Quiz 1 – Red Cell Indices

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By William Aird

Abbreviations:

Hb – hemoglobin

Hct – hematocrit

MCH – mean corpuscular hemoglobin

MCHC – mean corpuscular hemoglobin concentration

MCV – mean cell colume

RBC – red blood cell count

RDW – red blood cell distribution width

RDW-CV – RDW coefficient of variation

RDW-SD – RDW standard deviation

Note: The terms MCV, MCH and MCHC are all mean values and by definition apply to populations of red cells. To simplify matters, we use the term more loosely to include descriptions of single cells. For example, we may refer to a large red cell as one with a high MCV, or a cell with increased central pallor as one with a low MCHC.

Question 1

Which conditions are associated with microcytosis?

a
Iron deficiency anemia
b
Hypothyroidism
Anemia caused by hypothyroidism is usually normocytic, and less often macrocytic.
c
Sideroblastic anemia
Some types of sideroblastic anemia cause microcytosis, others cause macrocytosis.
d
Thalassemia

Question 2

Which conditions are associated with macrocytosis without anemia?

a
Iron deficiency anemia
Iron deficiency anemia is by definition an anemia. The MCV is typically low.
b
Pernicious anemia
Pernicious anemia, as the name applies, is associated with a reduced Hb.
c
Alcohol abuse
Alcohol abuse may cause leukopenia and thrombocytopenia, but rarely anemia. By contrast, alcohol is a common cause of macrocytosis.1
d
Hydroxyurea
Hydroxyurea is one of several drugs that can cause macrocytosis in the absence of anemia. Others include nucleoside reverse transcriptase inhibitors (for example, AZT), tyrosine kinase inhibitors such as imatinib or sunitinib, and methotrexate.

First report of hydroxyurea-associated macrocytosis was in the dermatology literature

Question 3

Which RBC parameter is evolutionarily conserved across species?

a
Hct
Animals have evolved to optimize oxygen delivery to the tissues, and that is virtually the sole function of red blood cells. Oxygen delivery is a function of cardiac output (which correlates inversely with blood viscosity and therefore Hct) and oxygen content of the blood (which correlates positively with Hb). Thus, evolution has selected for an optimal Hb/Hct whereby the benefits of Hb on oxygen carrying capacity of blood outweigh the costs of Hct on blood viscosity. Whether a species achieves optimal Hb/Hct using lots of small cells or fewer large cells does not seem to matter.
b
MCV
Some mammals have a low MCV and high red blood cell count, others have a higher MCV and lower RBC count. In all cases, the Hct (=MCV x RBC count) is around 40-45%.
c
RBC count
Some mammals have a low MCV and high red count, others have a higher MCV and lower RBC count. In all cases, the Hct (=MCV x RBC count) is around 40-45%.
d
MCH
The MCH correlates with the MCV. The MCH is also be influenced by the MCHC, but the latter value is conserved across species (32-36 g/dL).

Spun hematocrits

The mouse deer has the lowest recorded MCV of all mammalian species, while the anteater has the highest MCV among terrestrial mammals. Note that they adjust their red cell count so that they reach an optimal Hct of about 45%.

Question 4

What is MCV defined as?

a
Hct x RBC count
b
MCH x RDW
c
Hct/RBC count
Correct. Hct = MCV x RBC count, so MCV = Hct/RBC count.
d
MCH x RBC count

Remember:

Question 5

What does anisocytosis mean?

a
Large red cells
b
Variation in cell shape
c
Low RDW
d
Variation in red cell size
As assessed on a peripheral smear or as measured with an automated counter (red cell distribution width, RDW)

Question 6

Which of the following red cell indices is/are expressed as a concentration?

a
Hematocrit (Hct)
Expressed as a percentage.
b
Hemoglobin (Hb)
Correct. Hb is expressed in g/dL or g/L.
c
RDW
RDW-CV is expressed as a percentage. RDW-SD is expressed as a volume (fL).
d
MCH
MCH is expressed as a weight (grams).
e
MCHC
Correct. MCHC, like Hb, is expressed in g/dL or g/L. The difference is that Hb captures the concentration of Hb in whole blood, whereas MCHC measures concentration of Hb in the volume of blood consisting of red cells.

