Chapter 18 - Cardiovascular System - Blood

Substances Involved in Coagulation

Substances Involved in Coagulation • Blood coagulation is a process that requires numerous substances, including calcium, clotting factors, platelets, and vitamin K: o Note that the clotting factor numbers are in order of their discovery, and not their position in the clotting pathway o Most clotting factors are inactive enzymes, and most of these are produced by the liver • Vitamin K is a fat-soluble vitamin that is required for the synthesis of clotting factors II, VII, IX, and X; it acts as a coenzyme • Proteases such as factor VII and IX, when activated, act like scissors to convert another separate factor from its inactive to its active form - this active factor acts like scissors to convert yet another inactive factor to its active form; thus, the formation of a blood clot involves a cascade of changes

Agranulocytes

Agranulocytes • leukocytes that have such small specific granules in their cytosol - not clearly visible (light microscope) - include lymphocytes and monocytes

CLINICAL VIEW - Anemia

CLINICAL VIEW - Anemia Anemia • is any condition in which either the percentage of erythrocytes is lower than normal or the oxygen-carrying capacity of the blood is reduced (such as may occur if the hemoglobin is abnormal). In either case, there is decreased oxygen delivery to body tissues—and consequently, the heart must work harder to supply oxygen to the body. Symptoms of anemia include lethargy, shortness of breath, pallor of the skin and mucous membranes, fatigue, and heart palpitations. The types of anemia include the following: Aplastic anemia • is characterized by significantly decreased formation of both erythrocytes and hemoglobin. This condition results from defective red bone marrow, perhaps as a result of poisons, toxins, or radiation exposure. Congenital hemolytic anemia • occurs when destruction of erythrocytes is more rapid than normal. It is usually due to a genetic defect, which results in the production of abnormal membrane proteins that make the erythrocyte plasma membrane very fragile. Erythroblastic anemia • is characterized by the presence of large numbers of immature, nucleated cells (called erythroblasts and normoblasts) in the circulating blood. An accelerated pace of cell maturation causes immature cells to be present in the blood. These cells cannot function normally and thus anemia results. Hemorrhagic anemia • results from heavy blood loss. The hemorrhage may be caused, for example, by chronic ulcers or by heavy or prolonged menstrual flow. Macrocytic anemia • occurs when the average size of circulating erythrocytes is too large. Deficiencies in both vitamin B12 and folic acid presence or uptake cause the production of enlarged erythrocytes. Pernicious anemia • is a chronic progressive anemia of adults caused by failure of the body to absorb vitamin B12. This vitamin is found in fish and meat, so most individuals receive enough B12 in their diet, unless they are vegans or strict vegetarians. (Thus, it is recommended that all vegetarians take a B12 vitamin supplement.) A defect in the production of intrinsic factor, a glycoprotein secreted by stomach lining cells to protect B12 in the stomach and enhance B12 absorption in the small intestine, leads to pernicious anemia. Individuals who have pernicious anemia due to defective intrinsic factor production must receive B12 intramuscular or subcutaneous injections, since they are unable to absorb oral B12 supplements. Sickle-cell disease • is an autosomal recessive anemia that occurs when a person inherits two copies of the sickle-cell gene. Erythrocytes become sickle-shaped at lower blood oxygen concentrations, making them unable to flow efficiently through the blood vessels to body tissues and more prone to destruction (a process called hemolysis). Most anemias are treated by letting the patient's own bone marrow replace the erythrocytes. • This process may be facilitated through the use of pharmaceutical EPO. However, anemia is often a symptom of another disease or problem. For example, although many anemias are due to iron deficiency, the iron deficiency often is not because of diet, but rather the result of chronic blood loss, a process that depletes the body of its iron stores over months or years. The three most common causes of such chronic blood loss are excessive menstrual bleeding, undiagnosed stomach ulcer, and colon cancer. So, while restoring the patient's erythrocyte count, a physician should also look for any underlying cause of the anemia.

Dietary requirements for normal erythropoiesis -

Dietary requirements for normal erythropoiesis - o iron o B vitamins (e.g., folic acid, riboflavin) o amino acids (to build proteins)

Eosinophils

Eosinophils • have reddish or pink-orange granules in their cytosol o ~1-4% of the total number of leukocytes o nucleus is bilobed, and the two lobes are connected by a thin strand o ~1.5 times larger in diameter than an erythrocyte • phagocytize numerous antigen-antibody complexes or allergens (antigens that initiate a hypersensitive or allergic reaction) o If the body is infected by parasitic worms, the eosinophils release chemical mediators that attack the worms.

Erythrocytes & Erythropoietin (EPO)

Erythrocytes o >99% of formed elements o 4.2-6.2 x106 / mm3 - concentration o ~3 x106/ s - production rate Erythropoietin (EPO) increases rate of erythrocyte formation

Fibrinogen ( fiber)

Fibrinogen ( fiber) • ~4% of all plasma proteins • Fibrinogen as well as other clotting proteins are responsible for blood clot formation • Following trauma to the walls of blood vessels, fibrinogen is converted into long, insoluble strands of fibrin, which help form a blood clot • When the clotting proteins are removed from plasma, the remaining fluid is termed serum (whey)

Fibrinolysis

Fibrinolysis To destroy the fibrin framework of the clot, plasmin (or fibrinolysin) degrades the fibrin strands through fibrinolysis. o begins within 2 days of the clot formation and occurs slowly over a number of days

Formed Elements

Formed elements • Erythrocytes (or red blood cells) function to transport respiratory gases in the blood • Leukocytes (or white blood cells) contribute to defending the body against pathogens • Platelets help clot the blood and prevent blood loss from damaged vessels

Hemoglobin

Hemoglobin • red-pigmented protein that transports oxygen and carbon dioxide o blood - maximally loaded with oxygen - oxygenated (and appears bright red) o otherwise deoxygenated (and appears dark red) • Each hemoglobin molecule consists of four protein molecules called globins o alpha (α) chains & beta (β) chains o contain a heme group - porphyrin ring, iron ion (Fe2+) center o Oxygen binds to Fe2+ (heme) for transport • four heme groups - four Fe2+ o capable of binding four molecules of oxygen o oxygen binding is fairly weak allows rapid attachment and detachment of oxygen with hemoglobin o similar with carbon dioxide (not the Fe2+ )

extrinsic pathway

In contrast, the extrinsic pathway is initiated by damage to the tissue that is outside the vessel, and this pathway usually takes approximately 15 seconds. This pathway occurs more quickly because there are fewer steps required. The steps include the following: 1. Tissue factor (thromboplastin; factor III) released from damaged tissues combines with factor VII and Ca2+ to form a complex. 2. This complex converts inactive factor X to active factor X.

