Chapter 17: Blood Flashcards
Functions of Blood:
o Transport
o Protection
o Regulation
Protective Functions of Blood:
o Defense against pathogens & toxins: o Leukocytes (white blood cells). o Antibodies. o Complement proteins. o Interferon & other chemicals. o Clotting: o Platelets. o Clotting factors & fibrinogen. o Blood shunting.
Regulatory Functions of Blood:
o Regulation of pH (7.35 to 7.45):
o Many blood proteins & solutes act as buffers.
o Regulation of body temperature:
o Cutaneous vasodilation/vasoconstriction.
o High specific heat of water.
o Regulation of fluid volume (osmotic pressure critical!)
o Regulation of ion composition of interstitial fluids.
General Characteristics of Blood:
o Unique colors:
o Scarlet color if oxygen rich (bright red).
o Dull red if oxygen poor (port wine color).
o High viscosity (5X more viscous than H20)(RBCs!).
o Osmolarity: 280 – 296 mOsm/Liter.
o Reflects # of particles & ability to attract H2O.
o Represents 7 to 8% of body weight.
o There are about 5 liters of blood in a human body.
Withdrawing Blood:
o Venipuncture: o Walls of veins are thinner. o Blood pressure (BP) is lower in veins than in arteries. o Arterial puncture: o Measure blood gases. o Capillary sticks: o Fingers, ear lobes, heel.
Composition of Blood:
o Plasma (55% of volume of blood): o Water. o Solutes. o Proteins. o Formed Elements (cells/cell (cells/cell fragments): o Erythrocytes (RBCs). o Leukocytes (WBCs). o Thrombocytes (platelets). o RBCs = 45 percent of volume of whole blood. o This percentage is called the PCV or the HEMATOCRIT. o 47 percent +/- 5 percent in males. o 42 percent +/- 5 percent in females.
Composition of Plasma:
o Plasma = straw-colored, liquid part of blood.
o 90 percent water (with over 100 substances dissolved in it).
o 8 percent plasma proteins.
o 1 – 2 percent other solutes.
Plasma Proteins:
o Hundreds of types of proteins in plasma all are chains of amino acids
o More than 90% are made by the LIVER !
o Typically, these plasma proteins STAY IN THE BLOOD VESSELS (too big to squeeze through most capillaries).
o ALBUMIN: 3.2 to 5.5 grams/dL.
o About 60 percent of all plasma proteins.
o Made by liver.
o Globulins (36 percent): alpha/beta/gamma.
o Alpha and beta globulins made by liver.
o Gamma globulins = immunoglobulins = antibodies are made by plasma cells (a differentiated form of a WBC).
o Fibrinogen (4 percent)
o Made by liver.
o Essential for blood clotting (hemostasis).
o Regulatory proteins (less than 1 percent)
o Enzymes, proenzymes, hormones, prohormones.
Plasma Proteins:
Albumin
o Major contributor to blood osmotic pressure!!!!! (attracts water to blood).
o Major contributor to blood viscosity.
o Transports:
o Fatty acids and bilirubin.
o Hormones (steroid hm, thyroid hormone).
o Ions and nutrients (Ca++, Zn++, Vit. B-6).
o Buffer for pH homeostasis.
o Crude indicator of protein nutritional status.
o Protein storage pool (half life = 14 to 20 days).
Plasma Proteins:
Globulins
o Alpha globulins (smallest in general): o e.g., HDL, VLDL, prothrombin. o e.g., haptoglobulin (transports hemoglobin released by dead RBCs). o Beta globulins (medium size): o e.g., LDL, transferrin, complement proteins. o Gamma globulins (largest): o Immunoglobulins = antibodies. o Made by plasma cells.
Hypoproteinemia:
o Low levels of protein in the blood.
o Causes (Etiology) of Hypoproteinemia:
o Liver disease interfering with protein synthesis.
o Kidney disease that permits proteins to leak out of the blood and into the urine.
o Severe burns—proteins escape in exudate.
o Severe trauma (necessitating REPAIR!).
o Extreme starvation.
o Diets severely deficient in protein.
o Consequences of Hypoproteinemia:
o Decreased osmolarity of blood (blood doesn’t attract water as much, water diffuses into the interstitial spaces between cells).
o Edema = excess fluid in interstitial spaces.
o Ascites = excess fluid in the peritoneal cavity.
