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MLT Hematology > Unit 2 > Flashcards

Unit 2 Flashcards

1
Q

Describe mature erythrocyte

A
  • a bioconcave disc with a central pallor that occupies the middle one third of the cell.
  • has hemoglobin
  • average lifespan of 120 days
  • soft and pliable cell
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2
Q

What is the function of hemoglobin?

A
  • oxygen-carbon dioxide transport
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3
Q

Describe as the RBCs age

A
  • decrease in enzyme activity, especially glycolysis
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4
Q

Describe erythropoiesis

A
  • the process of erythrocyte production
  • encompasses differentiation form the HSC through the mature erythrocyte
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5
Q

Describe where erythropoiesis takes place?

A
  • erythroblastic islands
  • they consists of normoblasts (erytrhoblasts) clustered around an iron-laden macrophage. The macrophage provides the iron needed for hemoglobin maturation and also aids by providing cytokines for the developing normoblasts to mature into functional erythrocytes
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6
Q

What does heme pigment accomplish?

A
  • transport of oxygen to the tissues and transport of carbon dioxide from the tissues
  • heme pigment is synthesized as RBC matures
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7
Q

What are the basic substances needed for normal erythrocyte and hemoglobin production?

A
  • amino acids (protein)
  • iron
  • vitamin B12
  • vitamin B6
  • folic acid
  • trace mineral cobalt and nickel
  • abnormal erythropoiesis can result from deficiencies. Of any of these necessary substances
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8
Q

What is erythropoietin produced by?

A
  • 80-90% are produced by peritubular cells of the kidneys
  • 10-20% is produced in the liver, which is primary site of EPO production in the developing fetus
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9
Q

What are blood levels of EPO inversely related to?

A
  • to tissue oxygenation
  • the greater the hypoxia, the higher the EPO levels
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10
Q

What is the main function of EPO?

A
  • early-acting and lat-acting cytokine, acting on BFU-E and CFU- progenitors as well as the erythroblastic precursors
  • it also interacts with IL-3, GM-CSF, IL-1 and TSF to promote maturation and differentiation of other cell types
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11
Q

Describe maturation and development of a erythrocyte

A
  • once the stem cell differentiates into the erythroid cell line, a call matures through the nucleated cell stages in 4 or 5 days
  • Bone marrow reticulocyte psi have an average maturation period of 2.5 days
    -once young reticulocyte enters the circulating blood, they remain in the reticulocyte stage for an average of 1 day
  • reticulocyte represent approximately 0.5% to 1.5% of the circulating erythrocytes
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12
Q

What is the order for erythrocyte development?

A
  1. Rubriblast
  2. Prorubricyte
  3. Rubricyte
  4. Metarubricyte
  5. Reticulocyte
  6. Mature erythrocyte

OR
1. Pronormoblast
2. Basophilic normoblast
3. Polychromatic normoblast
4. Orthochromic normoblast
5. polychromatic erytrhocyte

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13
Q

Decribe rubriblast

A
  • 12-19 um in diameter
  • N:C ratio is 4:1
  • nucleus —> larger, round nucleus, fine pattern chromatin
  • 0-2 nucleoli
  • cytoplasm - distinctive basophilic color without granules
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14
Q

Describe prorubricyte

A
  • 12-17 um in diameter
  • Nucleus - chromatin is more clumped
  • nucleoli usually not apparent
  • cytoplasm has distinctive basophilic color
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15
Q

Describe rubricyte

A
  • 11-15 um is diameter
  • N:C ratio 1:1
  • nucleus - increased clumping of chromatin
  • cytoplasm - color: variable, with pink staining mixed with basophilia
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16
Q

Desribre metarubricyte

A
  • 8-12 um in diameter
  • nucleus - chromatin pattern is tightly condensed
  • cytoplasm color: reddish pink (acidophilic)
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17
Q

Describe the stain used for reticulocyte

A
  • methylene blue precipitates the ribosomal RNA in these cells to form a deep-blue, mesh-like network
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18
Q

What is the reticulocyte procedure used for?

A

As an indicator of the rate of erythrocyte production

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19
Q

Describe the reticulocyte count procedure

A
  • usually, the count is expressed as a % of total erythrocytes.
  • the normal range is:
    —> 0.5-1.5% in adults
    —> 2.5-6.5% in newborns, falls after the second week of life
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20
Q

What is the equation for corrected reticulocyte count?

A

CRC (%) = (Retic count (%) X patients PCV)/normal PCV

*normal PCV is based on age and sex

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21
Q

Describe Reticulocyte production index (RPI)

A
  • a simple percentage calculation of reticulocyte does not account for an existing anemia, which prematurely releases reticulocytes. These require an additional 0.5-1.5 days longer to mature
  • measures erythropoietic activity when stress reticulocytes are present. The rational for this is that life span of the circulating stress reticulocytes is 2 days instead of the normal 1 day
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22
Q

What is the RPI equation?

A

RPI = corrected reticulocyte count %/ maturation time in days

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23
Q

What are the maturation time correction factors?

A

Hct 45% —> 1.0 days
Hct 35% —> 1.5 days
Hct 25% —> 2.0 days
Hct 15% —> 2.5 days

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24
Q

Describe the mature erythrocytes

A
  • is anucleated
  • functions to transport oxygen to the tissues via hemoglobin
  • survives in circulation for 120 days
  • has average diameter of 6-8 um
  • lacks ability to make hemoglobin, lacks nucleus and functional organelles
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25
Q

How do mature erythrocytes metabolize glucose?

A

Anaerobic glycolysis `

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26
Q

What is polycythemia?

A
  • increased concentration of erythrocytes in the circulating blood that is above normal for gender and age
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27
Q

Describe secondary polycythemia

A
  • disorder of erythropoietin
  • also called absolute polycythemia
  • reflect an increase in erythropoietin production and should not be confused with polycythemia Vera
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28
Q

What are mechanisms that can produce secondary polycythemia?

A
  • presence of high oxygen affinity hemoglobin
  • chronic lung disease
  • smoking
  • dwelling in high altitudes
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29
Q

Describe Red cell increase

A
  • can result from conditions that are not related to increased erythropoietin production. These conditions include the relative polycythemia
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30
Q

Describe relative polycythemia

A
  • rarely has to do with the cells, but rather the proportion of cells to plasma volume
  • when plasma volume is lowered, for example, it will appear as through the Hct is higher than expected, but it is not
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31
Q

What is erythron?

A

Refers to all of the stages of erythrocyte development

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32
Q

What stimulates erythropoiesis?

A
  • Glycoprotein hormone (can cross placenta)
  • androgen hormone
  • thyroid hormone
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33
Q

What is hypoxia?

A
  • a decrease in the oxygen content within the tissues
  • produces dramatic increase in EPO production
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34
Q

How does EPO control red cell production?

A
  1. The number of hemoglobin-containing erythrocytes increases
  2. The oxygen-carrying capacity of the blood increases
  3. Th normal level of oxygen in the tissues can be restored
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35
Q

What does EPO have predominant effects on?

A
  • the committed erythroid cell, CFU-E, promoting their proliferation and differentiation into erythroblasts
  • also stimulates the differentiation of a more primitive erythroid differentiation of a more primitive erythroid progenitor, BFU-E, with bursting-promoting activity
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36
Q

What does EPO prevent?

A

Cell apoptosis

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37
Q

What are nutritional and regulatory factors can cause abnormalties in erythrocytes?

A
  • erythropoietin
  • iron
  • vitamins
  • hormones
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38
Q

What are conditions that cause inappropriate EPO production?

A
  • neoplasms
  • renal disorders that produce local hypoxia within the kidney
  • second polycythemia
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39
Q

Describe megaloblastic maturation

A
  • seen in certain anemias, such as vitamin B12 or folate deficiencies
  • most noticeable characteristics of this type of defect is the nuclear maturation lags behind cytoplasmic maturation
  • Because of an impaired ability of the cells to synthesize DNA, both the interphase and the phases of mitotic divisions are prolonged
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40
Q

How is the asynchronous patterns of megaloblastic maturation confusing?

A

Because the nuclear development of the cells is much younger looking than the actual development age, which is expressed by the cytoplasmic development

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41
Q

Describe the metabolic activities of erythrocytes

A
  • has limited ability to metabolized fatty acids and amino acids and lacks mitochondria for oxidative metabolism
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42
Q

Describe energy sources for RBCs

A
  • exclusively produced by anaerobic glycolysis, through the Embden-Meyerhof-Parma’s pathway, mainly, but also get assistance through:
    —> hexose monophosphate shunt
    —> methemoglobin reductase pathway
    —> luebering-Rapoport pathway
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43
Q

Describe overall pathway of erythrocyte glycolysis

A
  • may be subdivided into the following:
    —> major anaerobic embden-Meyerhof glycolytic pathway that generates ATP and maintains the function of the hemoglobin
    —>three supplementary pathways
    1. The methemoglobin reductase pathway
    2. The Rapoport-Luebering pathway
    3. The phosphogluconate pathway
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44
Q

Describe the reticulocyte membrane

A
  • in maturing reticulocyte, membrane vesiculation leads to loss of surface area
  • posses a significant amount of tubulin and actin in the membrane that mature RBC and therefore gets lost
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45
Q

What are the 3 major changes occur as a reticulocyte matures into an erythrocyte?

A
  • increase in shear resistance
  • loss of surface area because of membrane lipid loss
  • acquisition of a bioconcave shape
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46
Q

What are some characteristics of mature RBC membrane?

A
  • shape of erythrocyte constantly changes as it moves through the circulation
  • composed of a protein lattice-lipid bilayer to which the membrane skeleton is attached by trans bilayer (peripheral proteins)
  • deformable and tolerant against mechanical stress and various pH and salt concentrations in vivo and in vitro
  • cell shape changes reversibly depending on ATP level in the cell and intracellular calcium ion concentration
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47
Q

Describe the cytoskeleton of RBCs

A
  • composed for peripheral proteins that control cell shape, attachment to other cells and maintain organization of specialized membrane domains
  • major components are alpha- and beta- spectrin, ankyrin, band 3, band 4.2, and the glycophorins
  • together they form a complex meshwork tethered to the RBC membrane
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48
Q

What is the function of aquaporin 1?

A

Water transporter

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49
Q

What are the functions for Band 3 Anion exchanger 1?

A
  • anion transporter
  • support system for surface antigens of ABH blood groups antigens
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50
Q

What is the function of Duffy blood group antigens?

A

Calcium transporter

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51
Q

What are the functions of GLUT1?

A
  • glucose transport
  • supports ABH blood group antigens
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52
Q

What are the functions of Glycophorin A?

A
  • transport negatively charged sialic acid
  • supports MN blood group antigens
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53
Q

What are the functions of Glycophorin B?

A
  • transport negatively charged sialic acid
  • supports Ss blood groups antigens
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54
Q

What are functions of Glycophorin C?

A
  • transport negatively charged sialic acid
  • supports Gerbich blood group system antigens
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55
Q

What is the function ICAM4?

A
  • integrin adhesion
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56
Q

What are the functions of kell blood group antigens?

A
  • Zn binding endopeptidase
  • supports Kell blood group antigens
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57
Q

What is the function of Kidd blood group antigens?

A
  • urea transporter
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58
Q

What is the function Rh blood group antigens?

A

Supports D and CcEe blood group antigens

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59
Q

What are the functions of Rh antigen expression protein?

A
  • Supports DCcEe antigen expression
  • gas’ transporter (probably CO2)
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60
Q

What is the function of Embden-Meyerhof pathway?

