Guyton - Module 5

Red Blood Cells (Erythrocytes)

• Primary function is to transport hemoglobin, which carries oxygen
• Contain carbonic anhydrase, serving as an acid-base buffer
• Concentrations in men are normally 5.2 million per microliter
• Concentrations in women are normally 4.7 million per microliter
• Hemoglobin concentration maxes out at 34g per 100ml of cells
• Normal hemoglobin level in men is 15g per 100ml of blood
• Normal hemoglobin level in women is 14g per 100ml of blood
• Each gram of hemoglobin can bind 1.34ml of oxygen when fully saturated
• Early embryonic life production occurs in the yolk sac
• Middle trimester production occurs in spleen and lymph nodes
• Last month of gestation production occurs in bone marrow
• For those 5 years and below production occurs in bone marrow of all bones
• Those between 5-20 years old production occurs in marrow of long bones
• For those greater than 20 years old production occurs in marrow of membranous bones (vertebrae, sternum, ribs, ilium)
• All circulating blood cells originate from hematopoietic stem cells in the bone marrow
• Growth inducers and differentiation inducers control their life cycle; interleukin-3 promotes growth and reproduction of all types of committed stem cells
• Low oxygen levels cause growth induction and differentiation in red blood cell production
• Genesis sequence: Pro erythroblast → Reticular site
• Reticular sites can pass from bone marrow into blood capillaries and mature into erythrocytes within 1-2 days
• Reticular site concentration among red blood cells is normally less than 1%
• Volume is tightly controlled to ensure sufficient oxygen transport without impeding blood flow
• Inadequate oxygen transport and tissue hypoxia stimulate production
• Lack a nucleus, mitochondria, or endoplasmic reticulum
• Contain cytoplasmic enzymes for metabolizing glucose and forming ATP
• Enzymes maintain cell membrane pliability and membrane transport of ions, and keep iron in the ferrous state
• Enzyme activity decreases with cell age, leading to increased fragility
• Lifespan is 120 days
• Many self-destruct in the spleen due to narrow passages (3 micrometers wide)
• Spleen removal increases the number of old, abnormal red blood cells in circulation

Erythropoietin

• Primary hormone responsible for production
• 90% is formed in the kidneys, 10% in the liver
• Renal hypoxia increases transcription of the erythropoietin gene
• Hypoxia in other body parts also stimulates its production via norepinephrine, epinephrine, and prostaglandins
• Stimulates the production of peripheral blasts from hematopoietic stem cells within minutes to hours of tissue hypoxia
• New red blood cells appear in circulation about five days later
• With sufficient erythropoietin, iron, and nutrients, production can increase to ten times normal.

Vitamin B12 and Folic Acid

• Deficiency impairs DNA, causing failure of nuclear maturation and cell division

Hemoglobin

• Hemoglobin A is the most common type in adults, consisting of four hemoglobin chains
• Each chain has a heme group containing one iron atom that can bind one oxygen molecule
• Variations in amino acid composition can alter the physical characteristics and oxygen-carrying capacity of hemoglobin chains
• Binds loosely and reversibly with oxygen
• Iron is crucial for oxygen transport, with the body containing an average of 4-5g
• Iron is absorbed in the small intestine, and excess iron is stored in the liver hepatocytes
• When red blood cells are destroyed, iron is stored in the ferritin pool for reuse
• Men lose about 0.6mg of iron daily in feces
• Women lose about 1.3mg daily, accounting for menstruation
• Intestinal absorption of iron is low, with only a few milligrams absorbed daily, decreasing further when the body is saturated with iron

Anemia

• Categorized into blood loss anemia, aplastic anemia, megaloblastic anemia, and hemolytic anemia

Blood Loss Anemia

• Rapid blood loss: Plasma volume is replaced in 1-3 days, but red blood cell concentration takes 3-6 weeks to return to normal
• Chronic blood loss: Results in microcytic hypochromic anemia due to insufficient iron absorption

Aplastic Anemia

• Caused by bone marrow dysfunction
• Potential causes: High-dose radiation, chemotherapy, toxic chemicals (e.g., insecticides, benzene), autoimmune disorders (e.g., lupus)
• Idiopathic aplastic anemia occurs in about 50% of cases

Megaloblastic Anemia

• Red blood cells grow large with odd shapes (megaloblasts)
• Caused by deficiency of vitamin B12, folic acid, or intrinsic factor from the stomach mucosa
• Megaloblastic cells rupture easily, leading to anemia
• Pernicious anemia results from a failure to produce normal gastric secretions
• Parietal cells secrete intrinsic factor, which binds to vitamin B12 to protect it from digestion and facilitate absorption in the ileum
• Lack of intrinsic factor reduces B12 availability

