Hematology Week 1

Front 1

What is the central metal atom in cobalamin?

Back 1

Cobalt

Front 2

Is cyanocobalamine found in the body? What is its purpose?

Back 2

No, it is used to stabilize exogenous vitamin B12.

Front 3

For what synthesis reaction is methyl B12 a cofactor?

Back 3

Synthesis of methionine from homocysteine

Front 4

For what reaction is deoxyadenosyl B12 a cofactor?

Back 4

Propionyl CoA metabolism: Methylmalonyl Co A to succinyl CoA.

Front 5

What happens to the monoglutamate form of folic acid?

Back 5

It leaks back out of cells. It must be polyglutamated to remain inside.

Front 6

What is the N-5 methyl tetrahydrofolate trap hypothesis?

Back 6

When methionine levels are low, the enzyme that allows N5-methyl-FH4 to donate its methyl group to cobalamin is derepressed and N5, N10- methylene tetrahydrofolate preferentially goes toward the methionine synthesis pathway and becomes N-5 methyl FH4, rather than going to DNA synthesis. When B12 is deficient, the methionine synthesis pathway cannot move forward and folate is trapped as N-5 methyl FH4.

Front 7

Where is vitamin B12 found in the diet?

Back 7

In animal protein

Front 8

What does cobalamin bind in the stomach?

In the duodenum?

What happens in the distal ileum?

Back 8

R protein

Intrinsic factor

Intrinsic factor-cobalamin is internalized by specific receptors.

Front 9

What is the B12 transporter on the cell surface?

Back 9

Transcobalamin2

(Transcobalamin1 is a storage protein.)

Front 10

What are the three essential factors for RBC synthesis that come from the diet? Where in the gut are they absorbed?

Back 10

Iron: Duodenum
Folic acid: Jejunum
B12: Ileum

Front 11

Are B12 and folic acid heat stable?

Back 11

B12 is heat stable, but folic acid is not.

Front 12

Describe the relationship between stores of and requirement for vitamin B12.

Back 12

Approximately 1-2 ug/day of B12 are required, while most people take in 2-4 ug/day. Body stores are between 2 and 5 mg, so it would take years to show a dietary deficiency in vitamin B12.

Front 13

Describe the processing of folate in the digestive tract.

Back 13

Polyglutamated folate is deglutamated to folate monoglutamate. It is then absorbed in the jejunum, reduced and methylated, then transported in the serum.

Front 14

Where in the diet is folic acid found?

Back 14

Vegetables, fruits, eggs

Front 15

Describe the relationship between stores of and requirement for folic acid.

Back 15

Approximately 100-400 ug/day of food folate/50-200 ug/day are required. Intake is highly variable between people. The body stores around 5-10 mg. Deficiency can set in within 100-200 days.

Front 16

What is the cause of low hemoglobin in B12 or folic acid deficient patients?

Back 16

Ineffective red cell production

Front 17

Besides anemia, what do you see on the CBC of patients with B12 or folate deficiency?

What is this hematopoiesis process called?

Back 17

Neutropenia, thrombocytopenia, elevated MCV, elevated RDW, elevated indirect bilirubin, elevated LDH, elevated EPO, elevated precursors in marrow (die there)

Megaloblastic hematopoeisis

Front 18

Describe the morphologic characteristics of blood cells in megaloblastic anemia.

Back 18

RBC: Oval shaped macrocytes, loose chromatin in precursors in bone marrow

WBC: Hypersegmented neutrophils, loose chromatin

Front 19

List six etiologies of megaloblastic anemia.

Back 19

1. Cobalamin deficiency
2. Folic acid deficiency
3. Hereditary or acquired defects in cobalamin or folic acid transport or metabolism
4. Drugs interfering with DNA synthesis
5. Acute leukemia/myelodysplasia
6. Congenital dyserythropoietic anemia

Front 20

Explain why the GI sequelae of folic acid or cobalamin deficiency can exacerbate the initial problem.