Plasma Solutes (1-2 Percent of Plasma):
o Electrolytes. o Osmotic balance (especially sodium ion). o pH buffering (e.g., HCO3-). o Waste products of metabolism. o Protein metabolism produces NH3, urea. o Uric acid, creatinine, lactic acid. o Nutrients. o Glucose, but NOT glycogen! o Respiratory gases. o Miscellaneous (vitamins, growth factors, hm).
Formed Elements:
o Erythrocytes (RBCs) o 5 million RBCs/uL o Hematocrit = Percent of total blood volume occupied by RBCs = about 45 percent. o Leukocytes (WBCs) o 5,000 to 10,000 WBCs/uL. o 5 main types of WBCs. o Thrombocytes (platelets) o 150,000 to 400,000 platelets/uL. o Cell fragments.
Hemopoiesis (Hematopoiesis):
o Hemopoiesis = production of blood cells (all types).
o Location of hemopoiesis:
o Before birth: yolk sac, liver, spleen, thymus, lymph nodes.
o After birth: red bone marrow
• Sternum, ribs, clavicle, scapula, cranial bones
• Ilium of os coxae, vertebrae
• Proximal epiphyses of humerus/femur
Hemocytoblast:
o Type of stem cell that can differentiate into several cell LINES. o Lymphoid stem cell lines: o T lymphocytes. o B lymphocytes. o Myeloid stem cell line: o RBCs. o Platelets. o Neutrophils, eosinophils, basophils, monocytes (all of these are WBCs).
Regulation of Hemopoiesis:
o Erythropoiesis = formation of RBCs:
o Regulated by the hormone erythropoietin (EPO).
o EPO made primarily by kidney.
o Epoietin alfa = drug.
o Thrombopoiesis =formation of platelets:
o Regulated by hormone thrombopoietin (TPO).
o TPO (hormone made by liver) stimulates megakaryocyte production.
o Leukopoiesis = formation of WBCs:
o Regulation varies in response to pathogens.
o Production stimulated by cytokines, interleukins, and colony stimulating factors.
Characteristics of Erythrocytes:
o Biconcave disc about 7.5 um in diameter.
o Squeeze thru narrow capillaries.
o Live about 120 days.
o No nucleus in mature RBC.
o No mitochondria (no aerobic metabolism).
o Plasma membrane contains glycoproteins and glycolipids that we refer to as “antigens” which determine the different blood groups (A, B, AB, O).
o RBCs carry oxygen and other blood gases.
o Each RBC contains 250 to 280 million hemoglobin (Hb) molecules inside it!!!
o Each Hb molecule has the capacity to carry 4 oxygen molecules… so one RBC carries more than 1 billion O2 molecules!
o RBCs can also carry CO2, CO, and NO on their hemoglobin molecules.
Hemoglobin (Hb):
o PROTEIN CHAINS (part that can bind CO2):
o 2 alpha polypeptide chains.
o 2 beta polypeptide chains.
o HEME GROUPS (part that can bind O2):
o 4 non-protein porphyrin rings = heme.
o Each heme has an iron ion at its center.
o Each iron ion can carry one O2 molecule (reversibly).
o The shape of the polypeptide chains in hemoglobin are critical to the shape of the RBC!!!
o Fetal hemoglobin is different from adult Hb (binds O2 more readily).
o One way to treat sickle cell dz is to give meds that stimulate the production of FETAL Hb in adults!
o Normal Hb is approximately Hct/3 usually about 15 grams/dL.
o Males: 13 – 18 grams/dL.
o Females: 12 – 16 grams/dL.
Special Characteristic of Hemoglobins:
o Can monitor blood glucose control by a glycosylated hemoglobin test.
o HbA1-C test.
o Measures amount of glucose “sticking” to Hb over life of RBC.
o Should definitely be less than 7.0 percent.
o HbA1-C results less than 7.0 suggest that the diabetic is out of control.
o Normal FBS = 70 – 100 mg/dL.