Leukopoiesis

Leukopoiesis - production of leukocytes • Leukocytes o < 0.01% of formed elements o with concentration 4.5-11 x103 / mm3 • The Leukopoiesis involves three different types of maturation processes: - granulocyte maturation - monocyte maturation - lymphocyte maturation

Monocyte Maturation Process

Monocyte Maturation Process - > myeloid stem cell > progenitor cell (under the influence of M-CSF) > monoblast > promonocyte > monocyte

Monocytes

Monocytes • A monocyte can be up to three times the diameter of an erythrocyte o Monocytes usually constitute about 2-8% of all leukocytes o The nucleus of a monocyte is kidney-shaped or C-shaped • After approximately 3 days in circulation, monocytes exit blood vessels and take up residence within the tissues, where they transform into large phagocytic cells called macrophages • Macrophages phagocytize bacteria, viruses, cell fragments, dead cells, and debris

Neutrophils

Neutrophils • most numerous leukocyte in the blood is the neutrophil, ~50-70% of leukocytes o named for its neutral or pale-colored granules within a light lilac-colored cytosol o ~1.5 times larger in diameter than an erythrocyte o exhibit a multilobed nucleus; as many as five lobes are interconnected by thin strands. o polymorphonuclear (PMN) leukocytes - number of lobes & various shapes of their nuclei • Neutrophils usually remain in circulation for about 10 to 12 hours before they exit the blood vessels and enter the tissue spaces, where they phagocytize infectious pathogens, especially bacteria. o The number of neutrophils in a person's blood rises dramatically in the presence of a chronic bacterial infection, as more neutrophils are produced that target the bacteria.

Plasma

Plasma • fluid portion of blood containing plasma proteins and dissolved solutes

Protection

Protection • Blood contains leukocytes, plasma proteins, and various molecules that help protect the body against potentially harmful substances - these substances are part of the immune system • Components of blood (platelets and plasma proteins) also protect the body against blood loss

The Sympathetic Response to Blood Loss

The Sympathetic Response to Blood Loss • when > 10% blood loss - survival response is initiated - blood volume decreases, blood pressure decreases • the sympathetic nervous system is activated - - increased vasoconstriction of blood vessels - increased heart rate - increased force of heart contraction in an attempt to maintain blood pressure • Blood flow is also redistributed to the heart and brain to keep these vital structures functioning • effective in maintaining blood pressure until ~40% of the blood is lost • Blood loss >40% - insufficient blood volume - blood pressure unable to support life

colony-stimulating factors (CSFs)

• The maturation and division of hemopoietic stem cells is influenced by colony-stimulating factors (CSFs), or colony-forming units (CFUs). o These molecules are all growth factors, except for erythropoietin, which is a hormone.

Basophils

Basophils • ~1.5 times larger than erythrocytes. o least numerous of the granulocytes o ~0.5-1% of the total number of leukocytes o Exhibit a bilobed nucleus and abundant deep blue-violet granules in the cytosol The primary components of basophil granules are histamine and heparin • histamine release - cause vasodilation and increase capillary permeability The classic allergic symptoms of swollen nasal membranes, itchy and runny nose, and watery eyes are partially attributed to the release of histamine • The release of heparin from basophils inhibits blood clotting (a process called anticoagulation)

Blood

Blood • specialized fluid • transported through the cardiovascular system - composed of the heart and blood vessels

Composition of Blood Plasma

Blood Plasma • Composed primarily of water (about 92% of its volume), plasma proteins, and other solutes including electrolytes (e.g., Na+), nutrients (e.g., glucose), respiratory gases (e.g., CO2), and wastes (e.g., urea) • An extracellular fluid (ECF) - fluid found outside of cells o Similar concentrations of electrolytes, nutrients, and waste products as interstitial fluid o Protein concentration is higher in plasma than in the interstitial fluid

three formed elements of the blood, from the blood smear

Blood Smear All of the components of the formed elements can be viewed by preparing a blood smear: • Erythrocytes are the most numerous of the formed elements. These are anucleate cells and appear as pink or pale purple, biconcave discs. • Leukocytes are larger than erythrocytes. The nucleus is very noticeable in leukocytes. Several leukocytes (a lymphocyte, neutrophil, and two monocytes) are shown in figure 18.2. • Platelets appear as small fragments of cells.

hemocytoblasts

Hemopoiesis starts with hemopoietic stem cells called hemocytoblasts o pluripotent cells - can differentiate and develop into many different kinds of cells Two different hemocytoblasts lines for blood cell development: (1) The myeloid line forms erythrocytes, all leukocytes except lymphocytes (this would include granulocytes and monocytes), and megakaryocytes (cells that produce platelets) (2) The lymphoid line forms only lymphocytes

Initiation of the Coagulation Cascade

Initiation of the Coagulation Cascade Can occur by two separate mechanisms: - the intrinsic pathway (also known as the contact activation pathway) or - the extrinsic pathway (or tissue factor pathway). Both pathways converge, through a series of complicated steps, to the common pathway.

Regulation

Regulation - of body temperature, body pH, and fluid balance Body temperature. • Blood absorbs heat from body cells o e.g. - skeletal muscle, as it passes through blood vessels of body tissues o Heat is then released at the body surface through blood vessels of the skin Body pH. • Absorbs acid and base from body cells • Use chemical buffers (e.g., proteins, bicarbonate) that bind and release hydrogen ions (H+) to maintain blood pH until the excess is eliminated from the body Fluid balance. • Water is added to the blood from the gastrointestinal tract and lost in numerous ways o (including in urine, sweat, and respired air) • Constant exchange of fluid between the blood plasma in the capillaries and the interstitial fluid • Blood proteins and ions exert osmotic pressure to pull fluid back into the capillaries to help maintain normal fluid balance

Describe when and how blood is formed in the embryo, fetus, childhood, and adulthood.

The first primitive hemopoietic stem cells • develop in the yolk sac wall of the embryo by the 3rd week of development. The primitive hemopoietic stem cells go on to colonize other organs, such as the liver, spleen, and thymus. • In these organs, these very primitive stem cells develop into the hemocytoblasts that produce all of the formed elements. • Later in fetal development (beginning at 10 weeks), the hemocytoblasts begin to colonize red bone marrow, although the liver doesn't completely cease its blood cell production until close to birth.

