin or delivered to the red marrow for erythropoiesis. Iron stored as ferritin can also be delivered by transferrin to the red marrow if insufficient iron is delivered from the diet. In evaluating an anemic patient’s problem, the amount of iron bound to transferrin can be determined by a blood test. There’s a really tragic disorder in which iron is stored in the body to the point of toxicity and death. There can be so much iron in the body that it would set off a metal detector. Would you predict an iron deficiency in someone whose stomach is removed?
The immature RBCs reach the circulating blood while still in the reticulocyte stage. The small amount of remaining endoplasmic reticulum in these cells will disappear in a few days, but the cells can be distinguished with light microscopy. The reticulocyte count, normally 0.5 - 1.5% of circulating RBCs, is diagnostically useful: too high, and the RBC production must be high; too low indicates a depression in RBC production.
RBC destruction is also carefully regulated. Since RBCs
have a fairly short life span (about 120 days), and there are so many of them
(about 25 trillion total), there has to be a high capacity to remove them.
Macrophages in the liver and spleen catch, phagocytose, and digest RBCs (the
old, inflexible cells are most easily caught). Hemoglobin, along with
other cellular proteins, is broken down - the globin simply digested down to
amino acids, which are easily reused. The
iron from the heme is stored and recycled, using transferrin and ferritin. The rest of the
heme molecule is converted to bilirubin, one of the NPN wastes. If
its concentration gets too high, jaundice results. The liver is responsible for
removing bilirubin, by secreting it into the bile, which gets its green color
Bilirubin on its way to the liver binds to albumin (it’s a lipid, and won’t dissolve well in plasma). The liver conjugates the bilirubin to make it more water soluble; the conjugated bilirubin mostly goes into the bile, but some escapes into the blood. Too much might indicate blocked bile ducts in the liver or between the liver, gall bladder, and duodenum. A blood test can be used to distinguish conjugated bilirubin from unconjugated bilirubin, to help determine a cause for jaundice.
RBC Functions: transport of respiratory gases
The respiratory gases include oxygen and carbon dioxide. Review the chemistry of O2 and CO2. Are they polar or nonpolar? Neither of these is particularly hydrophilic; both are much more soluble in lipids (such as the plasma membrane of a cell) than in water. Because of this, the concentration of these gases in plasma is very low. Carbon dioxide is slightly more soluble than oxygen, and some of it can be converted to carbonic acid as well, slowly, in the plasma, just spontaneously.
Still, the amount of oxygen and carbon dioxide that has to be carried by the blood is huge – thus the need for 25 trillions RBCs (about 5 million in every microliter of blood). These cells are anucleate biconcave disks. This shape gives them a high surface area and a lot of flexibility – at least while they’re young. As they age, they become more brittle, likely to get caught in the tight turns of capillaries of the liver and spleen. RBCs don't have mitochondria - no risk, then, that they will consume the oxygen they are carrying.
Each iron in a Hb molecule can reversibly bind one molecule of oxygen, so each Hb can carry up to four oxygen molecules. In oxygenated blood in systemic arteries, almost every Hb carries 4 O2s, and we refer to it as 100% saturated and use the term oxyhemoglobin. With a normal Hb level of 15 g in 100 ml of blood, that much blood can hold 20 ml of oxygen. When a person is resting, blood returning to the lungs is about 75% saturated, meaning that on average each Hb is carrying about 3 O2s. With increasing activity levels, the amount of oxygen delivered to tissues increases, so blood returning to the lungs can have an O2 saturation as low as 25% (one O2 per Hb), but never 0%. Even so, blood returning to the lungs is called deoxygenated, although it can carry a lot of oxygen.
Review skin color in chapter 6, especially jaundice, cyanosis, pallor, and erythema. What is the color of deoxygenated blood?
The carbon dioxide is carried by loosely attaching to an amino acid on the globin part of the Hb molecule, and the combination is called carbaminohemoglobin. In the tissues, gas exchange occurs – for every oxygen given up to a cell, a carbon dioxide is picked up. The reverse happens in the lungs.
If you’re wondering why Hb has to be carried inside cells – see Insight 18.2.