Functions of RBCs:
o Contributes greatly to the viscosity of blood.
o Oxygen transport: 98.5% of all O2 is carried on the heme portion of Hb within the RBCs.
o Oxyhemoglobin.
o Deoxyhemoglobin.
o Carbon dioxide transport: ~20% of all CO2 is carried on the polypeptide chains of Hb within the RBCs (carbaminohemoglobin).
o Nitric oxide (NO) can also be carried by Hb… causes vasodilation of blood vessels.
o Carbon Monoxide binds to iron with a greater affinity than oxygen… dangerous!
Statistics About RBCs:
o 25 trillion RBCs in adult circulation! o 2.5 million RBCs destroyed each second! o Normal RBC count = 5 million RBCs/uL. o 5.1 – 5.8 million/uL in males. o 4.3 – 5.2 million/uL in females. o Represents about 45% of total blood volume (hematocrit)(know for exam). o 40 to 54 percent in males. o 38 to 46 percent in females.
Erythropoiesis:
o Under the regulation of Erythropoietin (EPO).
o 2.5 million RBCs destroyed each second!
o EPO is made by kidney cells in response to hypoxia: Anemias, High altitude, Increased O2 demand, Lung dz, Circulatory problems.
o Many nutrients are essential to erythropoiesis: iron, Vitamin B-12 and folate, Vitamn B-6, protein, Vitamin C.
Maturation of RBCs:
o Pluripotent Stem Cell-Myeloid stem cell- Colony forming unit E- proerythroblast- erythroblast- reticulocyte- mature RBC.
Reticulocytes:
o 0.5 to 1.5 percent of RBCs in peripheral blood.
o Have very few organelles (some RER and ribosomes for Hb production).
Lifespan/Death of RBCs:
o Lots of wear and tear going through narrow capillaries, RBC loses elasticity with age.
o No ability to repair itself.
o Lifespan is about 120 days (about 4 months).
o HbA1C test = diagnosis for diabetes.
o Removed from blood and destroyed by FIXED MACROPHAGES (phagocytes).
o Liver.
o Spleen.
o Red bone marrow.
Recycling of RBC:
o Globin (protein) portions separated from heme portions…globin just broken down into a.a. that are recycled.
o Heme pigment harder to recycle:
o IRON removed & attached to transferrin (a plasma protein that transports iron in blood).
o Free iron is toxic to cells! But necessary!!
o Transferrin delivers iron to wherever it is needed…stored as ferritin or hemosiderin.
Recycling of Heme Ring:
o Heme pigment converted to biliverdin, then unconjugated bilirubin, then (liver ) conjugated bilirubin, then secreted into bile, then (intestine) urobilinogen, then stercobilin (feces) or urobilin (urine).
Erythrocyte Disorders:
o Anemias: o Low numbers of RBCs. o Low amount of Hb inside an RBC. o Abnormal/defective Hb inside the RBC. o Polycythemias: o Extremely high numbers of RBCs. o Polycythemia vera. o Secondary polycythemias.
Anemia:
o Condition where the oxygen carrying capacity of the blood is reduced lots of disorders/diseases can cause this!!!
o Symptoms of anemia: Fatigue or lethargy, SOB on exertion, Pale skin, Cold intolerance, Picasm Serious cardiovascular consequences if severe.
3 Categories of Anemia:
o Low numbers of RBCs:
o Hemorrhagic anemia (excess blood loss)
• Sudden hemorrhage (e.g., aneurysms, trauma).
• Chronic blood loss (menses, ulcers, parasites, hemorrhoids, hemophilia).
o Hemolytic anemia (abn./premature rupture):
• Toxins, blood transfusions, drug reactions.
• Vitamin E deficiency, malaria, marathon running.
o Inadequate erythropoiesis:
• Chronic kidney dz.
• Inadequate nutrients for cell division (e.g., pernicious anemia from inadequate Vitamin B-12 absorption).
o Aplastic anemia (bone marrow failure):
• Cancer of bone marrow/radiation Rx.
• Some meds/poisons/bacterial toxins/viruses.
o Low amount of Hb inside RBCs:
o Lack of nutritional building blocks for Hb.
• Protein deficiency.
• Vitamin C, B-6, & copper deficiency.
• IRON DEFICIENCY (microcytic anemia).
o Defective Hb inside RBCs:
o The RBCs that are produced are fragile & rupture prematurely.
o Thalassemia:
• Mediterranean Sea countries.