Thrombopoiesis

Thrombopoiesis - production of platelets • Platelets (or thrombocytes) o < 1% of formed elements o with concentration 150-400 x103 / mm3 > myeloid stem cell > megakaryoblast (under the influence of thrombopoietin) > megakaryocyte - large size ~ 100μm D - dense, multilobed nucleus - produces thousands of platelets proplatelets • long extensions produced by megakaryocytes • While attached - extend through the blood vessel wall in the red bone marrow • blood flow force into the fragments - platelets

Transportation

Transportation - "delivery system" for the body Blood transports formed elements and dissolved molecules and ions throughout the body: • carries oxygen from and carbon dioxide to the lungs • nutrients absorbed from the gastrointestinal (GI) tract • hormones released by endocrine glands • heat and waste products from the systemic cells • delivers medication to the cells of your body

Hemostasis

When your blood vessels are healthy and functioning well, blood flows through them freely and does not clot unnecessarily. But if there is damage to a blood vessel, hemostasis - stoppage of bleeding • It consists of three sequential phases, although there is some overlap between phases: vascular spasm, platelet plug formation, and coagulation phase

vascular spasm

vascular spasm - first phase of hemostasis • whereby the blood vessel constricts suddenly • limits the amount of blood that can leak from this damaged vessel

Other Solutes

• Blood is also considered a solution o contains dissolved ions as well as organic and inorganic molecules o include electrolytes, nutrients, gases, and waste products • Polar or charged substances (e.g., glucose and salts) dissolve readily in the blood, • Nonpolar molecules (e.g., cholesterol, triglycerides, and fatty acids) do not readily dissolve in blood and require a carrier protein

Erythrocytes

• Erythrocytes o very small, flexible cells, with a diameter of approximately 7.5 μm o lacks a nucleus and cellular organelles o biconcave disc structure (at its narrowest point about 0.75 μm and at its widest point about 2.6 μm) o composed of a plasma membrane within which are housed about 280 million hemoglobin molecules • Erythrocytes transport oxygen and carbon dioxide between the tissues and the lungs. o carry respiratory gases more efficiently o biconcave shape and flexibility allow rouleau (stack & line up in single file) as they pass through capillaries o latticework of spectrin protein internally supports plasma membrane provides flexibility

Formed Elements in the Blood

• Formed Elements - Collectively, erythrocytes, leukocytes, and platelets ~45% of whole blood o mature erythrocytes contain neither nuclei nor organelles o platelets are merely fragments broken off from a larger cell

ABO Blood Group

ABO Blood Group • The best-known antigens are those that form the ABO blood group. o This group consists of two surface antigens (which are glycoproteins) called A and B. o The presence or absence of the A antigen, the B antigen, or both is the criterion that determines your ABO blood type, as shown in figure 18.9 and listed here: Type A blood has erythrocytes with surface antigen A only. Type B blood has erythrocytes with surface antigen B only. Type AB blood has erythrocytes having both surface antigens A and B. Type O blood has erythrocytes with neither surface antigen A nor B. • The ABO surface antigens on erythrocytes are accompanied by specific antibodies (or agglutinins) within the blood plasma. In general, an antibody is a Y-shaped protein that binds to a specific antigen that is perceived as foreign to the body (see section 22.4a). o The ABO blood group has both anti-A and anti-B antibodies that react with the surface antigen A and the surface antigen B, respectively. o You do not have antibodies in your blood plasma that bind to the surface antigens on your erythrocytes. o Within the ABO blood group, the following blood types and antibodies are normally associated as follows: Type A blood has anti-B antibodies within its plasma. Type B blood has anti-A antibodies within its plasma. Type AB blood has neither anti-A nor anti-B antibodies within its plasma. Type O blood has both anti-A and anti-B antibodies in its blood plasma.

Erythropoiesis

Erythropoiesis - erythrocyte production ~5 days > Hemocytoblasts (myeloid stem cell) - under the influence of multi-CSF > progenitor cell > proerythroblast (large, nucleated cell) > erythroblast (slightly smaller cell - produce hemoglobin) > normoblast (smaller cell - w/ more hemoglobin - ejected nucleus) > reticulocyte (lost all organelles except some ribosomes - continue to produce hemoglobin) o ~ 5 days - from myeloid stem cell to reticulocyte o Some reticulocytes finish maturation while circulating in blood vessels ~0.5-2.0% of the circulating blood after 1-2 days in circulation • the ribosomes degenerate • becomes a mature erythrocyte - w/o nucleus & organelles

Granulocyte Maturation Process

Granulocyte Maturation Process > myeloid stem cell (stimulated by multi-CSF and GM-CSF) > progenitor cell (under the influence of G-CSF.) > myeloblast > granulocytes (neutrophils, basophils, eosinophils)

Leukocytes - Main Function

Leukocytes • Defend the body against pathogens • Differ from erythrocytes in that they are ~1.5-3 times larger in diameter, contain a nucleus and cellular organelles, and do not contain hemoglobin. • The number of leukocytes in the blood normally ranges between 4500 and 11,000 per cubic millimeter (or microliter) of blood. • Leukocytes are motile (capable of movement within interstitial fluid) and remarkably flexible o most leukocytes are found within body tissues, as opposed to in the blood • Leukocytes enter the tissues from blood vessels by a process called diapedesis, whereby they squeeze between the endothelial cells of the blood vessel walls. • Chemotaxis is a process in which leukocytes are attracted to a site of infection by the presence of molecules released by damaged cells, dead cells, or invading pathogens - part of the inflammatory response

Lymphocyte Maturation Process

Lymphocyte Maturation Process > lymphoid stem cell > B-lymphoblasts and T-lymphoblasts > B-lymphoblasts > B-lymphocytes > T-lymphoblasts > T-lymphocytes (thymus) > Some lymphoid stem cells > natural killer (NK) cells

Lymphocytes

Lymphocytes Most lymphocytes reside in lymphatic organs and structures (e.g., lymph nodes, spleen). • Lymphocytes constitute about 20-40% of the total number of leukocytes in the blood. • Their dark-staining nucleus is typically rounded, and smaller lymphocytes exhibit only a thin rim of blue-gray cytosol around the nucleus. • A lymphocyte usually is about the same size as or slightly larger than an erythrocyte. When activated, lymphocytes grow larger and have proportionally more cytosol. • Thus, some of the smaller, nonactivated lymphocytes have a diameter less than that of an erythrocyte, whereas activated lymphocytes may be two times the diameter of an erythrocyte. There are three categories of lymphocytes. • T-lymphocytes (T-cells) manage and direct an immune response; some directly attack foreign cells and virus-infected cells. • B-lymphocytes (B-cells) are stimulated to become plasma cells and produce antibodies. • NK cells (natural killer cells) attack abnormal and infected tissue cells.

