Pbl Exam 2 Case 4

Front 1

1. Classification and functions of leukocytes and thrombocytes

Back 1

The leukocytes can be classified either as polymorphonuclear leukocytes (granulocytes) or mononuclear leukocytes, depending on the morphology of the nucleus in these cells.

The mononuclear leukocyte has a rounded nucleus, whereas the polymorphonuclear leukocytes have a multilobed nucleus.

Front 2

2. Granulocytes

Back 2

Named b/c of the presence of secretory granules visible on staining.

Include:
1. Neutrophils
2. Eosinophils
3. Basophils

Are activated in response to chemical stimuli and release their granule contents (degranulation)

Front 3

3. Staining color of neutrophils, eosinophils, and basophils?

Back 3

Neutrophils: pink

Eosinophils: red

Basophils: blue

Front 4

4. Role of neutrophils

Back 4

Phagocytic cells that migrate rapidly to areas of infection or tissue damage. As part of the response to acute infection, neutrophils engulf foreign bodies and destroy them, in part, by initiating the respiratory burst.

The respiratory burst creates oxygen radicals that rapidly destroy the foreign material found at the site of infection.

Front 5

5. Role of eosinophils

Back 5

Destroy parasites such as worm.

The eosinophilc granules are lysosomes containing hydrolytic enzymes and cationic proteins, which are toxic to parasitic worm.

Eosinophils have also been implicated in asthma and allergic response, although their exact role in the development of these disorders is still unknown.

Front 6

6. Role of basophils

Back 6

The least abundant of the leukocytes, participate in hypersensitivity reactions, such as allergic responses.

Histamine, produced by the decarboxylation of histidine, is stored in the secretory granules of basophils.

Release of histamine during basophil activation stimulates smooth muscle cell contraction and increases vascular permeability.

Th granules also contain enzymes such as proteases, β-glucoronidase, and lysophospholipase. These enzymes degrade microbial structures and assist in the remodeling of damaged tissue.

Front 7

7. Mononuclear leukocytes

Back 7

Consist of various classes of lymphocytes and the monocytes.

Front 8

8. Three major types of lymphocytes

Back 8

1. T-cells
2. B-cells
3. NK-cells

Front 9

9. What are the roles of macrophages in the spleen?

Back 9

Play an important role in maintaining the oxygen-delivering capabilities of the blood by removing damaged red blood cells that have a reduced oxygen carrying capacity.

Front 10

10. Platelets

Back 10

Heavily granulated disc-like cells that aid in intravascular clotting.

Like the erythrocyte, platelets lack a nucleus.

They arise by budding of the cytoplasm of megakaryocytes, multinucleated cells that reside in the bone marrow.

Front 11

11. Anemia

Back 11

The major function of erythrocytes is to deliver oxygen to the tissues. To do this, a sufficient concentration of hemoglobin is necessary for efficient oxygen delivery to occur.

When the Hb concentration falls below normal values, the patient is classified as anemic.

Front 12

12. Classifications of anemia

Back 12

Based on red cell size and hemoglobin concentration

Front 13

13. Microcytic, hypochromic anemias

Back 13

Functional deficit: Impaired hemoglobin synthesis

Possible causes:
1. Iron deficiency
2. Thalassemia mutation
3. Lead poisoning

Front 14

14. Macrocytic, normochromic anemias

Back 14

Functional deficit: Impaired DNA synthesis

Possible causes:
1. Vitamin B12 or folic acid deficiency
2. Erythroleukemia

Front 15

15. Normocytic, normochromic anemias

Back 15

Functional deficit: Red cell loss

Possible causes:
1. Acute bleeding
2. Sickle cell disease
3. Red cell metabolic defects
4. Red cell membrane defects

Front 16

16. MCV

Back 16

Mean corpuscular volume

This is the average volume of the red blood cell, expressed in femtoliters.

Normal MCV values range from 80-100 fL

A value of < 80 fL indicates microcytic cells

Front 17

17. MCHC

Back 17

Mean corpuscular hemoglobin concentration

This is the average concentration of hemoglobin in each individual erythrocyte, expressed in grams per liter.

The normal range is 32-37 g/L

A value of < 32 g/L indicates hypochromic cells

Front 18

18. Unique aspects of erythrocytes

Back 18

1. No nucleus
-no DNA, RNA or protein synthesis

2. No mitochondria
-no TCA cycle, oxidative phosphorylation, electron transport chain to generate ATP

3. Must survive oxidative environment
-passage thru lungs

4. Larger than capillaries
-must deform to pass thru

Front 19

19. Glycolysis and shunts in RBCs

Back 19

No mitrochrondria, no ATP from TCA cycle

Use glycolysis to produce ATP

Provide substrates for Hexose monophosphate shunt and Rapaport-Luberin Shunt, NADH, and NADPH for other reactions.

Front 20

20. Rapaport-Luberin Shunt

Back 20

Erythrocyte glycolysis uses this shunt to generate 2,3-BPG

Front 21

21. In order for hemoglobin to bind oxygen, what is necessary?

Back 21

The iron of Hb must by in the ferrous (+2) state.

However, reactive oxygen species can oxidize the iron to the ferric (+3) state, producing methemoglobin.

Front 22

22. What does the NADH produced by glycolysis accomplish?

Back 22

The NADH is used to regenerate hemoglobin from methemoglobin by the NADH-cytochrome b5 methemoglobin reductase system.

Cytochrome b5 reduces the ferric form of iron (+3) of methemoglobin.

The oxidized cytochrome b5 is then reduced by a flavin-containing enzyme, cytochrome b5 reductase, using NADH as the reducing agent.

Front 23

23. How is NADPH generated by RBCs?

What is the role of NADPH?

Back 23

Approx 5 - 10% of the glucose metabolized by RBCs is used to generate NADPH by way of the hexose monophosphate shunt.

The NADPH is then used to maintain glutathione in the reduced state.

The glutathione cycle is the RBC's chief defense against damage to proteins and lipids by reactive oxygen species.

Front 24

24. What enzyme catalyzes the first step of the hexose monophosphate shunt?

Back 24

G6PD

Glucose 6-phosphate dehydrogenase

The lifetime of the RBC correlates with G6PD activity.

Lacking ribosomes, the RBC cannot synthesize new G6PD protein.

Consequently, as the G6PD activity decreases, oxidative damage accumulates.

Front 25

25. Hexose monophosphate shunt

Back 25

1. Present in many cell types

2. Produces 5-carbon sugars (i.e. ribose)

3. Returns carbons to glycolysis in RBC's

4. Produces NADPH, which reduces glutathione for antioxidant effect

5. Protects cell

Front 26

26. Cytochrome b5

Back 26

Hb can become methemoglobin by a change in oxidation state of iron in heme

Will not carry oxygen to tissues - about 3% normally

NADH reduces cytochrome b5 which reduces iron

Front 27

27. What is the structure of the heme molecule?

Back 27

Heme consists of a porphyrin ring coordinated w/an atom of iron.

Four pyrrole rings are joined by methenyl bridges to form the porphyrin ring.

Eight side chains serve as substituents on the porphyrin ring, two on each pyrrole.

In heme, the order of these groups is characteristic of the porphyrins of the type III series, the most abundant in nature.

Front 28

28. Synthesis of heme

Back 28

Heme is synthesized from glycine and succinyl CoA which participate in a series of reactions to generate heme.

Two produce one molecule of heme:
1. 8 molecules each of glycine and succinyl CoA are required.
2. A series of porphyrinogens is generated in sequence
3. Finally, iron is added to produce heme.

Front 29

29. Regulation of heme synthesis

What else does heme regulate?

Back 29

Heme regulates its own production by repressing the synthesis of δ-aminolevulinic acid (δ-ALA) and by directly inhibiting the activity of this enzyme (allosteric modifier)

Thus, heme is synthesized when heme levels fall; as they rise, the rate of synthesis decreases.

Heme also regulates the synthesis of hemoglobin by stimulating synthesis of the protein globin. Heme maintains the ribosomal initiation complex for globin synthesis in an active state.

Front 30

30. δ-ALA dehydratase

Back 30

Contains zinc and ferrochelatase, which are inactivated by lead.

Thus, in lead poisoning, δ-ALA and protoporphyrin 9 accumulate, and the production of heme is decreased.

Anemia results from a lack of Hb, and energy production decreases b/c of the lack of cytochromes for the electron transport chain.

Front 31

31. Iron for heme

Back 31

1. Iron from diet must reach organs
2. Transferrin is major serum carrier
3. Ceruloplasmin changes oxidation state
4. Stored in liver as ferritin
5. Serum ferritin levels rise w/excess iron
6. Hemosiderin is storage form, and is not mobilized easily.

Front 32

32. Because free iron is toxic, how does the body handle it?

Back 32

It is usally found in the body bound to proteins.

Iron is carried in the blood as Fe 3+ by the protein apotransferrin, with which it forms a complex known as transferrin.

Front 33

33. Ferritin

Back 33

Storage of iron occurs in most cells but esp those of the liver, spleen and bone marrow.

In these cells, the storage protein, apoferritin, forms a complex with iron (Fe 3+) known as ferritin.

Normally, little ferritin is present in the blood. This amount increase, however, as iron stores increase.