• RBC count may be less than 2 million cells/uL.
o Sickle Cell Trait: one defective gene (heterozygous).
o Sickle Cell Anemia: 2 defective genes (homozygous).
Parietal Cells: Secrete Intrinsic Factor:
o B-12 bound to dietary protein in food.
o Pepsin and acid free it from this dietary pro.
o B-12 combines with cobalophilin (a protein from saliva).
o Pancreatic proteases cleave this bond.
o B-12 binds with intrinsic factor.
o Receptor mediated endocytosis in ileum.
Sickle Cell Anemia:
o Seen in populations that live in the malarial belt of equator.
o Causes RBCs to stick to capillary walls.
o Causes RBCs to lose K+ (essential to the survival of the malarial parasite).
o 1/500 black newborns in US.
o Erythropoiesis can’t keep up with hemolysis = severe anemia.
o Symptoms worse in conditions of low oxygen.
Polycythemias:
o “Many blood cells” (Hct is generally >55%).
o Types:
o Polycythemia vera (8-11 million RBC/uL). Very serious e.g., bone marrow Ca.
o Secondary polycythemias (6-8 million/uL)
o Blood doping, very high altitude, emphysema, smoking, severe dehydration, etc.
o Consequences:
o Increased viscosity of blood.
o Increased blood volume (increased BP).
o Embolism, stroke, heart failure.
Blood Transfusions:
o Sometimes we can’t compensate enough for blood loss.
o Losses 15-30 percent: pallor/weakness.
o Losses greater than 30 percent can cause severe shock.
o Represents 1.5 liters (about 6 cups).
o Can be whole blood (when blood loss is acute and high volume) vs. packed red cells (most plasma removed).
o Donated blood lasts about 35 days.
Blood Types:
o RBC cell surfaces contain glycoproteins called antigens (agglutinogens):
o Type A blood has Antigen A.
o Type B blood has Antigen B.
o Type AB has both Antigen A and B.
o Type O blood has neither Antigen A or B.
o Plasma contains antibodies (agglutinins) to specific “foreign” antigens!!
o These Ab attack the antigens on foreign RBCs.
o There are over 100 different blood groups!
Transfusion Reactions:
o War between the patient’s own blood and the blood that is being transfused!
o Can cause clumping & hemolysis of red blood cells… hemoglobin can be released into plasma
o Anemia, fever, chills, low BP, N and V, tachycardia (rapid heart rate)
o Kidney damage (free Hb damages the nephron tubules) leads to ARF leads to death!
o Clog small blood vessels in lungs, heart, brain, kidneys lead to death!
o Symptoms: Fever and chills, Tachycardia, Low blood pressure (hypotension), N and V, Decreased urine output.
Rh Factor:
o Rh (+) means you have the Rh antigen on the surface of your RBCs.
o Rh (–) means you don’t have the Rh antigen on the surface of your RBCs.
o 85% of whites, 88% of blacks, 99% of Asians are Rh (+).
o Antibodies against the Rh antigen DO NOT DEVELOP unless an Rh negative person is exposed to Rh positive blood.
o Transfusions of Rh (+) to a Rh (-) person.
o Transfer of blood between mother/fetus (problem only if mom is Rh (-) and baby is Rh (+).
Hemolytic Disease of Newborn (HDN):
o Rh negative mom has Rh positive baby.
o Usually not a problem in first pregnancy, later pregnancies potentially a problem if tear in placenta in 1st pregnancy that allows blood between mom/baby to mix.
o In the 2nd pregnancy, the mom’s production of anti-Rh antibodies can cross the placenta.
o The anti-Rh antibodies attack the RBCs of the fetus and cause hemolysis
o Can be prevented with RhoGAM injection at time of first birth.
o RhoGAM = immunoglobulin solution (serum) containing anti-Rh agglutinins that will bind to baby’s Rh factor & block the mom’s immune response.
Leukocyte (WBC) Functions:
o PROTECTION! o The many types of WBCs provide a mobile army to fight various pathogens, tumor cells, and toxins. o WBCs provide protection through: o Phagocytosis. o Mediating the inflammatory response. o Specific immune responses.