Hemolytic Anemia

• Red blood cells are fragile and rupture easily, especially in the spleen
• Red blood cell production may be normal or higher, but lifespan is significantly reduced
• Types include hereditary spherocytosis, sickle cell anemia, and erythroblastosis fetalis
• Hereditary spherocytosis: Red blood cells are small and spherical, making them unable to withstand compressive forces in the spleen
• Sickle cell anemia: Faulty beta chains in the hemoglobin molecule cause precipitation into long crystals inside red blood cells when exposed to low oxygen concentrations
• Low oxygen tension leads to sickling, causing rupture and further decreasing oxygen tension, creating a progressive cycle
• Erythroblastosis fetalis: RH-positive fetal red blood cells are attacked by antibodies from an RH-negative mother, causing them to become fragile and rupture, leading to anemia in the newborn

Circulatory Effects of Anemia

• Reduced blood viscosity (as low as 1.5 times that of water, compared to the normal three times)
• Decreased resistance, leading to increased blood flow
• Increased cardiac output
• Hypoxia-induced dilation of peripheral blood vessels further increases cardiac output and workload on the heart
• Increased cardiac output may compensate for reduced oxygen-carrying capacity, but further increases in demand can lead to cardiac failure

Polycythemia

• Secondary polycythemia occurs when tissues become hypoxic, leading to increased red blood cell production; this can be caused by high altitudes or failed oxygen delivery, such as in cardiac failure
• Vera is caused by a genetic aberration in hemoblastic cells, resulting in uncontrolled red blood cell production
• Total blood volume increases to almost twice normal
• Blood viscosity increases to almost ten times that of water
• Individuals typically have a ruby complexion due to increased blood in the skin venous plexus, with a bluish tint caused by cyanosis of the hemoglobin
• Sluggish blood flow leads to increased deoxygenation of hemoglobin, causing cyanosis

Circulatory Effects of Polycythemia

• Sluggish blood flow in peripheral blood vessels reduces venous return to the heart
• Increased blood volume increases venous return
• Cardiac output is nearly normal due to the balance of these effects
• Compensatory mechanisms remain intact, with only one-third of individuals experiencing hypertension

Blood Types

• Classified into four major types: O, A, and B, based on the presence or absence of A and B agglutinogens
• Blood group genetic locus has three alleles; the O allele is non-functional and recessive to both A and B

Agglutinins

• Type A develops anti-B if type A agglutinogens are not present in a person's red blood cells
• Type B blood develops anti-A
• Type O blood contains no agglutinogens but contains both anti-A and anti-B antibodies
• Anti-A or anti-B plasma agglutinins, when mixed with red blood cells containing A or B antigens, attach to the red blood cells, causing them to clump together
• This clumping is called agglutination and can plug small blood vessels
• Clumps of agglutinated red blood cells are attacked by phagocytic white blood cells, which causes the release of hemoglobin into the plasma
• Sometimes, the complement system activates, causing hemolysis of the red blood cells
• In blood typing, red blood cells are separated from the plasma and diluted with saline; the sample is mixed with intact agglutinogen and antibody agglutinogen; if clumping occurs, it indicates an antibody-antigen reaction

Rh Blood Types

• There are six common types of Rh antigens: C, D, E, c, d, and e
• If a person has a capital letter antigen, they do not have the lowercase version; if they are missing the capital letter, they will have the lowercase antigen
• The D antigen is the most prevalent and antigenic; those with the D antigen are Rh positive, and those without it are Rh negative
• If an Rh-negative person receives Rh-positive blood, anti-Rh agglutinins slowly develop; subsequent transfusions of Rh-positive blood can cause a severe reaction

Erythroblastosis Fetalis

• If a mother is Rh-negative and the father is Rh-positive, the baby may inherit the Rh-positive antigen from the father
• The mother can develop anti-Rh agglutinins from exposure to the fetus's Rh antigen
• These agglutinins can diffuse through the placenta and cause red blood cell agglutination in the fetus, leading to jaundice and anemia
• RH immunoglobulin globulin is administered to expectant mothers at 28 to 30 weeks of gestation and to Rh-negative women who deliver Rh-positive babies to prevent sensitization

Transfusion Reactions

• If a mismatch transfusion occurs, the donor blood's plasma portion becomes diluted by the recipient's blood
• Released hemoglobin is converted into bilirubin, which can cause jaundice if concentrations are high enough
• Acute kidney failure can result from transfusion reactions

Acute Kidney Failure From Transfusion Reactions

• Toxic substances cause renal vasoconstriction
• Hypotension due to red blood cell loss
• Free hemoglobin blocks the renal tubules