Question 7

Which of the following red cell indices are expressed as a weight?

a
Hematocrit (Hct)
b
Hemoglobin (Hb)
c
RDW
d
MCH
e
MCHC

Question 8

How would you describe the red cell on the right (schematic of a normal red cell is shown on the left)?

a
Macrocytic
b
Microcytic hypochromic
Right. The cell is smaller than normal (microcytic) and paler than normal (the ratio of central pallor to red cell diameters is increased) and is thus hypochromic.
c
Microcytic hyperchromic
d
Normocytic hypochromic

Question 9

What method(s) are used to measure/calculate the Hct?

a
Microcentrifuge
The Hct may be directly measured by spinning blood in a small centrifuge. This causes red cells to settle on the bottom and plasma on the top. The relative heights of the red cell and red cell + plasma columns = Hct (see next slide for additional explanation).
b
MCV x MCHC
c
MCV x RBC count
The MCV and RBC count are measured in automated counters and the values are used to calculate the Hct.
d
RDW/Hct

Spun Hct

Blood is drawn into a capillary tube.
The blood-filled tube is placed into a table-top centrifuge.
The centrifuge is run for a prescribed period of time.
The spun tube in which plasma is now separated from red cells is removed from the centrifuge.
Measurements are made of the height of the RBC layer and the height of the RBC + plasma layer. The relative height is the Hct (in this case, 60%)

Question 10

What is happening to the mean cell hemoglobin (MCH) moving left to right (assume a constant central pallor or MCHC)?

a
Decreases
b
Stays the same
c
Increases
That’s correct. The MCH is the weight of the RBC in Hb. In the schematic, think of the MCH as the total amount of red color inside the RBC. The bigger the cell, the more red color, the higher the MCH.

Question 10

MCH tracks with the MCV

Question 11

What is happening to the mean cell hemoglobin (MCH) in this series of red cells (moving left to right)? Note that the red cell volume is the same in all cells.

a
Decreasing
b
Staying the same
c
Increasing
Correct. So, not only does a higher red cell volume lead to increase MCH, but do too does increased MCHC.

Question 11

MCH also tracks with the MCHC

Question 12

What are two ways of calculating the RDW?

a
RDW-CV
Correct. RDW-CV is the RDW-coefficient of variation and is expressed as a percentage.
b
RDW-HT
c
RDW-SD
Correct. RDW-SD is the RDW-standard deviation and is expressed as a volume (fL).

Question 12 (cont’d)

The RDW-CV measures size dispersion by means of a ratio formula of 1 standard deviation to the MCV, and is expressed as a percentage of the MCV (reference range of 11% to 16%)

The RDW-SD is the arithmetic width of the distribution curve measured at the 20% frequency level and is expressed as standard deviation in femtoliters (fL) (reference range 39-46 fL)

Question 13

What happens to the RDW-CV when the MCV is low?

a
Increases
Right. And conversely when the MCV is elevated, the RDW-CV is decreased. That is because MCV is in the denominator of the formula used to calculate RDW-CV.
b
Doesn’t change
c
Decreases

Question 13 (cont’d)

Because the RDW-SD is not influenced by the MCV, it is considered by some to be the superior method for measuring the RDW.

Question 14

Which of the following may explain a normal MCV in iron deficiency anemia (IDA)?

a
Pernicious anemia and IDA
Correct. The smaller-than-normal red cells (microcytes) in IDA and the larger-than-normal red cells (macrocytes) in pernicious anemia may ‘cancel’ each other out, leading to a normal MCV.
b
IDA in patient with cirrhosis
Correct. The smaller-than-normal red cells (microcytes) in IDA and the larger-than-normal red cells (macrocytes) in cirrhosis may ‘cancel’ each other out, leading to a normal MCV.
c
IDA treated with multiple transfusions
Correct. If the patient with severe IDA receives enough transfused red cells, the MCV may approach that of the donor cells, reaching a low-normal value.
d
IDA treated with high doses of folic acid
Folic acid will not reverse the low MCV in IDA.

Question 15

Does a normal MCV rule out iron deficiency anemia (IDA)?

a
NO
Correct. As we saw in the previous question, some patients may have combined IDA and macrocytic anemia, leading to a normal MCV. In other cases, isolated IDA is not associated with a low MCV, especially in the early stages of the condition.
b
YES
Don’t rule out IDA on account of a normal MCV!

