Chapter 19 notes (Cardiovascular system)

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*started here on 01/11/10.
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l=Chapter 19: An Introduction to the Cardiovascular System=
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*75 trillion cells in the human body.
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*Essay tests!
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==Blood has several important functions and unique physical characteristics==
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*More articles.
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*There are 5 main functions of blood:
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*In general, what is presented in class is what is important.
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**The Transportation of Dissolved Gases, Nutrients, Hormones, and Metabolic Wastes.
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*She'll be doing 90% of the lecturing.
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**The Regulation of the pH and Ion Composition of Interstitial Fluids (via diffusions of over concentrated entities from or to the blood).
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*There is a snow day.
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**The Restriction of Fluid Losses at Injury Sites (via enzymes and other substances that respond to breaks in the vessel walls).
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*There are four equally weighted exams. "Final" is not cumulative.
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**Defense against Toxins and Pathogens (via delivery of white blood cells and antibodies).
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*The last exam will be of normal exam length.
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**Body temperature stabilization (via dispersion of excess heat or the conservation of heat).
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*Plasma is the fluid matrix in which cells are suspended.
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*The protein content of plasma makes it slightly more dense than water.
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*stopped here on 01/11/10.
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*'''Formed elements''' include RBCs (erythrocytes), WBCs (leukocytes), and platelets.
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*started here on 01/13/10.
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*There are five types of leukocytes, each with a specific function: neutrophils, eosinophils, basophils, lymphocytes, monocytes.
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*Platelets are membrane-bound cell fragments with enzymes and "other substances" for clotting.
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*Hematopoiesis = hemopoiesis = production of formed elements.
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*Myeloid and lymphoid stem cells generate the formed elements.
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*'''Whole blood''' is the combination of plasma and formed elements.
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*Blood from any location in the body has three characteristics:
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**a temperature of around 38C (100.4F),
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**a viscosity 5-times that of water (because of proteins, formed elements, and water molecules all sticking together),
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**a pH of about 7.35 to 7.45.
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*An adult male has between 5 and 6 liters of blood (5.3-6.4 quarts); women usually have between 4 and 5 liters (difference is due to body size, not physiological).
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**Dividing one's mass (kg) by 7 yields a rough estimate of liters of blood.
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=Blood=
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===Clinical note===
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*A venipuncture is usually used to obtain blood because:
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**superficial veins are usually easy to find,
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**the walls of a vein (compared to an equally sized artery) are thinner and therefore easier to puncture,
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**the blood pressure is lower in veins and therefore the puncture wound will seal more readily.
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*Arterial punctures can be useful for measuring the efficiency of gas exchange at the lungs.
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==Extracellular fluids==
 
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*Includes blood plasma, lymph, and interstitial fluid.
 
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*Lungs are a good model of interstitial fluid because the whole organ is bathed in a fluid that is critical for function but is outside of all the cells.
 
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===Extra versus intra cellular fluids===
 
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*Protein levels are different.
 
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*Difference is maintained by plasma membrane.
 
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*Sodium is high outside the cells, potassium is high inside.
 
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*Na+ and K+ are the molecules and gradients used to move things quickly across the membrane to equilibriate.
 
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===Extracellular fluid===
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==Plasma, the fluid portion of blood, contains significant quantities of plasma proteins==
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*Blood, lymph, and interstitial fluid are all similar in electrolytes.
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*They are not similar in the amount of blood cells, proteins, and lipids.
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*But the difference is less than between extra and intra- cellular.
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===Functions of blood===
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===The composition of plasma===
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*Transport, regulation of heat, ph, and fluid balance, and defense.
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*Plasma makes up 46-63% of the volume of whole blood.
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*Plasma is 92% water.
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*Most of the ECF of the body is plasma and water.
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*Plasma and ECF are pretty similar in composition.
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*Water, ions, and small solutes can flow freely between plasma and ECF at the capillaries.
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*Generally, in capillaries, more liquid and solutes are transferred from the blood to the ECF than ''vice versa''.  This is possible because the lymphatic system is draining ECF from tissue, thus decreasing the amount of ECF that needs to be drained (as the cells are generating more ECF).
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*The big differences between plasma and ECF are the concentrations of oxygen / carbon dioxide and the concentrations of dissolved proteins (because plasma proteins cannot diffuse across the capillary walls).
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====Transport====
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===Plasma Proteins===
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*Moves nutrients (sugars, aas, fatty acids, electrolytes, and water), gasses (O2 and CO2), wastes (urea, uric acid, water, CO2), and hormones.
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*The proteins that are found in the plasma are generally large, globular proteins and therefore cannot escape the circulatory system.
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*Blood can move things that are not very soluble in water.
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*The three major proteins are albumins, globulins, and fibrinogen; these make up 99% of the plasma proteins.
 +
*Other proteins include enzymes, hormones, and prohormones.
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====Regulation====
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====Albumins====
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*Heat: talked about it last semester.
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*Albumins make up 60% of the plasma proteins.
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*pH:
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*They are important for generating osmotic pressure.
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**metabolism produces pH changes but the blood has buffers to deal with this.
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*They transport fatty acids, thyroid hormones, some steroid hormones, and some other substances.
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**blood carries acids and bases to organs of excretion.
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**blood pH is slightly alkaline: 7.35-7.45.
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*Fluid balance:
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**Osmotic balance is normal even though osmolytes are different.
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====Defense====
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====Globulins====
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*Phagocytic cells:
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*Globulins make up 35% of plasma proteins.
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**Part of the innate immune system.
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*Globulins include antibodies and transport globulins.
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**Ingest microorganisms.
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*Antibodies = immunoglobulins = attack foreign proteins and pathogens.
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*Antibody producing cells, T cells,
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*Transport globulins transport things with low water solubility and things that might otherwise be filtered out by the kidneys.
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**Part of the specific immune system.
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**Hormone binding proteins, like thyroid-binding globulin or transcortin (ACTH), provide a reserve of hormones.
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*Chemicals to regulate blood flow and clotting.
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**Metalloproteins, like transferrin, transport metals.
 +
**Apolipproteins carry triglycerides and other lipids.
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**Steroid-binding proteins, like testosterone-binding globulin (TeBG), bind and transport steroid hormones.
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===Blood as a tissue===
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====Fibrinogen====
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*Blood is more viscous than water.
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*Fibrinogen makes up 4% of the plasma protein.
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**This is because of proteins, cells, etc.
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*In a blood sample, one must make sure that the fibrinogen doesn't get converted to fibrin, otherwise '''serum''' is generated and the sample is no longer a proper '''plasma''' sample.
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**Changing levels or proteins or cells can change viscocity which can mean it takes more work to pump it around.
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**If the blood volume is elevated, the resulting elevated blood pressure can damage vessels and strain the heart.
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==Blood - detail of components==
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====Other plasma proteins====
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*After centrifugation, you get the plasma (55%), the buffy coat (the leukocytes), and the erythrocytes (RBCs, 45%).
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*Other proteins found in the plasma include insulin, prolactin (PRL), TSH, FSH, LH, etc.
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*The erythrocyte fraction is called the hematocrit.
+
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*Anemia is not making enough RBCs and therefore presents with too low hematocrit.
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*Polycythemia is making too many RBCs and therefore presents with too high hematocrit.
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-
*Hydration can also change hematocrit, too.
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*Plasma and serum are different.  Serum results from allowing RBCs to clot and then spinning out.  If you put in anticoagulant in, then spin, you generate plasma.  So the difference is that plasma has clotting factors and serum doesn't.
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*95% of plasma proteins are albumins and globulins.
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*Fibrinogen makes up 4% of the plasma protein levels.
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===Plasma proteins===
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====Clinical note====
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*Albumin:
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*Plasma expanders can be used to increase blood volume temporarily.
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**Made by the liver.
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*These are better than donated plasma because donations can be contaminated with viruses or bacteria.
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**Most abundant protein in plasma.
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*Saline can be used but it is quickly absorbed into the ECF.
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**Transports lipid-soluble components.
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*So one can add solutes that cannot diffuse into the ECF, such as lactate in ''Ringer's solution''.
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**Add an osmotic force to the plasma.
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*Even lactate, however, is eventually absorbed by the liver, skeletal muscles, and other tissues.
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***Inside and outside of cells must be osmotically balanced and proteins can help with this.  So the albumins are blancing all the protein (like Hb) in blood cells.
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*So we could add saline with lots of albumin in it (because it cannot be absorbed through capillaries).
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*Globulins:
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*The best, however, is large carbohydrate molecules in saline.  Over time, these will eventually be phagocytized by phagocytes.
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**alpha, beta, and gamma globulins are called that because that's the way they came off the chromatography. So alphas are heaviest (carrying the heaviest stuff), then beta, then gammas are the lightest.
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*Note that these only increase blood volume, they do not increase oxygen levels.
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**One globulin of interest is transferrin.  It carries Fe around in the body.  It keeps Fe from wandering around and messing stuff up.  Transferrin allows the liver to store Fe.
+
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**The gamma globulin fraction of blood serum will have the antibodies needed after a snake bite.
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**Inside and outside of cells must be osmotically balanced and proteins can help with this.  So the globulins are blancing all the protein (like Hb) in blood cells.
+
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===Plasma protein function===
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====Origins of the plasma proteins====
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*Carriers as we've mentioned.
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*The liver generates more than 90% of the plasma proteins, including all the albumins, all the fibrinogen, most globulins, and some prohormones.
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*Act as buffers because they have lots of positive and negative side chains.
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**Therefore, liver problems can lead to blood problems.
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*They are part of the clotting cascade.
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*Lymphocytes generate plasma cells which generate antibodies.
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*They contribute from the osmotic pressure.  We call the choloital osmotic pressure to speak specifically of the effect of proteins on osmotic balance.
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*Proteins can be broken down into amino acids for energy (starvation).
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==Osmotic pressure - tonicity==
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==Red blood cells, formed by erythropoiesis, contain hemoglobin that can be recycled==
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*Isotonic means it has the same osmotic pressure of the plasma.  Isotonic saline (0.85% NaCl) can be used to increase blood volume.
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*RBCs are the most abundant cell in blood.
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*Hypertonic means that the tonicity of the plasma is higher than normal.  This can be because you have too much protein or because you have too little water.  This means water will move out of the cells.
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*They have hemoglobin which is a red pigment that binds oxygen.
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*Hypotonic means the tonicity of the plasma is lower than normal.  This could occur because of liver disease (albumin can't be made).  This decreases the choloital osmotic pressure.  This causes adema because the cells will take up water to balance osmotic pressure.
+
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==Formed elements==
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===Abundance of RBCs===
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*We call them formed elements because most of them are not cells.
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*A single drop of blood has 260 million RBCs.
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*Platelets nor RBCs are cells; RBCs have no nuclei and platelets are just chunks of cells.
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*There are approximately 25 trillion RBCs in the whole body.
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*We don't have to memorize the intermediate states of the cells (myelocytes, band cells, etc.).
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*Hematocrit is the percentage of the whole blood volume made up of formed elements (which is 99.9% RBCs).
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*''Blast'' means not fully differentiated.
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*Adult males have hematocrit of about 46% while females are about 42%; this is primarily because the androgens found in men stimulate RBCs generation.
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*HSCs are committed to the hematopoietic line.
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*Hematocrit is measured via centrifugal separation of plasma, WBCs / platelets, and RBCs.
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*Factors that stimulate HSC development:
+
*Because RBCS outnumber all other formed elements so easily, hematocrit is often reported as the ''volume of packed red cells'' (VPRC) or the ''packed cell volume'' (PCV).
-
**EPO -> RBCs
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*Hematorcit levels can vary from dehydration, EPO stimulation, or other factors.
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**Thromopoietin -> platelets
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*An abnormal hematocrit level is usually not evidence enough for diagnosis, but is an indicator that more specific tests are needed.
-
**Colony stimulating factor -> WBCs
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-
**Cytokines -> WBCs
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***Released by WBCs themselves.
+
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*You can stimulate how long it takes to generate a cell but only by a day or two.
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*RBCs live for only a couple of weeks.
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-
*WBCs (particularly those for...) can live for years.
+
-
===Erythrocytes===
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===Structure of RBCs===
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*Fully mature has no nucleus or organelles.
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*RBCs are highly specialized and this is reflected in their shape: a biconcave disc with a thin central region and a thicker outer marigin.
-
*It is a biconcaved disc for increased surface area to volume ratio and flexibility.
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*The shape of a RBC is important for three reasons:
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*We can make about 2 million RBCs / second!  That's 230 billion / day.
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**increased surface-area-to-volume-ratio for fast, efficient exchange of oxygen from intracellular proteins to tissue (through capillaries),
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*You can make RBCs in the spleen and liver, but this is only under extreme conditions.
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**ability to form ''rouleaux'' (stacks of RBCs) that can flow easily through capillaries that are only slightly wider than a RBC,
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*RBCs die after 4 months because they have no nucleus so they cannot repair themselves.
+
**ability to flex in order to fit through capillaries as narrow as 4 micrometers (half the normal diameter of a RBC).
-
*They are broken down by macrophages in the spleen, liver, and marrow.
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*RBCs have few organelles (and no nucleus in mammals) and no mitochondria and therefore have low energy demands.
-
*Hemocytoblasts -> myeloid stem cells -> proerythroblast -> bone marrow -> erythroblasts (basophilic, polychromatophilic, normoblast) -> start generating lots of Hb and turning red -> loss of nucleus -> reticulocyte (still has some small organelle) -> enter circulation -> finish up making Hb -> mature red blood cell.
+
*The energy they do need, they generate via glycolysis of glucose absorbed from blood plasma.
 +
*RBCs cannot generate proteins.
-
====Stuff required for erythropoiesis====
 