Name two other conditions that may lead to cobalamin and folate deficiency.

Back 20

Increased cell death and turnover in the gut as a result of one of these deficiencies may lead to difficulties in nutrient absorption.

1. Gluten enteropathy/sprue (folate first, then cobalamin)
2. Pernicious anemia (gastric atrophy)

Front 21

Name six clinical sequelae of cobalamin and folic acid deficiency.

Back 21

1. Hematologic abnormalities
2. GI cell death
3. Reproductive infertility
4. Cardiopulmonary problems (secondary to severe anemia)
5. Neuropsychiatric problems (cobalamin)
6. Neural tube defect (folic acid)

Front 22

What are some readily available lab tests to look for cobalamin and folic acid deficiencies?

Back 22

Folic acid and cobalamin levels

Homocysteine and methylmalonyl CoA levels (both would be elevated in cobalamin deficiency, only homocystein would be elevated in folic acid deficiency)

Front 23

Name the four categories of causes of cobalamin deficiency.

Which category is the most common cause?

Back 23

1. Inadequate intake
2. Inadequate absorption
3. Oxidation of cobalamin
4. Defective transport or metabolism

Inadequate absorption: hereditary or acquired intrinsic factor deficiency, gastrectomy, gastritis, pancreatic insufficiency, small bowel diseases

Front 24

What agent oxidizes cobalamin?

Back 24

Nitrous oxide

Front 25

What is pernicious anemia?

Back 25

Pernicious anemia is an autoimmune disease in which the body forms autoantibodies to the gastric sodium potassium ATPase. It usually occurs in patients over 60 of all ethnicities and is associated with other autoimmune diseases. 90% of patients form autoantibodies to parietal cells and 60-70& of patients develop autoantibodies to intrinsic factor. Gastin levels are increased. Incidence of gastric cancer is higher in this population.

Front 26

Does cobalamin deficiency become more or less common with age?

Back 26

More common due to pernicious anemia, malabsorption, and unknown causes.

Front 27

Name the causes of folic acid deficiency.

Back 27

1. Inadequate intake (common w/ alcoholism and nutritional deficiencies)
2. Inadequate intake (pregnancy, hemolysis, hemodialysis or peritoneal dialysis)
3. Inadequate absorption (sprue, Crohn's disease, lymphoma or amyloidosis of small bowel, diabetic enteropathy, intestinal resections)
4. Drugs that inhibit folic acid metabolism (dihydrofolate reductase inhibition)

Front 28

What happens to the components of RBCs when they are destroyed?

Back 28

Most components are recycled, but the protoporphyrin ring of heme is broken down into biliverdin and then bilirubin, which we can use as a measurement of RBC destruction.

Front 29

What technique is used to measure RBC survival when bilirubin, LDH, and reticulocyte counts are not clear?

Back 29

Chromium 51

Front 30

How is target reticulocyte index calculated?

Back 30

1/RBC survival in days

Front 31

Is LDH RBC specific?

Back 31

No, LDH can come from any tissue that is damaged.

Front 32

How much erythropoiesis is effective in a normal individual?

Back 32

90%

Front 33

What product of bilirubin breakdown is found in the stool?

Back 33

Stercobilinogen

Front 34

What enzyme is responsible for conjugation of bilirubin?

Back 34

Glucuronyl transferase

Front 35

How does a macrophage know that a RBC is no longer viable?

Back 35

The RBC has reduced enzymes and energy production and loses its ability to maintain the osmotic gradient. The cell membrane becomes rigid and reduces the SA:V ratio. Loss of sialic acid and exposure of phosphatidyl serine increases adherence to macrophages. Other protein sequences may be exposed, encouraging Ig binding and macrophage engulfment.

Front 36

Name five factors that are part of normal, aging RBC destruction.

Name the factors in pathologic RBC destruction.