Therefore, the amt of ferritin in the blodo is the most sensitive indicator of the amt of iron in the body's stores.

Front 34

34. Excess iron goes to where?

Back 34

When excess iron is absorbed from the diet, it is stored as hemosiderin, a form of ferritin complexed w/additional iron that cannot be readily mobilized.

Front 35

35. Degradation of heme

Back 35

Heme is degraded to form bilirubin, which is then conjugated w/glucoronic acid and excreted in the bile.

Although heme from cytochromes and myoglobin also undergoes conversion to bilirubin, the major source of this bile pigment is Hb.

Front 36

36. Steps in the degradation of heme

Back 36

1. After RBCs die, the globin is cleaved to its constituent AAs, and iron is returned to the body's iron stores.

2. Heme is then oxidized and cleaved to produce carbon monoxide and biliverdin.

3. Biliverdin is reduced to bilirubin, which is transported to the liver complexed w/serum albumin.

4. In the liver, bilirubin is converted to a more water soluble compound by reacting with UDP-glucuronate to form bilirubin monoglucuronide, which is converted to the diglucuronide. This conjugated form of bilirubin is excreted into the bile.

Front 37

37. What happens to the bilirubin diglucuronide in the intestine?

Back 37

Bacteria deconjugate bilirubin diglucuronide and convert the bilirubin to urobilinogens.

Some urobilinogen is absorbed into the blood and excreted in the urine.

However, most of the urobilinogen is oxidized to urobilins, i.e. stercobilin, and excreted in the feces.

These pigments give feces their brown color.

Front 38

38. The red cell membrane

Back 38

To survive in the circulation, the red cell must be highly deformable. Damaged red cells that are no longer deformable become trapped in the passages in the spleen, where they are destroyed by macrophages.

The reason for this deformability lies in its shape and in the organization of the proteins that make up the red blood cell membrane.

Front 39

39. Red cell membrane proteins

Back 39

1. Membrane proteins can have a variety of functions. Major proteins are:
a. spectrin
b. actin
c. band 4.1
d. band 4.2
e. ankyrin

2. Glycophorin provides large negative change, and prevents aggregation

3. Band 3 is a chloride-bicarbonate exchange transporter

4. Associate with cytoskeleton.

Front 40

40. Spectrin

Back 40

Is the major protein in the cell membrane; multiple spectrins can bind to each actin filament, resulting in a branched membrane cytoskeleton

Front 41

41. Ankyrin

Back 41

The first membrane-cytoskeleton anchor.

The spectrin cytoskeleton is connected ot the membrane lipid bilayer by ankyrin, which interacts with beta-spectrin and the integral membrane protein, band 3. Band 4.2 helps to stabilize this connection.

Front 42

42. Band 4.1

Back 42

The other membrane-cytoskeleton anchor.

Membrane proteins associate with ankyrin and band 4.1 proteins.

Band 4.1 anchors the spectrin skeleton with the membrane by binding the integral membrane protein glycophorin C and the actin complex.

Front 43

43. What happens when the RBC is subjected to mechanical stress?

Back 43

The spectrin network rearranges.

Some spectrin molecules become uncoiled and extended; others become compressed, thereby changing the shape of the cell, but not its surface area.

Front 44

44. Agents that affect oxygen binding

Back 44

1. Hydrogen ions
2. 2,3-BPG
3. Covalent binding of CO2

Front 45

45. 2,3-BPG

Back 45

Formed in RBCs from the glycolytic intermediate 1,3-BPG.

2,3-BPG binds to Hb in the central cavity formed by the four subunits, increasing the energy required for the conformational changes that facilitate the binding of oxygen.

Thus, 2,3-BPG lowers the affinity of Hb for oxygen.

Therefore, oxygen is less readily bound (i.e. more readily released from tissues) when Hb contains 2,3-BPG.

Front 46

46. Bohr effect

Back 46

The binding of protons by Hb lowers it affinity for oxygen, contributing to a phenomenon known as the Bohr effect.

As the pH decreases, the affinity of Hb for oxygen decreases, shifting the curve to the right.

Front 47

47. CO2 and oxygen binding

Back 47

Although most of the CO2 produced by metabolism in teh tissues is carried to the lungs as bicarbonate, some of teh CO2 is covalently bound to Hb.

In the tissues, CO2 reacts with the amino groups of the deoxyhemoglobin and stabilizes the deoxy conformation.

Front 48

48. Erythropoiesis

Back 48

1. Start as hematopoietic stem cells

2. These form pluripotent stem cells

3. Stem cells form mixed myeloid progenitor cells (GFU-GEMM)

4. GFU-GEMM form burst forming unit - erythroids (BFU-E)

5. BFU-E forms colony forming unit - erythroids (CFU-E)

6. CFU-E forms the first recognizable red cell precursor, the normoblast.

Front 49

49. Final steps in RBC differentiation

Back 49

1. Normoblasts are committed progenitors

2. They divide 4 times after which Hb synthesis begins

3. Nucleus becomes inactive, and then extruded

4. Released in circulation as reticulocyte; later matures in 1-2 days.

Front 50

50. Regulation of erythropoiesis

Back 50

Regulated by the demands of oxygen delivery to the tissues.

In response to reduced tissue oxygenation, the kidney releases the hormone erythropoietin, which stimulates the multiplication and maturation of erythroid progenitors

Front 51

51. Nutritional anemias

Back 51

1. Vitamin deficiencies
-Folate and vitamin B12 needed for nucleotide synthesis
2. Deficiency slows mitosis of progenitors
3. Cells divide too few times

Front 52

52. Iron deficiency

Back 52

These cells are microcytic and hypochromic. The lack of iron results in decreased heme synthesis, which in turn affects globin synthesis.

Iron deficient RBCs continue dividing past their normal stopping point, resulting in small red cells. They are also pale, because of the lack of Hb, compared with normal cells.

Front 53

53. Folate or vitamin B12 deficiencies

Back 53

Can cause megalobastic anemia, which the cells are macrocytic.

Folate and B12 are required for DNA nucleotide synthesis, and when these are deficient, DNA replication and nuclear division do not keep pace w/ the maturation of the cytoplasm.

Consequently, the nucleus is extruded before the requisite number of cell divisions has taken place, and the cell volume is greater than it should be, and fewer blood cells are produced.

Front 54

54. Thalassemias

Back 54

For optimum function, the Hb α- and β- globin chains must have the proper structure and be synthesized in a 1:1 ratio.

A large excess of one subunit over the other results in thalassemia.

These anemias are clinically very heterogeneous, and they provide resistance to malaria in the heterozygous state.

Front 55

55. Causes of thalessemias?

α-thalessemias and β-thalessemias?

Back 55

1. Hemoglobin single AA replacement mutations that give rise to a globin subunit of decreased stability

2. More common are mutations that result in decreased synthesis of one subunit:

α-thalessemias usually result from complete gene deletions

β-thalessemias can result from deletions, promoter mutations and splice-junction mutations

Front 56

56. α-thalessemias

Back 56

Two copies of the α-globin gene are found on each chromosome 16, for a total of 4 α-globin genes per precursor cell.

If one copy of the gene is deleted, the size and Hb concentration of the individual RBCs is minimally reduced.

The more copies that are deleted, the more the RBCs will become microcytic and hypochromic

Absence of 3 α-globin genes causes moderately severe microcytic hypochromic anemia with splenomegaly

Absence of all four α-globin chains is usually fatal in utero (hydrops fetalis)

Front 57

57. β-thalessemias

Back 57

Many different variations; can be asymptomatic all the way to severe anemia. β°β° homozygotes are the most severely affected.

In general, disease of β-chain deficiency are more severe than disease of α-chain deficiency.

Front 58

58. Why are diseases of β-chain deficiency are more severe than diseases of α-chain deficiency?

Back 58

Excess β-chains form a homotetramer, HbH, which is useless for delivering oxygen to the tissues b/c of its high oxygen affinity. As RBCs age, HbH precipitates in the cells, forming inclusion bodies.

RBCs with inclusion bodies have shortened lifespans, b/c they are more likely to be trapped and destroyed in the spleen.

Excess α-chains are unable to form a stable tetramer. However, excess α-chains precipitate in erythrocytes at every developmental stage. The α-chain precipitating results in their widespread destruction. They also damage RBC membranes, particularly band 4.1.

Front 59

59. Hereditary persistence of fetal hemoglobin

Back 59

HbF, the predominant Hb of teh fetal period, consists of two α-chains and two γ-chains, whereas adult Hb consists of two α- and two β-chains.

The process that regulates the conversion of HbF to HbA is called hemoglobin switching.

Hb switching is not 100%; most individuals continue to produce a small amt of HbF in place of HbA.

Front 60

60. What is the relationship between patients with sickle cell anemia or β-thalassemia and HbF levels?

Back 60

Those patients with hemoglobinopathies frequently have less ever illnesses if their levels of HbF are elevated.

Front 61

61. Hereditary persistence of fetal hemoglobin (HPFH)

Back 61

These individuals express HbF past birth

Caused by:
1. Point mutations in the Aγ and Gγ promoters; these mutations can have ameliorating effects on sickle cell or β-thalassemia, b/c of increased production of the γ-chain

2. Both the entire δ- and β-genes have been deleted from one copy of chromosome 11 and only HbF can be produced.

Front 62

62. Difference between individuals w/ δ°β°-thalassemia and those with deltion HPFH?

Back 62

Difference between the two is believe to be the site at which the deletions end within the β-globin gene cluster.