After Hb, the most abundant protein in RBCs (a very distant second) is the enzyme carbonic anhydrase, which speeds the conversion of carbon dioxide to carbonic acid, increasing the amount of carbon dioxide that can be carried in the blood.
Hemoglobin is a colloidal protein – as such, it can attract the hydrogen ions freed when carbonic acid dissociates (making Hb a fine buffer). The bicarbonate, although formed inside the RBCs, is carried in the plasma.
We'll go over this again, and add more detail, when we study the respiratory system.
How are they inherited?
What antibodies are found in the plasma of individuals with each type?
What reaction occurs when the wrong type of blood is transfused into someone?
How can this reaction cause death?
What are blood types in the Rh group?
How does transfusion reaction to Rh differ from reactions to A or B?
Why are Rh positive fetuses of Rh negative women at risk?
How are other blood types used?
You will not be tested over the population percentages for each blood type.
There are two basic ways to categorize WBCs: by how they look in a differential stain, and how they are formed.
By appearance, WBCs are divided into 2 groups: granulocytes and agranulocytes.
By derivation, lymphocytes differentiate at a much earlier stage than all other cells. (Refer back to the earlier study of hemopoiesis.) Lymphoid stem cells are scattered throughout the body, in small clusters of lymphoid tissue found in mucous membranes, tonsils, thymus, and spleen.
Myeloid stem cells stay in the red marrow, differentiating into RBCs, platelets, and all other kinds of WBCs. The myeloid stem cell, under the influence of growth factors, can differentiate into a granulocyte-macrophage colony forming unit. Other growth factors (sometimes referred to as colony stimulating factors, or CSFs) can stimulate an increase in granulocytes or monocytes, which differentiate into macrophages in the peripheral tissues. Further differentiation of the 3 kinds of granulocytes probably depends on other CSFs.
Many WBCs apparently stay in the marrow; others move into the peripheral tissues, so that the circulating numbers in the blood can rise very quickly in just a few hours. Too few WBCs is called leukopenia.
WBCs are involved in defense against infection and reaction to cell damage; their functions will be studied in a later chapter.
Study these in lab.
Platelets come from giant cells in the red marrow, called megakaryocytes. These cells come from the myeloid stem cells, just as RBCs, granulocytes, and monocytes. The megakaryocytes accumulate cytoplasmic granules and specialized membrane along their margins; these pinch off in little pieces about half the diameter of RBCs, the platelets. Because these are not whole cells, they are not officially included in whole cell counts; to include platelets, use the term 'formed elements' instead of 'blood cells.' Still, they are often referred to as thrombocytes and conditions of platelets often are derived from this term, such as thrombocytopenia and thrombopoietin.
Platelets look like they can’t do much – but they are like little chemical bombs waiting for the signal to explode. They can crawl around on vessel surfaces, and swallow small particles, too. The surface of platelets bristles with receptors and signaling molecules, and new tests can determine from a simple blood sample if platelets have been activated anywhere in the body, a sign of blood clotting (although, they can’t pinpoint where!). At least one potential cancer drug was dropped, because it caused a reaction by the platelets. Platelets’ main function is to plug small leaks in vessel walls, and start the process of stopping big leaks as well, but there is still much about these cell fragments that is simply not known.
A positive feedback loop occurs when platelets are activated. The usual cause of activation is exposure of the collagen deep to the lining of blood vessels (the endothelial cells). This occurs when a vessel is torn or cut, but also when an endothelial cell is infected or damaged, as can happen with the plaque formation associated with atherosclerosis. In this situation, a clot can form in a vessel already partially blocked by the plaque, cutting off blood flow entirely.
Platelets, once activated, become sticky – and other platelets stick, and become activated, and stick; the growing platelet plug can block a small vessel, and initiate clotting in a large vessel. Any platelet that is activated but doesn’t stick initiates a second mechanism that prevents it from starting a plug elsewhere. Healthy endothelium is coated with prostacyclin, which repels platelets.
One of the functions augmented by platelets is vascular spasm. The spasm is initiated by smooth muscle in a vessel wall; smooth muscle automatically contracts when it’s irritated, as when it is cut or more so when it’s torn. Infection or other chemical stimuli can also trigger a spasm in a vessel that’s not bleeding; such a spasm can trigger a transient ischemic attack, or TIA.