Back 36

1. Fragmentation
2. Osmotic lysis
3. Cell rigidity
4. Phagocytosis
5. Complement cytolysis

The factors are the same in the pathological state, just exaggerated.

Front 37

What proportion of RBC death occurs in macrophages? Intravascularly?

Back 37

90%

10%

Front 38

When is free hemoglobin found in the plasma?

Back 38

In hemolytic anemias because increased overall hemolysis means increased intravascular hemolysis, which saturates the liver's ability to break down the hemoglobin.

Front 39

What is the defect in paroxysmal nocturnal hemoglobinuria?

Back 39

Cells lose CD55 and CD59 and become more sensitive to complement cytolysis, leaking hemoglobin into the plasma.

Front 40

What are the two types of hemolytic anemias? (as far as origin is concerned)

Give some examples of categories that fit into these two types.

Back 40

Intrinsic (congenital): membrane defects, hemoglobinopathies, enzyme deficiencies

Extrinsic (acquired): membrane defects, immunohemolytic, fragmentation syndromes, infectious, toxins

Front 41

What are some morphologies that you should see on a blood smear of hemolytic anemia?

Back 41

Non-specific: polychromasia, shift cells, nucleated RBCs

Specific: spherocytes, elliptocytes, leptocytes, drepanocytes, acanthocytes, Hb C crystals, fragmentation, parasites

Front 42

What are the seven hemolytic anemia syndromes that primarily have intravascular hemolysis?

Back 42

1. Thalassemia
2. Unstable Hb
3. G6PD deficiency
4. Immune-IgM
5. Fragmentation
6. Parasitism
7. PNH

Front 43

What do stomatocytes look like?

Back 43

They have a linear central pallor, sometimes multiple lines per RBC, instead of the normal round central pallor.

Front 44

What do target cells on a peripheral blood smear indicate?

Back 44

Hemoglobinopathy (thalassemia, sickle cell, or Hb C) or liver disease

Front 45

What does a rhomboid crystal on a peripheral blood smear indicate?

Back 45

Hb C

Front 46

What three syndromes create Heinz bodies?

What do they look like?

Back 46

Thalassemia, G6PD deficiency, unstable Hb

A Heinz body is a small dark circle on the periphery of a RBC.

Front 47

What are the two most common RBC enzyme deficiencies?

Back 47

G6PD
Pyruvate kinase

Front 48

What does agglutination of blood in a peripheral smear indicate?

Back 48

IgM

Front 49

What happens with endothelial hyperplasia, thrombotic thrombocytopenic purpura, or hemolytic uremic syndrome?

Back 49

Red cells get hung up on endothelial cell junctions because of ICAM, and fragmentation occurs.

Front 50

What is the normal range for hematocrit for males and females?

Back 50

Males: 39-51
Females: 37-47

Front 51

What is the normal range for hemoglobin for males and females?

Back 51

Males: 13-17
Females: 12-16

Front 52

What is the normal range for RBC for males and females?

Back 52

Males: 4.5-6.0 x 10^6/uL
Females: 4.0-5.3 x 10^6/uL

Front 53

What are the criteria for anemia for males and females?

Back 53

Males: Hct 39, Hgb 13, RBC 4.5
Females: Hct 37, Hgb 12, RBC 4.0

Front 54

What do the words anisocytosis and poikilocytosis mean?

Back 54

Anisocytosis is variation in RBC size, and poikilocytosis is variation in RBC shape.

Front 55

What is the normal range for plasma iron?

Back 55

70-150 ug/100 mL

Front 56

What is the normal range for TIBC?

Back 56

250-350 ug/100 mL

Front 57

What is the normal range for % iron saturation?

Back 57

15-45%

Front 58

What is the normal ferritin level in both females and males?

Back 58

Females: greater than 20 ng/mL

Males: greater than 100 ng/mL

Front 59

What is the normal amount of Hb F at birth, 1 year, and older than 2 years?