In deletion HPFH, power enhancer sequences 3' of the β-globin gene are resituated b/c of the deletion so that they activate the γ-promoters.

In individuals w/ δ°β°-thalassemia, the enhancer sequences have not been relocated so that they can interact w/ the γ-promoters.

Front 63

63. Hb switching

Back 63

1. Globin genes are in two complex loci
2. Several genes in each, in order of appearance during development

3. Embryonic and fetal forms are present

4. Fetus not affected by many mutations; premature newborns convert from HbF to HbA on schedule w/their gestational ages.

Front 64

64. Spherocytosis

Back 64

The red blood cells are deficient in spectrin. This deficiency impairs the ability fo the erythrocytes to maintain teh redundant surface area necessary to maintain deformability.

Mechanical stresses in the circulation cause progressive loss of pieces of membrane. As membrane components are lost, the RBCs become spherical and unable to deform.

Splenomegaly occurs b/c of the large numbers of RBcs that have become trapped within it.

This hemolytic process results in anemia.

Front 65

65. What causes hereditary spherocytosis?

Back 65

Mutations in the genes for ankyrin, β-spectrin, or band 3 account for 3/4ths of the cases of hereditary spherocytosis.

Mutations in the genes for α-spectrin or band 4.2 account for the remainder.

Results in improper pformation of the membrane cytoskeleton.

Splenectomy is often recommended as the spleen is the major source of RBC destruction that causes anemia.

Front 66

66. What happens with an inherited deficiency in pyruvate kinase?

Back 66

Leads to hemolytic anemia.

B/c the amt of ATP formed from glycolysis is decreased by half, RBC ion transporters cannot function effectively.

The RBCs tend to gain calcium and lose potassium and water.

The water loss increases the intracellular Hb concentration, the internal viscosity of the cell is increased to the point that the cell becomes rigid, and, therefore more susceptible to damage by shear forces in the circulation.

However, the effects of the anemia are freq moderated by the 2-3x elevation in 2,3-BPG concentration that results form the blockage of the conversion of phoenolpyruvate to pyruvate.

Front 67

67. Congenital methemoglobinemia

Back 67

The presence of excess methemoglobin

Found in people w/an enzymatic deficiency in cytochrome b5 reductase or in people who have inherited hemoglobin M.

Methemoglobinemia Can be acquired by ingestion of certain oxidants such as nitrites, quinone, aniline, and sulfonamides.

Can be treated by the administration of reducing agents, such as methylene blue or ascorbic acid.

Front 68

68. Hemoglobin M

Back 68

A single AA substitution in the heme-binding pocket stabilizes the ferric Fe 3+ oxygen.

Front 69

69. G6PD deficiency

Back 69

The most common enzyme defiency in humans, probably, in part, b/c individuals w/ this are resistant to malaria.

The resistance to malaria counterbalances the deleterious effects of the deficiency.

G6PD-deficient red cells have a shorter life span and are more likely to lyse under conditions of oxidative stress.

Front 70

70. G6PD deficiency gene and variants

Back 70

Gene is found on the X chromosome.

All known G6PD variant genes contain small in frame deletions or missense mutations.

The corresponding proteins, therefore, have decreased stability or lowered activity, leading to a reduced half-life or life span of the red cell.

Front 71

71. Pyridoxine (vitamin B6) deficiencies are often associated w/microcytic, hypochromic anemia.

Why?

Back 71

In a B6 deficiency, the rate of heme production is slow b/c the first reaction in heme synthesis requires pyridoxal phosphate.

Thus, less heme is synthesized, causing red blood cells to be small and pale. Iron stores are usually elevated.

Front 72

72. Porphyrias

Back 72

A group of rare inherited disorders resulting from deficiencies of enzymes int he pathway for heme biosynthesis.

Intermediates of the pathway accumulate and may have toxic effects on the nervous system that cause neuropsychiatric symptoms.

When prophyrinogens accumulate, they may be converted by light to porphyrins, which react w/molecular oxygen to form oxygen radicals, which may cause severe damage to the skin.

Related to werewolf legends due to increased scarring and facial hair seen in some porphyrias.

Front 73

73. Phenobarbital

Back 73

Induce enzymes of the drug metabolizing systems of the ER that contain cytochrome p450.

b/c heme is used for synthesis of cytochrome p450, free heme levels fall and δ-ALA synthase is induced to increase the rate of heme synthesis.

Front 74

74. In an iron deficiency, what characteristics will blood exhibit?

Back 74

Results in a microcytic, hypochromic anemia.

Front 75

75. Leukemias

Back 75

Malignancies of the blood

Arise when a differentiating hematopoietic cell does not complete its developmental program but remains in an immature, proliferative state.

Leukemias have been found in every hematopoietic lineage.

Front 76

76. X-linked severe combined immunodeficiency disease (SCID)

Back 76

In the most common form of SCID, circulating T lymphocytes are not formed, and B lymphocytes are not active.

The affected gene encodes the γ-chain of the IL2 receptor.

Mutant receptors are unable to activate JAK3, and the cells are unresponsive to the cytokines that stimulate growth and differentiation.

Front 77

77. Mutant erythropoietin (epo) receptor

Back 77

The receptor is unable to bind SHP-1, a tyrosine phosphatase necessary for proper development of myeloid and lymphoid lineages.

Individuals w/the mutant epo receptor have a higher than normal percentage of RBCs in the circulation, b/c the mutant epo receptor cannot be deactivated by SHP-1.

Front 78

78. Perturbed JAK/STAT signaling is associated with development of ...?

Back 78

1. Lymphoid and myeloid leukemias

2. Severe congenital neutropenia

3. Fanconi anemia, which is characterized by bone marrow failure and increased susceptibility to malignancy.

Front 79

79. A sickle cell crisis can lead to ...?

Back 79

Increased formation of gallstones.

A sickle cell crisis accompanied by the intravascular destruction of RBCs increases the amt of unconjugated bilirubin that is transported to the liver.

If the concentration of this unconjugated bilirubin exceeds the capacity fo the hepatocytes to conjugate it to the more soluble diglucuronide thru interaction w/hepatic UDP glucuronate, both the total and the unconjugated bilirubin levels in the blood increase.

This results in precipitation within the gallbladder lumen, leading to the formation of pigmented gallstones.

Front 80

80. HbS/HbC

Back 80

HbS/HbC individuals have significantly more hematopathology than individuals w/ sickle cell trait (HbA/HbS)

Polymerization of deoxygenated HbS is dependent on the HbS concentration within the cell. The presence of HbC in the compound heterozygote increases the HbS concentration by stimulating potassium and water efflux from the cell.

B/c the HbC globin is produced more slowly than HbA or HbS, the proportion of HbS tends to be higher in HbS/Hbc cells than in the cells of individuals with sickle cell trait (HbS/HbA).

Front 81

81. Does HbF have a lower or higher affinity for 2,3-BPG compared to adult Hb?

Back 81

HbF has a lower affinity for 2,3-BPG than adult hemoglobin (HbA)

Therefore, the oxygen released from the mother's hemoglobin is readily bound by HbF in the fetus.

Differences due to the structural changes caused by the different composition of hemoglobin subunits

Front 82

82. F-cell-producing locus on the short arm of the X chromosome

Back 82

Is thought not to be susceptible to X inactivation.

Both normal individuals and individuals w/hemoglobinopathies vary in the amount of HbF they produce.

The FCP locus is responsible for a substantial amt of the variation in hemogloin F seen among sickle cell patients.

Front 83

83. A and B antigens

Back 83

Two antigens, type A and type B occur on teh surfaces of the RBCs in a large proportion of humans.

It is these antigens that cause most blood transfusion reactions.

Because of the way these agglutinogens are inherited, people may have neither of them on their cells, they may have one, or they may have both simultaneously.

Front 84

84. Type O blood

Back 84

Genotype OO

Neither A nor B agglutinogen is present

Anti-A and Anti-B agglutinins

Front 85

85. Type A blood

Back 85

Genotype OA or AA

A agglutinogens

Anti-B agglutinins

Front 86

86. Type B blood

Back 86

Genotype OB or BB

B agglutinogens

Anti-A agglutinins

Front 87

87. Type AB blood

Back 87

Genotype AB

A and B agglutinogens

No agglutinins are present

Front 88

88. Titer of the agglutinins at different ages

Back 88

Immediately after birth, the quantity of agglutinins in the plasma is almost zero. 2-8 months after birth, an infant begins to produce agglutinins.

A maximum titer is usually reached at 8-10 years of age, and this gradually declines throughout the remaining years of life.

Front 89

89. Origin of agglutinins in the plasma

Back 89

The agglutinins are gamma globulins, as are almost all antibodies an they are produced by the same bone marrow and lymph gland cells that produce antibodies to any other antigens. Most of them are IgM and IgG immunoglobulin molecules.

Front 90

90. Why do these agglutinins produce in people that do not have the respective agglutinogens in their RBC's?

Back 90

Small amts of type A and B antigens enter the body in food, in bacteria, and in other ways, and these substances initiate the development of the anti-A and anti-B agglutinins.