Characteristics of WBCs:
o Complete cells!
o Make up less than 1 percent of total blood volume.
o Typical WBC count:
o 5,000 to 10,000 WBCs/uL.
o Leukocytosis = excessive number of WBCs.
o Leukopenia = insufficient number of WBCs.
o Very few WBCs in the BLOOD, they only use the circulatory system as a “subway system” for getting to the areas of the body where they are needed for inflammatory or immune responses.
The 4 Methods of WBC Mobilization:
o 1. Chemotaxis
o Ability of WBCs to follow a chemical trail.
o Chemicals come from damaged cells, microbial toxins, or colony stimulating factors (CSFs).
o 2. Margination
o WBC rolls along endothelium, cell adhesion molecules (selectins) displayed by endothelial cells allow molecules on WBCs (integrins) to stick like velcro!
o 3. Emigration = Diapedesis.
o Squeezing between endothelial cells.
o 4. Movement through tissue spaces.
Classifications of WBCs:
o Never Let Monkeys Eat Bananas!
o Neutrophils: 50 to 70 percent of all WBCs.
o Lymphocytes: 25 to 45 percent of all WBCs.
o Monocytes: 3 to 8 percent of all WBCs.
o Eosinophils: 2 to 4 percent of all WBCs.
o Basophils: less than 1 percent of all WBCs.
Granulocytes:
o Have conspicuous granules in their cytoplasm. Macrophages!
o Neutrophils.
o Eosinophils.
o Basophils.
Agranulocytes:
o Granules are NOT conspicuous, but still present.
o Lymphocytes.
o Monocytes.
Neutrophils:
o Granules are small, evenly distributed; take both acidic and basic stains… stain pale lilac in color.
o Represent more than half of all WBCs.
o 9 to 12 microns in diameter almost 2X as big as RBCs.
o Nucleus: variable size and variable number of lobes = polymorphonuclear leukocytes (PMNs).
o Younger neutrophils are called “bands” because their nucleus is more rod or horseshoe-shaped.
Neutrophil Counts:
o Expect an increase in neutrophils: Acute bacterial infections (e.g. appendicitis, meningitis, pneumonia), Inflammation, Burns
o See a decrease in neutrophils: Radiation or drug toxicity to bone marrow, Vitamin B-12 deficiency.
Life of a Neutrophil:
o Short-lived cells: released from bone marrow, remain in blood less than 10 hours, then escape to interstitial spaces where they might live 1 to 4 days.
o Microphages: Phagocytes of bacteria, debris, dead cells, 1st to arrive!
o Main cellular constituent of PUS.
o Release chemicals from their granules:
o Lysozyme and strong oxidants (H2O2 and OCL- = hypochlorite anion).
o Release defensins = proteins that poke holes in microbial membranes.
Eosinophils:
o 2 to 4 percent of all WBCs.
o 10 to 15 microns in diameter.
o Nucleus: bi-lobed (occasionally 3 lobes).
o Granules are coarse and acidophilic, usually bright red may even cover up most of the nucleus.
o Eosinophils can cause inflammation, but they also seem to MODULATE inflammation.
o Some of their granules release HISTAMINASE, an enzyme that breaks down histamine and, thus, slows down inflammation.
Eosinophil Count:
o See an increase in eosinophils: Allergies, Autoimmune diseases, Bronchial asthma, Parasitic infections.
o See a decrease in eosinophils: Conditions/meds causing elevated cortisol levels, Drug toxicity.
Basophils:
o Less than 1 percent of all WBCs.
o 8 to 10 microns in diameter.
o Nucleus: 2 to 3 irregular lobes, but usually completely covered up by large granules.
o Granules: basophilic, stain dark blue/purple to black.
o Secrete histamine and heparin, just like mast cells…. see increases in basophils:
o Hypersensitivity reactions (anaphylactic shock).
o Cancers (including some leukemias).
Agranulocytes:
o Monocytes:
o Turn into macrophages in the tissue spaces.
o Lymphocytes (percent in blood circulation):
o B-lymphocytes (15 percent of lymphocytes).
o T-lymphocytes (80 percent of lymphocytes).
o Natural Killer cells (5 percent of lymphocytes).