A
  • maintains cellular energy by generating ATP
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61
Q

What is the function of oxidative pathway (herxose monophosphatase shunt)?

A
  • prevents denaturation of globin of the hemoglobin molecule by oxidation
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62
Q

What is the function of the methemoglobin reductase pathway?

A
  • keeps hemoglobin in the reduced state, which prevents oxidation of hemoglobin (heme iron)
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63
Q

What is the function of Luebering-Rapoport pathway?

A

Regulates oxygen affinity of hemoglobin

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64
Q

What are the transmembrane proteins function as transporter or pumps?

A
  1. Water transporter, aquaporin 1
  2. glucose transporters (GLOTI1 and GLUT3), sodium/hydrogen exchanger 1
  3. Na-K-ATPase
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65
Q

What is the progression of erythropoiesis from prenatal life to adulthood?

A
  1. Yolk sac
  2. Liver and spleen
  3. Red bone marrow
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66
Q

What is erythropoietin secreted by?

A

Liver and spleen

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67
Q

What does tissue hypoxia stimulate?

A

EPO

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68
Q

With a normal diet, an erythrocyte remains in the reticulocyte stage in the circulating blood for how many days?

A

1

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69
Q

What is a reticulocyte that has a blue appearance?

A
  • polychromatophilia
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70
Q

When does relative polycythemia exist?

A

When the plasma volume is decreased

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71
Q

What occurs when increased there are increased amounts of 2,3-DPG?

A
  • decreases the oxygen affinity of the hemoglobin molecule
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72
Q

What occurs after a molecule of hemoglobin gains the first two oxygen molecules?

A

The molecule expels 2,3 DPG

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73
Q

Why does the RBC have limited metabolic ability?

A
  • no mitochondria for oxidative metabolism
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74
Q

What are the contents of the RBC cytoplasm?

A
  • high in potassium ions
  • glucose and enzymes necessary for glycolysis
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75
Q

The Embden-Meyerhof pathway net gain of ATP provides high energy phosphates to do what?

A
  • maintain membrane lipids
  • power the cation pump needed for sodium-potassium concentration pump and calcium flux
  • preserve the shape and flexibility of the cellular membrane
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76
Q

What is the end product of Embden-Meyerhof pathway of glucose metabolism in the erythrocytes?

A
  • lactate
  • 2 ATPS
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77
Q

What is the most common erythrocytic enzyme deficiency involving the embden- Meyerhof glycolytic pathway?

A

Pyruvate kinase

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78
Q

What will result from a defective oxidative pathway (hexose monophosphate shunt)?

A
  • insufficient amounts of reduced glutathione
  • denaturation of globin
  • precipitation of Heinz bodies
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79
Q

To maintain reduced levels of methemoglobin in the RBC, what chemical is necessary to maintain heme iron in a functional (2+) state?

A

NADH

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80
Q

What would a patient have Heinz bodies in their RBCs?

A

Reduced amounts of glutathione

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81
Q

What occurs in erythrocytic glycolysis in the condition of acidosis?

A

Glycolysis is reduced

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82
Q

What occurs as RBCs age?

A
  • enzyme activity, particularly glycolysis, decreases
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83
Q

Where does extravascular RBC destruction occur?

A

Macrophages of the spleen

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84
Q

What are characteristics of the aging cell membrane?

A
  • age-related changes can be monitored using plasma membrane calcium (PMCA) and glycated hemoglobin (Hgb A1C)
    —> PMCA strength declines as the RBC ages
    —> Hgb A1C increases as the RBC ages
  • these cause densification of the RBC membrane that contributes to the membrane instability seen in senescent RBCs
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85
Q

What are characteristics of the RBC cytoplasm?

A
  • in addition to hemoglobin, the enzymes synthesized during early cell development have to be sufficient to provide the energy needed for these processes
    —> main thing hemoglobin iron in an active ferrous (Fe2+) state
    —> driving the cation pump needed to maintain intracellular sodium ion (Na+) and potassium ion (K+) concentrations despite the presence of a concentration gradient
    —> maintaining the sulfrahydryl groups of globins, enzymes, and membranes in an active reduced state
    —> preserving the integrity of the membrane
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86
Q

Describe blocked or inadequate metabolic pathways?

A
  • the life span of the erythrocyte is reduced and hemolysis results. Defects in metabolism can include the following
    —> failure to provide sufficient reduced glutathione,which protects other elements in the cell from oxidation
    —> insufficient energy-providing co-enzymes such as NADH, NADPH, and ATP
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87
Q

Describe the two most common erythrocytic enzyme deficiencies

A
  • involves the Embden-Meyerhof Parnas glycolytic pathway, are deficiencies of:
    —> G6PD
    —> pyruvate Kinase (PK)
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88
Q

What is G6PD responsible for?

A
  • responsible for converting glucose-6 phosphate (G6P) to 6-phosphogluconate (6PG)
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89
Q

What is pyruvate kinase responsible for?

A
  • converting pyruvate (pyruvic acid) to lactic acid
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90
Q

Describe the Embden-Meyerhof pathway

A
  • generates 2 ATP from anaerobic glycolysis
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91
Q

Describe hexose monophosphate shunt

A
  • couples oxidative catabolism of glucose with NADP reduction, which is required for glutathione reduction
  • failure to reduce glutathione causes denaturation of globin and the formation of Heinz bodies
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92
Q

Describe the Luebering-Rapoport Pathway

A
  • allows for optimal oxygen transport in hypoxic conditions and acid-base disturbances though the accumulation of 2,3-DPG
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93
Q

Describe genetic inheritance of hemoglobin

A
  • normal adult hemoglobin A is inherited in simple Mendelian fashion
  • four polypeptide chains (574 amino acids)
    —> two alpha and two beta chains
    —> each has an attached heme group
  • genotype for normal hemoglobin is A/A
  • there are approximately 350 variants types
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94
Q

Describe role of 2,3-DPG

A
  • the oxygen affinity of the hemoglobin molecule is associated with the spatial rearrangement of the molecule and is regulated by the concentration of phosphates, particularly 2,3-DPG in the erythrocyte
  • 2,3-DPG combines with the beta chains of deoxyhemoglobin and diminishes the molecules affinity for oxygen
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95
Q

Describe oxygen dissociation and alterations

A
  • 2,3-DPG combines with beta chains of deoxyhemoglobin and diminishes the molecules affinity for oxygen
  • heme groups unload oxygen in tissues and beta chains are pulled apart and 2,3-DPG form salt bridges
  • results in lower affinity of oxygen
  • oxygen uptake in lungs causes salt bridges to be broken and 2,3-DPG to be expelled
  • in cases of tissue hypoxia, oxygen moves from hemoglobin to tissues and amount of deoxyhemoglobin increases in RBC
  • produces binding of 2,3-DPG which lowers hemoglobin affinity of oxygen
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96
Q

What occurs if hypoxia persists?

A
  • depletion of free 2,3-DPG leads t increased production of more 2,3-DPG and a persistently lowered affinity of the hemoglobin molecule for oxygen
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97
Q

What are changes in oxygen affinity of the molecules responsible for?

A
  • the ease with which hemoglobin can be loaded with oxygen in the lungs and unloaded in tissue
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98
Q

What does the shape and position of the oxyhemoglobin dissociation curve graphically describe?

A

The relationship between oxygen content (% saturation) and partial pressure of oxygen (PO2)

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99
Q

Define P50 value

A
  • the partial pressure of oxygen required to produce half saturation of hemoglobin when the deoxyhemoglobin concentration equals the oxyhemoglobin concentration at a constant pH and temperature
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100
Q

What is the pH and temperature of humans?

A
  • 7.4
  • 37.5 C
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101
Q

What can a decrease in DPG cause?

A
  • an increase in oxygen affinity is demonstrated by a shift to the left
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102
Q

What can an increase of DPG cause?

A

A decrease in oxygen affinity is represented by a shift to the right, by a decrease in pH (Bohr effect), increase in temperature or hypoxia conditions

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103
Q

What are the 3 ways carbon dioxide can be carried to the lungs?

A
  • indirectly by erythrocytes
  • directly by erythrocyte
  • in plasma
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104
Q

Describe indirect erythrocyte mechanism of carbon dioxide transport

A
  • predominant mechanism
  • approximately 3/4 of the activity for removing carbon dioxide, carbon dioxide diffuses into the erythrocytes, is catalyzed by the enzyme carbonic anhydrase, and is transformed into carbonic acid

H2O + CO2 —> H2CO3

  • the hydrogen ion of carbonic acid is accepted by the alkaline deoxyhemoglobin, and the bicarbonate ion diffuses back into the plasma

H2CO3 —> H+ + HCO3-

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105
Q

Describe chloride shift

A
  • free bicarbonate diffuses out of RBC into plasma
  • plasma chloride diffuses into cell
  • in the lungs, bicarbonate is converted back into carbon dioxide and water and eliminate from lungs through respiration
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106
Q

What happens to a 1/4 of carbon dioxide?

A
  • directly bound with deoxyhemoglobin forming carbamino hemoglobin
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107
Q

What happens to 5% of carbon dioxide?

A
  • carried in solution in the plasma to the lungs
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108
Q

What cause defects of hemoglobin?

A
  • amino acid substitution (hemoglobinopathies)
  • diminished production of the polypeptide chains (thalassemias)
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109
Q

Describe formation of heme from porphyrin

A
  • hemoglobin is synthesized during most of the erythrocytic maturation process
  • 65% of cytoplasmic hemoglobin is synthesized before the nucleus is extruded
  • 35% is synthesized in the early reticulocyte
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110
Q

What is the erythrocyte precursor?

A

Heme

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111
Q

Where is heme produced?

A
  • mainly in the red bone marrow and liver
  • heme produced in the erythroid precursors is chemically identical to that in the cytochromes and myoglobin
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112
Q

Describe iron of hemoglobin

A
  • iron is delivered by transferrin to the membrane of immature cell
  • iron in the ferric form (Fe3+) affixes to cell membrane and transferrin is released
  • iron enters cell and proceeds to mitochondrion
  • excess iron accumulates as ferritin aggregates in the cytoplasm of immature erythrocyte
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113
Q

What does the amount of non-heme iron deposited depend on?

A
  • the ratio between the plasma iron level and the iron required by the cell
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114
Q

What is globin structure and production governed by?

A

Genetics

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115
Q

What is the rate of globin chain synthesis?

A
  • is a function of the rate at which the DNA code is transcribed
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116
Q

What is Alpha Globin Locus?

A

Chromosome 16 governs alpha chain production in adults and zeta chain production in the fetus
- each cell has two chromosome 16 ( a total of 4 alpha chains in each cell)
- mechanism of this coordination is unknown

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117
Q

What is Beta Globin Locus?

A

Chromosome 11 governs the beta globin chains, which in order of sequence is epsilon, gamma, delta, and beta
- two copies of gamma gene on each chromosome 11

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118
Q

Describe production of functional hemoglobin

A

Pairs two alpha globin chains and two beta globin chains together

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119
Q

What does hemoglobin alpha and beta chains in an adult consist of?

A
  • 141 amino acids in each alpha chain
  • 146 amino acids in each beta chain
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120
Q

What is the P50 value for whole blood in humans under the accepted standard conditions (pH and temp)?