Front 91

91. What happens when bloods are mismatched during tranfusions?

Back 91

The red cells agglutinate as a result of the agglutinins' attaching themselves to the RBCs.

B/c the agglutinins have two bindings sites (IgG type) or 10 binding sites (IgM type), a single agglutinin can attach to two or more RBCs at the same time, thereby causing the cells to be bound together by agglutinin.

This causes the cells to clump, which can cause plugs in the small blood vessels throughout the circulatory system.

During ensuing hours to days, either physical distortion of the cells or attack by phagocytic white blood cells destroys the membranes of the aggultinated cells.

Front 92

92. Acute hemolysis in some transfusion reactions

Back 92

Sometimes, when a recipient and donor bloods are mismatched, immediate hemolysis of RBCs occurs in the circulating blood.

The antibodies activate the complement system, which releases proteolytic enzymes that rupture cells membranes.

Front 93

93. Which is more common, immediate intravascular hemolysis or delayed hemolysis?

Back 93

Delayed hemolysis, because not only does there have to be a high titer of antibodies for lysis to occur, but also a different type of antibody seems to be required, mainly the IgM antibodies; these antibodies are called hemolysins.

Immediate hemolysis is far less common than agglutination followed by delayed hemolysis

Front 94

94. Rh blood type system

Back 94

Unlike the OAB type system, in the Rh type system, spontaneous agglutinins almost never occur.

Instead, the person must first be massively exposed to an Rh antigen, such as by transfusion of blood containing the Rh antigen, before enough agglutinins cause a significant transfusion reaction to occur

Front 95

95. Rh Antigens

Back 95

There are six common types of Rh antigens, each of which is called an Rh factor, designated C, D, E, c, d, and e.

A person who has a C antigen does not have the c antigen, but the person missing the C antigen always has the c antigen. Huh?

The same is true for the D-d and E-e antigens.

Also, b/c of the manner of inheritance of these factor, each person has one of each of the three pairs of antigens.

Front 96

96. Type D Rh antigen

Back 96

Type D antigen is widely prevalent in the population and considerably more antigenic than the other Rh antigens. Anyone who has this antigen is said to be Rh positive, whereas a person who does not have type D antigen is said to be Rh negative.

About 85% of all white people are Rh positive, and about 15% Rh negative.

In American blacks, 95% are Rh positive, whereas in African blacks - virtually 100% positive.

Front 97

97. Rh immune response; formation of Anti-Rh agglutinins

Back 97

When RBCs containing Rh factor are injected into a person whose blood does not contain the Rh factor, anti-Rh agglutinins develop slowly, slowly reaching maximum concentration of agglutinins about 2-4 mos later.

With multiple exposes to the Rh factor, an Rh-negative person eventually becomes strongly sensitized to Rh factor.

Front 98

98. Characteristics of Rh transfusion reactions

Back 98

Acute reactions are not likely if Rh-negative people have never been exposed to Rh-positive blood.

However, anti-Rh antibodies can develop in sufficient quantities during the next 2-4 weeks to cause agglutination of those transfused cells that are still circulating in the blood.

Front 99

99. Erythroblastosis fetalis

Back 99

A disease of the fetus and newborn child characterized by agglutination and phagocytosis of the fetus's red blood cells.

In most instances of this, the mother is Rh negative and the father Rh positive.

The baby has inherited the Rh+ antigen from the father, and the mother develops anti-Rh agglutinins from exposure to the fetus's Rh antigen.

In turn, the mother's agglutinins diffuse through the placenta into the fetus and cause RBC agglutination.

Front 100

100. Incidence of erythroblastosis fetalis

Back 100

An Rh- mother having her first Rh+ child usually does not develop sufficient agglutinins to cause any harm.

However, about 3% of second Rh+ babies exhibit some signs of erythroblastosis fetalis; about 10% of third babies exhibit the disease; and the incidence rises progressively w/subsequent pregnancies.

Front 101

101. Clinical characteristics of newborns w/erythroblastosis fetalis

Back 101

The jaundiced, erythroblastotic newborn baby is usually anemic at birth, and the anti-Rh agglutinins from the mother usually circulate in the infant's blood for another 1 to 2 months after birth, destroying more and more RBCs.

The heatopoietic tissues of the infant attempt to replace the hemolyzed RBCs. The liver and spleen become greatly enlarged and produce RBCs in the same manner that they normally do during the middle of gestation.

B/c of the rapid rpoduction of red cells, many early forms of RBCs, including many nucleated blastic forms, are passed from the baby's bone marrow into the circulatory system, ant it is b/c of the presence of these cells that the disease is called erythroblastosis fetalis.

Mental impairment is not uncommon b/c of kernicerus

Front 102

102. Treatment of newborn w/erythroblastosis fetalis

Back 102

Replace the neonate's blood w/Rh- blood.

This procedure may be repeated several times during the first few weeks of life, mainly to keep the bilirubin level low and thereby prevent kernicterus.

By the time these transfused Rh- cells are replaced w/the infant's own Rh+ cells, the anti-Rh agglutinins that had come from the mother will have been destroyed.

Front 103

103. Prevention of erythroblastosis fetalis

Back 103

The D antigen of the Rh blood group system is the primary culprit in causing immunization of an Rh- mother to an Rh+ fetus.

Giving Rh immunoglobulin globin, an anti-D antibody to the mother starting at 28-30 wks of gestation greatly reduces the risks of developing large amounts of D antigens.

Front 104

104. Mechanism by which Rh immunoglobulin globin prevents sensitization of the D antigen

Back 104

Not completely understood, but one effect of the anti-D antibody is to inhibit antigen induced B lymphocyte antibody production in teh expectant mother.

The administered anti-D antibody also attaches to D-antigen sites on Rh+ fetal RBCs that may cross the placenta and enter the circulation of the mother, thereby interfering with the immune response to the D antigen.

Front 105

105. When a transfusion reaction occurs, whose blood agglutinates - donor or recipient?

Back 105

The RBCs of the donor's blood are agglutinated b/c the plasma portion of the donor blood immediately becomes diluted by all the plasma of the recipient, thereby decreasing the titer of the infused agglutinins to a level usually too low to cause agglutination.

Will eventually cause either immediate or delayed hemolysis resulting from hemolysins or from phagocytosis of agglutinated cells, respectively.

Front 106

106. What is one of the most lethal effects of transfusion reactions?

Back 106

Kidney failure, which can begin within a few minutes to a few hours and continue until the person dies of renal failure

Front 107

107. What causes the renal failure in transfusion reactions?

Back 107

Results from three causes:
1. The antigen-antibody reaction of the transfusion reaction releases toxic substances from the hemolyzing blood that cause powerful renal vasoconstriction.
2. Loss of circulating red cells int he recipient, along w/production of toxic substances from the hemolyzed cells and from the immune reaction, often causes circulatory shock. The arterial BP falls very low, and renal blood flow and urine output decrease.
3. If the total amt of free Hb released into the circulating blood is greater than the quantity that can bind with haptoglobin, much of the excess leaks thru the glomerular membranes into the kidney tubules - this causes Hb to precipitate and block many of the kidney tubules.

Front 108

108. Autograft

Back 108

Transplant of a tissue or whole organ from one part of the same animal to another part

No reactions

Front 109

109. Isograft

Back 109

From one identical twin to another

No reactions

Front 110

110. Allograft

Back 110

From one human being to another or from any animal to another animal fo the same species

Front 111

111. Xenograft

Back 111

From a lower animal to a human or from an animal of one species to one of another species

High risk of reactions within 1 day to 5 weeks.

Front 112

112. HLA complex of antigens

Back 112

The most important antigens for causing graft rejection are a complex called the HLA antigens.

Six of these antigens are present on teh tissue cell membranes of each person, but there are about 150 different HLA antigens to choose from. Therefore, this represents more than a trillion possibilities.

Thus, it is virutally impossible for two persons, except for twins, to have the same six HLA antigens. Development of significant immunity against any one of these antigens can cause graft rejection.

Front 113

113. If no two people have the same six HLA antigens, how can transplants occur?

Back 113

Some of the HLA antigens are not severly antigenic, for which reason a precise match of some antigens between donor and recipient is not always essential to allow allograft acceptance.

The best success has been with tissue type matches between siblings and between parent and child.

Front 114

114. What are three different therapeutic agents that have been used to prevent graft rejection?

Back 114

1. Glucocorticoid hormones isolated from adrenal cortex glands, which suppress the growth of all lymphoid tissue and, therefore, decrease formation of antibodies and T cells.

2. Various drugs that have a toxic effect on the lymphoid system and, therefore, block formation of antibodies and T cells, especially the drug azathioprine.

3. Cyclosporine, which has a specific inhibitory effect on the formation of helper T cells and, therefore, is especially efficacious in blocking the T-cell rejection reaction. This drug is especially useful b/c it does not depress some other portions of the immune system.