Question 16

What conditions may be associated with iron deficiency without the presence of anemia?

a
Polycythemia vera (PV)
Correct. Patients with PV may present with an elevated hemoglobin and iron deficiency. A clue is the presence of a low MCV. Iron supplementation in these patients may lead to a further increase in Hct and symptoms of hyperviscosity.
b
Iron depletion
Correct. There are several stages in iron deficiency. The first is depletion of iron stores, primarily from macrophages in the bone marrow, spleen and liver. During this stage, the red cells manage to “hang on by skin of their teeth”, with red cell precursors in the bone marrow gobbling up every last morsel of iron. Only after stores are depleted does the Hb begin to fall and anemia set in.
c
Thalassemia minor
Thalassemia is not a cause of iron deficiency. It can sometimes be confused with iron deficiency because the MCV is low.

Stage 1 – iron depletion

  • Storage iron depleted (primarily macrophages)
  • Only remaining iron is in the transport and functional (e.g. Hb) pools
  • Serum ferritin (marker of iron stores) low

Stage 2 – Iron deficient erythropoiesis

  • Reduction of transport iron
  • Decreased serum iron
  • Increased total iron binding capacity (TIBC) to maximize iron transport to red cells
  • Increased expression of transferrin receptor on RBC membrane to promote iron uptake

Stage 3 – Iron deficiency anemia

  • RBCs are no longer able to compensate, and production falls

Question 17

Describe the CBC (answer on next slide)

WBCHbHctMCVMCHCRDW-SDPLT
5.617.854703352440

Question 17 (cont’d)

Description of CBC: Leukocytosis, polycythemia, microcytosis, elevated RDW and thrombocytosis

This was a patient with polycythemia vera who presented, as many do, with iron deficiency (presumably from slow GI blood loss and increased iron requirements for erythropoiesis)

Question 18

What is the Mentzer index (one of many indices used to distinguish between iron deficiency anemia and thalassemia minor) (see NOTES page for other)?

a
RDW/RBC
b
MCV/RBC
Correct. The Mentzer index captures the fact that while red cells are small in both iron deficiency anemia and thalassemia minor, erythropoiesis is not impaired in thalassemia as it is in iron deficiency. Thus for a given MCV, the patient with thalassemia makes more red cells to compensate and reach near normal Hb/Hct.
c
MCH/RBC
d
RBC count
e
Platelet count

Discriminatory formulas for distinguishing thalassemia from iron deficiency in patients with microcytic anemia (the Mentzer index is third from the top)

From Clin Chem Lab Med 1017;55:1582

Question 19

What are the 2 ways to lower the MCH?

a
Decrease the RDW
b
Decrease the MCV
Yes, and this is why MCH has been used a surrogate marker for red cell volume.
c
Decrease the MCHC
Correct, and this is an argument against the use of MCH as a surrogate marker for the MCV.

Question 20

Which parameters correlate with MCHC?

a
Central pallor on a peripheral smear
On peripheral blood smears, the central pallor of red cells (or more precisely, the diameter of the central pallor relative to the diameter of the cell) correlates with the MCHC.
b
RBC size
The size or volume of red cells (without consideration of the hemoglobin content) is not related to the MCHC. Small red cells can have low, normal or high MCHC, and the same is true for normal and large cells.
c
RBC weight in Hb
This refers to the MCH. It is true that for a given cell volume, an increase in MCHC will increase the MCH, but the MCH can vary without any change in the MCHC. In theory you could have a red cell as large as planet earth with an astronomically high MCH but a normal MCHC.

Question 22

What is a red cell with reduced MCHC called?

a
Hyperchromic red cell
Also known as a spherocyte
b
Microcytic red cell
This refers to a smaller-than-normal cell, or a cell with a low MCV.
c
Hypochromic red cell
Correct. A hypochromic red cell is one with a low MCHC. On a peripheral smear it has larger fractional area of central pallor.

Question 23

Fill in the parameters: Normal, increased or decreased (answer on next page)

Question 23 (cont’d)

Fill in the parameters: Normal, increased or decreased (answer on next page)

Question 24

How would you describe these results (see next slide for answer)?

