Understanding Polycythemia and Erythropoiesis

• Chapter 18 lecture outlines

Introduction

• Blood holds many mysteries and myths in its history
• Some myths about blood include it being a mysterious "vital force"
• The draining of "bad-blood" for medical reasons was thought to help
• It was once thought hereditary traits were transmitted through blood
• Blood cells were seen with the first microscopes
• Hematology refers to the study of blood
• Recent developments in the study of blood help save lives

18.1 Introduction

• Expected learning outcomes include describing the functions and major components of the circulatory system
• The components and physical properties of blood, blood plasma composition should all be described
• Explain the significance of blood viscosity and osmolarity
• Describe how general blood is produced.

Functions of the Circulatory System

• Circulatory system consists of the heart, blood vessels, and blood
• Cardiovascular system refers only to the heart and blood vessels
• Hematology refers to the study of blood
• The functions of the circulatory system include:
  • Transport of O2, CO2, nutrients, wastes, hormones, and stem cells
  • Protection via Inflammation, limit spread of infection, destroy microorganisms and cancer cells, neutralize toxins, and initiate clotting
  • Regulation of fluid balance, stabilize pH of ECF, and temperature control

Components and General Properties of Blood 1

• Adults have 4 to 6 L of blood, and male adults typically have more blood than female adults
• Blood is a liquid connective tissue consisting of cells and an extracellular matrix
• Plasma acts as a matrix of blood with fibers
  • It has a clear, light yellow fluid
• Formed elements include blood cells and cell fragments
  • For example, red blood cells, white blood cells, and platelets

Components and General Properties of Blood 2

• There are seven kinds of formed elements
  • Erythrocytes: red blood cells (RBCs) are one type
  • Platelets are another
  • Cell fragments from special cell in bone marrow
  • Leukocytes: white blood cells (WBCs)
  • Five leukocyte types divided into two categories
  • Granulocytes (with granules) such as 3) Neutrophils, 4) Eosinophils, 5) Basophils
  • Agranulocytes (without granules) 6)Lymphocytes, and 7) Monocytes

Components and General Properties of Blood 3

• Hematocrit involves centrifuge blood to separate components
  • Erythrocytes are heaviest and settle first, and account for 37% to 52% total volume
  • White blood cells and platelets account for 1% total volume
  • This is also known as a Buffy coat
  • The plasma is the rest of the volume, with the solids being the previously mentioned
  • Accounts for 47% to 63% of the blood
• Blood is a complex mixture of water, proteins, nutrients, electrolytes, etc.

Blood Plasma 1

• Plasma is the liquid portion of the blood
• A serum remains fluid when blood clots and solids are removed, and does not have fibers
  • It is identical to plasma except for the absence of fibrinogen
• There are three major categories of plasma proteins
  • Albumins are the smallest and most abundant plasma proteins, at 16%
  • They contribute to viscosity and osmolarity; influence blood pressure, flow, and fluid balance
  • Globulins (antibodies)
  • Provide immune system functions
  • Alpha, beta, and gamma globulins all have immune system functions
  • Fibrinogen is a precursor of fibrin threads that help form blood clots
• Plasma proteins, except globulins which are produced by plasma cells are formed by the liver

Blood Plasma 2

• Nitrogenous compounds are found in blood plasma
  • This includes free amino acids from dietary protein or tissue breakdown
  • Nitrogenous wastes (urea) are also found
  • Toxic end products of catabolism
  • Normally removed by the kidneys
• Nutrients such as Glucose, vitamins, fats, cholesterol, phospholipids, and minerals
• Dissolved,, and nitrogen
• Blood has electrolytes, which Charge things
• These makes up 90% of plasma cations
• 92% of plasma is water

Blood Viscosity and Osmolarity 1

• Viscosity refers to the resistance of a fluid to flow, resulting from the cohesion of its particles
• Whole blood 4.5 to 5.5 times as viscous as water, and rises the pressure of blood
• Plasma is 2.0 times as viscous as water
  • This is important in circulatory function