Front 115

115. Role of blood in the body

Back 115

1. Transport of nutrients and oxygen directly to cells

2. Transport of wastes and carbon dioxide away from cells

3. Delivery of hormones and other regulatory substances to and from cells and tissues

4. Maintenance of hemostasis by acting as a buffer and by participating in coagulation and thermoregulation

5. Immune function

Front 116

116. Hematocrit (HCT)

Back 116

Percentage of the volume of cellular elements vs. total volume

39-50% in males

35-45% in females

Front 117

117. Percentage of neutrophils in granulocytes

Back 117

50-70%

Front 118

118. Percentage of eosinophils in granulocytes

Back 118

2-5%

Front 119

119. Percentage of basophils in granulocytes

Back 119

0.3%

Front 120

120. Percentage of lymphocytes in the agranulocytes

Back 120

25-30%

Front 121

121. Percentage of monocytes in the agranulocytes

Back 121

8%

Front 122

121. Percentages of erythrocytes vs. leukocytes/platelets and derivatives in the blood

Back 122

Erythrocytes & derivatives: 99%

Leukocytes, platelets, and derivatives: 1%

Front 123

122. What do blood cells and their derivatives include?

Back 123

1. Erythrocytes, RBCs
2. Leukocytes, WBCs
3. Thrombocytes, platelets

Front 124

123. Plasma

Back 124

91-92% water

7-8% protein

1% electrolytes, nonprotein nitrogen substances, nutrients, blood gases, and regulatory substances

Front 125

124. Albumin

Back 125

Smallest plasma protein

Maintains colloid osmotic pressure

Is a carrier protein for hormones (thyroxine), metabolites (bilirubin), and drugs (barbituates)

Front 126

125. γ-globulins vs. α- and β-globulins

Back 126

γ-globulins: immunoglobulins

α- and β-globulins: nonimmunoglobulins
-secreted by the liver
-helps clot formation
-maintains colloid osmotic pressure
-carrier protein for:
1. copper (coeruloplasmin)
2. iron (transferrin)
3. hemoglobin (haptoglobin)

Front 127

126. Fibrinogen

Back 127

Largest plasma protein secreted by the liver; involved in a series of cascade reactions with other coagulation factors.

Soluble fibrinogen is made into fibrin, which then rapidly polymerize to form long, insoluble fibers.

These fibers become cross-linked and form an impermeable net at the site of damaged blood vessels that prevents further blood loss.

Front 128

127. Morphology of the erythrocyte

Back 128

1. Anucleate eosinophilic cells devoid of typical organelles
2. Biconcave disc, 7.8 um
3. Extremely deformable
4. Binds oxygen and carbon dioxide
5. 120 days life span
6. Broken down in the spleen, bone marrow and liver

Front 129

128. What are the integral membrane proteins that maintain the shape of the RBC?

Back 129

Two major families:
1. Glycophorins
-Glycophorin C plays an important role in attaching the underlying cytoskeletal protein network to the cell membrane

2. Band 3 protein
-binds hemoglobin and acts as an additional anchoring site for the cytoskeletal proteins

Front 130

129. What are some of the peripheral membrane proteins that help maintain the shape of the RBC?

Back 130

1. The lattice of the membrane is composed of :

1. Spectrin tetramers
2. Actin
3. Band 4.1
4. Adducin
5. Band 4.9
6. Tropomyosin
7. Ankyrin
8. Band 4.2

These are organized into a hexagonal lattice network.

Front 131

130. Heriditary elliptocytosis

Back 131

Caused by a deficiency in band 4.1 protein that results in elliptic erythrocytes.

Results in hemolysis

Front 132

131. Hemoglobin

Back 132

1. Transport oxygen and carbon dioxide
2. Responsible for the eosinophilic staining of the RBC
3. Consists of 4 polypeptide subunits
4. Each subunit contains a heme
5. Four different types of globin chains, α,β,γ,δ bound in pairs

Front 133

132. HbA

Back 133

Most prevalent in adults, accounting for about 96% of the total Hb.

Consists of two α- and two β- chains

Front 134

133. HbA2

Back 134

Accounts for 1.5 - 3% of total Hb in adults.

Consists of two α- and two δ- chains

Front 135

134. HbF

Back 135

Accounts for less than 1% of total Hb in adults

Contains two α- and two γ- chains and is the prinicpal form of Hb in the fetus.

Although it persists in slightly higher percentages than normal in sickle cell disease and thalassemia, it does not appear to have a pathologic role.

Front 136

135. Cause of sickle cell anemia

Back 136

Caused by a single point mutation in the gene that encodes the β- globin chain of HbA.

Valine is substituted with glutamic acid in position 6

Front 137

136. Neutrophils

Back 137

Named after the lack of the characteristic cytoplasmatic staining

Nucleus:
-Multilobed nucleus (usually tri-lobed)
-Heterochromatin in periphery of nucleus
-Euchromatin in the middle of nucleus
-Barr bodies in females

Granules are small, barely visible

Small golgi apparatus and few mitochondria

Front 138

136. Neutrophil granules

Back 138

1. Azurophylic granules 1˚
-Larger granules, more numerous
-Lysosomes containing myeloperoxydase that generates bactericidal hypoclorite
-Cationic proteins called defensins which also have bactericidal properties

2. Specific granules 2˚
-Smallest granules, most numerous
-Contains:
i. Enzymes (type IV collagenase, phospholipidase)
ii. Complement activators
iii. Bactericidal agent (lysosyme)

Tertiary granules 3˚
Two types:
i. Phosphatase containing
ii. Metalloproteinase (gelatinase and collagenase) containing which facilitate migration of neutrophils thru the connective tissue.

Front 139

137. Important property of neutrophils

Back 139

Their motility.

They are the most numerous of the first wave of cells to enter an area of tissue damage.

Their migration is controlled by the expression of adhesion molecules on the neutrophil surface that interact w/the corresponding ligands on endothelial cells.

Front 140

138. Migration of neutrophils to injury site

Back 140

1. Selectins interact w/selectin receptor on the endothelium
2. Integrins are activated by chemokine signals of the endothelium
3. Integrins and immunoglobulins on the neutrophils bind to their receptors on the endothelium
4. Mast cells release histamine and heparin that opens a gap on the capillary
5. Neutrophil migrates in to the connective tissue
6. Further migration is directed by chemoattractant molecules to the injury site - chemotaxis.

Front 141

139. Neutrophil phagocytosis

Back 141

1. Fc receptors recognize the antibodies coating the antigen
2. Antigen is engulfed by the neutrophil
3. Phagosome is formed, digestion is started by oxidases
4. Specific and azurophilic granules fuse with phagosome (degranulation)
5. Digestion is completed by the enzymes
6. Digested material is either exocytosed or stored w/in the cell as a residual body

Front 142

140. Eosinophils

Back 142

Names after the large eosinophilic granules in the cytoplasm.

Nucleus:
-Typically bilobed
-Herterchromatin in the periphery of the nucleus
-Euchromatin in the middle of the nucleus

Small golgi apparatus
Few mitochondria

Front 143

141. Eosinophil granules

Back 143

Specific granules:
1. Crystalloid body
-Major basic protein, cytotoxic to protozoans and helmintic parasites
2. Granule matrix
i. eosinophil cationic protein
ii. eosinophil peroxydase
iii. eosinophil derived neurotoxin - causes nervous system dysfunction in parasites
iv. Histaminase - neutralizes histamine
v. Arylsulfatase
vi. Collagenase
vii. cathepsins

Azurophylic granules
-lysosomes containing hydrolytic enzymes

Front 144

142. Basophils

Back 144

Names after the large basophilic granules in the cytoplasm

Closely related to mast cells of the connective tissue

Nucleus:
-Typically bilobed nucleus obscured by the granules
-Heterochromatin in the periphery
-Euchromatin in the middle

Small golgi apparatus
Few mitochrondria

Front 145

143. Basophil granules

Back 145

Specific granules: grainy texture
-Heparan sulfate; responsible for basophilia
-Histamine; vasodilation
-SRS-A; slow reacting substance A; vasodilation

Azurophylic granules
-lysosomes containing acid hydrolases

Front 146

144. Basophil plasma membrane

Back 146

1. Possesses Fc receptors for IgE
-IgE triggers the release of substances from the granules

2. Expresses CD40L protein that interacts w/the complementary receptor on the B lymphocytes; this increases IgE synthesis

Front 147

145. B-lymphocytes

Back 147

1. 20-30% of lymphocytes

2. Matures in the bone marrow

3. Variable life span, involved in production of circulating antibodies

4. Mature B cells express IgM, IgD, and MHC-II molecules

5. Express CD9, CD19, CD20, and CD24 marker proteins on their surface

Front 148

146. T-lymphocytes

Back 148

1.Differentiate and mature in the thymus

2. Long life span, involved in cell mediated immunity

3. Express CD2, CD3, CD7 marker proteins on their surface

4. DO NOT express antibodies on the cell surface

5. Subclassified on the basis of the presence of CD4 and CD8 proteins

6. 60-80% of lymphocytes

Front 149

147. Subclassifications of T-lymphocytes

Back 149

1. Cytotoxic CD8+ lymphocytes
2. Helper CD4+ lymphocytes
3. Suppressor CD8+, CD45RA+ lymphocytes

Front 150

148. Cytotoxic CD8+ lymphocytes

Back 150

1. Primary effector in cell mediated immunity
2. Recognize antigen-bound MHC-I molecules on virus infected and neoplastic cells
3. Secretes lymphokines and perforins that produce ion channels in the infected cell membrane leading to its lysis
4. Play role in rejection of allografts and in tumor immunology

Front 151

149. Helper CD4+ lymphocytes

Back 151

1. Recognize antigen-bound MHC-II molecules on antigen presenting cells
2. Activated helper cell produces interleukins stimulating proliferation and differentiation of more CD4+ cells
3. Newly differentiated cells secrete lymphokines that affect differentiation of B cells, T cells, and NK cells and turn B cells into plasma cells

Front 152

150. Natural killer cells (NK cells)

Back 152

1. 5-10% of lymphocytes
2. Programmed to kill certain virus infected cells and tumor cells
3. Larger than T and B cells
4. Kidney shaped nucleus, several large cytoplasmic granules
5. Express CD16, CD56, CD94 marker proteins on their surface

Front 153

151. Suppressor CD8+, CD45A+ lymphocytes

Back 153

1. Suppress antibody formation by B cells
2. Suppress the ability of T cells to initiate the immune response
3. May also regulate the erythroid cell maturation of the bone marrow.