WBCHbHctMCVMCHCRDW-SDPLT
6.113.340843344384
Parameter Value Normal value
Iron4230-160 ug/dL
Total iron binding capacity417260-470 ug/dL
Ferritin1213-150 ng/ml
a
Pernicious anemia
b
Iron deficiency anemia
c
Hereditary hemochromatosis
d
Iron deficiency
Correct. These results show that Iron stores are depleted but not yet to the point where erythropoiesis is affected.

Question 25

What are spurious causes of macrocytosis?

a
Cold agglutinins
Cold agglutinins may result in spurious increase in MCV as RBC doublets pass through the aperture in the automated counter and get counted as one cell, resulting in falsely high MCV (and falsely low RBC count).
b
Hyperglycemia
When a CBC is performed a small amount of patient blood is added to isotonic diluent; it gets diluted thousands-fold. In the diluent, the RBC, which were adapted to a hyperosmolar environment in the patient’s bloodstream, are suddenly exposed to an isotonic solution, which they experience as hypotonic. As a result, water moves into the RBC, causing cell swelling and macrocytosis.
c
Hyponatremia
For the same reason hyperglycemia is associated with macrocytosis, so too is hypernatremia . Hyponatremia has the opposite effect of causing red cell shrinkage when the cells are processed for CBC.
d
Marked leukocytosis
White blood cells (WBC) and RBCs are counted in the same channel of an automated counter so that the MCV is actually the mean of both WBC and RBC volumes. Normally, RBCs vastly outnumber WBCs, so the latter have little effect on the MCV. However, in situations related to high WBC counts (especially when > 100 x 109/L, and low RBC counts (for example leukemias), the MCV may be increased by up to 15-20 fL.2

Question 25

What are the three most common causes of microcytosis?

a
Anemia of inflammation
Most cases of anemia of inflammation are normocytic. About 20% are microcytic. Anemia of inflammation is a less common cause of microcytosis than iron deficiency or thalassemia.
b
Fragmentation syndrome
This is rare cause of microcytosis caused by fragmentation of normal sized red cells into smaller pieces (schistocytes). It may be seen in patients with severe thrombotic thrombocytopenic purpura.
c
Thalassemia trait
d
Iron deficiency
e
Lead poisoning
A rare cause of microcytosis, typically seen in children.

Question 26

What is the prevalnce of macrocytosis in the genral population?

a
10-15%
b
45-50%
c
>1%
d
3-5%

Question 27

What happens to the mean cell volume of red cells as people age?

a
Decreases
b
Stays the same
c
Increases
One study showed a 4 fL difference in MCV between ages <18 and >85 years.3

Question 28

Does alcohol intake cause macrocytosis independent of liver disease?

a
Yes
In fact, alcohol is one of the most common causes of macrocytosis in the primary care setting.
b
No

Question 29

What is wrong with the following statement (answer on next slide)?

Question 13 (cont’d)

Hypochromia is represented by a low MCHC, not MCH

Question 30

Increased numbers of reticulocytes can increase the MCV. What is the effect of anemia on reticulocytosis-mediated macrocytosis?

a
Increases the MCV further
The effect of an absolute reticulocyte count on the MCV is more pronounced in patients with severe anemia because of their disproportionate representation among the total red cell population.
b
No effect
c
Blunts the effect of Reticulocytosis on the MCV

Question 31

Which RBC best describes the phenotype in hypernatremia when measured in vitro (as part of a CBC)?

a
A
b
B
c
C
d
D
e
E
Yes. When exposed to isotonic diluent before measuring MCV in an automated counter, RBCs from patients with hypernatremia will take on water, swell and increase their volume. Because the Hb content does not change, the increased volume causes a reduction in the MCHC.

Question 32

Is the RBC count low, normal or high in this patient (answer on the next slide)?

WBCRBCHbHctMCVMCHCRDW-SDPLT
9.2?12.136.310633.351.4219

Question 32 (cont’d)

Is the RBC count low, normal or high in this patient?

WBCRBCHbHctMCVMCHCRDW-SDPLT
9.23.412.136.310633.351.4219

The RBC is low. Evolution has selected for an optimal Hb/Hct. In this case because the MCV is increased, the RBC count is correspondingly reduced to maintain a normal Hb/Hct.

