Blood: Composition and Functions

Blood Overview

• Blood accounts for about 8% of total body weight, equivalent to around 5 liters
• Blood is a fluid connective tissue that circulates inside blood vessels continuously
• The two major components of blood are plasma and the "formed elements"
• Formed elements include cells, along with cell fragments which are found suspended in plasma
• Erythrocytes are red blood cells (RBCs)
• Leukocytes are white blood cells (WBCs)
• Platelets are small cellular fragments
• In a centrifuged blood sample, the top layer is plasma, and makes up approximately 55% of the total
• The middle layer contains leukocytes and platelets, known as the buffy coat, and makes up only about 1% of the total volume
• The bottom layer, about 44% of the total volume, is erythrocytes
• Hematocrit signifies the percentage of blood volume composed of erythrocytes

Blood Functions

• Blood functions include exchanging gases, specifically transporting both oxygen and carbon dioxide
• Blood distributes solutes: plasma transports ions, nutrients, hormones, and wastes
• Blood regulates ion concentrations in tissues
• Blood performs immune functions: leukocytes and immune system proteins transported throughout the body
• Blood maintains body temperature: it carries away heat generated by chemical reactions
• Blood functions in clotting: platelets and certain proteins form blood clots to seal damaged vessels
• Blood preserves acid-base homeostasis, maintaining a pH between 7.35 and 7.45 with buffering systems
• Blood stabilizes blood pressure, blood volume being a major contributing determinant

Plasma

• Plasma’s volume is 90% water, and it appears as a pale yellow liquid
• Water in plasma affects blood viscosity/thickness
• Less water content leads to greater viscosity and a sluggish blood flow
• Plasma proteins make up about 9% of plasma
• Albumin is a large protein, synthesized in the liver, responsible for colloid osmotic pressure
• Colloid osmotic pressure draws water into the blood by osmosis
• Immune proteins, or gammaglobulins (antibodies), are made by leukocytes and are components of the immune system
• Transport proteins bind to lipid-based molecules for transportation through the water-based plasma
• Clotting proteins stop bleeding from injured blood vessels by forming blood clots, assisted by platelets
• Small molecules make up the last 1% of plasma volume, and are mostly dissolved in the water.
• Small molecules, dissolved in plasma, form a solution
• Blood can readily exchange these molecules with the interstitial fluid in capillary beds

Erythrocyte Structure

• The shape and components of erythrocytes facilitate the transport of oxygen and carbon dioxide
• The typical erythrocyte has a biconcave disc shape, meaning it is flattened and donut-shaped, and concave on both sides
• RBC shape increases surface area; this is vital for gas exchange
• Mature RBCs lack a nucleus and most other cellular organelles; known as being anucleate
• Creates room in the cytosol for enzymes and nearly 1 billion hemoglobin (Hb) proteins per cell
• Hemoglobin is a large protein consisting of four polypeptide subunits: two alpha chains and two beta chains
• Each polypeptide binds to a heme group, which contains iron
• An iron ion in each heme group is oxidized when it binds to oxygen in high oxygen concentration areas like the lungs
• Binding of oxygen and hemogloblin, forms the red molecule oxyhemoglobin, (HbO₂)
• Hemoglobin releases oxygen into regions where oxygen concentration is low, such as the tissues near systemic capillaries
• Hemoglobin also binds to carbon dioxide (CO₂) to form carbaminohemoglobin, which accounts for about 23% of CO₂transported in blood.
• Hemoglobin also binds to carbon monoxide (CO) to form carboxyhemoglobin, due to hemoglobin's strong bond with iron ion than oxygen
• Hemoglobin shape changes when bound to carbon monoxide, making it unable to unload oxygen to oxygen-deprived tissues, and can result in death

Erythrocyte Life Span

• Erythrocytes have a relatively short life span, ranging from 100–120 days
• The harsh environment in which they exist causes them damage
• RBCs lack organelles for repair
• The body must continuously create new erythrocytes