Front 154

152. Monocytes

Back 154

1. Largest of leukocytes
2. Travel from bone marrow to the body tissues where they differentiate into various tissue macrophages
3. Phagocytize and degrade antigens, presenting their fragments on MCH II molecules sitting on the cell surface to helper CD4+ lymphocytes for recognition
4. Remain in the blood for only 3 days
5. Nucleus is bean (embryo) shaped
6. Cytoplasm contains small mitochondria, sER, rER, and small azurophillic granules.

Front 155

153. Zones of platelet structure: from outside to inside

Back 155

1. Peripheral zone
2. Structural zone
3. Organelle zone
4. Membrane zone

Front 156

154. Peripheral and structural zones of platelets

Back 156

Peripheral zone:
Cell membrane covered by glycocalyx

Structural zone:
1. Microtubules
2. Actin filaments
3. Myosin
4. Actin-binding proteins supporting the plasma membrane (disc shape)

Front 157

155. Organelle zone of platelets

Back 157

1. Mitochondria
2. Peroxisomes
3. Glycogen particles
4. α-, *δ-, **λ-granules

*δ-granules contain ADP, ATP, serotonin, and histamine which facilitate platelet adhesion and vasoconstriction

**λ-granules contain several hydrolytic enzymes similar to lysosomes which help function in clot resorption during later stages of vessel repair

Front 158

156. Membrane zone of platelets

Back 158

Open canalicular system (remnant of demarcation zones)

Dense tubular system (storage of calcium ions)

Front 159

157. Stages of erythrocytic differentiation

Back 159

1. Proerythroblast
2. Basophilic erythroblast
3. Polychormatophillic erythroblast
4. Orthochromatophillic erythroblast (normoblast)
5. Polychromatophillic erythroblast (reticulocyte)
6. Erythrocyte

Front 160

158. Which stage of erythrocytic differentiation has a small, compact, densely stained nucleus?

Back 160

The orthochromatophilic erythroblast (normoblast)

No longer capable of division at this stage

Front 161

159. Which stage of erythrocytic differentiation has a large spherical nucleus w/one or two visible nucleoi?

Back 161

Proerythroblast

Front 162

160. Which stage of erythrocytic differentiation has extruded its nucleus?

Back 162

The polychromatophilic erythrocyte (reticulocyte)

Constitute about 1-2% of the total erythrocyte count.

Front 163

161. Which stages of erythrocytic differentiation have mitotic division?

Back 163

1. Proerythroblasts
2. Basophilic erythroblasts
3. Polychromatophilic erythroblasts.

Front 164

162. Band cells

Back 164

In the neutrophil line, the band cell precedes development of the first distinct nuclear lobs.

The nucleus of the band cell is elongated and of nearly uniform width, giving it a horseshoe like appearance.

The % of band cells in the circulation is almost always low, however, they may increase in acute or chronic inflammation

Front 165

163. Developmental stages of granulocytes

Back 165

1. Myeloblasts
2. Promeylocytes
3. Myelocytes
4. Metamyelocytes

Front 166

164. Which type of immature granulocytes are the only ones to produce aurophilic granules?

Back 166

Promyelocytes

Front 167

165. Which type of immature granulocytes are the first to exhibit specific granules?

Back 167

Myelocytes

Front 168

166. Which type of immature granulocytes clearly exhibit their lines of differentiation as well as numerous specific granules?

Back 168

The metamyelocyte is the stage at which neutrophil, eosinophil, and basophil lines can be clearly identified by the presence of numerous specific granules

Front 169

167. Granulocyte macrophage colony stimulating factor GM-CSF

Back 169

Source: T cells, endothelial cells, fibroblasts

Targets:
1. CFU-GEMM
2. CFU-E
3. CFU-GM
4. CFU-Eo
5. CFU-Ba
6. CFU-Meg
7. All granulocytes
8. Erythrocytes

Front 170

168. Granulocyte colony stimulating factor G-CSF

Back 170

Source: endothelial cells, monocytes

Targets:
1. CFU-E
2. CFU-GM
3. CFU-Eo
4. CFU-Ba
5. CFU-Meg

Front 171

169. Monocyte colony stimulating factor M-CSF

Back 171

Source: monocytes, macrophages, endothelial and adventitial cells

Targets:
1. CFU-GM
2. CFU-M
3. Monocytes
4. Macrophages
5. Osteoclasts

Front 172

170. Erythropoietin EPO

Back 172

Source: kidney, liver

Targets:
CFU-E and CFU GEMM

Front 173

171. Thormbopoietin

Back 173

Source: bone marrow

Targets: CFU-Meg and megakaryocytes

Front 174

172. IFN-γ

Back 174

Source: CD4+ T cells, NK cells

Targets:
1. B cells
2. T cells
3. NK cells
4. Neutrophiles
5. Monocytes

Front 175

173. IL-1

Back 175

Source: neutrophils, monocytes, macrophages, and endothelial cells

Targets: CD4+ T cells and B cells

Front 176

174. Normocellular bone marrow

Back 176

THe number of hemopoietic cells decreases with age.

Bone marrow with a normal age-specific index is called normocellular bone marrow

Front 177

174. Hypocellular bone marrow

Back 177

Occurs in aplastic anemia or after chemo

Only a small number of blood forming cells can be found in a marrow biopsy.

Front 178

175. Hypercellular bone marrow

Back 178

Characteristic of bone marrow affect by tumors originating from hematopoietic cells.

Front 179

176. Red bone marrow

Back 179

Active bone marrow

The cords of hemopoietic cells contain predominantly developing blood cells and megakaryocytes.

The cords also contain macrophages, mast cells, and some adipose tissue.

Front 180

177. Yellow bone marrow

Back 180

Inactive bone marrow - contains predominantly adipose tissue.

It is the chief form of bone marrow in the medullary cavity of bones in the adult that are no longer active, such as the long bones of the arms, legs, fingers, and toes

Front 181

181. Differences between acute blood loss and chronic blood loss

Back 181

Clinical and morphological reactions depend on the rate of hemorrhage.

Acute blood loss can lead to shock and death

Chronic blood loss can cause anemia when iron reserves are depleted.

Front 182

182. Hemolytic anemias

Back 182

Characterized by premature RBC destruction, accumulation of Hb catabolites (e.g, bilirubin) and markedly increased erythropoiesis with associated reticulocytosis.

Can occur intravascularly or extravascularly

Front 183

183. Intravascular hemolysis

Back 183

RBCs are damaged by mechanical injury or complement (e.e.g mismatched blood transfusion)

Patients exhibit:
1. hemoglobinemia
2. hemoglobinuria
3. hemosiderinuria
4. jaundice
5. reduced serum haptoglobin

Front 184

184. Extravascular hemolysis

Back 184

Occurs in mononuclear phagocytes of spleen (and other organs)

Predisposing factors include red blood cell membrane injury, reduced deformability, or opsonization.

Manifestations are similar to intravascular hemolysis but w/o hemoglobinemia and hemoglobinuria

Front 185

185. Hereditary spherocytosis

Back 185

Autosomal dominant disorder in which RBC cytoskeletal membrane protein defects render erythrocytes spheroidal, less deformable, and vulnerable to splenic sequestration and destruction

Front 186

186. Pathophysiology of hereditary spherocytosis

Back 186

Defects in several different membrane proteins can cause HS; all lead primarily or secondarily to deficiencies in spectrin.

Spectrin-deficient RBCs have unstable membranes and spontaneously lose fragments - thus they are easily trapped in the splenic cords.

Front 187

187. Morphology of HS

Back 187

In the peripheral blood, spherocytic RBCs appear small and lack central pallor.

There is marked congestion and prominent phagocytosis of RBCs in the splenic cords of Billroth.

Bone marrow exhibits normoblastic hyperplasia.

Front 188

188. Clinical features of HS

Back 188

1. Anemia
2. Moderate splenomegaly
3. Jaundice
4. Infection triggered hemolytic crisis or aplastic crisis by parvovirus infection
5. Gallstones in 50% of those affected.

The MCHC is increased as a result of cellular dehydration.

Front 189

189. G6PD Deficiency

Back 189

G6PD is an enzyme in the hexose monophosphate shunt that produces reduced glutathione, a molecule that protects RBCs from oxidative injury

In G6PD deficient cells oxidant stresses induce hemoglobin denaturation.