A

26.52 Hg

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121
Q

Describe the oxyhemoglobin 3D structure

A

Salt bridges are broken, and the hemoglobin molecule is describe as being relaxed (R) structure or state

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122
Q

Describe the deoxyhemoglobin 3D structure

A
  • tetramer is stabilized by intersubunit salt bridges and is described as the tense (T) structure or state
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123
Q

Compare T configuration with R configuration

A

T configuration is a low-oxygen affinity shape compared to the R configuration that is a high-oxygen conformation

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124
Q

Describe oxygenation of hemoglobin molecules

A
  • oxygenation of one site on a hemoglobin molecule enhances affinity for oxygen at a different but chemically identical site
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125
Q

Describe when the oxygen dissociation curve shifts to the left

A
  • in response to raised pH, decreased CO2, decreased temperatures or decreased 2,3-DPG
  • also seen in hemoglobin F and hemoglobin variants
  • increased oxygen affinity
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126
Q

Describe when the oxygen dissociation curve shifts to the right

A
  • in response to lowered pH, increased CO2, increased temperature, or increased 2,3-DPG
  • decrease in oxygen affinity
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127
Q

What are types of hemoglobin can be found during normal human growth and development?

A
  • A
    —> A1 and A2
  • F
  • embryonic forms
  • each has a distinctive composition of polypeptide chains
  • Many other types of variant (abnormal) hemoglobin’s
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128
Q

What is the best known hemoglobinopathy?

A

Sickle cell anemia

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129
Q

What factors can effect on the concentration of hemoglobin?

A
  • age
  • gender
  • pregnancy
  • altitude
  • smoking
  • associated disease
  • altered hemoglobin derivatives
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130
Q

What are the steps of heme synthesis?

A
  1. Begins in the mitochondrion with the condensation of succinyl-CoA and glycine to form 5-aminolevulinic acid
  2. Series of steps in cytoplasm produce corproporphyrinogen III, which re-enters the mitochondrion
  3. Iron is inserted into the ring structure of protoporphyrin IX to produce heme
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131
Q

Where does most iron entering the blood plasma come from?

A
  • recycling; an appropriate amount of iron is absorbed from the diet to compensate for losses and to main nontoxic amount in storage
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132
Q

Describe the rate of polypeptide synthesis

A
  • is a function of the rate at which the DNA code is transcribed into messenger ribonucleic acid (mRNA)
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133
Q

What are the steps of assembly of a hemoglobin molecule?

A
  1. Alpha and Beta-globin polypeptides are translated from appropriate mRNAs
  2. Once heme contain iron binds to each of the four polypeptide chains, the protein folds into a native 3D structure
  3. The alpha and Beta units bind to each other by electrostatic bonding
  4. An unstable intermediate encounter complex can rearrange the units to form a stable alphaBeta dimer
  5. Two dimmers combine to form the functional hemoglobin molecule, an a2B2 tetramer
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134
Q

What are the polypeptide chains of Gower-1?

A

2 zeta
2 epsilon

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135
Q

What are polypeptide chains of Gower-2?

A

2 alpha
2 epsilon

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136
Q

What are the polypeptide chains of Portland-1

A

2 zeta
2 gamma

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137
Q

What are the polypeptide chains of hemoglobin F?

A

2 alpha
2 gamma

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138
Q

What are the polypeptide chains for Hemoglobin A?

A

2 alpha
2 beta

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139
Q

What are the polypeptide chains of Hemoglobin A2?

A

2 alpha
2 delta

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140
Q

What are some disorders associated with inherited defects of heme?

A
  • rare autosomal recessive conditions
  • congenital erythropoietic porphyria
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141
Q

What are some disorders associated with acquired defects of heme?

A
  • lead poisoning
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142
Q

Define porphyria

A
  • a disease of heme metabolism in which a primary abnormality in porphyrin biosynthesis leads to excessive accumulation and excretion of porphyrin or their precursors by the biliary and/or renal route
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143
Q

Porphyria can be classified based on what characteristics?

A
  • clinical presentation
  • source of enzyme deficiency
  • site of enzyme deficiency in the heme biosynthetic pathway
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144
Q

What are symptoms of porphyria?

A
  • neurological complications
  • skin problems
  • some have no symptoms
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145
Q

What are the two sub groups of porphyria’s?

A
  • acute neurological
  • nonacute cutaneous
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146
Q

What color is porphyric urine?

A

Red wine color

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147
Q

How is porphyria tested for in urine?

A

Adding Ehrlich’s aldehyde reagent

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148
Q

What occurs when porphyria synthesis is impaired?

A
  • mitochondria becomes encrusted with iron and some granules exist around the nucleus
  • can be seen with Prussian blue stain
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149
Q

What are the 3 compartments that iron is distributed in?

A
  1. Storage: primarily ferritin in bone marrow macrophages and liver cells
  2. Transport: with serum transferrin
  3. Functional: as hemoglobin, myoglobin, and cytochromes
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150
Q

Describe iron deficiency anemia

A
  • normal iron status continues as iron intake lags behind iron loss, but eventually the loss will be too great from the intake to keep up —> depletion of iron stores —> iron deficiency anemia
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151
Q

What are causes of sideroblastic anemia?

A
  • congenital defect: hereditary sex linked, autosomal (most males)
  • acquired defect: primary ; may evolve into acute myelogenous leukemia
  • association with malignant disorders: acute myelogenous leukemia, polycythemia vera, myeloma, myelodysplastic syndromes
  • secondary to drugs: isoniazid (INH), chloramphenicol; after chemotherapy
  • toxins, including alcohol, and chronic lead poisoning
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152
Q

Describe hereditary hemochromatosis types

A
  • HFE gene related (type 1)
  • different mutations of the HJV gene responsible for juvenile hemochromatosis (or type 2 hemochromatosis)
  • Type 3 hemochromatosis is a different form of the disease that usually appears in midlife
  • Type 4 is related to the SLC40A1 gene that encodes for ferroportin
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153
Q

Describe disorders of globin synthesis

A
  • when globin synthesis is impaired, protoporphyrin synthesis is correspondingly reduced
  • similarly, when porphyrin synthesis is impaired, excess globin is not produced
  • there is no fine regulation of iron uptake with impairment of either protoporphyrin or globin synthesis.
  • when globin production is deficient, iron accumulates in the cytoplasm of cells as ferritin aggregates
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154
Q

Defect of globin synthesis are manifested in the __________

A

Thalassemias

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155
Q

Describe embryonic hemoglobins

A
  • embryonic hemoglobins are primitive hemoglobins by immature erythrocytes in the yolk sac
  • include Gower 1, Gower 2 and Portland types
  • they are found in human embryo and persists until approximately 12 weeks of gestation
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156
Q

Describe fetal hemoglobin

A
  • Hemoglobin F is the predominant hemoglobin variety in the fetus and newborn
  • has two alpha and two gamma chains
  • appears by the 5th week of gestation and persists for several months after birth
    —> diminish to low levels, but constant levels throughout adulthood
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157
Q

Describe hemoglobin A

A
  • found in 95-97%
  • made up for two alpha and two beta chains
  • produced in uteri in small concentrations and converts to high concentrations 3-6 months after birth
  • subfraction of A is A1
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158
Q

Describe hemoglobin A2

A
  • makes up 2-3%
  • made of two alpha chains and two delta chains
  • production begins shortly before birth and continues at a slow rate throughout the person’s life
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159
Q

Describe hemoglobin A1

A
  • this subfraction can be termed glycolsylated hemoglobin and includes the separate hemoglobin fractions A1a, A1b, and A1C
  • formed during RBC maturation
  • 3-6% in normal person.
  • stable hemoglobin and is structurally the same as hemoglobin A except for the addition of a carbohydrate group as the terminal valine of the beta chain
  • the concentration of glycolsylated hemoglobin accurately reflects the patients blood glucose level
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160
Q

What are some variant forms of normal hemoglobin?

A
  • carboxyhemoglobin
  • sulfhemoglobin
  • methemoglobin
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161
Q

Describe carboxyhemoglobin

A
  • hemoglobin has higher affinity for carbon monoxide (200x) than oxygen does.
  • this results in oxygen deprivation and tissue necrosis if left untreated
  • normal levels: 1-3%
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162
Q

Describe sulfhemoglobin

A
  • the binding of hemoglobin to hydrogen sulfide produces an irreversible change in the polypeptide chains (produces green color)
  • this causes denaturation and precipitation of Heinz bodies
  • can combine with carbon monoxide and produce carboxysulfhemoglobin
  • can be formed by action of certain oxidizing drugs
  • normal: <1%
  • elevated = cyanosis
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163
Q

Describe methemoglobin

A
  • hemoglobin with iron in the ferric state, instead of the ferrous state
  • results in poor delivery of oxygen. Cyanosis occurs with methemoglobin levels at greater than 10% and hypoxia at greater than 60%
  • normal: 2% produced per day
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164
Q

Describe variant forms of normal hemoglobin

A
  • typified by differing from normal hemoglobin only by the molecule that replaces oxygen
  • unable to transport oxygen
  • most cases are acquired
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165
Q

What are symptoms when carboxyhemoglobin levels are 20-30%?

A
  • dizziness
  • nausea
  • headache
  • muscular weakness
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166
Q

What are symptoms when carboxyhemoglobin levels are at 40%?

A
  • sudden loss of consciousness
  • rapid death
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167
Q

What is the treatment for carbon monoxide poisoning?

A

Supplement oxygen

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168
Q

Describe abnormal hemoglobin

A
  • usually results from mutant, codominant genes
  • mutant genes may be homozygous (such as SS in sickle cell disease) or heterozygous(such as SA in sickle cell trait)
    —> sickle cell gene may occur with C, E, or D giving rise to SC, SE, or SD disease
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169
Q

Describe defective hemoglobin S

A
  • amino acid valine at 6th position of the beta globin chain instead of glutamic acid
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170
Q

What are ways to analyze hemoglobin?

A
  • hemoglobincyanide (cyanmethoemoglobin) (defunct)
  • alkaline electrophoresis
  • citrate agar electrophoresis
  • denaturation procedures
  • chromatography
  • molecular testing
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171
Q

Describe alkaline electrophoresis

A
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172
Q

What is the principle of alkaline electrophoresis?

A
  • hemoglobin molecules in an alkaline solution have a net negative charge and move toward the anode
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173
Q

Describe alkaline electrophoresis

A
  • screening procedure that separates Hgbs A, F, S, and C
  • fast hemoglobins are those that move furthest from the point of application
    —> include Hgb A, F, Barts, H and I
  • slow hemoglobins are those that move close to the application point
    —> include Hgb C, E, O and A2
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174
Q

What is the principe of Citrate agar electrophoresis?

A
  • citrate agar separates hemoglobin fractions that migrate together on cellulose acetate— hgbs S, D, G, C, E and O
  • takes place at an acid pH
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175
Q

Describe citrate agar electrophoresis

A
  • in this method, Hgbs are separated on the basis of a complex interaction between hemoglobin, agar, and citrate buffer ions
  • due to similar migration patterns on cellulose acetate, all Hgb specimens that show an abnormal electrophoresis pattern in alkaline media should undergo electrophoresis pattern in alkaline media should undergo electrophoresis on acid citrate agar
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176
Q

What test is commonly used to determine the amount of fetal blood that has mixed with maternal blood following delivery?

A

Kleihauer-Betke

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177
Q

Describe Kleihauer-Betke test

A
  • denaturation test because we expose the specimen that denatures adult hemoglobin
    —> fetal hemoglobin (F) is resistant to acid lysis and therefore stays intact and stains pink with safranin
    —> adult Hgb (A) is susceptible to acid lysis and therefor will be faintly colored
    —> the number of fetal cells to adult cell is counted and a percentage is determined, which is compared to a reference range
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178
Q

What is the clinical significance of Kleihauer-Betke test?