Platelets - structure & function

Platelets • Irregular-shaped, membrane-enclosed cellular fragments that are about 2 µm in diameter (less than one-fourth the size of an erythrocyte) - in stained preparations, they exhibit a dark central region o thrombocytes - name is inappropriate because they are not true cells, but cell fragments, and unlike erythrocytes, they never had a nucleus o Continually produced in the red bone marrow by megakaryocytes. o Platelets serve an important function in hemostasis • Normally, the concentration of platelets in an adult ranges ~150-400 x103 / mm3 of blood, although the count may rise further during times of stress. o Platelets can circulate in the blood for 8-10 days, unless they are needed earlier for hemostasis; thereafter, they are broken down, and their contents are recycled o Approximately 30% of platelets are stored in the spleen

Regulatory proteins

Regulatory proteins • form a very minor class of plasma proteins o < 1% total plasma proteins • include enzymes to accelerate chemical reactions in the blood and hormones being transported throughout the body to target cells

Hemopoiesis (hematopoiesis)

Hemopoiesis, hematopoiesis • Produce formed elements (relatively short life span) • The red bone marrow (myeloid tissue) is responsible for hemopoiesis o occurs in most bones in young children, but as an individual reaches adulthood, hemopoiesis is restricted to selected bones primarily in the axial skeleton

Blood Types

Blood Types • The plasma membrane of an erythrocyte has numerous molecules called surface antigens (or agglutinogens), which project from the surface. o These antigens have significant implications for blood transfusion, and in some cases, pregnancy. o There are two groups of surface antigens that determine a person's blood type: the ABO blood group and the Rh protein.

general functions of blood

Blood carries out a variety of important functions as it circulates throughout the body; these functions can be grouped as transportation, regulation, and protection

Albumins (white of egg)

Albumins (white of egg) • are the smallest and most abundant of the plasma proteins o ~58% of all plasma proteins o it exerts the greatest colloid osmotic pressure • act as transport proteins that carry ions, hormones, and some lipids in the blood

Physical Characteristics of Blood

Blood is a type of connective tissue that can be described based on its physical characteristics including color, volume, viscosity, plasma concentration, temperature, and pH: Color. • Depends upon whether it is oxygen-rich or oxygen-poor o Oxygen-rich blood is bright red or almost scarlet o Oxygen-poor blood is not blue; oxygen-poor blood is dark red • The bluish appearance of our veins can be attributed to both (1) the fact that we can see the blood traveling through the superficial veins in the skin (2) how light is reflected back to the eye from different colors • Lower-energy light wavelengths, like red, are absorbed by the skin and not reflected back to the eye, but higher-energy wavelengths like blue are reflected back to the eye, so the eyes can perceive only the blue coloration from the veins Volume. • The average volume of blood in an adult is 5 liters (L) o Males tend to have, on average, 5 to 6 L o Females have, on average, 4 to 5 L o The greater amount of blood in males is due to their larger average size • Sustaining a normal blood volume is essential in maintaining blood pressure Viscosity. • Blood is about 4 to 5 times more viscous than water, meaning that it is thicker • Depends upon the amount of dissolved substances in the blood relative to the amount of fluid - viscosity is increased if the amount of substances—primarily erythrocytes—increases or the amount of fluid decreases, or both Plasma concentration. • Relative concentration of solutes (e.g., proteins and ions) in plasma • Normally @ 0.09% concentration o determines whether fluids move into or out of the plasma by osmosis as blood is transported through capillaries o e.g. - when an individual is dehydrated, the plasma becomes hypertonic, and fluid moves into the plasma from the surrounding tissues • Used to determine intravenous (IV) solution concentrations, which are usually isotonic to plasma Temperature. • blood temperature is ~ 1°C higher than measured body temperature o if your body temperature is 37°C (98.6°F), your blood temperature is about 38°C (100.4°F) o blood warms areas through which it travels Blood pH. • Slightly alkaline, with a pH between 7.35 and 7.45 • If blood pH is altered from the normal range - plasma proteins denature

types of plasma proteins -general function

Blood is considered a colloid - contains plasma proteins include albumin, globulins, fibrinogen and other clotting proteins, and regulatory proteins such as enzymes and some hormones: • Most are produced in the liver, including albumin, alpha- and beta-globulins, and both fibrinogen and other proteins involved with clotting • gamma-globulins - produced by leukocytes • regulatory proteins - produced by other organs

Blood vessels

Blood vessels form a circuit away from the heart and back to the heart that includes: • Arteries transport blood away from the heart • Veins transport blood toward the heart • Capillaries are permeable, microscopic vessels between arteries and veins o serve as the sites of exchange between the blood and body tissues o where oxygen and nutrients exit the blood o where carbon dioxide and cellular wastes enter the blood