The altered Hb precipitates as Heinz bodies, which attach to the inner cell membrane.

Heinz bodies damage cell membranes sufficiently to cause both intravascular and extravascular hemolysis.

Front 190

190. G6PD Deficiency prevalence

Back 190

This is an X linked disorder

Although there are sever variants, only two, G6PD A- and G6PD Mediterranean, lead to clinically significant hemolysis.

A- is present in about 10% of American blacks, and is associated with progressive loss of G6Pd in older RBCs. B/c the younger cells are not affected, hemolytic episodes are self limited.

In the Mediterranean variant, G6PD levels are much lower and hemolytic episodes are more severe. Ingestion of fava beans can cause hemolysis in G6PD deficiency b/c these legumes generate oxidants.

Front 191

191. Sickle cell disease

Back 191

This is a hereditary hemoglobinopathy resulting from the substitution of a valine for a glutamic acid at the sixth position of the β-globin chain, transforming normal hemoglobin A into the mutant hemoglobin S.

Front 192

192. What is the most important factor in the sickling phenomenon?

Back 192

The amount of HbS and its interaction with other Hb chains in the cell.

Heterozygotes have little tendency to sickle, whereas homozygotes have mostly HbS and will have full blown sickle cell anemia.

Front 193

193. When do newborns present with sickle cell anemia?

Back 193

They do not manifest disease complications until 5-6 months of age; at that time, RBC HbF concentration approaches adult levels.

Front 194

194. HbC

Back 194

Another variation of hemoglobin

Has a greater tendency to aggregate with HbS than HbA

Individuals w/HbSC have more severe disease than patients with sickle cell train alone.

Front 195

195. MCHC in sickle cell anemia

Back 195

High HbS concentrations increase the rate of contact and interaction between individual HbS molecules.

Dehydration is one factor that increases MCHC, thereby facilitating sickling and occlusion of small blood vessels.

Concurrent diseases that reduce MCHC (thalassemias) lessen sickling severity

Front 196

196. Consequences of sickling

Back 196

1. Chronic hemolysis

2. Microvascular oclusions

Front 197

197. Morphology of sickle cell disease

Back 197

1. The spleen is enlarged in early childhood due to sickled cell trapping in splenic cords.

2. Bone marrow shows normoblastic hyperplasia; if severe enough, can cause bone resorption

3. Microvascular occlusions produce tissue damage and infarction in several organs

Front 198

198. Clinical features of sickle cell anemia

Back 198

1. Chronic hemolytic anemia
-propensity for gallstones, hyperbilirubinism
2. Vaso-occlusive crises
3. Aplastic crisis due to transient suppression of erythropoiesis
4. Progressive splenic fibrosis and impairment of the alternate complement pathway predispose to infections

Front 199

199. Thalassemia major

Back 199

Homozygotes for β-thalessemia genes have sever, tranfusion-dependent anemia

This form is the most common in Mediterranean countries, parts of Africa, and Southeast Asia.

RBCs are microcytic, hypochromic and are stipled or fragmented.

Clinical course is generally brief; without transfusions, death occurs at an early age from profound anemia.

Blood transfusions lessen the anemia and suppress the secondary changes related to excessive erythropoiesis (bone deformities).

Front 200

200. Talassemia minor

Back 200

Heterozygotes for β-thalessemia genes are usually asymptomatic due to sufficient β-globin synthesis.

This form is more common and affects the same ethnic groups.

RBC's show hypochromia, microcytosis, basophilic stippling and target cells.

Recognition of β-thalassemia trait is important for genetic counseling

Front 201

201. Thalassemia intermedia

Back 201

Clinical features and severity are intermediate between the major and minor forms.

This patients are genetically heterogeneous.

Front 202

202. α-thalassemia

Back 202

Classification and the severity of the anemia is related to the number of α-globin genes deleted.

Front 203

203. Silent carrier state in α-thalassemia

Back 203

This type is completely asymptomatic; resulting from a single α-globin gene deletion

Reduction in α-globin synthesis is barely detectable

Front 204

204. α-thalassemia trait

Back 204

Either one chromosome has both α-globin genes or each chromosome has a deletion of one gene.

The clinical picture is comparable to β-thalessemia.

Although these two genotypes are clinically identical, they differ in whether offspring are at risk for severe α-thalassemia (> three α-chains deleted)

Front 205

205. HbH disease

Back 205

Deletion of three α-globin genes causes marked suppression of α-chain synthesis, and formation of unstable tetramers of excess β-globin HbH.

Clinically, HbH disease resembles β-thalassemia intermedia

Front 206

206. Hydrops fetalis

Back 206

Deletion of all four α-globin genes.

In the fetus, excess gamma-globin chains form tetramers (HbBarts) with extremely high oxygen affinity and inability to release O2 to tissues.

Not compatible with life.

Front 207

207. Paroxysmal nocturnal hemoglobinuria (PNH)

Back 207

Is a rare disorder characterized by chronic intravascular hemolysis.

It is the only hemolytic anemia resulting from an acquired (rather than inherited) membrane defect.

RBCs have an increased sensitivity to complement-mediated lysis due to deficient expression of a family of proteins normally anchored to the cell membrane via GPI.

Their deficiency renders RBC hypersensitive to complement, which is activated spontaneously at low rates.

May arise due to an autoimmune response to GPI-linked proteins on hematopoietic stem cells.

Aplastic anemia sometimes precedes the development of PNH; it also rarely transforms to acute leukemia.

Front 208

208. Warm antibody hemolytic anemia

Back 208

This anemia is idiopathic in 60% of cases.

IgG anti-red blood cell antibodies coat the RBCs; they do not fix complement but do act as opsonins.

RBCs are speherocytic due to membrane fragment loss thru macrophage phagocytosis; they are eventually sequestered and destroyed in the spleen.

Thus, splenomegaly is a characteristic.

Front 209

209. Mechanism of antibody formation in drug induced hemolytic anemias

Back 209

1. Hapten model
-Drugs bind to the RBC surface; antibodies then interact with the drug or the RBC-drug complex

2. Autoantibody model
-Drugs initiate production of antibodies directed against intrinsic RBC antigens

Front 210

210. Cold agglutinin immune hemolytic anemia

Back 210

Anemia is caused by IgM antibodies that agglutinate RBCs at low temperatures.

Acute hemolysis occurs during recovery from certain infections (EBV). It is usually self-limited and rarely induces significant hemolysis

Chronic hemolysis occurs w/lymphoproliferative disorders or may be idiopathic. Clinical symptoms result form RBC agglutination and complement fixation in areas of the body that are 30˚ or lower

Front 211

211. Cold hemolysin hemolytic anemia

Back 211

This anemia occurs in paroxysmal cold hemoglobinuria, manifesting as acute intermittent massive intravascular hemolysis after exposure to cold.

Autoantibodies are IgG directed against the P blood group antigen.

They attach to the RBCs and fix complement at low temps; when the temp is elevated, hemolysis occurs.

Most cases follow infections

Front 212

212. Megaloblastic anemias

Back 212

Most commonly due to deficiency of vitamin B12 or folate

Front 213

213. Morphology of megaloblastic anemias

Back 213

1. Abnormally large erythroid precursors (megaolblasts) in which nuclear maturation labs behind cytoplasmic maturation
2. Ineffective erythropoieses with compensatory megaloblastic hyperplasia
3. Prominent anisocytosis
3. Abnormal granulopoiesis with giant megamyelocytes and hypersegmented neutrophils

Front 214

214. Pathophysiology of megaloblastic anemias

Back 214

Vitamin B12 and folate are essential for the production of thymidine, a building block of DNA

Deficiency results in deranged or inadequate DNA synthesis, but normal RNA and protein synthesis.

Anemia results from a combination of ineffective erythropoiesis and abnormal red cells that are unusually susceptible to premature removal by phagocytes.

These deficiencies also affect all rapidly dividing cells, including myeloid precursors and GI epithelium.

Ineffective granulopoiesis and thrombopoiesis often results in pancytopenia.

Front 215

215. Vitamin B12 deficiencies

Back 215

Anemias of vitamin B12 deficiency

Can result from impaired absorption, which has several causes:
1. Achlorhydria, which impairs viatamin B12 release from teh R protein bound form
2. Gastrectomy, which leads to the loss of intrinsic factor
3. Pernicious anemias
4. Resection of the distal ileum, which prevents absorption of intrinsic factor-B12 complex
5. Malabsorption syndromes
6. Increased requirements (i.e. pregnancy)
7. Inadequate diet (very uncommon)

Front 216

216. Pernicious anemia

Back 216

Likely due to an autoimmune response to gastric parietal cells resulting in chronic atrophic gastritis and marked parietal cell loss, followed b deficient intrinsic factor production.

Gastric injury is probably initiated by autoreactive T cells, secondarily generated autoantibodies to various components of the vitamin B12 uptake pathway are also present in the serum and gastric secretions of most patients.

Front 217

217. What are some of the autoantibodies involved in pernicious anemia?

Back 217

1. Type I antibodies block the binding of vitamin B12 to intrinsic factor (IF)
2. Type II antibodies prevent IF or IF-B12 complex from binding to the ileal receptor.
3. Antibodies against the gastric proton pump bind to parietal cells and affect acid secretion.