Graft Rejection

• Autografts and isografts contain the same antigens and survive normally
• Xenografts almost always cause immune reactions and death without therapy
• There are 150 different antigen choices for human leukocyte antigen antigens, meaning there are over 1 trillion possible combinations
• T-cells are the primary cause of graft rejection, so their suppression is most important for preventing rejection
• Immunosuppressive drugs suppress T cells, but can increase the risk of bacterial and viral infections and cancer

Hemostasis

• Achieved through four mechanisms when a blood vessel is cut: vascular constriction, formation of a platelet plug, formation of a blood clot, and growth of fibrous tissue

Vascular Constriction

• Results from myogenic spasm, factors from traumatized tissue, and nervous reflexes
• Myogenic spasm is mediated by local humoral factors like thromboxane A2, causing vasoconstriction
• Nervous reflexes are initiated by pain nerve impulses

Platelet Plug Formation

• Damage to the cellular surface causes platelets to swell and become irregular, with pseudopods protruding from their surface
• Platelets contract and release active factors while becoming sticky, adhering to collagen and von Willebrand factor
• Platelets secrete ADP, platelet-activating factor, and thromboxane A2

Platelets

• Lack nuclei and cannot reproduce
• Contain actin and myosin molecules that enable them to contract
• Have residuals of the endoplasmic reticulum and Golgi apparatus, which synthesize enzymes and store calcium
• Have mitochondria and enzyme systems that enable them to form ATP and prostaglandins
• Contain a protein-fiber stabilizing factor and a growth factor that causes vascular cell growth
• A glycoprotein coating on the platelet cell membrane prevents adherence to normal endothelium but causes adherence to injured areas
• Platelets are active in the blood for 8 to 12 days and are then eliminated by the macrophage system

Blood Coagulation

• More than 50 substances affect blood coagulation, with the formation of prothrombin activator being the rate-limiting factor
• Prothrombin activator, in the presence of calcium, converts prothrombin to thrombin
• Prothrombin is a plasma protein formed in the liver that splits into thrombin
• Thrombin acts on fibrinogen to create fibrin
• The clot is composed of a mesh network of fibrin fibers that traps blood cells and plasma
• Clot retraction expresses fluid called serum, which lacks clotting factors
• Thrombocytopenia can cause a failure of clot retraction
• Thrombin acts on many blood clotting factors, creating a positive feedback loop that promotes more clotting

Extrinsic and Intrinsic Pathways

• Prothrombin activator is formed through these pathways
• These pathways involve inactive forms of proteolytic enzymes that, when converted to active forms, cause cascade reactions
• The extrinsic pathway involves a positive feedback effect of thrombin acting on factor five to accelerate clotting
• The intrinsic pathway begins with trauma to the blood or exposure to collagen, activating factor 12 and releasing platelet phospholipids
• The final step in both pathways is the same: activated factor ten combines with factor five to form prothrombin activator
• Calcium is required for all blood clotting reactions except for the first two steps of the intrinsic pathway

Anticoagulants

• The most important anticoagulants remove thrombin
• Fibrin fibers remove thrombin from circulation
• Antithrombin three combines with thrombin to block its effects
• Heparin increases antithrombin three effects
• Plasmin digests fibrin fibers and other protein coagulates, causing clot lysis
• Tissue plasminogen activator (TPA) converts plasminogen to plasmin
• The plasmin system removes minute clots from peripheral blood vessels

Other Factors in Blood Coagulation

• Almost all clotting factors are formed by the liver
• Liver disease can increase bleeding
• Vitamin K is synthesized in the intestinal tract by bacteria
• GI disease or obstruction of bile tracts can cause poor vitamin K absorption, decreasing the production of thrombin and other clotting factors
• Hemophilia is caused by an abnormality of factor eight (85% of cases) or factor nine (15% of cases) and occurs almost exclusively in males
• A loss of one component of factor eight causes hemophilia, while a loss of the other component causes von Willebrand's
• Thrombocytopenia is a low platelet count (normal is between 240,000 and 450,000 per microliter); below 30,000 increases bleeding risk, and below 10,000 is usually fatal
• A clot in a vessel is a thrombus, and a free-flowing clot is an embolus
• Two causes of thrombus include rough endothelial surface of a vessel and very slow blood flow, such as during bed rest
• Disseminated intravascular coagulation (DIC) often results from large amounts of traumatized or dying tissue releasing tissue factor, causing microclots

Blood Coagulation Tests

• Bleeding time normally lasts 1 to 6 minutes, but a lack of clotting factors, especially platelets, can prolong it
• Clotting time is no longer used in most clinics
• Prothrombin time measures the extrinsic and final common pathways
• The international normalized ratio (INR) was created to standardize measurement of prothrombin time