A
  • sensitization for HDN occurs when there is too much intermingling of fetal and maternal blood
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179
Q

Describe chromatography of hemoglobin analysis

A
  • quantitation of hemoglobin A1 can be accomplished by cation exchange minicolumn chromatography
  • the results can be affected by several types of Hgb in addition to Hgb A1
  • cellulose acetate and citrate agar electrophoresis should be used in conjunction with cation exchange chromatography to eliminate the possibility of interference by Hgb variants
  • other assay methods for glycolylated Hgb include high-pressure liquid chromatography (HPLC) and colorimetric methods
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180
Q

Describe molecular testing of hemoglobin analysis

A
  • gene deletions and mutations causing thalassemias and hemoglobinopathies can be identified using molecular testing
  • since Hgb (particularly the globin component) is maintained under genetic control, determining the genetic influence of hemoglobinopathies and thalassemias is beneficial
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181
Q

What processes occur as erythrocytes age?

A
  • the membrane becomes less flexible
  • the concentration of cellular Hgb increases
  • enzyme activity, particularly glycolysis, diminishes
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182
Q

What is the standard method for the determination of Hgb?

A

Hemoglobincyanide

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183
Q

Describe hemoglobincyanide

A
  • using lysing agent in reagent solution to release Hgb from intact erythrocytes
  • free hemoglobin combines with potassium ferricyanide in the reagent. This converts Hgb iron state from ferrous to ferric form
  • intensity of color is proportional to the concentration of Hgb in the solution.
184
Q

Describe extravascular catabolism of erythrocytes

A
  • when an erythrocyte is phagocytized and digested by the macrophages of the spleen, the hemoglobin molecule is disassembled
  • the resulting components are as follows
    —> iron
    —> protoporphyrin
    —> globin
185
Q

Why is iron transported in the plasma by transferrin in extravascular catabolism?

A
  • to be recycled by the red bone marrow in the manufacture of new hemoglobin
186
Q

Describe catabolism of globin in extravascular catabolism

A
  • catabolized in the liver into its constituent amino acids and enters the circulating amino acid pool
187
Q

Describe intravascular catabolism of erythrocytes

A
  • is an alternate pathway for erythrocyte breakdown
  • this process normally accounts for less than 10% of erythrocytic destruction
188
Q

What are the results of intravascular catabolism?

A
  • hemoglobin is released directly into the bloodstream and undergoes dissociation into alpha and beta dimers, which are quickly bound to the plasma globulin haptoglobin
  • haptoglobin binds to the alpha and beta dimers forming a haptoglobin-hemoglobin complex that prevents urinary excretion of plasma hemoglobin
  • the complex is removed by the liver and processed
  • thus in active intravascular hemolysis, the haptoglobin levels in plasma are low
  • once the haptoglobin is consumed, the alpha and the beta dimers are rapidly filtered by the glomeruli in the kidneys, reabsorbed a converted to hemoglobin
189
Q

What is the renal tubular uptake capacity of filtered hemoglobin?

A

5 g per day
- beyond this level, hemoglobin appears in the urine (hemoglobinuria)

190
Q

What pigments appear when hemoglobin is oxidized in the urinary tract?

A
  • oxyhemoglobin (alkaline urine)
  • methemoglobin (acidic urine)
191
Q

What happens to hemoglobin that isn’t processed by the kidneys nor bound to haptoglobin?

A
  • becomes methemoglobin in circulation
    —> carrier: hemopexin
    —> excess binds to albumin to form methemalbumin
192
Q

What can renal processing of filtered hemoglobin produce?

A
  1. Hemoglobin alone, if hemolysis is severe
  2. Excretion of hemosiderin by itself
  3. Excretion of both hemosiderin and hemoglobin; if desquamated tubular cells contains hemosiderin granules
193
Q

What are the major components of hemoglobin?

A

Heme
Globin

194
Q

What are major defects in the hemoglobin molecule?

A
  • amino acid substitutions
  • diminished production of one of the polypeptide chains
  • homozygous A/A inheritance
195
Q

After a molecule of hemoglobin gains the first two oxygen molecules, the molecule..

A

Expels 2,3-DPG

196
Q

Fetal hemoglobin has ______ affinity for oxygen then normal adults

A

A greater

197
Q

Oxyhemoglobin is a ____ than deoxyhemoglobin

A

Stronger acid

198
Q

If a young male was preparing for Olympic competition and had his blood drawn for the measurement of oxygen dissociation, this result would demonstrate..

A

A shift to the right

199
Q

In case of chronic carboxyhemoglobin exposure, the patients oxygen dissociation curve would exhibit….

A

A shift to the left

200
Q

When iron availability is depleted in a cell, the translational rates of ferritin mRNA is…

A

Decreased oxygen affinity

201
Q

The initial condensation reaction in the synthesis of porphryin preceding heme formation takes place in the ______ and requires __________

A
  • mitochondria
  • vitamin B6
202
Q

The final step in heme synthesis, including the formation of protoporphyrin, take place in …

A

The mitochondria

203
Q

What is the major hemoglobin synthesized in the second trimester fetus?

A

F

204
Q

What hemoglobin types is the major type present in normal adults?

A

A

205
Q

What are Heinz bodies associated with?

A
  • sulfhemoglobin
206
Q

What is the altered solubility of hemoglobin molecule due to?

A
  • substitution of a non polar amino acid residue for a polar reside near the surface of the chain
207
Q

What hemoglobin commonly occurs in the sickle gene>

A

Bart

208
Q

What does the alkaline denaturation test detects the presence of?

A

Hemoglobin F

209
Q

What is the type of hemoglobin that is detectable with the Kleihaur-Betke test?

A

F

210
Q

What is the physical difference in the detectable type of hemoglobin in the Kleihauer-Betke test?

A
  • resists denaturation in the procedure
211
Q

What is the slowest common hemoglobin?

A

C

212
Q

Erythrocyte abnormalities occur due to:

A
  • variation in size: called anisocytosis
  • variation in shape: called poikilocytosis
  • alteration in color: suffix-chromia
  • inclusions in the erythrocytes
  • alterations to the erythrocyte distribution on a PB smear
213
Q

What are the erythrocyte indices used for?

A
  • to mathmatically define cell size and the concentration of hemoglobin within the cell.
    —> Mean corpuscular volume (MCV)
    —> Mean corpuscular hemoglobin (MCH)
    —> Mean corpuscular hemoglobin concentration (MCHC)
214
Q

Describe MCV

A
  • expresses the average volume (size) of an erytrhocyte
  • reference range: 80-96 fL

(Hct/Rbc) x 10 = fL (femtoliters)

215
Q

Describe MCH

A
  • expressed the average weight (content) of hemoglobin in an average erythrocyte. It is directly proportional to the amount of hemoglobin and the size of the erythrocyte
  • reference value is 27-32 pg

(Hgb/RBC) x 10

216
Q

Describe MCHC

A
  • expresses the average concentration of hemoglobin per unit volume of erythrocytes. It is also defined ass the ration of the weight of Hgb to the volume of erthrocytes
  • reference range: 32-36%

(Hgb/Hct) x 100 = g/dL or %

217
Q

Describe normocytic erytrhocytes

A
  • average diameter of 7.2 um
  • range: 6.2-8.2 um
  • can also be classified by the MCV falling between 80-96 fL
218
Q

Describe macrocytic erytrhocytes

A
  • cells larger than leukocytes nucleus
  • > 96 fL
219
Q

Describe microcytic

A
  • cells smaller than leukocyte nucleus
  • <80 fL
220
Q

Describe poikilocytosis

A
  • general term for mature erytrhocytes that have a shape other than the normal round, bioconcave appearance on a stained blood smear, or variations
  • used cautiously
221
Q

What is a clinical condition associated with anisocytosis?

A
  • significant in severe anemias
222
Q

What is a clinical condition associated with macrocytes?

A
  • megaloblastic anemias and macrocytic anemias (folic acid deficiency and pernicious anemia)
  • (hereditary lipoprotein deficiency)
223
Q

What clinical conditions are associated with microcytes?

A
  • iron deficiency anemia
  • hemoglobinopathies
224
Q

What clinical conditions are associated with acanthocytes?

A
  • Abetalipoproteinemia
  • cirrhosis of the liver with associated hemolytic anemia
  • following heparin administration
225
Q

What clinical conditions are associated with blister cells?

A
  • pulmonary emboli in sickle cell anemia
  • microangiopathic hemolytic anemia
226
Q

What clinical conditions are associated with burr cells?

A
  • variety of anemias
  • bleeding gastric ulcers
  • gastric carcinoma
  • peptic ulcers
227
Q

What clinical condition is associated with crenated RBCs?

A

Results from osmotic imbalance

228
Q

What clinical conditions are associated with elliptocytes?

A
  • anemia associated with malignancy
  • Hb C disease
  • hemolytic anemias
  • iron deficiency anemia
229
Q

What clinical conditions are associated with poikilocytosis?

A
  • hemolytic anemias
  • thalassemias
  • myelofibrosis
230
Q

Describe ancanthocytes

A
  • pointy irregular shaped projections that are unevenly dispersed around the red cell
231
Q

What clinical conditions is associated with keratocytes?

A

DIC

232
Q

Describe keratocytes

A
  • blister cells ruptured
  • looks like a bite out of the cell
233
Q

Describe schistocytes

A
  • mechanical tearing of RBC
  • looks “ripped”
  • blister cells and keratocytes are generally grouped together under schistocytes
234
Q

Describe Burr cell

A
  • also called echinocyte or crenated RBC
  • round projections evenly dispersed around the red cell
235
Q

Describe elliptocytes

A
  • cigar shaped
  • they represent a membrane defect in which the membrane is radically affected and suffers a loss of integrity
236
Q

Describe ovalocytes

A
  • oval or football shape
237
Q

Describe schistocytes

A
  • fat crescent shape
  • irregular edges
  • remains after the rupturing of a blister cell
  • forms as a result of the physical process of fragmentation
  • these cell fragments are formed in the spleen and intravascular fibrin clots
238
Q

Describe polychromasia

A
  • slightly larger
  • slightly bluer when stained with Wright’s stain
239
Q

Describe sickle cells

A
  • also called drepanocytes
  • elongated, thin crescent
  • at least one end must be pointed
  • results from the gelation of polymerized deoxygenated Hb S.
240
Q

Describe spherocytes

A
  • very round
  • no central pallor
  • have lost bioconcave shape
  • usually small than 6 um in size
  • occurs as the ratio of the surface area of the erythrocyte to the volume of the cell contents decreases because of the loss of the cell membrane. This loss creates membrane instability
241
Q

Describe stomatocytes

A
  • pallor is shaped as a slit
  • results from increase Na+ ion and decrease in K+ ion concentration within the cytoplasm of erythrocyte
242
Q

Describe target cells

A
  • also called codocytes
  • have centers that look like targets
243
Q

Describe teardrop

A
  • also called dacryocytes
  • shaped like a tear drop
  • usually smaller than normal erytrhocytes
244
Q

Describe the color of a normal erytrhocytes

A
  • moderately pinkish-red appearance with a light center when stained with a conventional blood stain
245
Q

What does the color of an erythrocyte reflect?

A
  • the amount of Hgb present in the cell.
  • the lighter color in the middle, thinner portion of the cell does not normally exceed one third of the cell’s diameter and is referred to as the central pallor
  • ALSO can reflect state of cell immaturity
246
Q

What is anisochromasia?

A

Variation of normal coloration

247
Q

Describe hypochromia

A

When central pallor exceeds one third of the cell’s diameter

248
Q

What is expected to see with iron deficiency anemia?

A

Microcytic/hypochromic

249
Q

Why do reticulocytes have a blue color?