There is significant association of pernicious anemia with other autoimmune disorders of the adrenal and thyroid glands.

Front 218

218. Morphology of pernicious anemia

Back 218

1. Bone marrow changes including megaloblastic erythroid hyperplasia, giant myelocytes and metamyelocytes, hypersegmented neutrophils, large multilobed nuclei in megakaryocytes

2. Alimentary canal; includes atrophic glossitis; the tongue is shiny, glazed and red

3. CNS: lesions are found in 75% of cases. They are characterized by demyelination of dorsal and lateral spinal cord tracts, and, if advanced, result in spastic paresis and sensory ataxia.

Front 219

219. Clinical features of pernicious anemia

Back 219

Onset is insidious; patients are usually 40-60 w/symptoms due to anemia and posterolateral spinal tract involvement.

There is an increased risk of gastric cancer.

Dx is based on serum vitamin B12 levels, the detection of anti-IF antibodies, and hematologic responses (reticulocytosis) after parenteral vitamin administration

Front 220

220. Anemia of folate deficiency

Back 220

Induces a megaloblastic anemia clinically and hematologically indistinguishable from that seen in vitamin B12 deficiency

EXCEPT that gastric atrophy and the neurologic changes of vitamin B12 deficiency do not occur.

Dx requires demonstration of reduced serum or RBC folate levels.

Front 221

221. Causes of folate deficiency

Back 221

1. Inadequate intake, usually in those living on marginal diets (i.e.chronic alcoholics, elderly, and the indigent)

2. Malabsorption syndromes

3. Increased demand (pregnancy)

4. Admin of folate antagonists such as methotrexate, a chemotherapeutic agent.

Front 222

222. Etiology of iron deficiency anemia

Back 222

Negative iron balance and consequent anemia can result from:

1. Low dietary intake (rarely the cause of iron deficiency by itself in the US b/c the avg daily intake is more than enough for men and adequate for most women) malabsorption, excessive demand, and chronic blood loss.

2. Malabsorption caused by sprue and celiac disease or after gastrectomy

3. Increased demands

4. Chronic blood loss; this is the most important cause of iron deficiency in the western world.

Front 223

223. Clinical features of iron deficiency anemia

Back 223

1. Peripheral blood: RBCs are hypochromic and microcytic, and variable in shape

2. Marrow: There is mild hyperplasia of normoblasts, but stainable iron in marrow macropahges are absent

3. Other organs: if severe enough, depletion of essential iron containing enzymes can cause allopecia, koilonychia (nail disease), and atrophy of the tongue and gastric mucosa. Plummer-Vinson triad may occur

Front 224

224. Please inform me; what the f*ck is the Plummer-Vinson triad?!?

Back 224

1. Hypochromic, microcytic anemia
2. Atrophic glossitis
3. Espophageal webs

Front 225

225. Aplastic anemia

Back 225

Characterized by a failure or suppression of multipotent myeloid stem cells; neutropenia, anemia, and thrombocytopenia (pancytopenia) result.

Front 226

226. Causes of aplastic anemia

Back 226

Idiopathic in 60% of cases

Known causes are:
1. Myelotoxic drugs or chemicals
2. Total body irradiation
3. Infections
4. Inherited diseases (e.g. Fanconi anemia)

Front 227

227. Pathogenesis of aplastic anemia

Back 227

Stem cell alterations may be due to environmental insults, drug exposure, or infections. In idiopathic cases, stem cell failure may be due to:

1. Primary defect in the number or function of stem cells; in some case due to mutagen exposure. Occasionally, genetically damaged stem cells can transform to acute leukemias.

2. Suppression of antigenically altered stem cells by T cell mediated immune mechanisms.

Front 228

228. Morphology and clinical features of aplastic anemia

Back 228

Hypocellular marrow (hematopoietic cells replaced by fat cells) with secondary effects due to granulocytopenia and thrombocytopenia.

Onset is insidious w/symptoms related to loss of RBCs, neutrophils, and platelets. Splenomegaly is absent.

More commonly, bone marrow transplantation or immunosuppression is required.

Front 229

229. Pure red blood cell aplasia

Back 229

A form of marrow failure due to absence of RBC precursors; this type of anemia may appear acutely and transiently in chronic hemolytic states due to parvovirus infection.

Front 230

230. Myelophthisic anemia

Back 230

Space occupying lesions that destroy or distort the marrow architecture depress productive capacity

Associated w/pancytopenia and frequently w/the appearance of white and red blood cell precursors in the peripheral blood.

Most common cause is metastatic cancer.

Front 231

231. Diffuse liver disease (toxic, infectious or cirrhotic) anemia

Back 231

The anemia is primarily due to bone marrow failure; often exacerbated by variceal bleeding or folate deficiency

Front 232

232. Chronic renal failure and anemia

Back 232

Chronic renal failure is almost always associated w/anemia.

The basis is multifactorial, but inadequate erythropoietin production is most important.

Treatment w/recombinant erythropoietin usually yields significant improvement.

Front 233

233. Polycythemia

Back 233

A relative or absolute increase in teh concentration of RBCs in the peripheral blood.

Relative increases may be due to decreased plasma volumes associated with dehydration or due to stress polycythemia, an obscure condition of unknown cause also called Gaisbock syndrome.

Absolute increases may be primary or secondary.

Front 234

234. Primary polycythemia

Back 234

Increased RBC mass is due to a myeloid neoplasm, polycythemia vera, in which red blood cell precursors proliferate in an erythropoietin independent fashion

Front 235

235. Secondary polycythemia

Back 235

Increased RBC mass is due to increased erythropoietin, which may be physiologic (lung disease, high altitude living) or pathophysiologic (erythropoietin-secreting tumors).

Front 236

236. What conditions caused increased vascular fragility?

Back 236

1. Infections, esp meningoccus and rickettsia
2. Drug reactions
3. Poor vascular support (Ehlers-Danlos syndrome, Cushing syndrome)
4. Henoch-Schönlein purpura

Front 237

237. Henoch-Schönlein purpura

Back 237

Systemic hypersensitivity reaction of unknown cause characterized by purpuric rash, abdominal pain, polyarthralgia, and acute glomerulonephritis

Associated with vascular and glomerular mesangial deposition of immune complexes

Front 238

238. Causes of thrombocytopenia?

Back 238

1. Decreased production
2. Decreased survival
3. Sequestration (by spleen)
4. Dilution
5. HIV

Front 239

239. Immune thombocytopenia purpura (ITP)

Back 239

Two forms:

1. Acute ITP: this self limited disorder is seen most often in children after a viral infection. Platelet destruction is due to transient antiplatelet autoantibodies

2. Chronic ITP: Platelet autoantibodies are usually directed toward one of two platelet antigens. Destruction of antibody-coated platelets occurs in the spleen. Splenectomy benefits 75-80% of cases.

Front 240

240. Clinical features of ITP

Back 240

Typically occurs in adults, particularly women of childbearing age.

Usually a long history of easy bruising or nosebleeds but sometimes onset can be sudden, with a shower of petechial hemorrhages or internal bleeding.

Subarachnoid or intracerebral hemorrhage is rare but serious.

The iodiopathic form must be distinguished fom that occurring in the context of SLE, AIDS, drug exposure, and lymphoid neoplasms.

Front 241

241. Morphology of ITP

Back 241

The spleen is normal in size but shows sinusoidal congestion and prominent germinal centers.

Bone marrow megakaryocyte numbers are increased.

Front 242

242. Dx of ITP

Back 242

Based largely on clinical features, such as petechiae and thrombocytopenia

Bone marrow biopsy can be performed to confirm increased megakaryocyte numbers.

The bleeding time is prolonged, while the PT and PTT times are normal.

If splenomegaly and lymphadenopathy are present, a lymphoid neoplasm should be suspected.

Front 243

242. Drug induced thrombocytopenia

Back 243

A wide variety of drugs can cause immune mediate platelet destruction by acting as haptens or participating in the formation of immune complexes that deposit on platelet membranes.

In most instances, drug induced antibodies cause rapid removal of platelets via the reticuloendothelial system and result in bleeding symptoms.

Front 244

243. Thrombotic thrombocytopenic purpure (TTP)

Back 244

Usually affects women. Thrombocytopenia, microangiopathic hemolyic anemia, fever, and transient neurologic defects.

Associated with inherited or acquired defiencies in AADAMTS13, a serum metalloprotease that limtites the size of vWF multimers int eh plasma.

In its absence, very high molecular weight vWF multimers accumulate that are capable of promoting platelet aggreation throughout the circulation.

The the case of acquired TTP, patients often have antibodies against ADAMTS13.

Front 245

244. Hemolytic uremic syndrome (HUS)

Back 245

Often occurs in young children and the elderly during outbreaks of food poisoning.

Thrombocytopenia, microangiopathic hemolyic anemia, fever, renal failure.

Most commonly follows GI infections with E. coli.

Front 246

245. Similarities between HUS and TTP

Back 246

In some patients, there are overlapping symptoms.

Most of the clinical manifestations are due to widespread hyaline microthrombi in arterioles and capillaries composed of dense aggregate of platelets and fibrin.