Chapter 12: Red cell disorders - Blood loss and Hemolytic anemia

Question 1

What are three general causes of anemia?

Answer 1

Bleeding (hemorrhage)

Increased red cell destruction (hemolysis)

Decreased red cell production

Question 2

Blood loss that causes anemia can be acute or chronic. Name examples of an acute cause of blood loss and a chronic cause of blood loss.

Answer 2

Acute: trauma Chronic: gastrointestinal tract lesions, gynecologic disturbances.

Question 3

What can be the cause of impaired production (hematopoiesis)? (Name three examples)

Answer 3

1. Disturbed proliferation and differentiation of stem cells
2. Disturbed proliferation and maturation of erythroblasts
3. Marrow displacement/infiltrations

Question 4

What is an example of disturbed proliferation and differentiation of stem cells?

Answer 4

Aplastic anemia

Question 5

What is an example of disturbed proliferation and maturation of erythroblasts?

Answer 5

Megaloblastic anemia

Question 6

What can be a cause of disturbed proliferation and maturation of erythroblasts (megaloblastic anemia)?

Answer 6

Defective DNA synthesis due to deficiency/impaired use of vitamin B12 or folic acid.

Question 7

What is an example of marrow displacement/infiltrations?

Answer 7

Metastasis or leukemia

Question 8

Name three intrinsic hereditary causes of hemolytic anemia (increased destruction).

Answer 8

Membrane abnormalities

Enzyme deficiencies

Disorders of hemoglobin synthesis

Question 9

Name an intrinsic acquired cause of hemolytic anemia (increased destruction).

Answer 9

Membrane defect

Question 10

What is an example of a membrane abnormality during hemolytic anemia?

Answer 10

Spherocytosis

Question 11

What is an example of an enzyme deficiency during hemolytic anemia?

Answer 11

Glucose-6 phosphate dehydrogenase (G6PD)

Question 12

What is an example of a disorder of hemoglobin synthesis during hemolytic anemia?

Answer 12

Thalessemia and sickle cell anemia

Question 13

What is an example of a membrane defect during hemolytic anemia?

Answer 13

Paroxysmal nocturnal hemoglobinuria (complement system targets membrane)

Question 14

Name two extrinsic causes of hemolytic anemia.

Answer 14

Antibody mediated

Mechanic trauma to erythrocytes

Question 15

What is an example of antibody mediated hemolytic anemia?

Answer 15

Transfusion, autoimmune disease

Question 16

What is an example of mechanic trauma to erythrocytes during hemolytic anemia?

Answer 16

Defective cardiac valves

Question 17

What are (six) symptoms of anemia?

Answer 17

Shortness of breath, fatique, whiteness (palor), nail defect, jaundice, splenomegaly.

Question 18

What are the effects of acute bleeding (hemorrhage) mainly caused by?

Answer 18

By the loss of intravascular volume. If this is massive, it can lead to cardiovascular collapse, shock and death.

Question 19

What is typical of chronic blood loss?

Answer 19

Iron stores are gradually depleted.

Question 20

What are hallmarks of hemolytic anemia and why?

Answer 20

Erythroid hyperplasia and reticulocytosis are hallmarks of all hemolytic anemias. This is because the loss of red blood cells, results in low tissue O2 levels. This triggers the production of erythropoietin (kidneys) which in turn stimulates the growth of reticulocytes (immature red blood cells) from the bone marrow.

Question 21

Extrinsic hemolysis is caused by defects that…

Answer 21

increase the destruction of red cells by phagocytes (particularly in the spleen).

Question 22

Why does extrinsic hemolysis particularly happen in the spleen?

Answer 22

Because the spleen contains large numbers of macrophages, who are responsible for the removal of damaged or antibody-coated red cells. When deformed/coated red blood cells circulate through the spleen, they become stuck due to the narrow passage through the spleen.

Question 23

When looking at the clinical manifestations of extrinsic hemolysis, what’s typical for extrinsic hemolysis compared to intrinsic hemolysis?