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*2/3 of the body's iron is in RBCs.
 
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*We don't want to waste Fe, so we use ferritin and transferrin to store (in the liver) and transfer iron.
 
-
Why is copper required?
 
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*B12 is required so you can make erythrocyte maturation factor and thus mature your RBCs.
 
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*Pyridoxine and folic acid are required for DNA synthesis since we're making lots of protein.
 
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====Hormonal control of RBC production====
 
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*EPO
 
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**Causes HSCs to go down RBC lineage.
 
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**Increases speed of differentiation.
 
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**Comes from kidney in response to hypoxia.
 
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*The stimulus is low blood oxygen, not necessarily low numbers of RBCs.  So it could be:
 
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**reduced numbers of RBCs which means there is less oxygen getting carried around,
 
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**reduced O2 in the RBCs because of high altitude,
 
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***This is altitude sickness: can't catch breath, heart is going a mile a minute, etc.  Gets better because you make more RBCs.
 
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**increased tissue demand for O2 because of aerobic exercise.
 
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*EPO extends the life of patients on dialysis.  It used to be that they handed out EPO to the most needy dialysis patients.  Now that we have a purified form, it is abused by athletes.
 
-
**EPO increases RBCs which increases O2 carrying ability which leads to increased stamina.  However, more RBCs also means increased viscocity and makes the heart work harder.
 
-
===Article about EPO abuse===
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===Hemoglobin===
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*There have been 18 deaths among top cyclists because of EPO.
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*RBCs lose any organelles not directly involved in transport of oxygen.
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*Hard to measure abuse of EPO because it is natural.
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*Hemoglobin (Hb) makes up 95% of intracellular protein in RBCs.
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*So we try to measure the hematocrit (RBCs) but this can be counter-acted with saline injection.  Well, this leads to increased volume and harder work on the heart and death.
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*Doping is when you take some blood out before the event and inject them back in before the event.
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*So, this is hard to catch, too, because hematocrit levels are quite variable based on temperature, work load, etc.
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*So this article suggests that we measure via transferrin receptor : ferritin ratio.
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*Transferring receptors are released by the RBC precursor cells so Transferrin receptor will go up whenever RBC production is up.
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*Ferritin gets broken down if it doesn't have Fe bound.
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*If you're making lots of RBCs, then Ferritin isn't storing any Fe, so it is going down.
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*So the ratio will be very sensitive because one factor (transferrin receptor) is going up and the other (ferritin) is going down.
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===More regulation of RBC production===
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====Hemoglobin structure====
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*Intrinsic factor is required for absorbing B12 from diet.
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*Hemoglobin is made up of four globular chains, 2 alpha and 2 beta units.
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*B12 + IF bind to form erythrocyte maturation factor which is required for the last steps of RBC maturation.
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*Each chain, like myoglobin, contains a heme unit which is a non-protein pigment complex.
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*If you don't have this, your RBCs will not be carrying as much oxygen and a form of anemia will occur.
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*Each heme group contains an iron ion which can easily bind and unbind oxygen.
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*When the iron binds oxygen, the hemoglobin unit is called oxyhemoglobin.  These are bright red.
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*When the iron does not bind oxygen, it is called deoxyhemoglobin.  These appear dark red or burgundy.
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*stopped here on 01/13/10.
 