Blood Viscosity and Osmolarity 2

• Osmolarity of blood is the total molarity of those dissolved particles that cannot pass through the blood vessel wall, and involves the regulation of sodium ions, proteins, and red blood cells
• If osmolarity is too high, blood absorbs too much water, increasing the blood pressure
• If it is too low, too much water stays in tissue, blood pressure drops, and edema occurs You will feel tired and cannot breath
• Optimum osmolarity is achieved by the body's regulation of sodium ions, proteins, and red blood cells

Starvation and Plasma Protein Deficiency

• Eating less protein leads to Starvation and Plasma Protein Deficiency
• Hypoproteinemia is a Deficiency of plasma proteins
  • This is caused by extreme starvation, Liver or kidney disease, and Severe burns
• Kwashiorkor is a disease in Children with severe protein deficiency
  • The children are Fed on cereals once weaned
  • Leads to Thin arms and legs, and Swollen abdomen

How Blood is Produced 1

• Every day, adults produce 400 billion platelets, 100-200 billion RBCs, and 10 billion WBCs
• Hemopoiesis refers to production of blood, especially its formed elements, and its connected with the the umbrium
• Hemopoietic tissues produce blood cells
  • Yolk sac produces stem cells for first blood cells
  • Colonize fetal bone marrow, liver, spleen, and thymus
  • Liver stops producing blood cells at birth
  • Spleen remains involved with lymphocyte production

How Blood is Produced 2

• Red bone marrow is where the bodies make blood cells
• Red bone marrow produces all seven formed elements
  • Pluripotent stem cells (PPSC) -can produce any kind of blood cell
  • Formerly called hemocytoblasts or hemopoietic stem cells
  • Colony-forming unit-specialized stem cells only producing one class of formed element of blood
• Myeloid hemopoiesis is specifically blood formation in the bone marrow consisting of (White and Red blood cells)
• Lymphoid hemopoiesis is blood formation in the lymphatic organs
  • Beyond infancy this only involves lymphocytes

18.2 Erythrocytes

• Expected learning outcomes include discussing erythrocyte structure and function, and describe the structure and function of hemoglobin
• State and define some clinical measurements of RBC and hemoglobin quantities
• Describe the life cycle of erythrocytes
• Name and describe the types, causes, and effects of RBC excesses and deficiencies

Erythrocytes

• Erythrocytes have two principal functions
  • Carry oxygen from lungs to cell tissues
  • Pick up from tissues and bring to lungs
  • Are known as red blood cells
• Insufficient RBCs can cause death in minutes due to lack of oxygen to tissues
• Erythrocytes are disc-shaped cell with thick rim
  • 7.5 µm diameter and 2.0 µm thick at rim
• Lose nearly all organelles during development, and erythrocytes are need for oxygen
  • Lack mitochondria
  • Anaerobic fermentation to produce ATP
  • Lack of nucleus and DNA

Form and Function 1

• Blood type is determined by surface glycoproteins and glycolipids, and is a unique characteristic
  • They attach to sugar
• Cytoskeletal proteins (spectrin and actin) give membrane durability and resilience
  • Stretch and bend as squeezed through small capillaries

Form and Function 2

• Oxygen and carbon-oxygen are transported by erythrocytes

  • This is their major function
  • Increased surface area/volume ratio increases the transport
  • Due to loss of organelles during maturation
  • Increases diffusion rate of substances
  • 33% of cytoplasm is hemoglobin (Hb)
  • 280 million hemoglobin molecules on one RBC

• O2 delivery to tissue and CO2 transport to lungs

• Carbonic anhydrase (CAH) in cytoplasm

  • Produces carbonic acid from CO2 and water
  • Important role in gas transport and pH balance

Hemoglobin

• Each Hb molecule consists of:
  • Four protein chains-globins
  • Adult HB has two alpha and two beta chains
  • Fetal Hb contains two alpha and two gamma chains
  • Globins bind CO2 (5% of CO2 in blood)
• Four heme groups
  • Heme groups are Nonprotein moiety that binds O₂ to ferrous ion (Fe) at its center