Monocytes:
o 3 to 8 percent of all WBCs in circulation.
o 12 to 20 microns in diameter—largest of the WBCs.
o Nucleus is “U” or “kidney-bean” shaped stain is not as intense as other WBCs.
o Cytoplasm is very light blue (can’t see granules) and a little foamy looking (from numerous vacuoles in cytoplasm).
o May live for several months.
o Leave blood by emigration… differentiate into MACROPHAGES once they enter the tissue spaces:
o Fixed macrophages:
o Kupffer cells in liver.
o Macrophages in spleen.
o Alveolar macrophages (dust cells).
o Wandering macrophages.
o Major phagocyte: take longer to arrive, but arrive in larger numbers to destroy pathogens and clean up dead tissue.
o Macrophages (differentiated monocytes) also activate lymphocytes!
o Increased in chronic infections like TB and Valley Fever, malaria, Rocky Mountain spotted fever, many other viral, fungal, or bacterial infections.
Lymphocytes:
o 25 to 45 percent of all WBCs circulating in blood, can live for YEARS!
o Huge number of lymphocytes in body, but only small proportion in the blood
o Range of diameters—most 8 to 10 microns
o Nucleus: spherical (sometimes indented) large, taking up most of cell volume.
o Scant cytoplasm in small lymphocyte, usually just a thin rim (stains light blue) around big nucleus (stains dark blue or purple).
Function of Lymphocytes:
o B-lymphocytes (15% of circ. Lymphocytes):
o Humoral immunity.
o Differentiate into PLASMA CELLS, which secrete specific antibodies to fight extracellular pathogens and their toxins.
o T-lymphocytes (80% of circ. Lymphocytes):
o Cell-mediated immunity.
o Attack cells invaded by viruses and other pathogens.
o Attack cancer cells.
o T-killer cells, T-helper cells, T-suppressor cells.
Increased Lymphocytes If:
o Viral infections.
o Rejection of transplanted organs/grafts.
o Transfusion reactions.
o Leukemias.
o Infectious mononucleosis.
o Chronic infections.
o B-lymphocytes are especially effective against extracellular bacteria and their toxins!!!
o T-lymphocytes are especially effective against intracellular pathogens (viruses, fungi, some bacteria that work inside cells).
Leukopoiesis:
o Generation/production of WBCs.
o Cytokines are local hormones (typically glycoproteins) that stimulate WBC production.
o Interleukins (e.g., IL-3, IL-6).
o CSFs = colony stimulating factors.
o Most important source of cytokines are macrophages and T-lymphocytes.
Leukocyte Disorders:
o Leukopenia (less than 5000 cells/uL):
o Radiation or chemotherapy.
o Immunosuppressant meds.
o Glucocorticoids (e.g., prednisone).
o Some infectious diseases (AIDs, chicken pox, influenza, polio, measles, mumps).
o Abnormal Leukocytosis (more than 10,000/uL)
o Infection (e.g., Infectious mononucleosis).
o Leukemias:
• Myeloid leukemias.
• Lymphoid leukemias.
Platelets (Thrombocytes):
o 150,000 to 400,000 platelets/microliter.
o Fragments of bizarre cells called megakaryocytes (60 to 100 microns in diameter) that rupture within the bone marrow …release 2000 to 3000 anucleated “pieces” into blood = platelets (under influence of TPO).
o Involved in very complex clotting reactions and in repair of injured tissues.
Anatomy of a Platelet:
o Surface has proteins that allow platelets to ATTACH to other molecules.
o HOWEVER, platelets usually don’t stick to endothelial lining because endothelial cells secrete prostacyclin ( think “teflon”).
o Impressive array of chemicals, contained within vesicles of platelets.
o Clotting factors and calcium ion.
o Thromboxane A-2 (a prostaglandin).
o PDGF = platelet derived growth factor (hm).
o ADP and ATP.
o Serotonin, actin and myosin.
Functions of a Platelet:
o PDGF stimulates mitosis in fibroblasts and smooth muscle that help repair vascular endothelium.
o Secrete vasoconstrictors (e.g., serotonin & thromboxane A-2) that cause vascular spasms in broken blood vessels.
o Form platelet plugs that stop bleeding.
o Secrete chemicals that attract neutrophils and monocytes to the site.
o HEMOSTASIS = sequence of responses that STOPS BLEEDING!!!
Hemostasis:
o Do NOT confuse this term with homeostasis or hemopoiesis!!!
o HEMOSTASIS: stop bleeding!!!
o Hemostasis involves 3 mechanisms that reduce blood loss:
o 1. Vascular spasm.
o 2. Platelet plug formation.
o 3. Coagulation (blood clot formation).