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==Hemoglobin==
 
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==Blood - ?==
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*Infants have fetal hemoglobin (hemoglobin F) which binds oxygen more readily.  In this way a fetus can "steal" oxygen from it's mother's blood stream.
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*Hemoglobin F can be stimulated via hydroxyurea or butyrate and thus treat blood disorders like sickle cell anemia or thalassemia.
 +
 
 +
====Hemoglobin function====
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*Each RBC has about 280 million hemoglobin (Hb) proteins which each have four heme groups.  Thus, each RBC can carry over 1 billion molecules of oxygen.
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*98.5% of all oxygen in the blood is carried by Hb molecules inside RBCs.
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*When plasma oxygen levels drop, Hb releases oxygen.
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*When plasma CO2 levels increase, the alpha and beta chains of Hb bind CO2.  This state is called carbaminohemoglobin.
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*These binding balances shift in the capillaries and the lungs where gas exchange is occurring.
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*If hematocrit levels decrease or Hb levels within RBCs decrease, not enough oxygen will be delivered to tissues--anemia.
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*Anemia can present with weakness, lethargy, and confusion as muscles, organs, and the brain are all being deprived of oxygen.
 +
 
 +
===RBC formation and turnover===
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*RBCs must be constantly replaced because they incur much damage in their 700 mile, 120 day lifespan.
 +
*Phagocytes engulf and digest aging RBCs upon detection of damage.
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*1% of all RBCs are produced and digested each day--that's a rate of 3 million new RBCs each second!
 +
 
 +
====Clinical note: Abnormal hemoglobin====
 +
*Two well known genetic disorders resulting in abnormal hemoglobin are thalassemia and sickle cell anemia.
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*Thalassemia results from the too-slow production of alpha or beta units, the subsequent low concentration of Hb in RBCs, fragile and short-lived RBCs, and thus problems with development and growth of systems throughout the body.
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*Patients with thalassemia may require transfusions to increase components of the blood.
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*Sickle cell anemia is due to a mutation in the beta chain of Hb.
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 +
 
 +
 
 +
====Hemoglobin conservation and recycling====
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*The heme prosthetic group in hemoglobin and myoglobin is heme B.
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*Macrophages and phagocytes of the liver, spleen, and bone marrow engulf deteriorating RBCs, generally (90% of the time) before they rupture (hemolyze).
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*If a RBC does hemolyze, the hemoglobin will deteriorate into alpha and beta chains and be excreted via the kidneys which may lead to hemoglobinuria (red or brown urine).
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*Upon damage to the kidney or vessels along the urinary tract, hematuria may occur such that fully intact RBCs are found in the urine.
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*The amino-acid chains of hemoglobin are broken down into aas in the macrophages and either used in the macrophage or secreted into the blood for use by other cells.
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*The heme units first have there iron molecules removed making them biliverdin (a greenish color that shows up in bruises) which gets converted into bilirubin (an orangish color) and dropped into the bloodstream where albumin transports it to the liver for excretion via bile.
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**Macrophage + heme -> biliverbin -> bilirubin -> bloodstream + albumin -> liver -> bile -> out.
 +
*If the liver cannot absorb or secrete bilirubin, the bilirubin will build up in peripheral tissues like the sclera and the skin and cause '''jaundice'''.
 +
*Bilirubin are converted into urobilinogens and stercobilinogens by bacteria in the large intestine.  Upon exposure to oxygen, these turn into urobilins and stercobilins which give urine and feces their yellow-brown, brown color.
 +
 
 +
 
 +
 
 +
====Iron====
 +
*Iron released into the blood at the liver upon destruction of heme units is bound to transferrin for transport in the blood.
 +
*Bone marrow tissue absorbs iron so that it can generate new Hb.
 +
*Ferritin and hemosiderin are used by the liver and spleen to store excess amounts of iron.
 +
*This recycling program of iron from digested heme to generation of new heme is quite efficient--only 1-2 mg of iron is needed in the diet while 26 mg are used each day to produce heme units.  That is, only 1-2mg of the 26mg of iron generated from the breakdown of RBCs is lost each day.
 +
*So, too little iron (which will decrease RBC production) or too much iron (which will increase irons stores in the liver and cardiac tissue) can cause health issues.
 +
 
 +
===RBC production===
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*Embryonic blood cells appear in the blood stream at week three.
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*For the first 8 weeks, the yolk sac is where most blood is generated.
 +
*As other organs develop, some ESCs move into the liver, spleen, thymus, and bone marrow where they will differentiate into stem cells that generate blood cells.
 +
*The liver and spleen are the primary organs producing blood cells for months 2-5 of development-until the bone can mature into having marrow.
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*In adults, RBCs are generated ''only'' in the marrow.
 +
*RBCs are generated in red bone marrow (myeloid tissue).
 +
*Red bone marrow is found in the vertebrae, scapulas, ribs, sternum, pelvis, skull, and the proximal limb bones.
 +
*Yellow marrow can be converted to red marrow upon extreme and sustained duress.
 +
 
 +
====Stages in RBC maturation====
 +
*Hemocytoblasts can generate myeloid stem cells and lymphoid stem cells which will generate red / white blood cells and lymphocytes, respectively.
 +
*Hemocytoblasts -> myeloid stem cells -> proerythroblasts -> erythroblasts (basophilic -> polychromatophilic -> normoblast) -> reticulocyte -> mature RBC.
 +
*Erythroblasts actively generate hemoglobin and are named based on their size, the amount of hemoglobin presnet, and the appearance of their nucleus.
 +
*As a reticulocyte, the cell enters circulation with 80% of its Hb generated.  Though the nucleus is gone, the RNA needed to generate the last 20% of Hb is still present.  After 24 hours in circulation, all the Hb has been generated and the RNA is gone.
 +
 
 +
 
 +
 
 +
====Regulation of Erythropoiesis====
 +
*Generating RBCs requires that the bone marrow get enough nutrients, including vitamin B12.
 +
*B12 comes from dairy and meat in our diet.
 +
*The stomach generates something called ''intrinsic factor'' which is required for absorbing B12.
 +
*When there isn't enough B12, pernicious anemia occurs.
 +
**This can occur because of too little B12 in the diet, too little production of ''intrinsic factor'' or because of an abnormality with B12/''intrinsic factor'' absorption.
 +
*Generating RBCs can be stimulated with erythropoietin, thyroxine, androgens, and growth hormone.  Note, however that estrogen does not stimulate RBC generation.
 +
*EPO is a glycoprotein.
 +
*EPO is produced by the liver and kidneys.
 +
*EPO is generated when peripheral tissues or the kidneys experience hypoxia which might occur because of:
 +
**anemia,
 +
**decreased blood flow to kidneys,
 +
**decreased oxygen concentration in respired air (high altitude),
 +
**damaged lung respiratory surfaces.
 +
*EPO acts on the stem cells found in bone marrow to increase generation of erythroblasts from their progenitors and to increase erythroblast division.
 +
*EPO also acts to increase RBC maturation rates, sometimes up to 30 fold faster!
 +
*EPO arc: Kidney / peripheral tissues suffer hypoxia -> Liver / kidney produce / release EPO -> blood stream -> bone marrow -> myeloid cells generate more erythroblasts, erythroblasts divide more rapidly to make more RBCs, and RBCs mature faster.
 +
*Using EPO to increase RBC counts in for athletes is dangerous because it puts a strain on the heart because of increased viscocity.
 +
*'''Blood doping''' is when you take blood out of an athlete, sequester the RBCs, and then reinfuse them at a later date to increase RBC counts.
 +
*Blood tests can be used to quickly, cheaply, and unobtrusively assess a patient's health in several ways.
 +
 
 +
 
 +
 
 +
==The ABO blood types and Rh system are based on antigen-antibody response==
 +
*Antigens are usually proteins but some other organic molecules can also act as antigens.
 +
*Our own cells have surface antigens that mark them as native, also called agglutinogens.
 +
*RBCs have over 50 surface antigens, but three of particular importance are A, B, and Rh (D).
 +
*These 50 antigens are integrated glycoproteins or integrated glycolipids.
 +
*Type O: 46%, type A: 40%, type B: 10%, type AB: 4% (of US population).
 +
*Blood plasma contains '''agglutinins''' which attack cells with foreign antigens and cause a clumping together called agglutination.
 +
*Rh antigens are a little different in that an Rh negative patient will not have anti-Rh antigens until they have been ''sensitized'' or exposed (perhaps via pregnancy with an Rh positive child or via a transfusion).
 +
 
 +
 
 +
 
 +
===Cross-reactions in transfusions===
 +
*When blood antigen types are not matched for a transfusion, the agglutinogens will cause the foreign cells to clump together which can block blood vessels in lethal areas like the lungs, heart, brain, or kidneys.
 +
*Remember that the reaction of the recipient's plasma antigens against the donor's RBCs is more important when considering cross-reaction potential because the donation will only include a very small amount of the donor's plasma such that it's attack on the recipient's RBCs will probably not generate harmful clumping.
 +
**This means that one must consider most carefully the antigens on the donor's RBCs.
 +
*One unit of blood is 500ml, of which 275ml is plasma (because the plasma content has been reduced).
 +
 
 +
===Testing for transfusion compatibility===
 +
*Before a transfusion, a compatibility test is run which identifies the antigens of the donor and then shows the results of a cross-match test.
 +
*To identify antigens on a donor's RBCs, two separate drops are exposed to anti-A and anti-B antigens; if there is a reaction with both, the blood type is AB, if only with one, then A or B, respectively.
 +
*Rh is also noted (but the book didn't say how this test was run, which is interesting because one wouldn't necessarily have anti-Rh antigens even if they are Rh-).
 +
*When time permits, we try to match all 50 antigens because, though it is rare, it is possible to have a reaction to one of the other 48 antigens.
 +
*Blood typing is inherited and therefore is used in paternity testing and in crime scene detection.
 +
**Testing for the other 48 antigens increases accuracy and DNA testing can generate 100% surety.
 +
 