Quantities of Erythrocytes and Hemoglobin 1

• RBC count and hemoglobin concentration indicate amount of O2 blood can carry
• Hematocrit (packed cell volume): percentage of whole blood volume composed of RBCs
  • Men 42% to 52% cells; women 37% to 48% cells
• Hemoglobin concentration of whole blood
  • Men 13 to 18 g/dL; women 12 to 16 g/dL
• RBC count
  • Men 4.6 to 6.2 million/µL; women 4.2 to 5.4 million/µL

Quantities of Erythrocytes and Hemoglobin 2

• Values are lower in women, and women require them
  • Androgens stimulate RBC production
  • Women have periodic menstrual losses
  • Hematocrit is inversely proportional to percentage of body fat

Erythrocyte Production 1

• Erythropoiesis refers to RBC production
• 1 million RBCs are produced per second
• Average lifespan of about 120 days
• Development takes 3 to 5 days
  • Reduction in cell size, increase in cell number, synthesis of hemoglobin, and loss of nucleus
• First committed cell-erythrocyte colony-forming unit
  • Has receptors for erythropoietin (EPO) from kidneys
  • Called Red blood pared
• Erythroblasts (normoblast) multiply and synthesize hemoglobin
• Nucleus discarded to form a reticulocyte
  • Named for fine network of endoplasmic reticulum
  • 0.5% to 1.5% of circulating RBCs are reticulocytes

Iron Metabolism 1

• Remaining transferrin is distributed to other organs where it is used for example, Mane ke magrodfin, imyagot, etc
• Bonds to apoferritin to be stored as ferritin
• In liver, some transferrin releases for storage
• In blood plasma, Fe2+ binds to transferrin
• Mix of iron and ingested acid
• Stomach acid converts Fe3+ to Fe2+
• Gastroferritin transports to small intestine for absorption

Iron Metabolism 2

• Iron is a key nutritional requirement
• Lost daily through urine, feces, and bleeding
• Men 0.9 mg/day and women 1.7 mg/day
• Low absorption rate of iron requires consumption of 5 to 20 mg/day

Iron Metabolism 3

• Dietary iron includes: ferric (Fe3+) and ferrous (Fe2+)
• Stomach acid converts Fe3+ to absorbable Fe2+
• Gastroferritin binds Fe2+ and transports it to small intestine
• Absorbed into blood and binds to transferrin for transport to bone marrow, liver, and other tissues
• Bone marrow for hemoglobin, muscle for myoglobin, and all cells use for cytochromes in mitochondria
• Liver apoferritin binds to create ferritin for storage

Iron Metabolism 4

• Vitamin and folic acid are important for Iron Metabolism
  • Rapid cell division and DNA synthesis that occurs in erythropoiesis requires these
• Vitamin C and copper are also important for iron metabolism
  • These are Cofactors for enzymes synthesizing hemoglobin
  • Copper is transported in the blood by an alpha globulin called ceruloplasmin

Erythrocyte Homeostasis

Negative feedback helps mantain in normal ranges of erythrocyte counts

• Drop in RBC count causes hypoxemia detected by kidney, who then detect low oxygen and produce
• Kidney production of erythropoietin stimulates bone marrow
• RBC count increases in 3 to 4 days
• Stimuli for increasing erythropoiesis
  • Low levels O2 (hypoxemia)
  • High altitude
  • Increase in exercise
  • Loss of lung tissue in emphysema

Erythrocyte Death and Disposal

• RBCs rupture (hemolysis) in narrow channels of spleen and liver
• Macrophages found in spleen
  • Digest membrane bits
  • Separate heme from globin, is a protein
  • Globins hydrolyzed into amino acids
  • Iron removed from heme
  • Heme pigment converted to biliverdin (green), but before that its red blood pared
  • Biliverdin converted to bilirubin (yellow)
  • Released into blood plasma (kidneys-yellow urine)
  • Liver removes bilirubin and secretes into bile - Concentrated in gallbladder, released into small intestine, bacteria