CLINICAL VIEW - Bleeding and Blood Clotting Disorders

CLINICAL VIEW - Bleeding and Blood Clotting Disorders • If hemostasis fails to occur when needed, uncontrolled bleeding and death could result. • On the other hand, if hypercoagulation develops, then unwanted blood clots could form in the blood and lead to the risk of deep vein thrombosis (blood clot in the leg), pulmonary embolism (blood clot in the lung), stroke (blood clot in the brain), or heart attack. Here we discuss several blood clotting disorders. Bleeding Disorders • Bleeding disorders can be caused by several different conditions including hemophilia, a vitamin K deficiency, thrombocytopenia, or intake of various drugs. Hemophilia is a group of bleeding disorders caused by specific genetic mutations. • The two most common types of hemophilia are hemophilia A and hemophilia B, both of which are inherited in an X-linked recessive pattern. • Females typically are carriers of the gene but may not experience symptoms because they have two X chromosomes, and one of the two X chromosomes may be normal. • In contrast, males typically exhibit the full-blown disease because they have only one X chromosome. Hemophilia A, also known as classic hemophilia, represents the vast majority of all hemophilias. • It results in a deficiency or complete lack of normal factor VIII protein in the clotting cascade; the protein is abnormal and typically cannot participate in the proper clotting of the blood. • This hemophilia occurs in approximately 1 in 5000 males in the United States. Hemophilia B is a deficiency of factor IX. It occurs in approximately 1 in 25,000 males in the United States. Hemophilia C is a relatively rare autosomal dominant deficiency of factor XI. Vitamin K Deficiency • Vitamin K is a fat-soluble vitamin used by liver cells to produce many of the clotting factors. • Vitamin K deficiency is more common in newborns than adults (because the newborn liver is immature and breast milk contains little vitamin K) and in individuals with liver or biliary diseases or chronic problems with fat absorption. Thrombocytopenia is a deficiency in platelet count. • This may be caused by an increased breakdown of platelets or decreased production of new platelets, as may occur with some bone marrow infections or cancers. Bleeding Disorder due to intake of various drugs • Various drugs, such as aspirin, ibuprofen (and other nonsteroidal anti-inflammatory drugs [NSAIDs]), and warfarin (Coumadin), and some herbal supplements (e.g., ginkgo biloba, garlic supplements) interfere with blood clotting and may cause bleeding if taken at sufficiently high doses. • Physicians always should be monitoring their patients for bleeding disorders if they are taking any of these medications regularly. • Additionally, they should ask their patients what herbal supplements they may be taking, so as to avoid any herbal supplement-drug interactions. Hypercoagulation Problems • The term hypercoagulation refers to an increased tendency to clot blood. Hypercoagulation can lead to a thrombus, which is a clot within a blood vessel. o If the thrombus dislodges and travels within the blood, it is called an embolus. o An embolus is particularly dangerous because it can wedge within an artery and obstruct blood flow. o A pulmonary embolism occurs in the pulmonary circulation of the lungs and can lead to breathing problems and perhaps death if not treated, whereas an embolus that travels to the blood vessels of the brain can cause a stroke. o Treatment for a thrombus or embolus typically is with blood thinning medication (e.g., warfarin, heparin, or low-molecular-weight heparin). • Hypercoagulation can also have drug-related, environmental, and genetic causes. o Certain medications such as birth control pills or hormone replacement therapy are associated with an increased risk of developing blood clots. o Smoking greatly increases your risk, as nicotine is a vasoconstrictor, and it appears smoking increases levels of blood components related to clotting. o Environmental causes include prolonged bedrest, surgery, pregnancy, or sitting in an airplane seat for a long time. o In all of these cases, blood may pool in veins that are not being worked by exercise, and clotting can occur. • Genetic causes of hypercoagulation can be due to mutations of several genes, the most common of which is the Leiden mutation, which is a mutation of the gene for the synthesis of factor V. o This mutation is present in 3% of the population and 3-15% of all Caucasians, and it accounts for 20-40% of all venous thromboses. o Individuals with this mutation are unable to inactivate factor V in the clotting cascade, causing hypercoagulation and increased risk of thrombus formation. o Young (under age 50), active individuals who present with a thrombus or embolus, and who don't have other significant risk factors for clotting, may need to be screened for these genetic mutations.

CLINICAL VIEW - Blood Doping

CLINICAL VIEW - Blood Doping • Ehance their performance in endurance events • Boost their bodies' ability to deliver oxygen • Increasing the number of erythrocytes o Can be increased naturally is by living and training at high altitude • 2 two different methods for blood doping o 1st (older) - donates erythrocytes to himself Prior to competition, the athlete has a unit of blood removed and stored. kidneys detect the decreased blood oxygen erythropoietin (EPO) is released - bone marrow - increase erythrocytes production just before competition - erythrocytes transfused back o 2nd (pharmaceutical EPO) - treat anemia - injected • Potentially deadly dangers are inherent in blood doping. o Increases the viscosity of the blood o heart must work harder to pump this more viscous blood o Lead to permanent cardiovascular damage - lead to death

CLINICAL VIEW - Leukemia

CLINICAL VIEW - Leukemia Leukemia is a malignancy (cancer) in the leukocyte-forming cells. • There are several categories of leukemia, but all are marked by abnormal development and proliferation of leukocytes, both in the bone marrow and the circulating blood. • Leukemias represent a malignant transformation of a leukocyte cell line, and as abnormal leukocytes increase in number, the erythrocytic and megakaryocytic lines typically decrease in numbers because the proliferating malignant cells overtake the marrow and leave no room for the normal cells. • This decrease in erythrocyte and platelet production results in both anemia and bleeding, which are often the first signs of leukemia. • Leukemias are classified based on their duration as either acute or chronic. Acute leukemia progresses rapidly, and death typically occurs within a few months after the onset of symptoms (severe anemia, hemorrhages, and recurrent infections). • Acute leukemias tend to occur in children and young adults. • Chronic leukemia progresses more slowly; survival usually exceeds 1 year from the onset of symptoms. • Symptoms include anemia and a tendency to bleed. • Chronic leukemias usually occur in middle-aged and older individuals. Viral infections, such as mumps, rubella, or mononucleosis, typically produce an increased number of lymphocytes. • Lymphocyte values can increase to 20,000 in extreme cases. • Additionally, the lymphocytes develop morphologic changes, in which their cytosol appears watery. • Other conditions that can cause lymphocytosis include chronic bacterial infections, some leukemias, and multiple myeloma (a cancer of plasma cells, which are derived from B-lymphocytes). • Decreased lymphocyte counts can occur with HIV infection, other leukemias, and sepsis, which is the presence of a pathogenic organism or substance in the blood. Eosinophil numbers can increase in response to allergic reactions, parasitic infections, or some autoimmune diseases. • Monocyte numbers may increase with chronic inflammatory disorders or tuberculosis, and may decrease due to prolonged prednisone (steroid) drug therapy. • Finally, basophil counts can increase due to myeloproliferative disorders (which result from an overproduction of some formed elements in the bone marrow) and can decrease due to acute allergic and stress reactions.