A
  • lacks the full amount of hemoglobin, and the blue color is caused by diffusely distributed residual RNA in the cytoplasm
250
Q

What are the erythrocyte inclusions?

A
  • parasitic
    —> malaria, Babesia, leishmania
  • nonparasitic
    —> basophilic stippling (fine or coarse)
    —> Cabot rings
    —> Heinz bodies
    —> Howell-Jolly bodies
    —> pappenheimer bodies (aka siderotic granules)
251
Q

Describe fine basophilic stippling

A
  • appears as tiny, round, solid staining, dark-blue granules. The granules are usually evenly distributed throughout the cell and often require careful examination to detect them
252
Q

Describe coarse basophilic stippling

A
  • sometime referred to as punctate stippling
  • these granules are larger than in the fine form and are considered to be more serious in terms of pathological significance
253
Q

Describe basophilic stippling

A
  • stippling represents granules composed of ribosomes and RNA that are precipitated during the process of staining of a blood smear.
  • stippling is associated with clinically with disturbed erythropoiesis, lead poisoning, and severe anemias
254
Q

Describe Heinz bodies

A
  • 0.2-2.0 um in size
  • can be see with a stain such as crystal violet or brilliant cresyl blue
  • must be a supravital stain
  • represents precipitated, denatured hemoglobin
255
Q

What clinical conditions are associated with Heinz bodies>?

A
  • congenital hemolytic anemia
  • G6PD deficiency
  • hemolytic anemias
  • some hemoglobinopathies
256
Q

Describe Howel-Jolly bodies

A
  • are round, solid-staining, dark-blue to purple inclusions (only one or two)
  • 1-2 um in size
  • are nuclear remnants predominantly composed of DNA and not seen in normal erythrocytes
  • this ruminant DNA is normally pitted out by the macrophages in the spleen, so the presence of H.J. Bodies are a sign of splenic dysfunction of absence
257
Q

Describe pappenheimer bodies

A
  • also called siderotic granules
  • may be observed ubiquitous wright-stained smears as three to four purple dots aggregated in one area of the cell
  • are frequently seen in peripheral blood smears
258
Q

What are pappenheimer bodies aggregates of?

A
  • mitcochondria
  • ribosomes
  • iron particles
259
Q

What clinical conditions are associated with pappenheimer bodies?

A
  • iron-loading anemia
  • hyposplenism
  • hemolytic anemias
260
Q

Compare pappenheimer bodies in peripheral blood versus siderotic granules?

A
  • probably identical structures
  • siderotic granules are dark-staining particles of iron in the erytrhocyte that are visible with a special iron stain— Prussian blue
  • siderotic granules can also be visualized around the nucleus in ringed sideroblasts in sideroblastic anemia, refractory anemia, and iron overload conditions
261
Q

What is agglutination?

A
  • the clumping of erythrocytes in a random, nonspecific arrangement
  • caused by the presence of antibodies reacting with antigens on the erythrocyte
262
Q

What is Rouleaux?

A
  • arrangement of erythrocytes in groups that resemble stacks of coins
  • is usually present in the thick portions of the normal blood smears. If the rouleaux exist in thin areas of the blood smear where the erythrocytes should just touch each other or barely overlap, pathological rouleaux are present
  • formation is associated with the presence of circulating cryoglobulins or paraproteins
263
Q

What clinical conditions are associated with schistocytes?

A
  • hemolytic anemia related to burns or prosthetic implants
  • renal transplant rejection
264
Q

What clinical condition is associated with sickle cells?

A

Sickle cell anemia

265
Q

What clinical conditions are associated with spherocytes?

A
  • ABO hemolytic disease of the newborn
  • acquired hemolytic anemias
  • blood transfusion reactions
  • DIC
266
Q

What clinical conditions are associated with stomatocytes?

A
  • acute alcoholism
  • alcoholic cirrhosis
267
Q

What clinical conditions are associated with target cells?

A
  • hemoglobinopathies
  • Hb C disease
  • sickle cell
  • thalassemia
268
Q

What clinical conditions are associated with teardrops?

A
  • homozygous beta thalassemia
  • myeloproliferative syndromes
  • pernicious anemias
  • severe anemia
269
Q

What clinical condition is associated with hypochromia?

A

Iron deficiency anemia

270
Q

What clinical condition is associated with polychromatophilia?

A
  • rapid blood regeneration
271
Q

What can feulgen stain be used to detect?

A
  • Howell-Jolly bodies
272
Q

What can supravital stain be used to detect?

A
  • basophilic stippling
  • Howell- Jolly bodies
  • reticulocytes
  • pappenheimer bodies
  • Heinz bodies
273
Q

What can wright stain be used to detect?

A
  • basophilic stippling
  • cabot rings
  • Howel-Jolly bodies
  • polychromatophilia
  • pappenheimer bodies
  • Heinz bodies
274
Q

Describe Cabot RIngs

A
  • ring-shaped, figure-eight, or loop-shaped structures
  • stain red or reddish purple color
  • have no internal structure
  • represent remnants of microtubules from the mitotic spindle
275
Q

What clinical conditions are associated with Cabot rings?

A
  • lead poisoning
  • pernicious anemia
276
Q

Describe Hb C crystals

A
  • appears like rod shaped or angular opaque structures within some erythrocytes
  • found in Hb C disease
277
Q

Describe malaria

A
  • most severe form of parasitic inclusions
  • has 3 life-threatening manifestations
    1. Cerebral malaria
    2. Respiratory distress
    3. Severe malarial anemia
  • severe in kids and pregnant women
  • can cause hemolytic anemia
278
Q

What are the types of malaria?

A
  • plasmodium vivax
  • plasmodium falciparum
  • plasmodium malariae
  • plasmodium ovale
  • occurs in humans and mosquitos
279
Q

Describe disease phase in the mosquito

A
  • initiated when the female mosquito of anopheline mosquitoes bite an infected human
  • infected blood may contain male or female genotypes
  • female (macrogamecyte) matures into macrogamete
  • male (microgametocyte) undergoes maturation and results in production of microgametes
  • when male fertilizes female, it becomes a zygote (oocyte)
  • growth and development of oocyte results in production of large number of thread-like sporozoites,which circulate throughout the mosquito
  • sporozoites enter salivary glands of mosquito and are ready to be inoculated into the next bitten person
280
Q

What factors effect the light of the malaria cycle in a mosquito?

A
  • species type
  • ambient temperature
  • can be 8-35 days long
281
Q

Describe the disease phase of malaria in humans

A
  • after being injected with sporozoites from infected mosquito, they leave the circulatory system within 40 minutes and invade the liver cells
  • all found species undergo an asexual multiplication phase. This provides thousands of tiny merozoites in each infected cell
  • rupture of infected liver cells releases merozoites into the circulation
  • schizogony - asexual cycle takes place within erythrocytes, results in 4-36 parasites on each infected erythrocyte
282
Q

What are the steps of Malaria disease cycle plasmodium?

A
  1. Sporozoite invades RBC
  2. “Ring” stage of development
  3. Ameboid stage of development
  4. Asexual division
  5. Cell rupture with release of spore; reinfection of RBC by some spores
  6. Development of other spores into sexual forms
  7. Development into egg and sperm cells after mosquito sucks them in
  8. Fertilized cell developing into cyst
  9. Ruptured cyst releasing sporozoites
283
Q

What are symptoms of Malaria?

A
  • no symptoms until several continuous life cycles have been completed.
  • chills, followed by fever in a few hours
  • last 4-6 hours, and recur at regular intervals
284
Q

Describe RBC morphology of plasmodium vivax

A
  • enlarged RBC
  • inclusions: schuffner dots, accole forms, signet-ring forms
  • cytoplam - blue discs with red nucleus
  • 12-24 merozoites
285
Q

Describe RBC morphology of Plasmodium falciparum

A
  • Normal size
  • inclusions: Maurer dots
  • cytoplasm: minute rings, two chromatin dots, accole forms, gametes crescent shaped
  • 6-32merozoites
286
Q

Describe RBC morphology of Plasmodium malariae

A
  • normal size
  • inclusions: ziemann stippling
  • cytoplasm: one ring with one dot
  • 6-12 merozoites
287
Q

Describe RBC morphology of plasmodium ovale

A
  • enlarged RBC
  • inclusions: schuffner dots
  • cytoplasm: one ring form
  • 6-14 one ring form
288
Q

Describe plasmodium vivax

A
  • most predominant species worldwide
  • within the first few hours after symptoms start, infected erythrocytes will contain trophozoites
  • Giemsa stain
  • single nucleus divides repeatedly
  • exhibits various stages in the asexual life cycle and many gametocytes in blood
289
Q

Describe plasmodium falciparum

A
  • confined to the tropics and subtropics
  • advantages with group O
  • end may be pointed or rounded, elongated crease t or sausage shape
  • trophozoites and gametocyte are generally the only stages seen in peripheral blood
290
Q

Describe plasmodium malariae

A
  • occurs primarily in subtropical and temperate areas
  • all stages of development may be present on the peripheral blood smear
291
Q

Describe plasmodium ovale

A
  • widely distributed in tropical Africa and west African coast. Also has been reported in South America and Asia
  • all stages of development may be present on the peripheral blood smear.
292
Q

Describe Babesiosis

A
  • tick-born intraerythrocytic, protozoan parasite that can cause malaria-like symptoms and hemolytic anemia
  • resembles P. Falciparum
  • In humans, infections have been attributed to Babesia microti, derived from rodents
  • transmitted via blood transfusion
293
Q

Describe epidemiology of Babesiosis

A
  • humans are opportunistic hosts for Babesia when bitten by nymph or adult ticks.
  • Asplenic, elderly and immunocompromised patients are at greater risk for severe disease
  • found in North America, which includes northeastern and northwestern United States
  • particularity Long Island, New York, Nantucket, Martha’s Vineyard, MA
294
Q

What are the signs and symptoms of Babesiosis?

A
  • Fever
  • hemolytic anemia
  • hemoglobinuria
  • capillary blockage/microvascular stasis may occur as a result of RBC fragments
  • RBC destruction leads to hemolytic anemia
  • elicits a T and B cell response. T is primary
295
Q

Describe hematology of Babesiosis

A
  • most important test to confirm is viewing blood smear
  • wright and Giemsa stains
    -after staining, reveals the ring forms of Babesiosis
  • also may demonstrate merozoites arranged in a tetrad configuration that resembles Maltese cross.
  • other tests include CBC count and erythrocyte sedimentation rate (ESR, usually elevated)
296
Q

What should be looked for during a CBC count on patient suspected to have Babesiosis?

A
  • Howell-jolly bodies
  • leukopenia
  • lymphopenia
  • thrombocytopenia
297
Q

How are Malaria and Babesiosis differentiated from one another?

A
  • Babesiosis has absence of pigment hemozin
298
Q

What chemistry test should be ran for Babesiosis

A
  • serum protein electrophoresis
  • liver function tests to look for elevated ALT, elevated alkaline phosphate level hyperbilirubinemia, and decreased haptoglobin levels
299
Q

What are serology testing for Babesiosis?

A
  • IgM or IgG immune fluorescent assay
  • B. Microti titers
300
Q

Describe Leishmania

A
  • found primarily in the cells of the mononuclear phagocytic system and may at times be seen in the circulating blood in large mononuclear cells.
  • burst out of macrophages with characteristic nucleus and kinetoplast
301
Q

Describe Trypanosomatidae

A
  • include the hemoflagellates, contains two genera that parasitize humans
  • seen in circulating blood the cardiac muscle and CSF
302
Q

What is associated with a defect in nuclear maturation?