Erythrocyte Disorders

• An erythrocye disorder called Polycythemia is an excess of red blood cells, with too many cells in the blood
  • Primary polycythemia (polycythemia vera)
  • Cancer of erythropoietic cell line in red bone marrow
  • RBC count as high as 11 million RBCs/µL; hematocrit 80 -This creates denly problems
  • Secondary polycythemia
  • From dehydration, emphysema, high altitude, or physical conditioning
  • RBC count up to 8 million RBCs/μL
• Dangers of polycythemia, which Can lead to embolism, stroke, or heart failure
• It leads to Increased blood volume, pressure, viscosity

Anemia 1

• Types of Anemia include:
  • Not making enough blood cells, den 4 more blood cello
  • Causes of anemia fall into three categories with ~rupture of cells
  • Inadequate erythropoiesis or hemoglobin synthesis
  • Kidney failure and insufficient erythropoietin _ Iron-deficiency anemia _ Pernicious anemia-autoimmune attack of stomach tissue leads to inadequate vitamin absorption
  • Hypoplastic anemia-slowing of erythropoiesis
  • Aplastic anemia-complete cessation of erythropoiesis
  • Hemorrhagic anemias from bleeding
  • Hemolytic anemias from RBC destruction

Anemia 2

• Anemia has three potential consequences death of tissue, and den has more blood cello

• Hypoxia and necrosis Patient is lethargic Shortness of breath upon exertion Life-threatening necrosis of brain, heart, or kidney Blood osmolarity is reduced, producing tissue edema

• Blood viscosity is low Heart races and pressure drops Cardiac failure may ensue

Sickle-Cell Disease 1

• Sickle-Cell Disease refers to Hereditary defects that occur mostly among people of African descent
• It Caused by recessive allele that modifies structure of Hb (makes HbS)
  • Differs only on the sixth amino acid of the beta chain HbS does not bind oxygen well
  • RBCs become rigid, sticky, pointed at ends
  • Clump together and block small blood vessels This their problem.
• This way they can be stolnel in the Vassel
• Can lead to kidney or heart failure, stroke, joint pain, or paralysis
• Heterozygotes (only one sickle cell allele) are resistant to

18.3 Blood Types

• Expected learning outcomes include explain what determines a person's ABO and Rh blood types and how this relates to transfusion compatibility.
• List some blood groups other than ABO and Rh and explain how they may be useful; and describe the effect of an incompatibility between mother and fetus

Blood Types 1

• Blood types and transfusion compatibility are a matter of interactions between plasma proteins and erythrocytes
• Karl Landsteiner discovered blood types A, B, and O in 1900
  • He won a Nobel Prize in 1930
• Blood types are based on interactions between antigens and antibodies

Blood Types 2

• Antigens are Complex molecules on surface of cell membrane that activate an immune response
  • They are genetically unique to the individual
  • Used to distinguish self from foreign matter
  • Foreign antigens generate an immune response
  • Agglutinogens-antigens on the surface of the RBC that are the basis for blood typing

Blood Types 3

• Antibodies are Proteins (gamma globulins) secreted by plasma cells
  • Par of immune response to foreign matter
  • Bind to antigens and mark them for destruction
  • Forms antigen-antibody complexes
• Agglutinins-antibodies in the plasma that bring about transfusion mismatch
• Agglutination
  • Antibody molecule binding to antigens
  • Causes clumping of red blood cells

Blood Types 4

• RBC antigens are Called agglutinogens, such as antigen A and B
  • Determined by glycolipids on RBC surface
• Antibodies are Called agglutinins
  • Can be Found in plasma
  • There is Anti-A and anti-B

The ABO Group 1

• Your ABO blood type is determined by presence or absence of antigens (agglutinogens) on RBCs
• Blood type A person has A antigens
• Blood type B person has B antigens
• Blood type AB has both A and B antigens
• Blood type O person has neither antigen
  • Most common: type O
  • Rarest: type AB

The ABO Group 2

• Antibodies (agglutinins); anti-A and anti-B
• Appear 2 to 8 months after birth; maximum concentration by 10 years of age
• Antibody-A or antibody-B (or both or neither) are found in plasma
  • You do not form antibodies against your antigens