CLINICAL VIEW - Rh Incompatibility and Pregnancy

CLINICAL VIEW - Rh Incompatibility and Pregnancy • The potential presence of anti-D antibodies is especially important in pregnant women who are Rh negative and have an Rh positive fetus. o An Rh incompatibility may result during pregnancy if the mother has been previously exposed to Rh positive blood (such as can occur with a previously carried Rh positive fetus, typically at the time of childbirth). o As a result of the prior exposure, the mother has anti-D antibodies that may cross the placenta and destroy the fetal erythrocytes, resulting in severe illness or death. o The illness that occurs in the newborn is called hemolytic disease of the newborn (HDN), or erythroblastosis fetalis. o The newborn typically presents with anemia and hyperbilirubinemia (increased bilirubin in the blood) due to erythrocyte destruction. o In severe cases, the infant may develop heart failure and must be given a blood transfusion to survive. • Giving a pregnant Rh negative woman special immunoglobulins (e.g., RhoGAM) between weeks 28 to 32 of her pregnancy and at birth prevents the mother from developing anti-D antibodies. o Specifically, these immunoglobulins bind to fetal erythrocyte surface antigens—and in so doing, prevent the mother's immune system from recognizing Rh antigens and being stimulated to produce anti-D antibodies.

CLINICAL VIEW - Transfusions

CLINICAL VIEW - Transfusions • A transfusion is the transfer of blood or blood components from a donor to a recipient. o Whole blood is almost never transfused today, and it is not generally available. Rather, when you donate a unit of blood, it is almost immediately divided into three components: erythrocytes, clotting factors, and platelets. o When a person needs one of these blood products, the physician administers only what is required, thus allowing one whole blood donation to serve up to three people. • To prevent health-related problems, donor blood must be collected under sterile conditions. o The donated blood is first mixed with an anticoagulant to prevent clotting and is immediately refrigerated. o Then the donated unit is tested for a variety of infectious agents that cause diseases(e.g., hepatitis, AIDS). o Next, the blood is separated into erythrocytes, clotting factors, and platelets. o Should leukocytes be needed, they must be collected in a special apparatus that effectively filters the leukocytes from the blood and then returns the blood to the donor. o (A donor with healthy red bone marrow can quickly replace the donated leukocytes and does not have to wait the full 8 weeks before being able to donate blood again.)

components of a centrifuged blood sample

Centrifuged Blood • whole blood can be separated into its liquid and cellular components by using a centrifuge From bottom to top, the components of a centrifuged blood sample: • Erythrocytes - lower layer, ~ 44% of a blood sample • Buffy coat - thin middle layer - slightly gray-white layer, < 1% o composed of both leukocytes and platelets • Plasma - a straw-colored liquid - top layer, ~55%

Clinical Considerations About Blood Types

Clinical Considerations About Blood Types • Blood types become clinically important when a patient needs a blood transfusion. • Compatibility between donor and recipient must be ascertained prior to blood transfusions. • If a person is transfused with blood of an incompatible type, antibodies in the plasma bind to surface antigens of the transfused erythrocytes, and clumps of erythrocytes bind together in a process termed agglutination (ă-glū-tin-ā′shŭn; ad = to, gluten = glue). • Clumped erythrocytes can block blood vessels and prevent the normal circulation of blood (figure 18.10). • Eventually, some or all of the clumped erythrocytes may rupture, a process called hemolysis (hē-mol′i-sis; lysis = destruction). • The release of erythrocyte contents and fragments into the blood often causes further hemolytic reactions and ultimately may damage organs. • Therefore, compatibility between donor and recipient must be determined prior to blood donations and transfusions using an agglutination test.

Clot Retraction

Clot retraction Occurs as the clot is forming when actinomyosin, a contractile protein within platelets, contracts and squeezes the serum out of the developing clot. - This makes the clot smaller as the sides of the vessel wall are pulled closer together.

coagulation, or blood clotting

Coagulation, or Blood Clotting Most important and most complex component of hemostasis: • A blood clot has an insoluble protein network composed of fibrin - derived from soluble fibrinogen • This meshwork of protein traps other elements of the blood, including erythrocytes, leukocytes, platelets, and plasma proteins, to form the clot

colloid osmotic pressure

Colloid Osmotic Pressure Exerted by plasma proteins - prevent the loss of fluid from the blood as it moves through the capillaries • Draw fluids into the blood and prevent excess fluid loss from blood capillaries into the interstitial fluid - maintain blood volume and blood pressure • If plasma protein levels decrease - colloid osmotic pressure also decreases o Such as might occur due to liver disease (resulting in decreased production of plasma proteins) or kidney damage (resulting in increased elimination of plasma proteins) o Results in fluid loss from the blood and fluid retention in the interstitial space (i.e., edema)

conditions that bring about vascular spasm.

Conditions that bring about vascular spasm: • When a blood vessel is injured • The spasm continues during the next phase, as both platelets and the endothelial cells of the blood vessel wall release an array of chemicals to further stimulate the vascular spasms. • The vascular spasm phase usually lasts from a few to many minutes. o The more extensive the vessel and tissue damage, the greater the degree of vasoconstriction.

Differential Count and Changes in Leukocyte Profiles

Differential Count and Changes in Leukocyte Profiles • Abnormal numbers of leukocytes result from various pathologic conditions. o e.g. - a reduced number of leukocytes causes a serious disorder called leukopenia. This decreased number of leukocytes may increase the risk of a person developing an infection or decrease their ability to fight infection effectively o e.g. - leukocytosis results from a slightly elevated leukocyte count and may be caused by a variety of factors, such as a recent infection or stress • The term differential count, or white blood cell differential count, measures the amount of each type of leukocyte in your blood, and determines whether any of the circulating leukocytes are immature. o Infection, tissue necrosis, bone marrow failure, cancers, or some other stresses to the body can affect the total ranges or percentages of a specific type of leukocyte, so differential counts are useful for diagnosing ailments. • Acute bacterial infections, acute stress, and tissue necrosis typically are associated with an increase in neutrophils, called neutrophilia. o Their numbers will be in the tens of thousands, and some ailments may cause neutrophil counts of up to 50,000. o In addition, as the body tries to produce more and more neutrophils, some immature neutrophils (called band neutrophils, or band cells) enter the circulation and are detected by the differential count. o Increased presence of these immature neutrophils is referred to as a left-shifted differential. o This phrase reflects that historically a lab printout listed numbers of cells according to maturity from left to right, so that an increased number of immature neutrophils was listed on the left. • Decreased neutrophil count, called neutropenia, may occur with certain anemias, drug or radiation therapy, and from other causes.

