CHAPTER 13

THE RED BLOOD CELL AND ALTERATIONS IN OXYGEN TRANSPORT

Essentials of Pathophysiology

PRE LECTURE QUIZ (TRUE/FALSE)

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.

T

F

FF

F

PRE LECTURE QUIZ 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.

Aplastic

Erythrocytes 

Hemolytic

Jaundice

oxygen

ADULT HEMOGLOBIN

Two alpha chains Two beta chains Each protein chain

holds one iron-containing heme group

Oxygen binds to the heme groups

QUESTION

How many molecules of oxygen can be carried by one molecule of hemoglobin?

a. 1b. 2c. 3d. 4

ANSWER

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.

ERYTHROPOIESIS

• Why would a man receiving chemotherapy for cancer develop anemia?

• Why would a man with renal failure develop anemia?

decreased blood oxygen

kidneys secrete erythropoietin

bone marrow

stimulated

creates new red blood cells

RED BLOOD CELLS

bone marrow creates new red blood cells:

may release

immature RBCs

(nucleated)

reticulocytes (RBCs that still have their

endoplasmic reticulum)

mature RBCs

RBCS LAST ABOUT 120 DAYS

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

mature RBCs

circulate for 120

days

become damaged

MOST RBCS BREAK IN THE SPLEEN 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

break in capillaries

of the spleen

eaten by white blood cells in the spleen, liver, bone marrow, or lymph

nodes

hemoglobin processed

into bilirubin

THE FATE OF BILIRUBIN

Unconjugated bilirubin is toxic

Question: Why would a man

with liver failure develop jaundice?

unconjugated bilirubin in

blood

bilirubinemia

jaundice

liver links it to

gluconuride

conjugated bilirubin

bile

X

MALARIA PARASITES

WHEN RBCS ARE DESTROYED OUTSIDE THE SPLEEN…

Hemoglobinemia makes the plasma turn red

Hemoglobinuria makes the urine cola-colored

Question: Why was malaria

called “blackwater fever?”

break in capillaries outside

the spleen

hemoglobin released into the

blood

hemoglobinemia

hemoglobinuria

QUESTION

Red blood cells (erythrocytes) are made in the ________ and destroyed in the _________.

a. kidneys, liverb. kidneys, spleenc. bone marrow, spleend. bone marrow, liver

ANSWER

c. 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.

CAUSES OF ANEMIA

Blood loss Hemolysis Impaired RBC

production

SCENARIO

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?

ANEMIAS OF DEFICIENT RBC PRODUCTION

Iron deficiency anemia (often caused by blood loss)

Megaloblastic anemias Cobalamin (Vitamin B12) deficiency (Needed for

DNA replication)º 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

IRON-DEFICIENCY ANEMIA

Hypochromic and microcytic erythrocytes

Poikilocytosis (irregular shape) (poi'kə-lō-sī-tō'sĭs)

Anisocytosis (irregular size) (ān-ī'sō-sī-tō'sĭs)

(Rubin E., Farber J.L. [1999]. Pathology [3rd ed., p. 1077]. Philadelphia: Lippincott-Raven.)

VITAMIN B12 DEFICIENCY (PERNICIOUS ANEMIA)

Megaloblastic anemia Erythrocytes are large,

often with oval shape Poikilocytosis and

teardrop shapes Anisocytosis (Irreg.

size) Neutrophils are

hypersegmented

(Rubin E., Farber J.L. [1999]. Pathology [3rd ed., p. 1076]. Philadelphia: Lippincott-Raven.)

SCENARIO

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?

QUESTION

Which type of deficiency causes pernicious anemia?

a. Ironb. Vitamin B6

c. Vitamin B12

d. Folic acid

ANSWER

c. 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.

HEMOLYTIC ANEMIAS

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

º Alpha º Beta

G6PD deficiency (Glucose 6 Phosphate Dehydrogenase enzyme deficiency- limits RBC’s ATP production)

any of a group of inherited hypochromic anemias 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.

G6PD

G6PD Easily mistaken for malaria. Heinz bodies on the periphery

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”

SICKLE CELL DISEASE

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”

Valine

Glutamic acid

PROBLEMS CAUSED BY SICKLE CELL DISEASE

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

SICKLE CELL DISEASE INHERITANCE

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-Wienberg Equilibrum 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

s = Sickle Gene S= nonSickle percentage of their children

SICKLE CELL DISEASE INHERITANCE

Father

Mother

S

s

Ss

ss

Ss

ss

s s

50% have the disease, ss50% are Heterozygous, Ss

Mother has the disease, ss

Father has the Trait, Ss

Possible Children’s Genotype

SOLVE FOR FREQUENCY HETEROZYGOTES IN THE POPULATION

Use the Hardy-Wienberg Equilibrum 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

QUESTION

True or False.

Patients with sickle cell disease who also suffer from lung diseases are more prone to sickling.

ANSWER

TrueRationale: Hypoxia, which is more likely

to occur in lung/pulmonary disease, is an important exacerbating factor associated with increased sickling and vessel occlusion.

FETAL HEMOGLOBIN HAS NO BETA CHAINS 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

THALASSEMIAS

Alpha Beta• Defective gene for alpha-

chain synthesis

• May have 1–4 defective genes

• Affects both fetal and adult Hb

• In fetus, gamma4 Hb may form; in adult, beta4 Hb may form

• Defective gene for beta-chain synthesis

• May have 1–2 defective genes

• Affects only adult Hb

• Alpha4 Hb may form

SCENARIO

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?