The ABO Group 3

Each antibody can attach to several foreign antigens on several different RBCs at the same time

• Responsible for mismatched transfusion reaction
• Agglutinated RBCs block small blood vessels, hemolyze, and release their hemoglobin over the next few hours or days
• Hb blocks kidney tubules and causes acute renal failure

Charles Drew-Blood-Banking Pioneer

• Charles Drew was the First black person to pursue advanced degree in medicine to study transfusion and blood banking
• Used plasma rather than whole blood as this caused less transfusion reactions

The ABO Group 4

• Universal donor is Type O, as Type O is the the most common blood type
  • It Lacks RBC antigens
  • Donor's plasma may have both antibodies against recipient's RBCs (anti-A and anti-B)
  • May give packed cells (minimal plasma)
• Universal recipient is Type AB: rarest blood type -Lacks plasma antibodies; no anti-A or anti-B

The Rh Group 1

• Rh (C, D, E) agglutinogens discovered in rhesus monkey in 1940
• Rh D is the most reactive and a patient is considered blood type Rh+ if having D antigen (agglutinogens) on RBCs Rh frequencies vary among ethnic groups

The Rh Group 2

• Anti-D agglutinins not normally present
• Form in individuals exposed to blood
  • Woman with an fetus or transfusion of blood
  • No problems with first transfusion or pregnancy
• Prevention of Hemolytic disease of the newborn (HDN) occurs if mother has formed antibodies and is pregnant with second child
• Anti-D antibodies can cross placenta RhoGAM given to pregnant women
• Binds fetal agglutinogens in her blood so she will not form anti-D antibodies

18.4 Leukocytes

Expected Learning Outcomes Explain the function of leukocytes in general and the individual role of each leukocyte type. Describe the appearance and relative abundance of each type of leukocyte. Describe the formation and life history of leukocytes. Discuss the types, causes, and effects of leukocyte excesses and deficiencies.

Form and Function

• Least abundant formed element

5,000 to 10,000 WBCs/μL

• Protect against infectious microorganisms and other pathogens Conspicuous nucleus
• Spend only a few hours in the bloodstream before migrating to connective tissue Retain their organelles for protein synthesis Granules
• All WBCs have lysosomes called nonspecific (azurophilic) granules Granulocytes (some WBCs) have specific granules that contain enzymes and other chemicals employed in defense against pathogens

Types of Leukocytes

• Granulocytes
• Neutrophils (60% to 70%): polymorphonuclear leukocytes Barely visible granules in cytoplasm; three- to five-lobed nucleus Eosinophils (2% to 4%) Large rosy-orange granules; bilobed nucleus Basophils (less than 1%) Large, abundant, violet granules (obscure a large S-shaped nucleus)
• Agranulocytes Lymphocytes (25% to 33%) Variable amounts of bluish cytoplasm (scanty to abundant); ovoid/round, uniform dark violet nucleus Monocytes (3% to 8%)

Granulocytes 1

• Neutrophils—aggressively antibacterial
  • Neutrophilia—rise in number of neutrophils in response to bacterial infection
• Eosinophils—increased numbers in parasitic infections, collagen diseases, allergies, diseases of spleen and CNS Phagocytosis of antigen—antibody complexes, allergens, and inflammatory chemicals Release enzymes to destroy large parasites
• Basophils—increased numbers in chickenpox, sinusitis, diabetes

Agranulocytes 1

• Lymphocytes—increased numbers in diverse infections and immune responses Destroy cells (cancer, foreign, and virally infected cells) "Present" antigens to activate other immune cells Coordinate actions of other immune cells Secrete antibodies and provide immune memory

Agranulocytes 2

• Monocytes—increased numbers in viral infections and inflammation Leave bloodstream and transform into macrophages
  • Phagocytize pathogens and debris
  • "Present" antigens to activate other immune cells—antigen- presenting cells (APCs)