Refer to p. 703 for the complete list of platelet
Coagulation involves the activation of clotting factors from the plasma. As with platelet plug formation and vascular spasm, a clot forming where it isn’t needed can do more harm than good, so clotting is carefully regulated. Most of the clotting factors are proenzymes and form a cascade, in which each enzyme activates multiple copies of the next, until the amount of activated clotting factors is highly amplified. This system allows a large reaction in a short period of time, but any shortage or defect in any one of the clotting factors can bring the entire process to a halt. A common example of this is classic hemophilia, in which clotting factor VIII is deficient due to a sex-linked genetic mutation. Because the gene for factor VIII is carried on the X chromosome, and females carry two copies of this chromosome, they are less likely than males to fail to produce any normal factor VIII. (There are other forms of hemophilia that are not sex-linked.) Many of the clotting factors are formed by the liver, and several require vitamin K for their synthesis. While some vitamin K is formed by bacteria normally found in the colon, some comes in the diet as well. Vitamin K deficiency can occur if the colon must be removed, but liver disease is a more common cause of deficiency of these procoagulants. (See Insight 18.4.)
When a vessel breaks and bleeds, a clot forms not only within the broken vessel, but also in the tissue surrounding the vessel. This external clotting is triggered by tissue clotting factors and follows an extrinsic pathway. The clot within the vessel is triggered by platelets activated by exposure to collagen and follows an intrinsic pathway. The cascade for the intrinsic pathway has more steps, so is more amplified, than the extrinsic pathway. Both extrinsic and intrinsic pathways end in the same series of steps, so this part is called the common pathway. Calcium is required for all three pathways, so removing calcium from blood is one way to prevent coagulation in donated blood. The final steps involve activation of fibrin, which is found in the plasma as the inactive precursor fibrinogen. A deficiency of fibrinogen can cause excessive bleeding; during pregnancy, fibrinogen level climbs higher than usual.
Once a clot has stopped the bleeding, it needs to stop growing. Clotting factors are carried off downstream beyond the affected branch, and diluted and deactivated. At the clot itself, some anticoagulants will retard growth beyond what’s needed. The clot will retract, expelling serum, stabilizing the clot, and bringing the broken vessel walls closer together.
After the vessel heals, the clot needs to
dissolve. A major clot dissolver is the enzyme
plasmin, which was activated from its precursor plasminogen as the
clot was being formed; it is slow to act, and doesn’t usually dissolve the clot
until healing as occurred. Plasmin is activated by kallikrein, an enzyme whose
precursor is produced by the liver and is one of the proenzymes circulating as a
plasma protein (as is plasminogen). The activation of plasmin is also aided by
a chemical secreted by the endothelial cells, called tissue plasminogen
activator (tPA). This substance can also be given by injection to bust
clots in coronary or cerebral arteries, ending the heart attack or stroke.
Clots forming where they're not needed can cause major problems, but so can bleeding. The regulation of clotting allows for rapid activation to reduce blood loss, coupled with multiple triggers to make sure clots don't form unnecessarily. Diseased endothelium, such as is seen in atherosclerosis, is a common trigger of abnormal clotting, but in some cases clots will form simply because blood flow is stagnant. Two common occurrences of this are deep venous thrombosis (DVT) and atrial fibrillation. In DVT, venous stasis (slow blood flow) in the legs (such as in bedridden patients) or inflammation of the veins (phlebitis) can trigger clot formation. A thrombus is a clot forming attached to a vessel wall. The thrombus can break loose, forming an embolus (a flowing clot), which can lodge in a small vessel elsewhere. Because of the circulatory pattern, the next small vessel is usually in the lungs, and a pulmonary embolism forms, which can be fatal. In atrial fibrillation, the flow of blood stagnates, and clots form in the slowly moving blood. One strong heart beat can move the clots into circulation; if in the left side of the heart, the next small vessel is likely in the cerebral arteries, resulting in stroke.
Functions and properties of the blood affect every organ system, which is why we study it first. We will return, again and again, to reinforce and add to what you know and understand about the blood.