Back 59

Birth: 45-90%

1 year: 8%

Older than 2: 2%

Front 60

What is the normal amount of Hb A2?

Back 60

3.5%

Front 61

What is the upper limit for normal LDH?

Back 61

250 IU/L

Front 62

What are the upper limits for normal creatinine and BUN?

Back 62

Creatinine: 1.3 mg/dl
BUN: 20 mgm%

Front 63

What is a normal range for serum calcium?

Back 63

9-11 mg/dl

Front 64

What is the upper limit for normal serum alkaline phosphatase?

Back 64

100 units

Front 65

What are the normal ranges for serum albumin and globulin?

Back 65

Albumin: 3.5-4.5 g/100 ml
Globulin: 3.0-4.0 g/100 ml

Front 66

What are the three basic requirements for normal hematopoiesis (not specific)?

Back 66

1. Stem cells
2. Appropriate microenvironment
3. Hematopoietic growth factors/interleukins

Front 67

What are the components of the bone marrow stroma?

How does the stroma support hematopoiesis?

Back 67

Vascular endothelium
Fibroblasts
Macrophages
Osteoblasts

The stroma supports hematopoiesis by synthesizing growth factors and adhesion molecules.

Front 68

What cells produce G-CSF and in response to what?

What does G-CSF do?

Back 68

G-CSF is produced in monocytes, endothelial cells, fibroblasts, and neutrophils that have been stimulated by IL-1, TNF, IFN, and LPS.

G-CSF induces proliferation of granulocytes (CFU-GM) and blasts (CFU-blast), primes neutrophils for oxidative metabolism, and aids neutrophils in mediating antibody-dependent cytotoxicity.

Front 69

What growth factor influences differentiation of CFU-Mk?

Back 69

TPO/MGDF

Front 70

What factor is responsible for induction of EPO transcription?

Back 70

HIF-1

Front 71

What does EPO do?

Back 71

1. Induce division of CFU-E
2. Prevent apoptosis
3. Speed up marrow maturation of RBC precursors
4. Allow early release of immature RBCs into peripheral blood

Front 72

Name some conditions associated with inappropriately low levels of EPO.

Back 72

1. Renal failure
2. Chronic inflammatory state
3. Chronic infection
4. Cancer

Front 73

Name some conditions associated with inappropriately high levels of EPO.

Back 73

1. Polycystic kidney disease
2. Cerebral hemangioma
3. Other tumors

Front 74

In what two clinical conditions might EPO be administered?

Back 74

1. Renal failure
2. Anemia of chronic disease

Front 75

Concentration of what ion leads to rigidity of RBC membrane and hemolysis?

In what hereditary condition does this occur?

Back 75

Calcium

Sickle cell anemia

Front 76

What is Gardo's effect?

Back 76

Increased intracellular calcium opens potassium channels, resulting in potassium efflux.

Front 77

What is responsible for the conversion of methemoglobin back to hemoglobin?

Back 77

NADH-Cytochrome b5 reductase, with the help of NADH

Front 78

How does pyruvate kinase deficiency result in hemolysis?

Back 78

The RBC is unable to produce sufficient ATP to keep calcium out of the membrane, so deformability of the membrane is decreased and hemolysis occurs.

Front 79

How does G6PD deficiency result in hemolysis?

Back 79

Without G6PD, NADPH is not produced in the pentose phosphate pathway. Without NADPH, oxidized glutathione cannot be reduced back to its active form, resulting in cross-linking of other membrane proteins, stiffening the membrane and resulting in hemolysis.

Front 80

Which two phospholipids normally present on the inner leaflet of the plasma membrane may be found on the outer leaflet in sickled cells, resulting in increased thrombosis?

Back 80

Phosphatidylethanolamine
Phosphatidylserine

Front 81

Defect in which RBC cytoskeletal element results in these three clinical disorders:
Hereditary spherocytosis
Hereditary elliptocytosis
Acanthocytosis

Back 81

Spectrin