The Leukocyte Life History

• Leukopoiesis—production of white blood cells Hemopoietic stem cells (HSCs) differentiate into:
  • Myeloblasts—form neutrophils, eosinophils, basophils Monoblasts—form monocytes
  • Lymphoblasts give rise to all forms of lymphocytes T lymphocytes complete development in thymus Red bone marrow stores and releases granulocytes and monocytes

The Leukocyte Life Cycle

• Circulating WBCs do not stay in bloodstream Granulocytes leave in 8 hours and live 5 days longer Monocytes leave in 20 hours, transform into macrophages, and live for several years Lymphocytes provide long-term immunity (decades), being continuously recycled from blood to tissue fluid to lymph and back to the blood

Leukocyte Disorders 1

• Leukopenia—low WBC count: below 5,000 WBCs/μL Causes: radiation, poisons, infectious disease Effects: elevated risk of infection Leukocytosis—high WBC count: above 10,000 WBCs/μL Causes: infection, allergy, disease Differential WBC count: identifies what percentage of the total WBC count consist of each type of leukocyte

Leukocyte Disorders 2

• Leukemia—cancer of hemopoietic tissue usually producing a very high number of circulating leukocytes Myeloid leukemia: uncontrolled granulocyte production Lymphoid leukemia: uncontrolled lymphocyte or monocyte production Acute leukemia: appears suddenly, progresses rapidly, death within months Chronic leukemia: undetected for months, survival time 3 years Effects: normal cell percentages disrupted; impaired clotting; opportunistic infections

The Complete Blood Count

• Includes several values Hematocrit Hemoglobin concentration Total count for RBCs, reticulocytes, WBCs, and platelets Differential WBC count RBC size and hemoglobin concentration per RBC

18.5 Platelets and Hemostasis -The Control of Bleeding

• Expected Learning Outcomes Describe the body's mechanism for controlling bleeding. List the functions of platelets. Describe two reaction pathways that produce blood clots. Explain what happens to blood clots when they are no longer needed. Explain what keeps blood from clotting in the absence of injury. Describe some disorders of blood clotting. Platelets and Hemostasis
• The Control of Bleeding
• Hemostasis—the cessation of bleeding Stopping potentially fatal leaks Hemorrhage: excessive bleeding Three hemostatic mechanisms Vascular spasm Platelet plug formation Blood clotting (coagulation) Platelets play an important role in all three

Platelet Form and Function 1

Platelets—small fragments of megakaryocyte cells

• 2 to 4 μm diameter; contain "granules” Platelet contains a complex internal structure and an open canalicular system Amoeboid movement and phagocytosis Normal platelet count—130,000 to 400,000 platelets/μL

Platelet Form and Function 2

Platelet functions Secrete vasoconstrictors that help reduce blood loss Stick together to form platelet plugs to seal small breaks Secrete procoagulants or clotting factors to promote clotting Initiate formation of clot-dissolving enzyme Chemically attract neutrophils and monocytes to sites of inflammation Phagocytize and destroy bacteria Secrete growth factors that stimulate mitosis to repair blood vessels

Platelet Production

• Thrombopoiesis Stem cells (that develop receptors for thrombopoietin) become megakaryoblasts Megakaryoblasts Repeatedly replicate DNA without dividing Form gigantic cells called megakaryocytes with a multilobed nucleus
• 100 µm in diameter, remains in bone marrow Megakaryocytes—live in bone marrow adjacent to blood sinusoids Long tendrils of cytoplasm (proplatelets) protrude into the blood sinusoids: blood flow splits off fragments called platelets Platelets circulate freely for 5-6 days

Hemostasis 2

• Vascular spasm—prompt constriction of a broken vessel Most immediate protection against blood loss Causes Pain receptors Some directly innervate blood vessels to constrict Smooth muscle injury Platelets release serotonin (vasoconstrictor) Effects
• Prompt constriction of a broken vessel Pain receptors—short duration (minutes) Smooth muscle injury—longer duration