 +
 
 +
 
 +
==The various types of white blood cells contribute to the body's defenses==
 +
*In a microliter of blood, there are about 5-10K WBCs and 4-6M RBCs.
 +
*Most WBCs are found in the connective tissue or organs of the lymphoid system.
 +
*WBCs can be identified in a smear with a Wright stain or a Giemsa stain.
 +
**Granular leukocytes = granulocytes: neutrophils, eosinophils, and basophils with large secretion vesicles and lysosomes.
 +
**Agranular leukocytes = agranulocytes: monocytes and lymphocytes with much smaller vesicles and lysosomes.
 +
 
 +
===WBC circulation and movement===
 +
*WBCs mostly reside and migrate through the loose and dense connective tissue.
 +
*The only travel through the blood stream to get where they are going.
 +
*As they are traveling through the blood stream, they can exit upon detection of a signal indicating damage.
 +
*There are four characteristics of circulating WBCs:
 +
**they can exit the blood stream by adhering to the endothelial wall (margination) and squeezing through the endothelial wall (emigration or diapedesis),
 +
**they are capable of amoeboid movement through the ECM which requires ATP and Ca++,
 +
**they are sensitive to specific chemical stimuli which act as positive chemotaxants toward damaged tissue and other activated WBCs,
 +
**Neutrophils, eosinophils, and monocytes are capable of phagocytizing cells and materials.
 +
*Macrophages are just monocytes that have moved out of the blood stream and are actively phagocytic.
 +
 
 +
===Types of WBCs===
 +
*Neutrophils, eosinophils, basophils, and monocytes are nonspecific defenses.
 +
*Lymphocytes are specific defenses.
 +
 
 +
====Neutrophils====
 +
*Neutrophils are also called polymorphonuclear leukocytes because the nucleus has several dense lobes.
 +
*Neutrophils got their name from having a neutral coat that is hard to stain because it doesn't attract acidic or basic dyes.
 +
*Neuts make up 50-70% of circulating WBCs.
 +
*They have lysosomes with enzymes and bactericidal compounds.
 +
*Neuts are very fast and active and generally the first on the scene of an injury.
 +
*They can attack and digest bacteria and other cells that have been marked with complement proteins.
 +
*Once a neutrophils has engulfed a cell, it turns on it's metabolism to high (called ''respiratory burst'') in order to generate superoxides and hydrogen perioxides (called ''defensins'').
 +
*The phagocytized cell is then fused with the lysosomes (degranulation) and the enzymes destroy the cell by eating away it's membrane.
 +
*Neutrophils also release leukotrienes to attrack other leukocytes to the site of attack.
 +
*Neutrophils release prostaglandins in order to make the capillaries near the injury more permeable and therefore contribute to local inflammation.
 +
*Neutrophils live about 10 hours in the blood stream, perhaps only 30 minutes if they are attacking a bad guy.
 +
*Pus is a mixture of dead neutrophils, cellular debris, and other waste products.
 +
 
 +
 
 +
 
 +
====Eosinophils====
 +
*Eosinophils stain easily with eosin, a red dye.
 +
*They have a bilobed nucleus and are about the same size as a neut.
 +
*They make up only 2-4% of circulating WBCs.
 +
*These guys can engulf antibody laden bad guys but generally secrete nitric oxide and cytotoxic enzymes.
 +
*They are particularly good at attacking multicellular parasites.
 +
*Eosinophils multiply rapidly when parasitic infection occurs or allergens are detected.
 +
*Eosinophils help reduce inflammation by neuts and mast cells at a site of infection, keeping it from spreading to adjacent tissue.
 +
 
 +
====Basophils====
 +
*Basophils can be stained with basic dyes.
 +
*Basophils are smaller than neuts and eosinophils.
 +
*They make up only 1% of the WBC population.
 +
*Basophils release their granules into the interstitial fluid.
 +
*The granules include:
 +
**histamine to dilate blood vessels,
 +
**heparin to prevent blood clotting,
 +
**chemicals to reduce inflammation started by mast cells,
 +
**chemicals to attract eosinophils,
 +
**chemicals to attract more basophils.
 +
 
 +
====Monocytes====
 +
*Monocytes are the largest WBCs.
 +
*Monocytes make up 2-8 percent of the WBC population.
 +
*Monocytes have a kidney or oval shaped nucleus.
 +
*Monocytes are only in the bloodstream long enough to get to their tissue, then they become a resident macrophage.
 +
*Macrophages phagocytize aggressively.
 +
*While phagocytizing, macrophages release factors that attract neutrophils, monocytes, other phagocytic cells, and fibrocytes.
 +
*The fibrocytes will build scar tissue.
 +
 
 +
====Lymphocytes====
 +
*Lymphocytes are 20-30% of the circulating WBC population.
 +
*Lymphocytes have a large round nucleus with only a little cytoplasm surrounding it.
 +
*Lymphocytes are circulating through the blood, peripheral tissue, and lymphatic system constantly.
 +
*The circulating fraction is only a very small portion of all lymphocytes, however.
 +
*There are three functional classes of lymphocytes, none of which can be distinguished with a microscope:
 +
**T cells either attack foreign cells themselves or coordinate a response involving the other lymphocyte classes.  T cells are responsible for ''cell-mediated immunity''.
 +
**B cells are responsible for the ''humoral immunity'' (fluid immunity) of the body because as mature cells (plasma cells) they generate antibodies that attack antigens on foreign cells throughout the body.
 +
**Natural killer cells are responsible for immune surveillance--the detection and destruction of abnormal tissue cells like those of cancers.
 +
*Note that T cells must migrate to their target but B cells generate antibodies which can act anywhere in the body.
 +
 
 +
===The differential count and changes in WBC profiles===
 +
*We can often tell what is going on in a body by looking at the numbers of each type of WBC in a sample.
 +
*''penia'' means ''too little''.
 +
*''osis'' can mean ''too many''.
 +
*So ''leukopenia'' means there is a low count of leukocytes (WBCs) and ''lukocytosis'' means there may be too many.
 +
*''Leukemia'' refers to having boatloads of WBCs.
 +
 
 +
 
 +
 
 +
===WBC Production===
 +
*This image is pretty much all we need to know.
 +
 
 +
 
 +
 
 +
====Regulation of WBC production====
 +
*The thymus secretes hormones that stimulate the production of T cells, that is, until the thymus stops working in youth.
 +
*Therefore, in adults, it is the exposure to antigens that increases production of B and T cells.
 +
*The non-lymphocyte WBCs are stimulated by colony-stimulating factors (CSFs).
 +
*There are four CSFs:
 +
**M-CSf stimulates production of monocytes.
 +
**G-CSF stimulates the production of the granulocytes (neutrophils, eosinophils, and basophils).
 +
**GM-CSF stimulates the production of monocytes and granulocytes.
 +
**Multi-CSF accelerates the production of granulocytes, monocytes, platelets, and even RBCs.
 +
*Communcation between lymphocytes and other WBCs occurs via chemicals like the CSFs and EPO.
 +
*Some of these communicatory chemicals are approved for clinical use: like G-CSF = filgrastim = neupogen which is given to chemotherapy patients to increase their neutrophil count.
 +
 
 +
==Platelets, disc-shaped structures formed from megakaryocytes, function in the clotting process==
 +
*Platelets are called thrombocytes in nonmammals because they are still nucleated cells.
 +
*Platelets are important for clotting, along with plasma proteins and the cells and tissues of the blood vessels themselves.
 +
*About 1/3 of our platelets are found in the spleen and other vascular organs while 2/3 are circulating.
 +
*Platelets circulate for about 10 days before being phagocytized.
 +
*Thrombocytopenia (too few platelets) generally occurs because of bleeding along the digestive tract, withing the skin, or within the CNS (and thus platelets are lost faster than made).
 +
*Thrombocytosis (too many platelets) often results from accelerated production in response to infection, inflammation, or cancer.
 +
 
 +
===Platelet function===
 +
*Platelets:
 +
**release enzymes and other factors at the appropriate time to help initiate clotting,
 +
**form a clump of platelets to plug up injuries of vessels,
 +
**contract (via actin / myosin) to make the size of the clotted area / damaged area smaller.
 +
 