A

Megalocytes

303
Q

What is associated with decreased hemoglobin synthesis?

A

Microcytes

304
Q

What is the equivalent nomenclature for normal erytrhocyte ?

A

Discocyte

305
Q

What is the equivalent nomenclature for target cells?

A

Codocyte

306
Q

What is the equivalent nomenclature for sickle cells?

A

Drepanocyte

307
Q

What is the morphological description of schistocytes?

A
  • fragments of erythrocytes
308
Q

What is the morphological description of a spherocytes?

A
  • compact round shape
309
Q

What represents an imbalance between erythrocytic and plasma lipids?

A
  • acanthocytes
310
Q

What results from the gelation of polymerized deoxygenated Hb S?

A
  • sickle cells
311
Q

Where may microspherocytes may be seen?

A

HDN

312
Q

What is a specific term for a variation in the normal coloration of an erythrocyte?

A
  • polychromatophilia
313
Q

What does basophilic stippling represent?

A

Granules composed of ribosomes and RNA

314
Q

What does howell-jolly bodies represent?

A
  • DNA
315
Q

What does pappenheimer bodies represent?

A
  • aggregates of iron, mitochondria and ribosomes
316
Q

What does Heinz bodies represent?

A
  • precipitated denatured hemoglobin
317
Q

Babesiosis infection shares many of the same symptoms of what?

A

P. Falciparum

318
Q

Describe hemoglobinopathies

A
  • are inherited single-gene disorders that affect the amino acid residual sequence or production of normal hemoglobin
  • patient will demonstrate an alteration of hemoglobin distribution
  • encompasses a heterogenous group of disorders associated with genetic mutations in both the alpha-globin and beta-globin genes.
  • gene mutations in these genes produce qualitative protein changes; patient produces Hgb S, C, D, G, E, etc (instead of Hgb A, A2 or F)
319
Q

What do Mendelian genetics determine?

A
  • overall zygosity and quantity of Hgb produced
320
Q

Define disease

A
  • either the homozygous occurrence of the gene for the abnormality OR the possession of a heterozygous, dominant gene that produces a hemolytic condition
321
Q

Define trait

A
  • as the heterozygous and normally asymptomatic state
  • example: sickle cell anemia trait must be inherited from both parents
322
Q

What are the most common monogenic disease of men? Why?

A
  • SCD and B-thalassemia
  • they are found in the “malaria belt” that extends through the Mediterranean and sub-Saharan African through Southeast Asia and Southern China
  • These hemoglobin mutations occur at high incidences in these regions because heterozygous have have selective advantage against infection with P. Falciparum
323
Q

Describe the Etiology of hemoglobinpathies

A
  • estimated 7% of world population Carries a globin-gene
  • majority of the cases is inherited as an autosomal recessive trait. Disease associated with autosomal recessive genes need to be in the homozygous state to produce disease
  • some are caused by inheritance of an autosomal dominant gene that will produce hemolytic disease in its heterozygous state
  • may have hemolytic manifestations
  • 25% demonstrate decreased red cell survival due to red cell membrane deformity that characterizes hemolytic disease
324
Q

What is the common denominator for hemoglobinpathies?

A
  • inherited or genetic defects related to hemoglobin
325
Q

Abnormal erythrocytes including hemoglobinpathies and thalassemia are classified into 3 major group. What are these groups?

A
  • abnormal molecular structure
  • a defect in the rate of synthesis
  • disorders that are a combination of both
326
Q

Describe abnormal molecular structure

A
  • one of more of the polypeptide chains of globulin in the hemoglobin molecule, for example, sickle cell anemia
  • includes:
    —> Hb SS (SCD)
    —> Hb SA (sickle cell trait)
    —> Hb C (disease or trait)
327
Q

Describe a defect in the rate of synthesis

A
  • one or more particular polypeptide chains of globulin in the hemoglobin molecule
  • includes:
    —> beta and alpha thalassemia
328
Q

What is the composition of a normal adult hemoglobin?

A
  • Hb A —> 95-98%
  • Hb A2 —> 2-3%
  • Hb A1 —> 3-6%
  • Hb F —> <1%
329
Q

Describe Sickle Cell Disease

A
  • a general term for abnormalities of hemoglobin structure in which the sickle gene is inherited from at least one parent
  • ## characterized by the production of of Hb S, anemia and acute and chronic tissue damage secondary to the blockage of blood flow produced by abnormally shaped RBCs
330
Q

Describe Sickle cell anemia

A
  • the most common form of hemoglobinopathy
  • expression of inheritance of sickle gene from both parents.
331
Q

What do “other” sickle cell disorders result from?

A
  • from coinheritance of the sickle gene
  • common variants include Hb SC disease and Beta-thalassemia
332
Q

Describe etiology of sickle cell disease

A
  • sickle cell gene must be inherited from both parents in the sickle cell anemia
333
Q

How do Hb S and Hb A differ?

A
  • a single nucleotide change (GAT to GTT) that results in the substitution of valine got glutamic acid at the sixth position on the Beta chain of the hemoglobin molecule
334
Q

What does Hb S result in?

A
  • abnormalties in polymerization (or gelation), with deoxygenation that leads to sickling
  • the end results of the polymerization is a permanently altered membrane protein. Two-thirds of the RBCs are removed by extravascular mechanisms
335
Q

Describe the epidemiology of sickle cell

A
  • found mostly in persons of African ancestry, but it also affects persons of Mediterranean, Caribbean, South and Central American, Arab and East Indian ancestry
  • sickle cell carrier state confers a selective advantage of P. Falciparum malaria, because of preferential sickling of only the parasitized cells. The prevalence of the disease in some regions reflects this selective advantage or protective mechanism
336
Q

Describe pathophysiology of sickling

A
  • polymerization of Hb S occurs under conditions of extremely reduced oxygen and increased acidity in the blood
  • sickling is promoted by low oxygen tension, low pH, increased 2,3- diphosphoglycerate, high cellular concentration of hemoglobin, loss of cell water, Hb C and Hb O-Arab
  • sickling is retarded by Hb A, Hb F (at least 30%), Hb J, and alpha thalassemia
337
Q

When sickling occurs, what does it subsequently leads to?

A
  • increased MCHC in proportion to the number of moelcules in the deoxygenated state
  • deoxyhemoglobin S is less soluble than deoxyhemoglobin A or oxyhemoglobin S
338
Q

What is believed to cause a continuum of cellular changes?

A

Deoxygenation

339
Q

Describe Sickling of erythrocytes

A
  • first stage progresss from the formation of small amounts of polymer to larger amounts of highly ordered polymer as the result of severe and prolonged deoxygenation. This polymerization produces the resultant sickling
  • because cells that have large amounts of ordered polymer may be caught in capillaries and cause obstruction of vessel
  • this initiates a pattern of blood not flowing properly to the tissue and creating lack of oxygen.
  • lack of oxygen causes more sickling and more deprivation of oxygen to tissues. This can cause intense pain and tissue necrosis
  • decreased oxygen tension of the spleen makes it vulnerable to tissue necrosis after vasoocclusion . This causes splenic dysfunction and the presence of Howell-Jolly bodies in mature RBCs
340
Q

What occurs when sickled cells receive oxygen?

A
  • they return to their normal shape. Repeated cycles of sickling and unsickling lead to the RBCs becoming permanently damaged
  • this process ends in hemolysis, which leads to anemia
  • in addition, repeated episodes of this type lead to the necrosis of body tissues
341
Q

What is the ability to revert back to normal shape called?

A

Reversibility
- produces reversible sickles which are more boat shaped

342
Q

What happens to reversibility as sickle disorders progress?

A
  • diminished and production of irreversible sickles ensues.
  • this is sign of poorer prognosis for the patient as they become resistant to treatment.
343
Q

Describe morphology of irreversible sickles

A
  • serpentine-like
  • more slender with pronounced pointed ends
344
Q

Describe vasoocculation

A
  • the adherence of sickled erythrocytes to the vascular endothelium may contribute to painful vasoocculation
  • patients have increased susceptibility to opportunistic infections
345
Q

What are symptoms of vasoocclusive crisis

A
  • fever
  • acute pain
  • dehydration
  • cyanosis
  • extreme sensitivity to opportunistic infections
  • can lead to organ and tissue failure
346
Q

Describe acute vassooclusive crisis

A
  • caused by recurrent obstruction of the microcirculation by intravascular sickling
347
Q

What can years of sickling cause to the body?

A
  • can lead to organ or tissue failure
348
Q

What occur during both the sickle cell crisis and in the steady state?

A
  • significant activation of coagulation with consequent increase in fibrinolysis
349
Q

What are possible complications of severe SCD?

A
  • enlargement of the heart
  • progressive loss of pulmonary or renal function
  • stroke
  • arthritis
  • liver damage
  • other complications
350
Q

Describe SCD in children

A
  • splenic dysfunction is a life-threatening complication that develops during infancy
  • infant is vulnerable to to shock and infection from encapsulated bacteria due to the sickles getting trapped in the spleen
  • symptoms appear 6 months after birth
  • vasoocclusive disease develops between 1-6 years
  • development and growth delays
  • destruction of bone and joints with ischemia and infraction of the spongiosa
351
Q

Describe SCD in pregnancy

A
  • no increase disease manifestations
  • but there is an increase in maternal mortality of 20% and fetal mortality of 20%
352
Q

What are clinical manifestations in adults with SCD

A
  • SS homozygotes have severe HA with Hct values between 15-30%
  • RBCs with low Hb F have shortened life span
  • erythropoietic suppression is caused by: aplastic tissue or megaloblastic erythropoiesis
  • acute chest syndrome is a significant cause of death
  • higher blood viscosity that leads to complications
353
Q

What complications are caused by higher blood viscosity?

A
  • shoulder and hip abnormalities
  • mutliorgan dysfunction
  • pain
  • pigmented gallstones in 30-60% of adults
  • papillary necrosis
  • leg ulcers
354
Q

Describe pain of SCD

A
  • hallmark of the disease and most common complaint
  • vasoocclusive crises are predominantly what send patients to the hospital
  • high-dose methylprednisolone decreased pain duration in children
355
Q

Describe pulmonary complications of SCD

A
  • atelectasis and infiltrates
  • thoracic bone infarction is common in hospitalized SCD patients with acute chest pain
  • incentive spirometry can prevent atelectasis
356
Q

Describe strokes of SCD

A
  • 24% of patients have a stroke by 45 years of age
  • cerebral infarction in SCD is associated with an occlusive vasculopathy involving the distal intracranial segments of the internal carotid as well as the proximal middle and anterior cerebral arteries
  • blood transfusions decrease stroke rise by should be used with prudence due to:
    —> alloimmunization
    —> iron overload
    —> transfusion withdrawal
    -
357
Q

What Hgb types does SCD have?

A
  • C, E, and D, giving rise to SC, SE, and SD disease
358
Q

What are examples of disorders that are a combination of abnormal molecular structure and rate of synthesis?

A
  • Hb S-Hb C
  • Hb S-Beta thalassemia
359
Q

What is sickling?

A
  • Hb S is deoxygenated, it becomes polymerized and produces sickling
360
Q

What would be the laboratory findings of a patient with SDC?