Hemostasis 3

• Platelet plug formation Intact vessels have a smooth endothelium coated with prostacyclin—a platelet repellant Broken vessel exposes collagen Platelet pseudopods stick to damaged vessel and other platelets Pseudopods contract - draw together a platelet plug Platelets degranulate releasing a variety of substances Serotonin is a vasoconstrictor ADP attracts and degranulates more platelets Thromboxane A2, an eicosanoid, promotes platelet aggregation, degranulation, and vasoconstriction Positive feedback cycle is active until break in small vessel is sealed

Hemostasis 4

• Coagulation (clotting)—last and most effective defense against bleeding Conversion of plasma protein fibrinogen into insoluble fibrin threads to form framework of clot Procoagulants (clotting factors)—usually produced by the liver; are present in plasma Activate one factor and it will activate the next to form a reaction cascade Extrinsic pathway Factors released by damaged tissues begin cascade Intrinsic pathway

Coagulation

• Extrinsic pathway Initiated by release of tissue thromboplastin (factor III) from damaged tissue Cascade to factor VII, V, and X (fewer steps)
• Intrinsic pathway Initiated by platelets releasing Hageman factor (factor XII) Cascade to factor XI to IX to VIII to X
• Calcium required for either pathway

Completion of Coagulation

• Activation of factor X Leads to production of prothrombin activator Prothrombin activator Converts prothrombin to thrombin Thrombin Converts fibrinogen into fibrin monomers Monomers covalently bind to form fibrin polymer Factor XIII cross links fibrin polymer strands Positive feedback—thrombin speeds up formation of prothrombin activator Overall efficiency in coagulation can be measured with

The Fate of Blood Clots

• Clot retraction occurs within 30 minutes Platelet-derived growth factor secreted by platelets and endothelial cells Mitotic stimulant for fibroblasts and smooth muscle to multiply and repair damaged vessel Fibrinolysis—dissolution of a clot Factor XII speeds up formation of kallikrein enzyme Kallikrein converts plasminogen into plasmin, a fibrin-dissolving enzyme that breaks up the clot

Prevention of Inappropriate Clotting

• Platelet repulsion Platelets do not adhere to prostacyclin-coated endothelium Thrombin dilution By rapidly flowing blood Heart slowing in shock can result in clot formation Natural anticoagulants Heparin (from basophils and mast cells) interferes with formation of prothrombin activator Antithrombin (from liver) deactivates thrombin before can act on fibrinogen

Clotting Disorders 1

• Deficiency of any clotting factor can shut down the coagulation cascade Hemophilia—family of hereditary diseases characterized by deficiencies of one factor or another Sex-linked recessive (on X chromosome) Hemophilia A missing factor VIII (83% of cases) Hemophilia B missing factor IX (15% of cases) Hemophilia C missing factor XI (autosomal)

Clotting Disorders 2

• Physical exertion causes bleeding and excruciating pain Transfusion of plasma or purified clotting factors Factor VIII produced by transgenic bacteria Hematomas—masses of clotted blood in the tissues

Clotting Disorders 3

• Thrombosis—abnormal clotting in unbroken vessel
• Thrombus: clot Most likely to occur in leg veins of inactive people Pulmonary embolism: clot may break free, travel from veins to lungs Embolus—anything that can travel in the blood and block blood vessels

Clinical Management of Blood Clotting

• Goal—prevent formation of clots or dissolve existing clots Preventing clots Vitamin K is required for formation of clotting factors Coumarin, warfarin (Coumadin)—vitamin K antagonists Aspirin suppresses thromboxane Other anticoagulants discovered in animal research Medicinal leeches used since 1884 (hirudin) Snake venom from vipers (arvin)

Clinical Management of Blood Clotting 2

Dissolving clots that have already formed Streptokinase: enzyme made by streptococci bacteria Used to dissolve clots in coronary vessels Digests almost any protein Tissue plasminogen activator (TPA): works faster, is more specific, and now made by transgenic bacteria Hementin: produced by giant Amazon leech

Explore the characteristics, causes, and dangers of polycythemia, including primary and secondary types. Learn about erythropoiesis, from red blood cell production rates to the role of erythroblasts and reticulocytes. Also, examine sickle-cell disease, its genetic basis, and hemoglobin modification.