 +
===Platelet production===
 +
*The generation of platelets (thrombocytopoiesis) is facilitated by megakaryocytes in the bone marrow.
 +
*Megakaryocytes are large, have a large nucleus, and generate lots of proteins, enzymes, and membrane.
 +
*Then segments of the megakaryocyte's cell body are slowly sheered off by the blood stream and thus are made platelets.
 +
*Thrombocytopoiesis can be stimulated via:
 +
**thrombopoietin (TBO, AKA: thrombocyte-stimulating factor) which is a peptide hormone produced in the kidneys,
 +
**IL-6,
 +
**multi-CSF.
 +
 
 +
==Hemostasis involves vascular spasm, platelet plug formation, and blood coagulation==
 +
*Hemostasis literally means blood halting; it is about stopping blood loss.
 +
*There are three, intermixed stages: vascular, platelet, coagulation.
 +
 
 +
===The vascular phase===
 +
*The vascular phase begins first and includes the contraction of the smooth muscle that surrounds the injured vessel.  This cans slow or even stop blood loss.
 +
*Three changes in the endothelium occur during the vascular phase:
 +
**Endothelial cells contract and expose the underlying basal lamina to the blood stream,
 +
**Endothelial cells release chemical factors including ADP, tissue factor, prostacyclin, and endothelins.
 +
***Endothelins stimulate smooth muscle contraction and the division of endothelial cells, smooth muscle cells, and fibrocytes.
 +
**The endothelial cells of the vessel wall become sticky and thus stick together to help seal the break.  This also helps faciliate the beginning of the platelet phase.
 +
 
 +
===The platelet phase===
 +
*The platelet phase begins upon ''platelet adhesion'' to the sticky endothelial cells as well as collagen fibers.
 +
*Then the platelets aggregate to form a plug which can sometimes stop blood loss if the injury is small.
 +
*Platelet aggregation occurs within 15 seconds of an injury.
 +
*Platelets become activated as they arrive at the site of injury and thus they release:
 +
**ADP to stimulate platelet aggregation and secretion,
 +
**Thromboxane A2 and serotonin to stimulate vascular spasms,
 +
**Proteins that play a role in clotting (called ''clotting factors''),
 +
**PDGF, a peptide hormone that promotes vessel repair, and
 +
**calcium ions which help will aggregation and clotting.
 +
*Because each platelet is releasing all this stuff, there is positive feedback such that this process occurs rapidly.
 +
*Therefore, plug formation must be limited to the site of injury by several factors:
 +
**Prostacyclin is released by endothelial cells,
 +
**Inhibitory compounds are released by WBCs,
 +
**Plasma enzymes break down ADP (which is stimulating aggregation) near the plug,
 +
**Compounds (like serotonin) which, at high levels, block formation of more plug material, and
 +
**The formation of a blood clot isolates the plug (and therefore all the factors encouraging more plug formation) from the general circulation.
 +
 
 +
===The coagulation phase===
 +
*The coagulation phase takes about 30 seconds to sit in while the vascular and platelet take 0-15 seconds.
 +
*In the coagulation phase, the blood clot is formed over the platelet plug via a complex series of steps that convert fibrinogen (a soluble protein circulating in the blood) into a mesh of fibrin in which other blood cells and such get stuck to form a filled mesh that will become something like a scab and effectively stop blood loss.
 +
 
 +
 
 +
 
 +
====Clotting factors====
 +
*Clotting factors = procoagulants.
 +
*Clotting factors are generally proenzymes that go through a cascade of activation in order to start the clotting process.
 +
*Ca++ is also a clotting factor.
 +
*Clotting occurs through two pathways; the intrinsic pathway begins in the bloodstream while the extrinsic pathway begins outside the bloodstream, in the vessel wall.
 +
*Both pathways activate the common pathway (see diagram above) via ''factor x''.
 +
 
 +
 
 +
 
 +
====The extrinsic pathway====
 +
*The extrinsic pathway starts by the release of factor III by damaged endothelial cells.
 +
*Factor III interacts with Ca++ and other factors to activate factor x.
 +
 
 +
====The intrinsic pathway====
 +
*The intrinsic pathway begins when proenzymes in the blood are activated by exposure to collagen (or a glass test tube).
 +
*Then several platelet factors and clotting factors interact before they activate factor x.
 +
 
 +
====The common pathway====
 +
*The common pathway begins when factor x is activated which forms prothrombinase.
 +
*Prothrombinase converts prothrombin into thrombin which converts fibrinogen into fibrin.
 +
 
 +
====Interactions among the pathways====
 +
*The extrinsic pathway is shorter and faster and produces a quick, but small amount of thrombin.
 +
*Clotting occurs in a matter of minutes.
 +
 
 +
====Feedback control of blood clotting====
 +
*The common pathway speeds up both the extrinsic and intrinsic pathways via positive feedback, thus making clotting a very fast process.
 +
*Because there is such positive feedback, there are also many factors that inhibit clot formation:
 +
**Anticoagulants found in blood plasma,
 +
**Heparin, released by basophils and mast cells,
 +
**Thrombomodulin released by endothelial cells which activates '''protein C''' which deactivates fibrin strands,
 +
**Prostacyclin from the platelet phase.
 +
*Many clinical conditions require close regulation and manipulation of clotting and anticlotting factors.
 +
 
 +
====Calcium ions, vitamin K, and blood clotting====
 +
*Ca++ is required in all three pathways: intrinsic, extrinsic, and common.
 +
*Vitamin K is required for the liver to generate many of the clotting factor proteins found in plasma.
 +
*Therefore anything that messes up Ca++ or vitamin K levels can affect the patient's ability to clot.
 +
*Vitamin K is fat soluble.
 +
*Half our vitamin K needs are absorbed in the diet and half is generated by bacteria in the gut.
 +
 
 +
====Clot retraction====
 +
*Within about 30 to 60 minutes, a clot has formed and platelets are pulling together to reduce residual bleeding and to make it easier for fibrocytes, smooth muscle cells, and endothelial cells to complete their repairs.
 +
 
 +
===Fibrinolysis===
 +
*The fibrin network can be broken down via plasminogen.
 +
*For everything to work properly, blood has to keep flowing.  RBCs make about 2 circuits per minute.

Revision as of 02:41, 14 February 2010

l=Chapter 19: An Introduction to the Cardiovascular System=

  • 75 trillion cells in the human body.

Contents

Blood has several important functions and unique physical characteristics

  • There are 5 main functions of blood:
    • The Transportation of Dissolved Gases, Nutrients, Hormones, and Metabolic Wastes.
    • The Regulation of the pH and Ion Composition of Interstitial Fluids (via diffusions of over concentrated entities from or to the blood).
    • The Restriction of Fluid Losses at Injury Sites (via enzymes and other substances that respond to breaks in the vessel walls).
    • Defense against Toxins and Pathogens (via delivery of white blood cells and antibodies).
    • Body temperature stabilization (via dispersion of excess heat or the conservation of heat).
  • Plasma is the fluid matrix in which cells are suspended.
  • The protein content of plasma makes it slightly more dense than water.
  • Formed elements include RBCs (erythrocytes), WBCs (leukocytes), and platelets.
  • There are five types of leukocytes, each with a specific function: neutrophils, eosinophils, basophils, lymphocytes, monocytes.
  • Platelets are membrane-bound cell fragments with enzymes and "other substances" for clotting.
  • Hematopoiesis = hemopoiesis = production of formed elements.
  • Myeloid and lymphoid stem cells generate the formed elements.
  • Whole blood is the combination of plasma and formed elements.
  • Blood from any location in the body has three characteristics:
    • a temperature of around 38C (100.4F),
    • a viscosity 5-times that of water (because of proteins, formed elements, and water molecules all sticking together),
    • a pH of about 7.35 to 7.45.
  • An adult male has between 5 and 6 liters of blood (5.3-6.4 quarts); women usually have between 4 and 5 liters (difference is due to body size, not physiological).
    • Dividing one's mass (kg) by 7 yields a rough estimate of liters of blood.

Clinical note

  • A venipuncture is usually used to obtain blood because:
    • superficial veins are usually easy to find,
    • the walls of a vein (compared to an equally sized artery) are thinner and therefore easier to puncture,
    • the blood pressure is lower in veins and therefore the puncture wound will seal more readily.
  • Arterial punctures can be useful for measuring the efficiency of gas exchange at the lungs.


Plasma, the fluid portion of blood, contains significant quantities of plasma proteins

The composition of plasma

  • Plasma makes up 46-63% of the volume of whole blood.
  • Plasma is 92% water.
  • Most of the ECF of the body is plasma and water.
  • Plasma and ECF are pretty similar in composition.
  • Water, ions, and small solutes can flow freely between plasma and ECF at the capillaries.
  • Generally, in capillaries, more liquid and solutes are transferred from the blood to the ECF than vice versa. This is possible because the lymphatic system is draining ECF from tissue, thus decreasing the amount of ECF that needs to be drained (as the cells are generating more ECF).
  • The big differences between plasma and ECF are the concentrations of oxygen / carbon dioxide and the concentrations of dissolved proteins (because plasma proteins cannot diffuse across the capillary walls).