Erythrocyte Destruction

Erythrocyte Destruction • The absence of both a nucleus and cellular organelles comes at a cost to the erythrocyte and affects its longevity. o A mature erythrocyte cannot synthesize proteins either to repair itself or to replace damaged membrane regions. Aging and the wear-and-tear of circulation through blood vessels cause erythrocytes to become more fragile and less flexible. Therefore, the erythrocyte has a finite maximum life span of about 120 days. Every day, about 1% of the oldest circulating erythrocytes are removed from circulation. These old erythrocytes are phagocytized in both the spleen and liver by cells called macrophages. • Three molecular components must be accounted for in the destruction of hemoglobin: the globin protein, iron ion, and the heme group. o Two of the components are processed for recycling; the other component is metabolically altered and then excreted from the body, as shown in figure 18.8. • Globin proteins are broken down into free amino acids, most of which are used by the body for protein synthesis to make new erythrocytes or other body proteins. • The iron component in hemoglobin is removed and transported by a globulin protein called transferrin (trans-fer′in; trans = across, ferrum = iron) to the liver or spleen where the Fe2+ then is bound to storage proteins called ferritin (fer′i-tin) and hemosiderin ( hē′mō-sid′ĕr-in). o Ferritin is a large water-soluble protein that serves as the primary storage mechanism for iron. Iron is stored mainly in the liver and spleen, and it is transported by transferrin to the red bone marrow as needed for erythrocyte production. However, small amounts of iron, approximately 0.9 mg, are lost daily in sweat, urine, and feces. In females, additional iron is lost in those who have a monthly menstrual flow. • The heme group (minus the Fe2+) released from hemoglobin is converted within macrophages first into a green pigment called biliverdin (bil-i-ver′din; bilis = bile, verd = green). o Biliverdin is eventually converted into a yellowish pigment called bilirubin (bil-i-rū′bin; rubin = reddish), which is transported by albumin to the liver. Bilirubin is a component of a digestive secretion called bile, which is produced by the liver and released into the small intestine • Bilirubin is converted to urobilinogen (yur-ō-bi-lin′ō-jen, ouron = urine) in the small intestine. o Urobilinogen can either (1) continue through the large intestine and eventually be converted by the intestinal bacteria to stercobilin, a brown pigment that is expelled from the body as a component of feces; or (2) be absorbed back into the blood. In this latter case, it is converted to urobilin, a yellow pigment that is excreted by the kidneys.

Factor X

Factor X, activated by either the intrinsic or extrinsic pathway, is the first step in the common pathway: 1. Active factor X combines with factors II and V, Ca2+, and platelet factor 3 (PF3) to form prothrombin activator. 2. Prothrombin activator activates prothrombin to thrombin. 3. Thrombin converts soluble fibrinogen into insoluble fibrin. 4. In the presence of Ca2+, factor XIII is activated. Factor XIII cross-links and stabilizes the fibrin monomers into a fibrin polymer that serves as the "framework" of the clot. • Other components of blood become trapped in this spiderweb-like protein mesh. o Like platelet plug formation, the clotting cascade is regulated by positive feedback. o Once initiated by the intrinsic or extrinsic pathway, the events of the clotting cascade continue until a clot is formed (the climactic event). o The size of the clot is limited because thrombin is either trapped within the clot or thrombin is quickly degraded by enzymes within the blood.

Globulins (globule)

Globulins (globule) • are the second largest group of plasma proteins o ~37% of all plasma proteins • The smaller α alpha-globulins and the larger β beta-globulins o primarily bind and transport certain water-insoluble molecules and hormones, some metals, and ions • γ Gamma-globulins are also called immunoglobulins, or antibodies, o play a part in the body's defenses

Granulocytes

Granulocytes • Have specific granules in their cytosol that are clearly visible when viewed with a microscope • When a blood smear is stained to provide contrast, three types of granulocytes can be distinguished: o neutrophils, eosinophils, and basophils - names refer to the granules' affinities for certain stains

hematocrit, medical definition vs clinical usage

Hematocrit Percentage of the volume of all formed elements - medical dictionary definition - true hematocrit o clinical definition - equates the hematocrit to the percentage of only erythrocytes o In practice - virtually the same Hematocrit values vary somewhat and are dependent upon the age and sex of the individual • A very young child's hematocrit may vary from 30%-60%, and that range will narrow to 35%-50% as the child becomes older • Adult males tend to have a hematocrit ranging between 42%-56%, whereas adult females' hematocrits range from 38%-46% • Males typically have a higher hematocrit because testosterone stimulates the kidney to produce the hormone erythropoietin (EPO) - promotes erythrocyte production • An elevated hematocrit may indicate that the patient is either dehydrated or participating in blood doping, whereas a lowered hematocrit often suggests the patient is suffering from anemia

Processes of clot retraction and fibrinolysis.

Processes of clot retraction and fibrinolysis. A blood clot is a temporary measure to stop blood loss through a damaged vessel wall. • To return to normal, the blood vessel wall must be repaired and the clot eliminated. • Elimination of the blood clot includes both clot retraction and fibrinolysis. • A "balancing act" is occurring continually within your blood between clot formation processes and those processes that prevent clot formation. o The balance can be "tipped" so that blood clotting is initiated. o A damaged blood vessel, impaired blood flow, atherosclerosis, or inflammation of the blood vessels can all potentially initiate blood clotting. • Additionally, certain nutrients and vitamins must be present and available for blood clotting to occur normally. o e.g. - calcium is used during the clotting process, and vitamin K is required for the synthesis of certain plasma proteins by the liver. • Problems with the balance can lead to either bleeding or blood clotting disorders.

Rh Factor

Rh Factor • Another common surface antigen on erythrocyte plasma membranes determines the Rh blood type. o The Rh blood type is determined by the presence or absence of the Rh surface antigen, often called either Rh factor or surface antigen D. o When the Rh factor is present, the individual is said to be Rh positive (Rh+). o Conversely, an individual is termed Rh negative (Rh−) when the surface antigen is lacking (figure 18.9b). • In contrast to the antibodies of the ABO blood group, which may be found in the blood even without prior exposure to a foreign antigen, antibodies to the Rh factor (termed anti-D antibodies) appear in the blood only when an Rh negative individual is exposed to Rh positive blood. o This most often occurs as a result of an inappropriate blood transfusion. o Individuals who are Rh positive never exhibit anti-D antibodies, because they possess the Rh antigen on their erythrocytes. o Only individuals who are Rh negative can exhibit anti-D antibodies, and that can occur only after exposure to Rh antigens. • The ABO and Rh blood types are usually reported together. For example, types AB and Rh+ together are reported as AB+. o However, remember that ABO and Rh blood types are independent of each other, and neither of them interacts with or influences the presence or activities of the other group.