Erythropoiesis

• Hematopoiesis takes place in red bone marrow
• Formed elements in blood are produced by hematopoietic stem cells (HSCs)
• Erythropoiesis is the process that produces erythrocytes from HSCs, over approximately 5–7 days
• Erythropoiesis begins with HSCs differentiating into erythrocyte colony-forming units (CFUs)
• Erythrocyte CFUs are committed to becoming only one cell type
• Erythrocyte CFUs differentiate into proerythroblasts when erythropoietin (EPO) is available
• Erythropoietin (EPO) a hormone secreted by the kidneys
• Proerythroblasts develop into erythroblasts, which rapidly synthesize Hb and other proteins
• The nucleus in erythroblasts shrinks as it matures, and is eventually ejected resulting in reticulocytes
• After ejecting remaining organelles reticulocytes enter the bloodstream by exiting pores in sinusoidal capillaries of bone marrow

Regulation of Erythropoiesis

• Erythropoietin triggers a balancing negative feedback loop and maintains hematocrit
• This is an example of the Feedback Loops Core Principle
• Stimulus: blood oxygen levels fall below normal
• Receptor: kidney cells detect low oxygen levels
• Control center: kidneys produce more erythropoietin and release it into the bloodstream
• Effector/Response: erythrocyte production increases
• Effector/Response: an example of Cell-Cell Communication Core Principle
• Homeostasis: blood oxygen levels rise to normal

Erythrocyte Death

• The destruction of erythrocytes involves several steps
• Erythrocytes become trapped in the sinusoids of the spleen, which is located in the upper left abdominal cavity
• Spleen macrophages digest these erythrocytes
• Hemoglobin breaks down into amino acids, iron ions, and heme
• Heme converts to biliverdin (greenish pigment) then bilirubin (yellowish waste product)
• Iron ions and amino acids are recycled to red bone marrow to synthesize hemoglobin
• Iron ions are transported back to bone marrow in bloodstream by transferrin
• Bilirubin is sent to the liver for excretion

Anemia

• Anemia is a common condition when there is decreased oxygen-carrying capacity of blood
• The three primary causes of anemia involve decreased hemoglobin, decreased hematocrit and abnormal hemoglobin
• Anemia is associated with a variety of events that cause decreased oxygen delivery to tissues
• General anemia symptoms include pallor/pale skin, fatigue, weakness, and shortness of breath
• Many types of anemia can cause elevated numbers of circulating reticulocytes through increased EPO production in response to diminished oxygen-carrying capacity
• Severe anemia can elevate heart rate as the body attempts to increase cardiac output

Decreased Hemoglobin

• Iron deficiency anemia, the most common form of anemia, is caused by inadequate dietary iron intake, reduced intestinal absorption of iron, or slow blood loss
• Anemia of chronic disease is also common, and develops as result of another underlying disease state
• Chronic disease, such as cancer, interferes with iron transportation from the liver to red bone marrow.
• Vitamin B6 deficiency, malnutrition, poisoning with certain drugs or heavy metals like lead, and pregnancy can all decrease hemoglobin levels
• Without functional heme groups, erythroblasts are unable to synthesize oxyhemoglobin

Decreased Hematocrit

• Reduced erythrocyte numbers in blood causes a drop in hematocrit
• Blood loss can derive from stomach ulcers, leading to a significant loss of circulating erythrocytes
• Pernicious anemia results from vitamin B12 deficiency, which interferes with DNA synthesis of rapidly dividing cells; and bone marrow hematopoietic cells
• Erythrocyte destruction can result from bacterial infections, diseases of the immune system or liver, and lead poisoning, also known as hemolytic anemia
• Aplastic anemia's, caused by certain medications or ionizing radiation, inhibit or stop erythrocyte production in red bone marrow.
• Aplastic anemia's causes are often unknown