A
  • in addition to decrease Hgb, Hct, and RBC cell count, persistent increase of WBC count of 12,000 to 15,000 x 10^9/L is common
  • Reticulocytoisis (8-12%)
  • increased MCV to levels up to 100 fL
  • elevated serum: unconjugated bilirubin and methemalbumin
  • descreased serum haptoglobin and hemopexin
  • increased serum lactate dehydrogenase (LDH)
  • Mildly increased aspirate transaminase (AST)
  • increased urine urobilinogen
361
Q

Describe RBC morphology of a patient with SCD

A
  • morphology on peripheral blood smear can include moderate to significant:
    —> anisocytosis
    —> poikilocytosis
    —> hypochromia
  • red cell abnormalities
    —> target cells
    —> microcytes
    —> polychromatophilia
    —> basophilic stippling
  • Howell-Jolly bodies may be present if hyposplenism is present
  • if patient is in acute crisis state, sickled red cells may be seen on peripheral smears
362
Q

What are special tests for SCD ?

A
  • thin later isoelectric focusing (IEF)
  • High pressure liquid chromatography (HPLC)
  • Globin DNA analysis (costly and limited in what it can identify)
363
Q

What does a definitive diagnosis of SCD include?

A
  • reassessment of the hemoglobin phenotype
  • measurement of hemoglobin concentration and red cell indices
  • inspection of red cell morphology
  • correlation with the clinical history
364
Q

What would be the results of a Hgb electrophoresis of a patient with SCD?

A
  • Hb S —> 80-95%
  • Hb F —> 0-20%
  • a normal amount of Hb A
365
Q

Describe high-pressure liquid chromatography of SCD

A
  • electrophoresis at acid and alkaline pH has been used for years
  • cation-exchange HPLC is emerging as method of choice of quantification of Hb A2 and Hb F and ID Hgb variants
366
Q

Describe DNA analysis of SCD

A
  • All cases of SCD can be diagnosed by direct DNA analysis by PCR
  • most cases of thalassemia can be diagnosed by direct analysis by PCR
367
Q

Describe prenatal diagnosis of SCD

A
  • important because of the high frequency of SCD
  • fetal diagnosis can be made by amniocentesis at about the 14th week of gestation
  • the current widespread use of chorionic villus biopsy allows DNA diagnosis to be performed at the 7th-10th week of gestation
368
Q

Describe Hgb of Normal term newborns

A
  • principle Hgb is Hb F
  • distribution is 80% of Hb F and 20% is beta-globin
  • During last trimester, there is a progressive increase in beta-globin synthesis and a decrease in y-chain synthesis
  • approximately 80% of the non-alpha globulin is y-globin and 20% is beta-globin
369
Q

Why must newborn diagnosis of SCD by prompt?

A
  • the initiation of prophylactic antibiotics and pneumococcal conjugate vaccination by 2 months of age, children with sick cell anemia are vulnerable to life threatening pneumococcal infections
370
Q

Describe Screening of newborns for sickle cell anemia

A
  • screenings will ID approximately 50 sickle cell carriers for every infant diagnosed
  • confirmatory tests should occur no later than 2 months of age
  • blood collection on first day does not pose a threat to
  • sample is collected onto a filter paper from a heelstick. Remains stable for at least 1 weeks at room temperature. Extremely premature infants may have false positive
  • most state based screening programs use either thin-layer IEF or HPLC as initial screenings on capillariy blood collected from heelstick and absorbed onto a filter paper
371
Q

Describe infant with SCD laboratory findings

A
  • infant with sickle cell traits (SA) has both normal beta genes and a beta S gene
  • will have predominance of Hb F and both Hb A and Hb S.
  • There will always be more Hb A than Hb S in these infants because alpha chain preferentially pair with normal beta chains
372
Q

What does the management of SCD consist of?

A
  • monitoring the severity of the anemia and transfusing blood only when necessary
  • treating acute and chronic pain according to a rational guideline
  • diagnosing organ failure and administering appropriate therapy; over time, recurrent vasoocclusion and its associated vascuopathy result in significant progressive Organ failure
373
Q

What does treatment consists of in SCD?

A
  • bone marrow transplant offer the only potential cure for sickle cell anemia
  • general suppurative care includes daily oral folate supplementation, antibiotic prophylaxis in childhood, pneumovax, haemophilus influenza vaccine, meningococcal vaccine, a yearly flu shot, a yearly eye examination, prompt treatment of infections, and avoidance of dehydration
374
Q

What are examples of experimental testing of SCD?

A
  • gene therapy
  • butyric acid
  • clotrimazole
  • nitric oxide
  • Nicosan
375
Q

Describe gene therapy of experimental testing for SCD

A
  • inserting a normal gene or turning off the defective gene in SCD patients
376
Q

Describe Butyric acid experimental testing of SCD

A
  • food additive that may increase Hb F
377
Q

Describe clotrimazole experimental testing of SCD

A

Over the counter anti fungal medication that helps prevent water loss and mitigate sickle formation

378
Q

Describe nitric oxide experimental testing of SCD

A
  • inhibits vasoconstriction of the blood vessels to prevent vascoocclusive crises
379
Q

Describe Nicosan experimental testing of SCD

A
  • herbal treatment in early trials that prevents sickle crises; originally used in Nigeria, West Africa
380
Q

What is a priority of infectious diseases?

A
  • prevention
381
Q

What are some vaccinations for infectious disease?

A
  • pneuomococcal
  • influenza A
  • H. Influenzae
382
Q

Why is a splenectomy recommended in infectious diseases?

A
  • to minimize splenic sequestration and autosplenectomy
383
Q

What are major indications for blood transfusions?

A
  • improve oxygen-carrying capacity and transport
  • dilute circulating sickle cells to microvascular perfusion
384
Q

When should blood transfusions be considered?

A
  • Hb less than 5 g/dL with significant signs of anemia and hypoplasia
  • Angina or high-output failure
  • acute hemorrhage
  • acute CNS complications
  • acute chest syndrome with hypoxia
  • sequestration crisis
  • preoperative preparation
385
Q

What is screening newborns infants important for?

A

Disease control

386
Q

Describe drug therapy of SCD

A
  • Hydroxyurea, a ribonucleotide reductase inhibitor, stimulates the production of Hb F but suppresses bone marrow production
  • Fetal hemoglobin is a potent inhibitor of the polymerization of deoxyhemoglobin S
387
Q

What can Novel therapies do?

A
  • increase the production of Hb F
  • improve RBC hydration
  • increase the availability of of the nitric oxide
  • possess anti-inflammatory effects
388
Q

What are examples of novel therapies?

A
  • nitric oxide
  • anti-inflammatory agents, such as statins
  • anticoagulants and antiplatelet agents
389
Q

Describe prevention of SCD

A
  • genetic counseling may be useful in the prevention of sickle cell anemia
  • when the parents are both Hb SA (Carriers), antenatal diagnosis can be performed during the 18th to 20th weeks of pregnancy by analyzing DNA from amniotic fluid
  • experimental therapy includes induction of Hb F b the short-chain fatty acids (FA) and membrane-active drugs
    —> short chain FA appear to modulate gene expression directly by interacting with transcriptionally active elements of the genes
390
Q

Describe SS genotype

A
  • % of Hb S —> 80-98%
  • % of non-S Hb —> 2-15%(fetal)
  • clinical severity: 3-4
  • 10-20% reticulocytosis
  • rare splenomegaly
391
Q

Describe S beta-thalassemia

A
  • % Hb S —> 60-90%
  • % non-S Hb —> 10-30%
  • clinical severity: 1-3
  • splenomegaly
  • microcytosis
  • 4+ target cells
392
Q

Describe SC genotype

A
  • % Hb S —> 50%
  • % non- S Hb —> 50% (Hgb C)
  • clinical severity: 1-3
  • splenomegaly
  • 4+ target cells
393
Q

Describe AS sickle trait genotype

A
  • % Hb S —> 30-40%
  • % non-S Hb —> 60-70% (Hgb A)
  • clinical severity: 0
  • normal morphology
  • no splenomegaly
394
Q

Describe sickle Beta-thalassemia

A
  • inheritance of the sickle gene from one parent and Beta thalassemia from the other parent
    -can be diagnosed by examining the blood film and through hemoglobin electrophoresis
  • blood film reveals hypochromic, microcytic red cells with polychromatophilia, target cells, stippling and rarely sickled cells
  • electrophoresis reveals that 60-90% is Hb S and 10-30% is Hb F
  • spleen remains functional but retinopathy is more common
395
Q

Describe Sickle-C Disease

A
  • patient have only Hb S and C with an absence on Hb A and normal or increased levels of Hb F.
  • 50% of cells are target cells on blood smear
  • spleen remains functional
  • experience mild to moderate hemolytic anemia and usually have splenomegaly
396
Q

What are the two reason that Hb SC is a disease and Hb AS is benign?

A
  1. In SC RBC, the intracellular hemoglobin concentration is significantly elevated because of the presence of Hb C
  2. SC RBC have atleast a 10% higher level of Hb S than do SA red cells.
397
Q

What are complications of SC disease

A
  • retinopathy
  • hematuria from medically infarcts
  • aseptic necrosis of the femoral head
398
Q

Describe Sickle cell trait (AS)

A
  • approximately 8% of Black Americans are heterozygous for Hb S
  • provides a survival advantage over individuals with normal hemoglobin on regions where malaria, P. Falciparum, is endemic
  • sickling crises very rare
  • electrophoresis of whole blood reveals that 35-45% of hemoglobin in patients with sickle cell trait is Hb S
399
Q

What are signs and symptoms of sickle cell trait?

A
  • hematuria
  • splenic infarction At high altitudes
  • hyposthenuria
  • bacteriuria
  • pyelonephritis in pregnancy
400
Q

Describe demographics of thalassemia

A
  • growing global health problem
  • Hb E-Beta thalassemia and Hb H disease account for much of the projected increases in thalassemia
  • Hb E-Beta thalassemia is one of the most frequent hemoglobinopathies
  • Hb E is 60% of the population in Southeast Asia
  • Prevalence is growing rapidly along the coastal regions of North America
  • Alpha Thalassemia, often considered benign, is now recognized to be more severe than originally reported
401
Q

What causes thalassemia?

A
  • by an abnormality in the rate of synthesis of the globin chains. This is in contrast to an inherited structural defect in one of the globin chains that produces hemoglobin with abnormal physical or functional characteristics
402
Q

Describe inheritance of thalassemia

A
  • autosomal
  • whether it is autosomal dominant or recessive is questionable because heterozygotes are not always symptomatic
403
Q

What are the mutations that affect gene structure and function implicated in thalassemia?

A
  • Nonsense mutation leading to early termination of the globin chain
  • mutation in one of the noncoding intervening sequences of the original globin chain gene, which causes inefficient splicing to mRNA
  • mutation in the promoter area that decreases the rate of gene expression
  • mutation at the termination of the gene that leads to lengthening of the globin chain with additional amino acids rendering the mRNA unstable
  • total or partial depletion of a globin gene, probably due to unequal chromosomes crossing over
404
Q

Describe the pathophysiology of thalassemia

A
  • characterized by the absence or decrease in the synthesis of one of the two constituent globin subunits of a normal hemoglobin molecule
  • ## can be classified as alpha r beta depending on the affected subunits
405
Q

What does Mendelian genetics determine in thalassemia?

A
  • zygosity
  • quantity of Hgb produced
406
Q

Describe Alpha thalassemia

A
  • have higher severity than beta thalassemia since alpha chains comprise all normal hemoglobin fractions
  • decreased synthesis of alpha globin in accelerated red cell destruction because of the formation of insoluble Hb H inclusions in the mature erythrocyte
407
Q

Describe Beta thalassemia

A
  • one of the most common single-gene disorders
  • overall quantity of A1 is diminished, which is compensated by an increase in gamma and delta chain production
  • the more severe beta thalassemia reflects the extreme insolubility of alpha globin, which is present in excess in the red cells because of decreased B-globin synthesis
  • 200+ point mutations in/around Beta-globin gene are known to cause unstable alpha-globin chains —> ineffective erythropoiesis now appears to be caused by accelerated apoptosis
  • rarely by deletion
408
Q

What does studies of RNA metabolism in erythroid cells suggest?