Hemostasis Step 1:
Vascular Spasm
o Contraction of smooth muscle in the walls of blood vessels.
o Reduces blood loss for 20 to 30 minutes, allowing TIME for clotting and repair.
o Spasm likely caused by:
o Chemicals released by endothelial cells (e.g., endothelin) and injured smooth muscle.
o Chemicals released by platelets (e.g., serotonin and thromboxane A-2).
Hemostasis Step 2:
Platelet Plug Formation
o Stick then Release then Clump.
o 1. Platelet Adhesion: Platelets contact and stick to exposed collagen molecules on damaged endothelial wall of blood vessels.
o 2. Platelet Release Reaction:Adhesion activates platelets to release chemicals in their granules:
o ADP attracts more platelets and makes platelets sticky.
o Serotonin and Thromboxane A-2 are both vasoconstrictors & stimulate more degranulation.
o 3. Platelet Aggregation: Platelets start adhering to EACH OTHER, eventually forming a platelet plug.
Hemostasis Step 3:
Coagulation
o Coagulation = actual clot formation.
o Involves a very complex cascade of enzymatic reactions that ends up forming FIBRIN threads (think of a tough spider web).
o Clot = insoluble protein fibers (fibrin) and the chemicals and formed elements (RBCs, platelets, etc.) that are trapped within the fibrin “spider web.”
Aspirin and Cox-2 Inhibitors:
o Aspirin is NOT a blood thinner!!!!!!!
o Aspirin inhibits prostaglandin synthesis, thus thromboxane A-2 is not made by platelets
o Aspirin inhibits platelet aggregation, thus inhibiting platelet plug formation.
o Aspirin inhibits prostaglandin production in platelets (remember, thromboxane A-2 is a Pg), thus it discourages platelet plug formation and vascular spasm
o Cox-2 Inhibitors (Vioxx, Celebrex, Bextra) might work to inhibit prostacyclin (Prostacyclins are produced by healthy endothelial cells to INHIBIT platelet aggregation, so Cox-2 inhibitors actually might PROMOTE platelet aggregation… increased cardiovascular risk).
o Thromboxane A-2 promotes platelet plug formation; Prostacyclins inhibit platelet plug formation—always need a BALANCE!!!!
Substances Involved in Clotting Cascade:
o Clotting Factors: o Over 12 known—named by Roman numerals. o Most are proteins made in liver. o Defects/abnormalities = hemophilia. o Platelet Factors: o PF1 through PF4. o Procoagulants released by platelets. o ANTIcoagulants: o Factors that inhibit clotting (want to eventually get rid of the clot!).
The 3 Stages of Clotting (Coagulation):
o 1. Formation of the enzyme prothrombinase (prothrombin activator). o Extrinsic and intrinsic pathways—whole point is to form the enzyme prothrombinase. o 2. Common pathway to form Thrombin. o Prothrombin leads to Thrombin. o Requires the enzyme prothrombinase. o 3. Common pathway to form Fibrin. o Fibrinogen leads to Fibrin. o Requires the enzyme thrombin.
Extrinsic Vs. Internal Pathway:
o Extrinsic Pathway:
o External tissue trauma leads to release of Factor III =tissue factor (thromboplastin).
o Thus, external pathway starts with (Factor III) and ends with prothrombinase.
o Very fast (15 seconds).
o Internal Pathway:
o Uses clotting factors found only in the blood.
o Slower pathway (3-6 min).
o More clotting factors involved.
o Still ends with prothrombinase.
Events After Clot is Formed:
o Stabilization of Clot:
o Involves Factor XIII = fibrin stabilizing factor = cross-linking enzyme.
o Clot Retraction:
o Occurs within 30 - 60 minutes (actin and myosin in platelets contract, pulling on fibrin strands… squeezing out serum).
o Vessel Healing:
o PDGF stimulates smooth muscle and fibroblasts to divide and rebuild vessel wall.
o Endothelial cells multiply to restore endothelial lining.