Abnormal Hemoglobin

• The most common example of abnormal hemoglobin is sickle-cell disease
• Individuals with a single copy of defective gene have sickle-cell trait and are generally asymptomatic
• Individuals with two defective copies of the gene have sickle-cell disease
• Two defective copies result in abnormal hemoglobin called hemoglobin S (HbS)
• When oxygen levels are low, RBCs containing HbS transform to sickle shaped structures, leading to erythrocyte destruction and reduction in circulating erythrocytes

Leukocytes

• Leukocytes, also called white blood cells (WBCs), are larger than erythrocytes and have prominent nuclei
• Leukocytes use the bloodstream as transportation without performing their functions within the blood
• Leukocytes adhere to blood vessel walls, then squeeze to enter surrounding tissue
• Leukocytes are divided into two basic categories: granulocytes and agranulocytes
• Granulocytes are readily identified by their unusual nuclei; single nucleus composed of connected lobes
• Lysosomal granules, along with unique granules are released when granulocytes are activated
• Agranulocytes lack visible granules, but do contain lysosomes like granulocytes
• Neutrophils, lymphocytes, monocytes, eosinophils, and basophils are WBC types, listed from most to least abundant
• The pneumonic "Never Let Monkeys Eat Bananas" can help you remember their order

Granulocytes

• Neutrophils are active phagocytes
• Neutrophils ingest and destroy bacterial cells
• Neutrophils are the most common leukocyte at 3000-7000 neutrophils/mm³ of blood
• Account for 40-70% of WBCs, or white blood cells
• Neutrophils are uniquely shaped, with a nucleus composed of three to five lobes
• Polymorphonucleocytes (polys or PMNs) is another name for Neutrophils
• Injured cells release chemicals that attract neutrophils/chemotaxis;
• Granule contents directly kill bacterial cells
• Region is enhanced by the Granule contents attracting more neutrophils and leukocytes
• Eosinophils have bilobed nucleus – 100-400 eosinophil's per mm³ of blood or 1-4% of WBCs
• Eosinophils ingest foreign molecules due to being Phagocytes
• Eosiniphils respond to parasitic worms and allergic reactions
• Granules specific to Eosiniphils contain enzymes and toxins as well as chemicals that mediate inflammation
• Basophils are the least common leukocyte and have a(n) S-shaped nucleus
• The rarest of the WBCs are – 20-50 basophils per mm³ of blood and account for 0-1% of WBCs
• Basophil granules chemicals mediate inflammation using histamine-containing granules along with heparin as an anticoagulant

Agranulocytes

• Lymphocytes are the second most common leukocyte, with – 1,500-3,000 lymphocytes per mm of blood or 25-40% of WBCs
• Two basic types of lymphocytes: similar appearances aside from two basic types with different functions
• Lymphocytes activated by cellular markers called antigens
• Lymphocytes play a role in immune response
• B lymphocytes/B cells produce antibodies for removing antigens tissues when activated
• Each B lymphocyte population has secreted antibodies that bind only to a specific unique antigen
• Bone marrow is where B cells become immunocompetent
• T lymphocytes/T cells are activated by specific antigens but do not produce antibodies
• T cells have membrane-bound receptors for individual antigens
• T lymphocytes activate other immune system components
• T lymphocytes destroy abnormal body cells, such as cancer cells or virally infected cells
• Thymus is the location of T cell immunocompetence
• Monocytes are the largest leukocyte, having large U-shaped nuclei at – 100-700 monocytes per mm of blood
• Monocytes constitute about 4-8% of WBCs
• Only circulate in blood briefly before exiting capillaries to enter tissues where some mature into macrophages
• Macrophages ingest dead and dying cells, bacteria, antigens, and other cellular debris due are being phagocytic
• Macrophages activate other components of immune system by displaying phagocytosed antigens to other leukocytes