The Role of EPO in Erythropoiesis

The Role of EPO in Erythropoiesis • Erythropoiesis is controlled by the hormone erythropoietin (EPO). o The kidneys are the primary producers of EPO, although the liver also secretes a small amount of EPO as well. o The process by which EPO release is stimulated is shown in figure 18.7. o The initial stimulus is a decrease in blood oxygen levels. o This decrease may be caused by the continuous removal of aged erythrocytes, blood loss, or exposure to high altitudes (where atmospheric oxygen levels are lower). o Chemoreceptors within the kidney detect low blood oxygen levels as the blood travels through blood vessels within the kidney. o As a result, certain cells in the kidney release the hormone EPO into the blood. EPO is transported through the blood and reaches the red bone marrow. o There, EPO stimulates myeloid cells in the red bone marrow to increase the rate of erythrocyte production. o Additional erythrocytes are released into circulation (a process that takes a few days), so more oxygen can be transported from the lungs and delivered to the cells. o Blood oxygen levels increase as a result. Increased oxygen levels inhibit release of EPO from kidney cells through negative feedback. • The adrenal gland secretes small amounts of testosterone in both sexes (see section 17.8c), and the testes secrete large amounts of testosterone in males (see section 28.4b and table R.10 entitled • Regulating the Male Reproductive System). • In addition to its many other functions, testosterone stimulates the kidney to produce more EPO. o Because males have higher levels of testosterone, they also usually have a higher erythrocyte count and a higher hematocrit. • Environmental factors, such as altitude, can affect EPO release and ultimately affect the hematocrit. o Let us say a woman moves to a cabin high in the Rocky Mountains, where the atmospheric pressure is lower than it is at sea level. o (As you'll learn in section 23.7c, a lower atmospheric pressure means less oxygen availability.) o Each time she takes a breath at this altitude, she takes in relatively less oxygen than she would on an ocean beach. o Her body compensates by releasing more EPO and making more erythrocytes over time; more erythrocytes in the blood can carry more oxygen to the tissues. o However, having more erythrocytes increases the blood's viscosity, which could increase the chance of cardiovascular complications, such as major blood clots that lead to heart attacks or strokes. o The details for erythropoietin are listed in the summary table Regulating Erythrocyte Concentration in the Blood, which directly follows chapter 17 (see table R.6).

types of leukocytes - granulocytes & agranulocytes

The five types of leukocytes are divided into two distinguishable classes—based upon the visible presence or absence of secretory vesicles in the cytosol termed specific granules: o granulocytes and o agranulocytes

intrinsic pathway

The intrinsic pathway is triggered by damage to the inside of the vessel wall and is initiated by platelets. This pathway typically takes approximately 3 to 6 minutes: 1. Platelets adhering to a damaged vessel wall release factor XII. 2. Factor XII converts the inactive factor XI to the active factor XI. 3. Factor XI converts inactive factor IX to active factor IX. 4. Factor IX binds with Ca2+ and platelet factor 3 to form a complex that converts inactive factor VIII to active factor VIII. 5. Factor VIII converts inactive factor X to active factor X.

List some conditions that occur with the bone marrow and blood in the elderly.

• Hemopoiesis occurs in most bones in young children • In adulthood, hemopoiesis is restricted to selected bones in the axial skeleton • More red bone marrow is replaced with fat as individuals continue to age - older individuals have relatively less red bone marrow and may be more prone to developing anemia, which is a decrease in the number of circulating erythrocytes - older red bone marrow may be less able to meet any demands for an increased number of leukocytes • The leukocytes in the elderly may be less efficient and active than those in younger individuals, and the elderly also may have decreased numbers of leukocytes - Certain types of leukemias also are more prevalent among the elderly, probably due to the immune system (and its leukocytes) being less efficient

Platelet Plug Formation

• The next phase in hemostasis is the formation of a platelet plug. • Normally, the endothelial wall (inner lining of a blood vessel) is smooth and is coated with an eicosanoid (prostacyclin) which activates a pathway in both platelets and endothelial cells that involves production of cAMP to ultimately inhibit platelet activation o Prostacyclin serves as a platelet repellent • Once a blood vessel is damaged, however, the collagen fibers within the connective tissue beneath the endothelial cells in the vessel wall become exposed. o Platelets begin to stick to the exposed collagen fibers. o Platelets adhere to the collagen fibers with the assistance of a plasma protein called von Willebrand factor, which serves as a bridge between platelets and collagen fibers. • As the platelets start to stick to the vessel wall, their morphology changes dramatically; they develop long processes that further adhere them to the blood vessel wall. o As more and more platelets aggregate to the site, a platelet plug develops to close off the injury. o The timing of this entire phase typically is less than a few minutes for a small- to medium-sized injury. o Again, this is a temporary measure to block the flow of blood through the vessel wall where it is damaged. • Platelets undergo this morphologic change and become activated: their cytosol degranulates, releasing chemicals to assist with hemostasis. The following processes occur in response to these different chemicals: o Prolonged vascular spasms with the release of serotonin and thromboxane A2 (an eicosanoid) o Attraction of other platelets with the release of adenosine diphosphate (ADP) and thromboxane A2, which facilitates the degranulation and release of these chemicals in other platelets o Stimulation of coagulation with the release of procoagulants that enhance blood clotting (the third phase) o Repair of the blood vessel as platelets secrete substances to stimulate epithelial tissue, smooth muscle, and fibroblasts (cells of connective tissue) to replicate • Note that platelets are not only involved in the second phase of platelet plug formation, but they also increase events of the first and third phases, vascular spasm and coagulation phase, respectively. o Thus, through the release of specific substances, platelets increase all three processes of hemostasis. o Thus, decreased hemostasis becomes a concern in individuals with a low platelet count, known as thrombocytopenia. • The formation of the platelet plug is an example of positive feedback and typically is formed within 1 minute. o But what is to prevent a platelet plug from becoming too big and growing out of control? o As just mentioned, endothelial cells normally release prostacyclin. o The healthy endothelial cells near the site of injury are still releasing their prostacyclin, so the plug does not grow larger than what is needed. o The next phase, the coagulation phase, is beginning.