Answer 23

• Hyperbilirubinemia and jaundice, stemming from degradation of hemoglobin in macrophages.
• Varying degrees of splenomegaly due to work hyperplasia.
• If long-standing, formation of bilirubin-rich gallstones (pigment stones) and an increased risk of cholelithiasis.

Question 24

When looking at the clinical manifestations of intrinsic hemolysis, what’s typical for intrinsic hemolysis compared to extrinsic hemolysis?

Answer 24

• Hemoglobinemia, hemoglobinuria and hemosiderinuria. When red cells burst they release hemoglobine in the circulation.
• Loss of iron (leads to iron deficiency)

Question 25

Why is loss of iron not a feature of extravascular hemolytic anemia?

Answer 25

Because phagocytes recycle iron.

Question 26

When looking at the clinical manifestations of intrinsic and extrinsic hemolysis, what’s typical for both?

Answer 26

Decreased serum levels of haptoglobin.

Question 27

What is haptoglobin?

Answer 27

Plasma protein that binds free hemoglobin and is then removed from the circulation (when removed from the circulation, serum levels decrease).

Question 28

What is a general description of (hereditary) spherocytosis?

Answer 28

(intrinsic and inherited) defects in the red cell membrane that lead to formation of spherocytes. These cells are highly vulnerable to sequestration and destruction in the spleen.

Question 29

Just click and read about the membrane protein spectrin, which is usually mutated ing spherocytosis.

Answer 29

The major membrane skeleton protein is spectrin, a long, flexible heterodimer that self-associates at one end and binds short actin filaments at its other end. These contacts create a two-dimensional meshwork that is connected to the transmembrane proteins band 3 and glycophorin via the linker proteins ankyrin, band 4.2, and band 4.1.

Question 30

What is a common feature of the pathogenic mutations (like mutations in spectrin) in spherocytosis?

Answer 30

The mutations weaken vertical interactions between the membrane skeleton and intrinsic red cell membrane proteins.

Question 31

If you look at this picture. What is meant by anisocytosis and hyperchromic spherocytes?

Answer 31

Anisocytosis: red blood cells unequal in size.

Hypochromia: red blood cells have less color than normal when examined under a microscope.

Question 32

What are clinical features of spherocytosis?

Answer 32

Anemia, splenomegaly and jaundice.

Question 33

What is sometimes removed of a patient with spherocytosis?

Answer 33

The spleen (splenectomy).

Question 34

Sickle cell anemia is caused by a single amino acid substitution in β-globin that results in a …

Answer 34

tendency for deoxygenated HbS (sickle hemoglobin) to self-associate into polymers.

Question 35

What is meant by sickle hemoglobin HbS?

Answer 35

The deoxygenated HbS (sicle hemoglobin) is mutated and because of this associates into polymers with other HbS. This causes deformation of red blood cells into ‘sickels’.

Question 36

Just read

Answer 36

Three factors that are important in determining whether significant polymerization of HbS occurs are:

• The intracellular levels of hemoglobins other than HbS (HbA retards polymerization of Hbs).
• The intracellular concentration of HbS.
• The time required for red cells to pass through the microvasculature

Question 37

Just read

Answer 37

The sickling of red cells has two major pathologic consequences: chronic moderately severe hemolytic anemia, produced by red cell membrane damage, and vascular obstructions, which result in ischemic tissue damage and pain crises

Question 38

What is meant by aplastic crisis?

Answer 38

Caused by a sudden decrease in red cell production, the body does not make enough new red blood cells to replace the ones that are already in the blood. (Usually happens when infected by parvovirus B19 + sickle cell anemia).

Question 39

Thalassemia is an inherited disorder caused by mutations in globin genes. What does this result in?

Answer 39

Decrease in synthesis of α- or β-globin. This results in Hb deficiency and red cell damage (that is caused by precipitates formed from excess unpaired “normal” globin chains.)