Plasma Proteins

  • The proteins that are found in the plasma are generally large, globular proteins and therefore cannot escape the circulatory system.
  • The three major proteins are albumins, globulins, and fibrinogen; these make up 99% of the plasma proteins.
  • Other proteins include enzymes, hormones, and prohormones.

Albumins

  • Albumins make up 60% of the plasma proteins.
  • They are important for generating osmotic pressure.
  • They transport fatty acids, thyroid hormones, some steroid hormones, and some other substances.

Globulins

  • Globulins make up 35% of plasma proteins.
  • Globulins include antibodies and transport globulins.
  • Antibodies = immunoglobulins = attack foreign proteins and pathogens.
  • Transport globulins transport things with low water solubility and things that might otherwise be filtered out by the kidneys.
    • Hormone binding proteins, like thyroid-binding globulin or transcortin (ACTH), provide a reserve of hormones.
    • Metalloproteins, like transferrin, transport metals.
    • Apolipproteins carry triglycerides and other lipids.
    • Steroid-binding proteins, like testosterone-binding globulin (TeBG), bind and transport steroid hormones.

Fibrinogen

  • Fibrinogen makes up 4% of the plasma protein.
  • In a blood sample, one must make sure that the fibrinogen doesn't get converted to fibrin, otherwise serum is generated and the sample is no longer a proper plasma sample.

Other plasma proteins

  • Other proteins found in the plasma include insulin, prolactin (PRL), TSH, FSH, LH, etc.

Clinical note

  • Plasma expanders can be used to increase blood volume temporarily.
  • These are better than donated plasma because donations can be contaminated with viruses or bacteria.
  • Saline can be used but it is quickly absorbed into the ECF.
  • So one can add solutes that cannot diffuse into the ECF, such as lactate in Ringer's solution.
  • Even lactate, however, is eventually absorbed by the liver, skeletal muscles, and other tissues.
  • So we could add saline with lots of albumin in it (because it cannot be absorbed through capillaries).
  • The best, however, is large carbohydrate molecules in saline. Over time, these will eventually be phagocytized by phagocytes.
  • Note that these only increase blood volume, they do not increase oxygen levels.

Origins of the plasma proteins

  • The liver generates more than 90% of the plasma proteins, including all the albumins, all the fibrinogen, most globulins, and some prohormones.
    • Therefore, liver problems can lead to blood problems.
  • Lymphocytes generate plasma cells which generate antibodies.

Red blood cells, formed by erythropoiesis, contain hemoglobin that can be recycled

  • RBCs are the most abundant cell in blood.
  • They have hemoglobin which is a red pigment that binds oxygen.

Abundance of RBCs

  • A single drop of blood has 260 million RBCs.
  • There are approximately 25 trillion RBCs in the whole body.
  • Hematocrit is the percentage of the whole blood volume made up of formed elements (which is 99.9% RBCs).
  • Adult males have hematocrit of about 46% while females are about 42%; this is primarily because the androgens found in men stimulate RBCs generation.
  • Hematocrit is measured via centrifugal separation of plasma, WBCs / platelets, and RBCs.
  • Because RBCS outnumber all other formed elements so easily, hematocrit is often reported as the volume of packed red cells (VPRC) or the packed cell volume (PCV).
  • Hematorcit levels can vary from dehydration, EPO stimulation, or other factors.
  • An abnormal hematocrit level is usually not evidence enough for diagnosis, but is an indicator that more specific tests are needed.

Structure of RBCs

  • RBCs are highly specialized and this is reflected in their shape: a biconcave disc with a thin central region and a thicker outer marigin.
  • The shape of a RBC is important for three reasons:
    • increased surface-area-to-volume-ratio for fast, efficient exchange of oxygen from intracellular proteins to tissue (through capillaries),
    • ability to form rouleaux (stacks of RBCs) that can flow easily through capillaries that are only slightly wider than a RBC,
    • ability to flex in order to fit through capillaries as narrow as 4 micrometers (half the normal diameter of a RBC).
  • RBCs have few organelles (and no nucleus in mammals) and no mitochondria and therefore have low energy demands.
  • The energy they do need, they generate via glycolysis of glucose absorbed from blood plasma.
  • RBCs cannot generate proteins.


Hemoglobin

  • RBCs lose any organelles not directly involved in transport of oxygen.
  • Hemoglobin (Hb) makes up 95% of intracellular protein in RBCs.

Hemoglobin structure

  • Hemoglobin is made up of four globular chains, 2 alpha and 2 beta units.
  • Each chain, like myoglobin, contains a heme unit which is a non-protein pigment complex.
  • Each heme group contains an iron ion which can easily bind and unbind oxygen.
  • When the iron binds oxygen, the hemoglobin unit is called oxyhemoglobin. These are bright red.
  • When the iron does not bind oxygen, it is called deoxyhemoglobin. These appear dark red or burgundy.


  • Infants have fetal hemoglobin (hemoglobin F) which binds oxygen more readily. In this way a fetus can "steal" oxygen from it's mother's blood stream.
  • Hemoglobin F can be stimulated via hydroxyurea or butyrate and thus treat blood disorders like sickle cell anemia or thalassemia.

Hemoglobin function

  • Each RBC has about 280 million hemoglobin (Hb) proteins which each have four heme groups. Thus, each RBC can carry over 1 billion molecules of oxygen.
  • 98.5% of all oxygen in the blood is carried by Hb molecules inside RBCs.
  • When plasma oxygen levels drop, Hb releases oxygen.
  • When plasma CO2 levels increase, the alpha and beta chains of Hb bind CO2. This state is called carbaminohemoglobin.
  • These binding balances shift in the capillaries and the lungs where gas exchange is occurring.
  • If hematocrit levels decrease or Hb levels within RBCs decrease, not enough oxygen will be delivered to tissues--anemia.
  • Anemia can present with weakness, lethargy, and confusion as muscles, organs, and the brain are all being deprived of oxygen.

RBC formation and turnover

  • RBCs must be constantly replaced because they incur much damage in their 700 mile, 120 day lifespan.
  • Phagocytes engulf and digest aging RBCs upon detection of damage.
  • 1% of all RBCs are produced and digested each day--that's a rate of 3 million new RBCs each second!

Clinical note: Abnormal hemoglobin

  • Two well known genetic disorders resulting in abnormal hemoglobin are thalassemia and sickle cell anemia.
  • Thalassemia results from the too-slow production of alpha or beta units, the subsequent low concentration of Hb in RBCs, fragile and short-lived RBCs, and thus problems with development and growth of systems throughout the body.
  • Patients with thalassemia may require transfusions to increase components of the blood.
  • Sickle cell anemia is due to a mutation in the beta chain of Hb.


Hemoglobin conservation and recycling

  • The heme prosthetic group in hemoglobin and myoglobin is heme B.
  • Macrophages and phagocytes of the liver, spleen, and bone marrow engulf deteriorating RBCs, generally (90% of the time) before they rupture (hemolyze).
  • If a RBC does hemolyze, the hemoglobin will deteriorate into alpha and beta chains and be excreted via the kidneys which may lead to hemoglobinuria (red or brown urine).
  • Upon damage to the kidney or vessels along the urinary tract, hematuria may occur such that fully intact RBCs are found in the urine.
  • The amino-acid chains of hemoglobin are broken down into aas in the macrophages and either used in the macrophage or secreted into the blood for use by other cells.
  • The heme units first have there iron molecules removed making them biliverdin (a greenish color that shows up in bruises) which gets converted into bilirubin (an orangish color) and dropped into the bloodstream where albumin transports it to the liver for excretion via bile.
    • Macrophage + heme -> biliverbin -> bilirubin -> bloodstream + albumin -> liver -> bile -> out.
  • If the liver cannot absorb or secrete bilirubin, the bilirubin will build up in peripheral tissues like the sclera and the skin and cause jaundice.
  • Bilirubin are converted into urobilinogens and stercobilinogens by bacteria in the large intestine. Upon exposure to oxygen, these turn into urobilins and stercobilins which give urine and feces their yellow-brown, brown color.


Iron

  • Iron released into the blood at the liver upon destruction of heme units is bound to transferrin for transport in the blood.
  • Bone marrow tissue absorbs iron so that it can generate new Hb.
  • Ferritin and hemosiderin are used by the liver and spleen to store excess amounts of iron.
  • This recycling program of iron from digested heme to generation of new heme is quite efficient--only 1-2 mg of iron is needed in the diet while 26 mg are used each day to produce heme units. That is, only 1-2mg of the 26mg of iron generated from the breakdown of RBCs is lost each day.
  • So, too little iron (which will decrease RBC production) or too much iron (which will increase irons stores in the liver and cardiac tissue) can cause health issues.