A
  • that many patients with alpha thalassemia have a defect in RNA processing. This defect affects efficient RNA splicing during protein globin synthesis
409
Q

What would be the laboratory findings of Beta thalassemia?

A
  • decreased Hgb, Hct abd red cell count
  • Hgb concentration can be as low as 2-3 g/dL in homozygous patients
  • red cell indices are significantly reduced
  • RDW is increased because of anisocytosis
  • increased reticulocytes formation 5-10%
  • decreased osmotic fragility
  • moderately increased bilirubin
  • increased serum iron
  • saturated total iron-binding capacity (TIBC)
410
Q

What would the peripheral blood smear reveal with a patient suspected of having Beta thalassemia?

A
  • anisocytosis
  • poikilocytosis
  • microcytic (significantly)
  • hypochromic (significantly)
  • target cells
  • polychromatophilia
  • few to many nucleated red cells
411
Q

What does Hgb electrophoresis reveal with a patient with Beta thalassemia?

A
  • increased Hb F and decreased Hb A
412
Q

What does a variable form of homozygous alpha thalassemia demonstrate?

A
  • no Hb A
  • increased Hb A
  • decreased Hb F
  • the absence of Hb A is owing to the absence of Beta-chain synthesis
413
Q

Describe heterozygous Beta thalassemia laboratory findings

A
  • could be mistake for a mild iron deficiency anemia on a peripheral blood smear
  • decreased MCV
  • increaesed Hb A2 on electrophoresis
  • decreased osmotic fragility
414
Q

Describe prenatal diagnosis of Beta thalassemia

A
  • ideally is conducted in the first trimester of pregnancy using chorionic villus tissue for DNA analysis by PCR to detect point mutations or deletions
  • later, second trimester fetal blood analysis is done to estimate relative rates of synthesis of globin chains of hemoglobin. This is performed to estimate relative rates of synthesis of globin in mid-trimester fetuses and base the diagnosis on the beta-to-alpha (B/a) biosynthetic ratio
415
Q

Describe newborn screening of Beta thalassemia

A
  • most newborn screening programs employ HPLC or IET as the preferred first-line technique to make a presumptive diagnosis of a clinically significant hemoglobinopathy
  • if an abnormal is identified, ethnicity information and parental studies are helpful in guiding the sequence of diagnostic tests for specific hemoglobinopathies
416
Q

Describe treatment of Beta thalassemia

A
  • severe anemia requires blood transfusion
  • bone marrow or PSC transplant
  • frequent transfusion cause iron overload
    —> address with iron chelators (3)
417
Q

What are the 3 iron chelators of beta thalassemia treatment?

A
  1. Deferiprone
  2. Deferoxamine
  3. Deferastox (newest)
  • combined use of deferiprone and deferoxamine are effective at improving cardiac function and patient QoL.
418
Q

Describe prevention of Beta thalassemia

A
  • careful counseling
  • prenatal diagnosis in Sardinia reduced incidence of homozygous Beta thalassemia by more than 90%
419
Q

What is the major cause of alpha thalassemia?

A
  • deletion that removes one or both alpha-globin genes from the affected chromosome 16
420
Q

What factors determine how alpha thalassemia is classified?

A
  • basis of genotype and the total number of abnormal genes that result
421
Q

What are the 4 types of alpha thalassemia?

A
  • silent carrier state (one inactive/deleted alpha gene)
  • alpha thalassemia trait (two inactive/deleted alpha genes)
  • Hb H disease (three inactive/deleted alpha genes)
  • alpha thalassemia major; Hydrops fetal is with Hb Bart (four inactive/deleted alpha genes)
422
Q

Describe Hgb C disease

A
  • this hemoglobinopathy is prevalent in the same geographic area as Hb S (sickle cell) disease
  • Hb C differs from Hb A by the substitution of a single amino acid residual lysine, for glutamic acid in the 6th position from the amino (NH2) terminal end of the Beta chain. This is the exact point of substitution of Hb S; however, the amino acid is different
  • normally NC/NC
  • 50% target cells on peripheral blood smear
  • mild, chronic hemolytic anemia with associated splenomegaly
423
Q

Describe Hgb SC disease

A
  • results from the inheritance of one gene for Hb S from one parent and one gene for Hb C from the other parent.
  • the course of this disease is generally milder than SCD, although Hb C tends to aggregate and potentiate the sickling of Hb S
  • symptoms similar to mild sickle cell anemia
424
Q

What does the peripheral blood smear of Hgb SC disease reveal?

A
  • target cells
  • folded erythrocytes
  • intracellular crystal
425
Q

Describe Hgb D disease

A
  • Hb D has several variants
  • patients who are homozygous or heterozygous are asymptomatic
  • some target cells may be seen on the examination of peripheral blood smear
  • Hb D migrate to same position as Hb S and Hb G at alkaline pH
  • migrate to same position as Hb A at acid pH
426
Q

Describe Hgb E Disease

A
  • occurs with the greatest frequency in Southeast Asia
  • Hb E/Beta thalassemia is worldwide clinical problem
  • In Thailand, frequency is 50%
  • appear in both homozygous and heterozygous forms and as compound heterozygotes in combination with alpha, beta thalassemias, and other structural variants
  • results from substitution of lysine for glutamic acid in the beta chain of hemoglobin
  • clinical presentation is diverse. Can range from entirely asymptomatic to mildly to severely anemic
427
Q

Describe Hb H disease

A
  • mild to severe chronic hemolytic anemia
  • most frequently results from an absence of three of the four alpha-globin genes
  • primarily affects individuals throughout Asia, the Mediterranean islands, and parts of the Middle East
  • because of the large influx of immigrant from SouthEast Asia in the past 20-30 years, Hb H has increased significantly
  • Hb H migrates at a fast rate at alkaline pH during Hgb electrophoresis
428
Q

Describe methemoglobinemia

A
  • methemoglobinemia is a disorder associated with elevated methemoglobin levels in the circulating blood
  • causes of methemoglobinemia include acquired toxic substances, Hb M variants, and NADH-methemoglobin reductase (also called diaphorase) deficiency
  • Hb M has five variant forms. It displays a dominant inheritance resulting from a single substitution of an amino acid in the globin chain that stabilizes iron in the ferric form. NADH-disphorase is the enzyme that reduces cytochrome b5 which converts naturally occurring ferric iron back to the ferrous state
429
Q

Describe unstable Hgb

A
  • hemoglobin variants in which amino acid substitutions or deletions weaken the binding forces that maintain the internal portion of the globin chains of the Hgb molecule
  • ## most are inherited as autosomal dominant disorders
430
Q

What does instability cause abnormal Hgb to do?

A
  • denature and precipitate in erythrocytes such as Heinz’s bodies of an oxidizing drug or an infection.
  • Heinz bodies are associated with alpha or beta chain abnormalities. Tetramer of normal chains, such as Hb Bart and Hb H, appear in thalassemias
431
Q

Describe hereditary persistence of Fetal Hemoglobin (HPFH)

A
  • retention of Hb F into adult life is abnormal
  • it is a benign condition in which significant Hb F production continues well into adulthood, disregarding the normal shutoff point after which only adult-type hemoglobin should be produced
  • the level of expression is 15-30% of total hemoglobin
432
Q

What are the two distinct alpha thalassemia syndromes caused by acquired mutations of alpha globin gene?

A
  • Hb H disease associated with myeloproliferative or myelodysplastic disorders
  • Hb H disease associated with mental retardation
433
Q

Describe hydrops fetalis with Hb Bart

A
  • incompatible with life
  • affected fetuses die either in utero or shortly after birth
434
Q

Describe Hb C trait

A
  • no symptoms
  • laboratory findings include target cells and possibly mild hypochromia
435
Q

Describe laboratory findings of Hb H Disease

A
  • Hb H migrates as a fast rate at alkaline pH during Hgb electrophoresis
  • results similar to iron deficiency anemia, except RBC count and RDW are usually greater and the MCV is lower.
  • retic count is 5-10% but may be within normal range
  • Serum ferritin can be normal or elevated
436
Q

What does a peripheral blood smear reveal of Hb H disease?

A
  • target cells
  • ansiocytosis
  • poikilocytosis
  • polychromasia than in patients with iron deficiency
437
Q

What does a peripheral blood smear reveal of Thalassemia minor (trait)

A
  • mild anemia
  • microcytosis
  • abnormal RBC morphology
  • splenomegaly
438
Q

What does thalassemia intermedia laboratory findings reveal?

A
  • moderate anemia
  • ineffective erythropoiesis
  • microcytosis
  • abnormal erythrocytes morphology
  • splenomegaly
  • iron overload
  • not transfusion dependent
439
Q

What are the laboratory findings of Thalassemia major?

A
  • also called Cooleys anemia
  • severe anemia caused by ineffective erythropoiesis
  • transfusion dependent
  • organ damage (heart and liver) secondary to iron overload
  • extramedullary erythropoiesis
  • hepatosplenomegaly
440
Q

In the hemoglobinpathies, what is a trait described as?

A
  • heterozygous and asymptomatic
441
Q

What is sickle cell disease caused by?

A
  • a change of a single nucleotide (GAT to GTT)
  • the substitution of valine for glutamic acid at the sixth position on the beta chain of the Hgb molecule
442
Q

What is the most monogenetic disease of man?

A
  • sickle cell disease
443
Q

If the patient with sickle cell disease is in an acute crisis state, peripheral blood smears may exhibits what?

A
  • drepanocytes
444
Q

What factors contribute to the sickling of erythrocytes in a sickle cell disease crisis?

A
  • extremely reduced oxygen
  • increased acidity in the blood
445
Q

What do homozygous Beta thalassemia patients have?

A
  • severe transfusion-dependent anemia
446
Q

What is the primary risk to thalassemia major patients who receive frequent and multiple blood transfusions?

A

Iron overload

447
Q

How does the peripheral blood smear typically appear for alpha thalassemia?

A
  • NC/NC
448
Q

What is the characteristic Hgb concentration in a patients silent state with heterozygous Beta thalassemia?

A

Hb A levels normal

449
Q

What does deoxyhemoglobin C have?

A
  • decreased solubility
  • the ability to form intracellular crystals
450
Q

What are the most unstable Hgbs?

A
  • inherited autosomal dominant disorders
  • results from Amino acid substitutions or deletions
  • are hemoglobin variants
451
Q

What is the correct molecular composition of hemoglobin?

A
  • four heme groups
  • two alpha globin chains
  • two beta globin chains
452
Q

What is the result of a molecule of hemoglobin when it gains the first two oxygen molecules?

A

Expels 2,3-DPG

453
Q

What is the na,e of the inclusion that is the result of denaturation of hemoglobin?

A
  • Heinz bodies
454
Q

What is the name of the inclusion that is made up of DNA nuclear remnants?

A

Howell-Jolly bodies

455
Q

What are the name of the granules precipitated during the staining that are ribosomes and RNA?

A

Basophilic stippling

456
Q

What are the 3 major laboratory tests for Hgb analysis?

A
  • electrophoresis
  • solubility testing
  • denaturation of hemoglobin (acid or alkaline)
457
Q

What is the Hgb range for men and women?

A

Women - 12-16 mg/dL
Men- 14-18 mg/dL

MLT Hematology (7 decks)

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