Question 40

Defective synthesis of β-globin in β-thalassemia contributes to anemia through two mechanisms, these are….? (don’t learn this by heart)

Answer 40

• inadequate HbA formation, resulting in small (microcytic), poorly hemoglobinized (hypochromic) red cells
• by allowing the accumulation of unpaired α-globin chains, which form toxic precipitates that severely damage the membranes of red cells and erythroid precursors.

Question 41

What is meant with:

• Microcytosis
• Poikilocytosis

Answer 41

• Microcytosis: a condition in which red blood cells are unusually small as measured by their mean corpuscular volume.
• Poikilocytosis: Variation in cell shape

Question 42

What happens during G6PD deficiency?

Answer 42

Red cells are constantly exposed to endo- and exogenous oxidants which are normally inactivated by reduced glutathione (GSH). In G6PD deficiency (regeneration of) GSH is impaired, therefore endo- and exogenoys oxidants are free to attack red blood cells.

Question 43

Just read about Glucose-6-phosphate dehydrogenase deficiency

Answer 43

Oxidized hemoglobin denatures and precipitates, forming intracellular inclusions called Heinz bodies, which can damage the red cell membrane so severely that intravascular hemolysis results. Other cells with lesser damage lose their deformability and suffer further injury when splenic phagocytes attempt to “pluck out” the Heinz bodies, creating bite cells.

Question 44

What gene is mutated in paroxysmal nocturnal hemoglobinuria (PNH)? What is the function of this gene?

Answer 44

The gene PIGA is mutated, which normally is required for the synthesis van PIG, which serves as a membrane anchor for many proteins.

Question 45

What’s the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH)?

Answer 45

Mutated PIG proteins lack the ability to produce a ‘tail’ that among others limit the activity of the complement. As a result red cells with mutated PIG are highly vulnerable for lysis by the complement C5b-C9 MAC.

Question 46

What can happen (complication) as a result of paroxysmal nocturnal hemoglobinuria (don’t learn this by heart)?

Answer 46

Thrombosis, which often occurs within abdominal vessels such as the portal vein and the hepatic vein

Question 47

By now you’ve probably covered all flashcards about diseases that contribute to hemolytic anemia caused by intrinsic (hereditary or acquired) defects. *click*

Answer 47

One cause is left which are the extrinsic hemolytic causes. These can be antibody-mediated (immunohemolytic anemia) or mechanic trauma to red blood cells.

Question 48

What are characteristics of immunohemolytic anemia?

Answer 48

It is caused by antibodies that bind to determinants on red cell membranes. These antibodies may arise spontaneously or be induced by exogenous agents such as drugs or chemicals.

Question 49

Just read

Answer 49

Immunohemolytic anemia can be divided into:

• Warm Antibody Immunohemolytic Anemia, hemolysis results from the binding of high-affinity autoantibodies to red cells, which are then removed from the circulation by phagocytes in the spleen and elsewhere.
• Cold Antibody Immunohemolytic Anemia, usually is caused by low-affinity IgM antibodies that bind to red cell membranes only at temperatures below 30°C, such as occur in distal parts of the body (e.g., ears, hands, and toes) in cold weather.

Question 50

In which two situations can hemolytic anemia resulting from mechanical trauma of red cells occur?

Answer 50

• Traumatic hemolysis sometimes occurs as a consequence of defective cardiac valve prostheses. This creates turbulent blood flow to shear red cells (like a blender).
• More commonly, it occurs incidentally during an activity involving repeated physical pounding of one or more body parts (e.g., marathon racing, karate chopping, bongo drumming).

Question 51

What’s the connection between anemia and malaria?

Answer 51

Normally, red cells bear negatively charged surfaces that interact poorly with endothelial cells. When infected with malaria, adhesion molecules get expressed and interaction is enhanced. Endothelial cells interact with red blood cells, trapping red cells in postcapillary venules. Besides this, red cells get lysed when the parasites leave red cells. This causes hemolytic anemia.