RBC production

  • Embryonic blood cells appear in the blood stream at week three.
  • For the first 8 weeks, the yolk sac is where most blood is generated.
  • As other organs develop, some ESCs move into the liver, spleen, thymus, and bone marrow where they will differentiate into stem cells that generate blood cells.
  • The liver and spleen are the primary organs producing blood cells for months 2-5 of development-until the bone can mature into having marrow.
  • In adults, RBCs are generated only in the marrow.
  • RBCs are generated in red bone marrow (myeloid tissue).
  • Red bone marrow is found in the vertebrae, scapulas, ribs, sternum, pelvis, skull, and the proximal limb bones.
  • Yellow marrow can be converted to red marrow upon extreme and sustained duress.

Stages in RBC maturation

  • Hemocytoblasts can generate myeloid stem cells and lymphoid stem cells which will generate red / white blood cells and lymphocytes, respectively.
  • Hemocytoblasts -> myeloid stem cells -> proerythroblasts -> erythroblasts (basophilic -> polychromatophilic -> normoblast) -> reticulocyte -> mature RBC.
  • Erythroblasts actively generate hemoglobin and are named based on their size, the amount of hemoglobin presnet, and the appearance of their nucleus.
  • As a reticulocyte, the cell enters circulation with 80% of its Hb generated. Though the nucleus is gone, the RNA needed to generate the last 20% of Hb is still present. After 24 hours in circulation, all the Hb has been generated and the RNA is gone.


Regulation of Erythropoiesis

  • Generating RBCs requires that the bone marrow get enough nutrients, including vitamin B12.
  • B12 comes from dairy and meat in our diet.
  • The stomach generates something called intrinsic factor which is required for absorbing B12.
  • When there isn't enough B12, pernicious anemia occurs.
    • This can occur because of too little B12 in the diet, too little production of intrinsic factor or because of an abnormality with B12/intrinsic factor absorption.
  • Generating RBCs can be stimulated with erythropoietin, thyroxine, androgens, and growth hormone. Note, however that estrogen does not stimulate RBC generation.
  • EPO is a glycoprotein.
  • EPO is produced by the liver and kidneys.
  • EPO is generated when peripheral tissues or the kidneys experience hypoxia which might occur because of:
    • anemia,
    • decreased blood flow to kidneys,
    • decreased oxygen concentration in respired air (high altitude),
    • damaged lung respiratory surfaces.
  • EPO acts on the stem cells found in bone marrow to increase generation of erythroblasts from their progenitors and to increase erythroblast division.
  • EPO also acts to increase RBC maturation rates, sometimes up to 30 fold faster!
  • EPO arc: Kidney / peripheral tissues suffer hypoxia -> Liver / kidney produce / release EPO -> blood stream -> bone marrow -> myeloid cells generate more erythroblasts, erythroblasts divide more rapidly to make more RBCs, and RBCs mature faster.
  • Using EPO to increase RBC counts in for athletes is dangerous because it puts a strain on the heart because of increased viscocity.
  • Blood doping is when you take blood out of an athlete, sequester the RBCs, and then reinfuse them at a later date to increase RBC counts.
  • Blood tests can be used to quickly, cheaply, and unobtrusively assess a patient's health in several ways.


The ABO blood types and Rh system are based on antigen-antibody response

  • Antigens are usually proteins but some other organic molecules can also act as antigens.
  • Our own cells have surface antigens that mark them as native, also called agglutinogens.
  • RBCs have over 50 surface antigens, but three of particular importance are A, B, and Rh (D).
  • These 50 antigens are integrated glycoproteins or integrated glycolipids.
  • Type O: 46%, type A: 40%, type B: 10%, type AB: 4% (of US population).
  • Blood plasma contains agglutinins which attack cells with foreign antigens and cause a clumping together called agglutination.
  • Rh antigens are a little different in that an Rh negative patient will not have anti-Rh antigens until they have been sensitized or exposed (perhaps via pregnancy with an Rh positive child or via a transfusion).


Cross-reactions in transfusions

  • When blood antigen types are not matched for a transfusion, the agglutinogens will cause the foreign cells to clump together which can block blood vessels in lethal areas like the lungs, heart, brain, or kidneys.
  • Remember that the reaction of the recipient's plasma antigens against the donor's RBCs is more important when considering cross-reaction potential because the donation will only include a very small amount of the donor's plasma such that it's attack on the recipient's RBCs will probably not generate harmful clumping.
    • This means that one must consider most carefully the antigens on the donor's RBCs.
  • One unit of blood is 500ml, of which 275ml is plasma (because the plasma content has been reduced).

Testing for transfusion compatibility

  • Before a transfusion, a compatibility test is run which identifies the antigens of the donor and then shows the results of a cross-match test.
  • To identify antigens on a donor's RBCs, two separate drops are exposed to anti-A and anti-B antigens; if there is a reaction with both, the blood type is AB, if only with one, then A or B, respectively.
  • Rh is also noted (but the book didn't say how this test was run, which is interesting because one wouldn't necessarily have anti-Rh antigens even if they are Rh-).
  • When time permits, we try to match all 50 antigens because, though it is rare, it is possible to have a reaction to one of the other 48 antigens.
  • Blood typing is inherited and therefore is used in paternity testing and in crime scene detection.
    • Testing for the other 48 antigens increases accuracy and DNA testing can generate 100% surety.


The various types of white blood cells contribute to the body's defenses

  • In a microliter of blood, there are about 5-10K WBCs and 4-6M RBCs.
  • Most WBCs are found in the connective tissue or organs of the lymphoid system.
  • WBCs can be identified in a smear with a Wright stain or a Giemsa stain.
    • Granular leukocytes = granulocytes: neutrophils, eosinophils, and basophils with large secretion vesicles and lysosomes.
    • Agranular leukocytes = agranulocytes: monocytes and lymphocytes with much smaller vesicles and lysosomes.

WBC circulation and movement

  • WBCs mostly reside and migrate through the loose and dense connective tissue.
  • The only travel through the blood stream to get where they are going.
  • As they are traveling through the blood stream, they can exit upon detection of a signal indicating damage.
  • There are four characteristics of circulating WBCs:
    • they can exit the blood stream by adhering to the endothelial wall (margination) and squeezing through the endothelial wall (emigration or diapedesis),
    • they are capable of amoeboid movement through the ECM which requires ATP and Ca++,
    • they are sensitive to specific chemical stimuli which act as positive chemotaxants toward damaged tissue and other activated WBCs,
    • Neutrophils, eosinophils, and monocytes are capable of phagocytizing cells and materials.
  • Macrophages are just monocytes that have moved out of the blood stream and are actively phagocytic.

Types of WBCs

  • Neutrophils, eosinophils, basophils, and monocytes are nonspecific defenses.
  • Lymphocytes are specific defenses.

Neutrophils

  • Neutrophils are also called polymorphonuclear leukocytes because the nucleus has several dense lobes.
  • Neutrophils got their name from having a neutral coat that is hard to stain because it doesn't attract acidic or basic dyes.
  • Neuts make up 50-70% of circulating WBCs.
  • They have lysosomes with enzymes and bactericidal compounds.
  • Neuts are very fast and active and generally the first on the scene of an injury.
  • They can attack and digest bacteria and other cells that have been marked with complement proteins.
  • Once a neutrophils has engulfed a cell, it turns on it's metabolism to high (called respiratory burst) in order to generate superoxides and hydrogen perioxides (called defensins).
  • The phagocytized cell is then fused with the lysosomes (degranulation) and the enzymes destroy the cell by eating away it's membrane.
  • Neutrophils also release leukotrienes to attrack other leukocytes to the site of attack.
  • Neutrophils release prostaglandins in order to make the capillaries near the injury more permeable and therefore contribute to local inflammation.
  • Neutrophils live about 10 hours in the blood stream, perhaps only 30 minutes if they are attacking a bad guy.
  • Pus is a mixture of dead neutrophils, cellular debris, and other waste products.


Eosinophils

  • Eosinophils stain easily with eosin, a red dye.
  • They have a bilobed nucleus and are about the same size as a neut.
  • They make up only 2-4% of circulating WBCs.
  • These guys can engulf antibody laden bad guys but generally secrete nitric oxide and cytotoxic enzymes.
  • They are particularly good at attacking multicellular parasites.
  • Eosinophils multiply rapidly when parasitic infection occurs or allergens are detected.
  • Eosinophils help reduce inflammation by neuts and mast cells at a site of infection, keeping it from spreading to adjacent tissue.

Basophils

  • Basophils can be stained with basic dyes.
  • Basophils are smaller than neuts and eosinophils.
  • They make up only 1% of the WBC population.
  • Basophils release their granules into the interstitial fluid.
  • The granules include:
    • histamine to dilate blood vessels,
    • heparin to prevent blood clotting,
    • chemicals to reduce inflammation started by mast cells,
    • chemicals to attract eosinophils,
    • chemicals to attract more basophils.

