Chapter 13 The Red Blood Cell and Alterations in Oxygen Transport

1. Essentials of Pathophysiology Chapter 13The Red Blood Cell and Alterations in Oxygen Transport

2. There are two major types of hemoglobin—adult hemoglobin (HbA) and fetal hemoglobin (HbF). • Sickle cell disease is a chronic disorder that results from changes in the size of red blood cells, not their shape. • Iron-deficiency anemia affects only infants and toddlers. • Hyperbilirubinemia is an increased level of serum bilirubin and very often causes cyanosis in the neonate. • Thalassemias are inherited disorders of platelet synthesis that cause severe bruising and bleeding. PRE LECTURE QUIZ (True/false) T F F F F

3. Mature red blood cells are also known as ____________________. • The function of red blood cells is to transport ____________________ from the lungs to the tissues. • If red blood cell destruction is excessive, bilirubin production is increased, causing a yellow discoloration of the skin called ______________________. • Rh disease of the newborn is an example of ____________________ anemia. • ____________________ anemia describes a primary condition of bone marrow stem cells that results in a reduction of all three hematopoietic cell lines—red blood cells, white blood cells, and platelets. PRE LECTURE QUIZ Aplastic Erythrocytes Hemolytic Jaundice oxygen

4. Two alpha chains Two beta chains Each protein chain holds one iron-containing heme group Oxygen binds to the heme groups Adult Hemoglobin

5. How many molecules of oxygen can be carried by one molecule of hemoglobin? • 1 • 2 • 3 • 4 Question

6. 4 Rationale:Each hemoglobin molecule has 2 alpha and 2 beta protein chains. Each chain contains 1 heme group. Each heme group (4 chains = 4 heme groups) is capable of carrying 1 molecule of oxygen. Answer

7. Erythropoiesis decreased blood • Why would a man receiving chemotherapy for cancer develop anemia? • Why would a man with renal failure develop anemia? oxygen kidneys secrete erythropoietin bone marrow stimulated creates new red blood cells

8. Red Blood Cells bone marrow creates new red blood cells: may release mature immature reticulocytes (RBCs RBCs RBCs that still have their (nucleated) endoplasmic reticulum)

9. Their membranes become weakened Because they have no nuclei, RBCs cannot make new membrane components, Why? Eventually, RBCs break as they squeeze through the capillaries RBCs Last About 120 Days mature RBCs circulate for 120 days become damaged

10. White blood cells living in the spleen are ready to process RBCs • Creating unconjugated bilirubin Question: • Why would a man with defective red blood cells develop hepatosplenomegaly? Answer: Spleen & Liver have sluggish circulation subject to clotting causing ischemia with lack of circulation to carry away toxins Most RBCs Break in the Spleen break in capillaries of the spleen eaten by white blood cells in the spleen, liver, bone marrow, or lymph nodes hemoglobin processed into bilirubin

11. Unconjugatedbilirubin is toxic Question: • Why would a man with liver failure develop jaundice? The Fate of Bilirubin unconjugated bilirubin in blood X liver links it bilirubinemia to gluconuride jaundice conjugated bilirubin bile

12. Malaria parasites

13. Hemoglobinemia makes the plasma turn red • Hemoglobinuria makes the urine cola-colored Question: • Why was malaria called “blackwater fever?” When RBCs Are Destroyed Outside the Spleen… break in capillaries outside the spleen hemoglobin released into the blood hemoglobinemia hemoglobinuria

14. Red blood cells (erythrocytes) are made in the ________ and destroyed in the _________. • kidneys, liver • kidneys, spleen • bone marrow, spleen • bone marrow, liver Question

15. bone marrow, spleen Rationale:Erythropoietin, made in the kidneys, stimulates the bone marrow to produce RBCs. Eventually, RBCs break up in the capillaries of the spleen and their hemoglobin is processed as bilirubin in the liver. Answer

17. Blood loss Hemolysis Impaired RBC production Causes of Anemia

18. A man had severe anemia and developed: • Weakness • Angina • Fainting • Tachycardia • Sweating and pallor • Pain in his bones and sternum Question: • Which symptoms are caused by decreased RBCs, O2? • By compensation using the GAS? • By attempts to replace the RBCs? Scenario

19. Iron deficiency anemia (often caused by blood loss) • Megaloblasticanemias • Cobalamin (Vitamin B12) deficiency (Needed for DNA replication) • Pernicious anemia • Folic acid deficiency (Needed for DNA replication) • Aplastic anemia (bone marrow depression) • Chronic disease anemias • Chronic inflammation • Lymphocyte cytokines suppress erythropoietin production • Chronic renal failure • Erythropoietin not produced Anemias of Deficient RBC Production

20. Hypochromic and microcytic erythrocytes • Poikilocytosis (irregular shape) (poi'kə-lō-sī-tō'sĭs) • Anisocytosis (irregular size) (ān-ī'sō-sī-tō'sĭs) Iron-Deficiency Anemia (Rubin E., Farber J.L. [1999]. Pathology [3rd ed., p. 1077]. Philadelphia: Lippincott-Raven.)