Role of Vitamin K:
o Indirectly involved in clotting process.
o Vitamin K is required for the synthesis of clotting factors made in the liver.
o Factors II, VII, IX, X.
o Warfarin (Coumadin) interferes with the action of Vitamin K interferes with clotting! Coumadin is an anti-coagulant!
o Vitamin K is produced by bacteria in our large intestines and also obtained in our diets (dark green leafy veggies).
Control Mechanisms for Hemostasis:
o Many times each day, tiny little clots start to form at spots of minor roughness in the endothelial lining.
o Things disrupting the normal endothelium:
o HTN.
o Trauma.
o Infection.
o Atherosclerosis.
o Blood stasis (allows clotting factors to accumulate locally in higher concentrations).
o Need a system to prevent these undesirable clots, a way to prevent normal clots from getting too big, and a way to dissolve clots once they are formed.
Factors Naturally Preventing Undesirable Clotting:
o Platelet repulsion:
o Keep endothelium smooth and intact via proper diet, exercise, low BP, meds.
o Prevention of Platelet adhesion or platelet aggregation:
o Endothelium produces NO and is also coated with prostacyclin; both which repel platelets like “teflon”.
o Natural anticoagulants found in blood:
o Antithrombin III (plasma protein made in liver)(blocks action of Clotting Factors II, IX, X, XI, XII).
o Heparin (inhibits intrinsic pathway, blocks action of thrombin on fibrinogen)(thus, less fibrin formed).
o Vitamin E Quinone.
o Activated Protein C (APC) (made in liver, inactivates Clotting Factors V & VIII).
o Some foods have anticoagulant activity.
Dissolving Clots:
Fibrinolytic System
o Clots are NOT a permanent solution to blood vessel injury—once repair of damage starts, then we start dissolving the unnecessary clot!
o Plasminogen leads to Plasmin.
o Thrombin.
o t-PA (tissue plasminogen activator).
o Activated Factor XII.
o Plasmin digests the fibrin threads & dissolves the clot!
Disorders of Hemostasis:
o Bleeding Disorders: o Thrombocytopenia (platelet deficiency). o Deficits in clotting factors . o LIVER DISEASE. o Thromboembolytic Disorders: o Thrombus vs. embolus o Risk factors & meds
Thrombocytopenia:
o Platelet deficiency (less than 50,000 per uL)
o Causes:
o 1. Anything that suppresses bone marrow.
o 2. Splenic sequestration (normally 1/3 of platelets are stored in spleen, splenomegaly can cause a problem!)
o 3. Liver dz (insufficient TPO).
o 4. Accelerated platelet destruction:
• Infections that destroy platelets.
• Autoimmune disorders, such as ITP (Immune Thrombocytopenia Purpura).
• DIC = Disseminated Intravascular Coagulation.
Deficits in Clotting Factors:
o Impaired liver function: o Can’t make clotting factors. o Insufficient bile for fat absorption. o Malnutrition (protein & Vitamin). o Hemophilias (hereditary bleeding d/o): o Hemophilia A = Factor VIII deficiency. o Hemophilia B = Factor IX deficiency. o Hemophilia C = Factor XI deficiency.
Thromboembolytic Disorders:
o Thrombus: clot that develops/persists in an unbroken blood vessel or heart chamber.
o More likely to occur in veins.
o More likely to occur in fibrillation d/o (blood pools in heart chambers).
o May block circulation if large enough.
o Embolus: clot that breaks away from vessel wall, floats freely in blood.
o Pulmonary embolus.
o Coronary embolus (causes MI).
o Cerebral embolus (causes stroke = CVA).
Risk Factors for Thrombus Formation:
o Conditions that roughen endothelium: o High BP. o Arteriosclerosis. o Severe burns. o Inflammation. o Slow-flowing blood or blood stasis: o Bed-ridden patients. o Long flights in economy class! o Disorders of heart fibrillation. o Oral contraceptives/hormone replacement.
Meds to Prevent Undesirable Clotting
o Aspirin (anti-prostaglandin).
o Heparin (IV med) & Lovenox (injection).
o Pre-op and post-op.
o Blood transfusions and dialysis.
o Warfarin (Coumadin) (rat poisoning!).
o New oral anticoagulants:
o Dabigatran (Pradaxa).
o Rivaroxaban (Xarelto), Apixaban (Eliquis).
o Acute thrombolytic agents “CLOT BUSTERS”.
o tPA, Streptokinase, Urokinase.