Complete Blood Count

• A Complete Blood Count (CBC) is an important anemia test used to assess other conditions
• A blood sample is examined under the microscope and by an automated analyzer to evaluate number and characteristics of blood cells
• CBC involves measuring the RBC count in cells per milliliter and is used to calculate hematocrit
• CBC measures hemoglobin concentration
• CBC determines the RBC characteristics such as size, volume, and concentration of hemoglobin in cytosol
• CBC determines platelet count and volume and the numbers and types of leukocytes

Leukemia

• Leukemias are cancers of blood cells or bone marrow, classified as acute or chronic based on speed of disease progression
• Acute leukemia involves a rapid increase in immature, nonfunctional, or poorly functional blood cells
• Chronic leukemia involves a slow accumulation of abnormal mature leukocytes
• Leukemia can derive from a lymphocytic or lymphoid cell line, generally with abnormal B lymphocytes
• Leukemia can derive from a myelogenous or myeloid cell line, where any of myeloid cells cells are involved
• Acute lymphocytic leukemia is the most common leukemia in children
• Leukemia's abnormal cells, which crowd marrow, and this reduces the ability to manufacture healthy cells
• Cancerous cells with leukemia enter the bloodstream traveling to other tissues where they spread/metastasize
• Leukemia's treatment and prognosis vary with the type of leukemia
• Acute forms of Leukemia metastasize earlier, thus requiring more aggressive management

Platelets

• Platelets are small cell fragments surrounded by plasma membrane
• The smallest of formed elements, platelets are key to the hemostasis process, responsible for stopping blood loss from vessels that are injured
• Platelets don't have nuclei or organelles
• Platelets have types of granules as well as clotting factors, enzymes, some mitochondria, and glycogen deposits
• Platelets are enabled to carry out oxidative catabolism by some mitochondria and glycogen deposits
• Platelets contain cytoskeletal elements such as microtubules associated with actin, myosin filaments

Thrombopoiesis

• Thrombopoiesis is the process of platelet formation that begins as as HSCs differentiate into megakaryoblasts from myeloid cell line
• Megakaryoblasts develop into megakaryocytes
• Megakaryocytes go through repeated cycles of mitosis without cytokinesis, and so the cell itself never divides
• This results in massive cell with multiple copies of DNA within single nucleus
• Mature megakaryocytes are stimulated by hormones, particularly, thrombopoietin and they send cytoplasmic extensions through clefts in bone marrow sinusoids into bloodstream
• The megakaryocyte extensions break off into thousands of platelets
• Platelets have limited lifespan of about 7–10 days
• Liver and spleen remove aged Platelets from circulation

Hemostasis

• Hemostasis is a series of five events that form a gelatinous blood clot to plug a broken vessel with the primary function of limiting blood loss
• Hemostasis part 1 involves the vascular spasm
• Hemostasis part 2 involves the platelet plug formation
• Hemostasis part 3 involves coagulation as an intrinsic and extrinsic pathway
• Hemostasis part 4 involves the clot retraction
• Hemostasis part 5 involves Thrombolysis

Hemostasis Vascular Spasm

• Hemostasis Part 1, vascular spasm, is an immediate response when vessel injury causes blood to leak extracellullarly.
• Vasoconstriction and increased tissue pressure both decrease blood vessel diameter
• Blood loss is minimized when blood pressure/ blood flow are reduced

Hemostasis Platelet Plug

• Hemostasis Part 2 is patch of platelet plug consisting mostly of adhering platelets limited only to injured site reduces blood loss more
• Endothelial cells injured in the vessel release von Willbrand factor, or vWF, which is a glycoprotein that binds to receptors on surface of platelets’ plasma membranes
• vWF with exposed collagen attracts and activates platelets clump together or aggregate
• Platelet aggregation forms the plug and seals the injured vessel temporarily

Hemostasis Coagulation

• Molecular glue for blood clotting is formed from Part 3 coagulation, which binds platelets