21. Megaloblastic anemia • Erythrocytes are large, often with oval shape • Poikilocytosisand teardrop shapes • Anisocytosis (Irreg. size) • Neutrophils are hypersegmented Vitamin B12 Deficiency (Pernicious Anemia) (Rubin E., Farber J.L. [1999]. Pathology [3rd ed., p. 1076]. Philadelphia: Lippincott-Raven.)

22. A boy presents with: • Pallor • Weakness • Low red blood cell count • Increased respiratory and heart rates • Yellow skin • Dark brown urine • Enlarged spleen and liver Question: • What is your diagnosis? • Is he lacking RBC production or hemolytic anemia? • Which symptoms are caused by decreased RBC count? • By GAS? • By hemolysis? Scenario

23. Which type of deficiency causes pernicious anemia? • Iron • Vitamin B6 • Vitamin B12 • Folic acid Question

24. Vitamin B12 Rationale:Intrinsic factor produced by cells of the gastric mucosa binds vitamin B12 and assists absorption of B12. When gastric mucosa cells are lacking often due to autoimmune antibodies attacking gastric mucosa production of IF is reduced and B12 is not absorbed. Answer

25. Membrane disorders , RBC shape and fragility • Hereditary spherocytosis (shape holding inner membrane) • Acquired hemolytic anemias(chemicals drugs, antibodies)hemolytic disease of the newborn-Rh incompatibility • Hemoglobinopathies • Sickle cell disease • Thalassemia • Alpha • Beta • G6PD deficiency (Glucose 6 Phosphate Dehydrogenase enzyme deficiency- limits RBC’s ATP production) Hemolytic Anemias any of a group of inherited hypochromicanemias and especially Cooley's anemia controlled by a series of allelic genes that cause reduction in or failure of synthesis of one of the globin chains making up hemoglobin and that tend to occur especially in individuals of Mediterranean, African, or southeastern Asian ancestry —sometimes used with a prefix (as alpha-, beta-, or delta-) to indicate the hemoglobin chain affected.

26. G6PD Easily mistaken for malaria. • Heinz bodies on the periphery G6PD

27. Sickle Cell Disease • Mutation in beta chains of hemoglobin • When hemoglobin is deoxygenated, beta chains link together  Forming long protein rods that make the cell “sickle”

28. Mutation in beta chains of hemoglobin • At a single location in the protein chain valine is substituted for glutamic acid • When hemoglobin is deoxygenated, beta chains link together, forming long protein rods that make the cell “sickle” Sickle Cell Disease Valine Glutamic acid

29. Sickled cells block capillaries • Acute pain • Infarctions cause chronic damage to liver, spleen, heart, kidneys, eyes, bones • Pulmonary infarction  acute chest syndrome (Pneumonia) • Cerebral infarction  stroke • Sickled cells more likely to be destroyed • Releasing excess bilirubin Jaundice Problems Caused by Sickle Cell Disease

30. Scenario: • A man has sickle trait (heterozygous for sickle cell) • His wife has sickle cell disease Question: • What percentage of their children will have the disease? • In a population, the gene frequency of the sickle cell allele is 10% • Assuming the gene is equally common in males and females and does not affect reproduction, what percentage of the next generation’s population will have sickle trait? • Use the Hardy-WienbergEquilibrum equations:p+q=1 ; p= probability of normal gene and q = prob. of Sickle • q2 + 2pq + p2 =1 ; 2pq= freq of occurrence of father’s genotype, heterozygous Sickle Cell Disease Inheritance

31. s = Sickle Gene S= nonSickle percentage of their children Sickle Cell Disease Inheritance Mother s s Father Mother has the disease, ss S s Ss ss Ss ss Possible Children’s Genotype 50% have the disease, ss 50% are Heterozygous, Ss Father has the Trait, Ss

32. Use the Hardy-WienbergEquilibrum equations:p+q=1 ; p= probability of normal gene and q = prob. of Sickle • q2 + 2pq + p2 =1 ; 2pq= freq of occurrence of father’s genotype, heterozygous • Given: Frequency of Sickle gene = 10% • In the Hardy-Wienberg equation q=.1 • Therefore p= 1-.1=.9 or 90% of genes are normal • q2 = percent with sickle disease = (.1)2 = .01 =1% Question: What is the % heterozygous • From equations 2pq= 2(.1*.9) =.18 or 18% have the trait without the disease Solve for frequency HETEROZYGOTES IN THE POPULATION

33. True or False. Patients with sickle cell disease who also suffer from lung diseases are more prone to sickling. Question

34. True Rationale:Hypoxia, which is more likely to occur in lung/pulmonary disease, is an important exacerbating factor associated with increased sickling and vessel occlusion. Answer

35. It has alpha chains and gamma chains • This means it cannot sickle • Persons with some fetal hemoglobin are partially protected from sickle cell disease • Some treatments include inducing HbF production Fetal Hemoglobin Has No Beta Chains

36. Thalassemias

37. A woman has β thalassemia. p219 • She has pale skin and gums, fatigue, and headaches • She has been treated with transfusions since childhood • Her jaw is enlarged; she has had two leg fractures in the past year(Thin cortical bone w/ enlarged marrow. Bone deposition on jaw) • She has Heinz bodies (precipitate aggregate of excess α chains in RBC) • Her liver is enlarged; she has jaundice and liver failure Question: • Which of these signs and symptoms are due to anemia, which to compensatory erythropoiesis, and which to treatment? Scenario