Monocytes

  • Monocytes are the largest WBCs.
  • Monocytes make up 2-8 percent of the WBC population.
  • Monocytes have a kidney or oval shaped nucleus.
  • Monocytes are only in the bloodstream long enough to get to their tissue, then they become a resident macrophage.
  • Macrophages phagocytize aggressively.
  • While phagocytizing, macrophages release factors that attract neutrophils, monocytes, other phagocytic cells, and fibrocytes.
  • The fibrocytes will build scar tissue.

Lymphocytes

  • Lymphocytes are 20-30% of the circulating WBC population.
  • Lymphocytes have a large round nucleus with only a little cytoplasm surrounding it.
  • Lymphocytes are circulating through the blood, peripheral tissue, and lymphatic system constantly.
  • The circulating fraction is only a very small portion of all lymphocytes, however.
  • There are three functional classes of lymphocytes, none of which can be distinguished with a microscope:
    • T cells either attack foreign cells themselves or coordinate a response involving the other lymphocyte classes. T cells are responsible for cell-mediated immunity.
    • B cells are responsible for the humoral immunity (fluid immunity) of the body because as mature cells (plasma cells) they generate antibodies that attack antigens on foreign cells throughout the body.
    • Natural killer cells are responsible for immune surveillance--the detection and destruction of abnormal tissue cells like those of cancers.
  • Note that T cells must migrate to their target but B cells generate antibodies which can act anywhere in the body.

The differential count and changes in WBC profiles

  • We can often tell what is going on in a body by looking at the numbers of each type of WBC in a sample.
  • penia means too little.
  • osis can mean too many.
  • So leukopenia means there is a low count of leukocytes (WBCs) and lukocytosis means there may be too many.
  • Leukemia refers to having boatloads of WBCs.


WBC Production

  • This image is pretty much all we need to know.


Regulation of WBC production

  • The thymus secretes hormones that stimulate the production of T cells, that is, until the thymus stops working in youth.
  • Therefore, in adults, it is the exposure to antigens that increases production of B and T cells.
  • The non-lymphocyte WBCs are stimulated by colony-stimulating factors (CSFs).
  • There are four CSFs:
    • M-CSf stimulates production of monocytes.
    • G-CSF stimulates the production of the granulocytes (neutrophils, eosinophils, and basophils).
    • GM-CSF stimulates the production of monocytes and granulocytes.
    • Multi-CSF accelerates the production of granulocytes, monocytes, platelets, and even RBCs.
  • Communcation between lymphocytes and other WBCs occurs via chemicals like the CSFs and EPO.
  • Some of these communicatory chemicals are approved for clinical use: like G-CSF = filgrastim = neupogen which is given to chemotherapy patients to increase their neutrophil count.

Platelets, disc-shaped structures formed from megakaryocytes, function in the clotting process

  • Platelets are called thrombocytes in nonmammals because they are still nucleated cells.
  • Platelets are important for clotting, along with plasma proteins and the cells and tissues of the blood vessels themselves.
  • About 1/3 of our platelets are found in the spleen and other vascular organs while 2/3 are circulating.
  • Platelets circulate for about 10 days before being phagocytized.
  • Thrombocytopenia (too few platelets) generally occurs because of bleeding along the digestive tract, withing the skin, or within the CNS (and thus platelets are lost faster than made).
  • Thrombocytosis (too many platelets) often results from accelerated production in response to infection, inflammation, or cancer.

Platelet function

  • Platelets:
    • release enzymes and other factors at the appropriate time to help initiate clotting,
    • form a clump of platelets to plug up injuries of vessels,
    • contract (via actin / myosin) to make the size of the clotted area / damaged area smaller.

Platelet production

  • The generation of platelets (thrombocytopoiesis) is facilitated by megakaryocytes in the bone marrow.
  • Megakaryocytes are large, have a large nucleus, and generate lots of proteins, enzymes, and membrane.
  • Then segments of the megakaryocyte's cell body are slowly sheered off by the blood stream and thus are made platelets.
  • Thrombocytopoiesis can be stimulated via:
    • thrombopoietin (TBO, AKA: thrombocyte-stimulating factor) which is a peptide hormone produced in the kidneys,
    • IL-6,
    • multi-CSF.

Hemostasis involves vascular spasm, platelet plug formation, and blood coagulation

  • Hemostasis literally means blood halting; it is about stopping blood loss.
  • There are three, intermixed stages: vascular, platelet, coagulation.

The vascular phase

  • The vascular phase begins first and includes the contraction of the smooth muscle that surrounds the injured vessel. This cans slow or even stop blood loss.
  • Three changes in the endothelium occur during the vascular phase:
    • Endothelial cells contract and expose the underlying basal lamina to the blood stream,
    • Endothelial cells release chemical factors including ADP, tissue factor, prostacyclin, and endothelins.
      • Endothelins stimulate smooth muscle contraction and the division of endothelial cells, smooth muscle cells, and fibrocytes.
    • The endothelial cells of the vessel wall become sticky and thus stick together to help seal the break. This also helps faciliate the beginning of the platelet phase.

The platelet phase

  • The platelet phase begins upon platelet adhesion to the sticky endothelial cells as well as collagen fibers.
  • Then the platelets aggregate to form a plug which can sometimes stop blood loss if the injury is small.
  • Platelet aggregation occurs within 15 seconds of an injury.
  • Platelets become activated as they arrive at the site of injury and thus they release:
    • ADP to stimulate platelet aggregation and secretion,
    • Thromboxane A2 and serotonin to stimulate vascular spasms,
    • Proteins that play a role in clotting (called clotting factors),
    • PDGF, a peptide hormone that promotes vessel repair, and
    • calcium ions which help will aggregation and clotting.
  • Because each platelet is releasing all this stuff, there is positive feedback such that this process occurs rapidly.
  • Therefore, plug formation must be limited to the site of injury by several factors:
    • Prostacyclin is released by endothelial cells,
    • Inhibitory compounds are released by WBCs,
    • Plasma enzymes break down ADP (which is stimulating aggregation) near the plug,
    • Compounds (like serotonin) which, at high levels, block formation of more plug material, and
    • The formation of a blood clot isolates the plug (and therefore all the factors encouraging more plug formation) from the general circulation.

The coagulation phase

  • The coagulation phase takes about 30 seconds to sit in while the vascular and platelet take 0-15 seconds.
  • In the coagulation phase, the blood clot is formed over the platelet plug via a complex series of steps that convert fibrinogen (a soluble protein circulating in the blood) into a mesh of fibrin in which other blood cells and such get stuck to form a filled mesh that will become something like a scab and effectively stop blood loss.


Clotting factors

  • Clotting factors = procoagulants.
  • Clotting factors are generally proenzymes that go through a cascade of activation in order to start the clotting process.
  • Ca++ is also a clotting factor.
  • Clotting occurs through two pathways; the intrinsic pathway begins in the bloodstream while the extrinsic pathway begins outside the bloodstream, in the vessel wall.
  • Both pathways activate the common pathway (see diagram above) via factor x.


The extrinsic pathway

  • The extrinsic pathway starts by the release of factor III by damaged endothelial cells.
  • Factor III interacts with Ca++ and other factors to activate factor x.

The intrinsic pathway

  • The intrinsic pathway begins when proenzymes in the blood are activated by exposure to collagen (or a glass test tube).
  • Then several platelet factors and clotting factors interact before they activate factor x.

The common pathway

  • The common pathway begins when factor x is activated which forms prothrombinase.
  • Prothrombinase converts prothrombin into thrombin which converts fibrinogen into fibrin.

Interactions among the pathways

  • The extrinsic pathway is shorter and faster and produces a quick, but small amount of thrombin.
  • Clotting occurs in a matter of minutes.

Feedback control of blood clotting

  • The common pathway speeds up both the extrinsic and intrinsic pathways via positive feedback, thus making clotting a very fast process.
  • Because there is such positive feedback, there are also many factors that inhibit clot formation:
    • Anticoagulants found in blood plasma,
    • Heparin, released by basophils and mast cells,
    • Thrombomodulin released by endothelial cells which activates protein C which deactivates fibrin strands,
    • Prostacyclin from the platelet phase.
  • Many clinical conditions require close regulation and manipulation of clotting and anticlotting factors.

Calcium ions, vitamin K, and blood clotting

  • Ca++ is required in all three pathways: intrinsic, extrinsic, and common.
  • Vitamin K is required for the liver to generate many of the clotting factor proteins found in plasma.
  • Therefore anything that messes up Ca++ or vitamin K levels can affect the patient's ability to clot.
  • Vitamin K is fat soluble.
  • Half our vitamin K needs are absorbed in the diet and half is generated by bacteria in the gut.

Clot retraction

  • Within about 30 to 60 minutes, a clot has formed and platelets are pulling together to reduce residual bleeding and to make it easier for fibrocytes, smooth muscle cells, and endothelial cells to complete their repairs.

Fibrinolysis

  • The fibrin network can be broken down via plasminogen.
  • For everything to work properly, blood has to keep flowing. RBCs make about 2 circuits per minute.
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