Question 33

A patient has a Hb 8 g/dL and Hct 29%. What is the most likely diagnosis?

a
Thalassemia-minor
b
Pernicious anemia
c
Iron deficiency anemia
MCHC = Hb/Hct = 8/29 = 27 g/dL. A normal MCHC is 32-36 g/dL. Therefore, this patient has a hypochromic anemia. None of the other conditions on this list are associated with such a severe degree of hypochromia.
d
Hypothyroidism

Question 34

What are the 2 most likely causes of MCV > 130 fL?

a
Vitamin B12 deficiency
b
Hypothyroidism
c
Medications
d
Liver disease
e
Reticulocytosis

Question 35

Which parameters is copper deficiency associated with?

a
Anemia
Of patients presenting with cytopenias secondary to copper deficiency, 30% reported to have isolated anemia.4
b
Pancytopenia
Of patients presenting with cytopenias secondary to copper deficiency, 10% reported to have pancytopenia.4
c
Macrocytosis
Copper deficiency anemia can be present as microcytic or normocytic or macrocytic.4
d
Microcytosis
Copper deficiency anemia can be present as microcytic or normocytic or macrocytic.4
e
Polycythemia
Copper deficiency is not associated with polycythemia.

Question 36

Which of the following is/are causes of transient change in the mean cell volume (MCV)?:

a
Spurious macrocytosis
b
Reticulocytosis
c
Transfusion
d
Liver transplantation in cirrhotic patient
e
Administration of erythropoietin

Question 37

Reticulocytes can be detected on Wright Giemsa, true or false?

a
True
b
False
Reticulocytes are defined by their staining using special intravital staining, or by demonstrating intracellular RNA using FACS (now a routine feature of automated counters). On Wright-stained peripheral blood smears they may appear as a polychromatophilic cells.

Wright Giemsa stain showing polychromatophilic cell. According to the College of American Pathologists, polychromatophilic cells are nonnucleated, round, or ovoid red cells staining homogeneously pink-gray or pale purple. They are larger than mature RBCs and usually lack central pallor

On supravital stains (meaning that the slide is stained without prior fixation – the RBCs are still “alive” when they are incubated with the staining solution), reticulocytes are identified by clumped granular material called reticulum (this is where the term “reticulocyte” comes from). Reticulum consists of aggregates of residual ribosomes mitochondria.

Question 38

What is the MCHC of a typical reticulocyte?

a
Lower than mature RBC
The MCHC of a reticulocyte is lower than that of a mature red cell. As the reticulocyte matures in the circulation (a process that normally takes 2-3 days) it loses volume, but not hemoglobin. Therefore the MCHC increases as reticulocytes transition into mature red cells.
b
Same as a mature RBC
c
Greater than a mature RBC

Question 39

Reticulocytosis may cause macrocytosis. What is the MCV of a typical reticulocyte?

a
100 fL
b
115 fL
Reticulocytes increase the MCV simply because they are bigger and they get counted and sized as RBCs in automated counters. Reticulocyte size is quite heterogeneous, making it difficult to translate changes in reticulocyte count to changes in the MCV.
c
130 fL

Reticulocytes are a heterogeneous population of cells at various stages of maturation, characterized by progressive loss of RNA and membrane proteins as well as changes in size, morphology and metabolic properties. About 2 million reticulocytes are released by the bone marrow per second. Their MCV averages about 115 fL, and the MCHC is lower than that of mature RBCs (indeed a low MCHC + high MCV may indicate reticulocytosis). As they mature, retics lose their remaining RNA and organelles, they lose about 20% volume (they become smaller) and they acquire a biconcave shape. Under stress, reticulocyte production can be increased 15-20-fold above steady state
values from increased production and shortening of marrow maturation time (leading to increased retic circulation time).

Question 40

How often is macrocytosis not associated with anemia?

a
5% of cases
b
25% of cases
c
50% of cases
d
65% of cases

The table shows the % of cases of macrocytic anemia associated with anemia (last column) in reported in the published literature. The studies are identified in the first column by their PMID number. Inserting that number into the search bar of PubMed will yield the paper of interest.
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