A single lab value

Before seeing the patient, consider the following:

The patient’s hemoglobin is 8.4 g/dL

Where do you go from here? Of the following labs, which are you most interested in?

a
Platelet count
Would not be the first choice.
b
White cell count
Would not be the first choice.
c
Red cell distribution width (RDW)
Would not be the first choice.
d
Mean cell volume (MCV)
Yes, anemia is normally classified as microcytic, normocytic or macrocytic (see next slide).
e
Mean corpuscular hemoglobin (MCH)
Not a very helpful lab parameter under any situation.

Morphological classification of anemia:

Here is the patient’s mean cell volume (MCV):

ParameterPatient value (fL)Normal range (fL)
MCV117 80-100

This test result is indicative of:

a
Microcytosis
b
Normocytosis
c
Macrocytosis

You have been told that the patient has a congenital form of anemia, and indeed you would be suspicious of a hereditary condition given his young age. What is the one likeliest cause of the elevated mean cell volume?

a
Vitamin B12 deficiency
b
Folate deficiency
c
Liver disease
d
Reticulocytosis
If the anemia is congenital, it is possibly hemolytic in nature. Hemolytic anemia is associated with reticulocytosis, and increased reticulocytes may increase the mean cell volume (MCV).
e
Alcohol abuse

Reticulocytosis appears on the morphological classification under macrocytosis, but sometimes an increased reticulocyte count does not elevate the mean cell volume above 100 fL. A better way of considering the reticulocyte count is to incorporate it as the first branch point in the morphological classification. It looks something like this:

According to this classification, the first test we really want after the hemoglobin – the one that provides the most discriminatory power – is the reticulocyte count. But you will have to wait for that result!

Assuming the elevated mean cell volume (MCV) is caused by reticulocytosis, which of the following 2 schematics is most likely to resemble the patient’s peripheral blood smear?

Hint: the diameter of a normal size red cell is approximately the same as the diameter of the nucleus of a small lymphocyte.

a
A
The red cells, which are all well hemoglobinized (i.e., mature), are larger than the diameter of the nucleus of the small lymphocyte. Thus, they are macrocytes.
b
B
Correct! The mature red cells are the same size (diameter) as the nucleus of the small lymphocyte. Thus, they are normocytes. However, the bluish cells, called polychromatophilic cells (they correspond to reticulocytes), are larger than the lymphocyte and account for the elevated mean cell volume (MCV).

Here is the patient’s reticulocyte count:

Reticulocyte count

That is, the reticulocyte count is:

  • 61.3% of the total red cell count
  • 1.65 x 1012/L = 1650 x 109/L

There are several ways of looking at the reticulocyte count:

  • As a percentage of red cells
  • As a corrected reticulocyte percentage:
  • As a maturation correction index, which accounts for a longer life span of the reticulocytes in the peripheral circulation as they take longer time to mature. The maturation correction index varies from 1.0 (Hct 36%-45%), 1.5 (Hct 26%-35%), 2.0 (Hct 16%-25%) to 2.5 (Hct 15% and below).
  • As a reticulocyte production index that takes both the Hct as well as the life span of the reticulocytes into account:

See Agarwal AM and Rets A. Int J Lab Hematol. 2020;42(Suppl. 1):107–112

  • As an absolute reticulocyte count
    • > 120 x 109/L is considered an appropriate response to anemia

Suggestion: Forget all the percentages and focus on the absolute reticulocyte count!

Normally, the lab will provide you with an absolute reticulocyte count. If they provide you with only the reticulocyte percentage, what lab value do you need to calculate the absolute count?

a
Total nucleated cell cells
b
Serum erythropoietin level
c
Hematocrit
d
Red cell count
Yes. Absolute reticulocyte count = total red cell count x % reticulocytes.

Consider the hypothetical patient with a total red cell count of 4 x 1012/L and a reticulocyte percentage of 5%.

Our patient’s mean cell volume (MCV) is 117 fL. Let’s assume that the MCV of the mature red cells is 90 fL. And let’s make the math simple and say that the reticulocyte count is 50%.

This patient has profound reticulocytosis. This degree of reticulocytosis is seen in very few conditions. In fact, there is an extremely high pretest probability for a rare condition, given his history of congenital anemia and this extreme value. But, we will come back to that!

What do you predict the mean corpuscular hemoglobin concentration (MCHC) to be?

a
Low
Reticulocytes have a lower MCHC compared to mature red cells. Reticulocytes get smaller as they mature into red cells, but the total amount of hemoglobin inside the cell remains constant. Thus the MCHC starts off on the low side and “normalizes” as the cell matures. A high MCV combined with a low MCHC is a clue to the presence of reticulocytosis.
b
Normal
c
High

Here is the patient’s mean corpuscular Hb concentration (MCHC):

ParameterPatient value (g/dL)Normal range (g/dL)
MCHC30.1 32-36

This test result is indicative of:

a
Hypochromia
b
Normochromia
c
Hyperchromia

Which smear is most likely to resemble the patient’s?

a
A
b
B
Correct. The mean corpuscular hemoglobin concentration (MCHC) of reticulocytes is lower than that of mature red cells, leading to a reduction in the overall MCHC.

What do you predict the red cell distribution width (RDW) to be?

a
Low
b
Normal
c
High
This patient has two populations of different size cells: one population of normal sized mature red cells and another population of larger reticulocytes. This will lead to an elevated RDW.

Here are are the results of the red cell distribution width (RDW):

Red cell distribution width
Schematic representation of peripheral smear and RDW histogram under normal conditions (left) and in a patient with anisocytosis (right).

Which RDW is most likely to resemble the patient’s?

a
A
b
B
c
C

Here are are the results of the red cell distribution width (RDW):

Red cell distribution width

Note that two different RDW values are provided for this patient:

  • RDW-coefficient of variation or RDW-CV (abbreviated simply as RDW in the above results)
  • RDW-standard deviation or RDW-SD
The RDW-CV measures size dispersion by means of a ratio formula of 1 standard deviation (SD) to the mean cell volume (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).

Based on the above information, which RDW measurement is influenced by the mean cell volume?

a
RDW-CV
b
RDW-SD

What should I do if both red cell distribution width (RDW) values are provided?

  • Focus on just one of the two values, RDW-CV or RDW-SD. There is nothing to be gained from looking at both.
  • The RDW-SD is more accurate than the RDW-CV because the latter is influenced by the mean cell volume (MCV).
  • Consider the RDW-SD if it is available.
  • RDW-SD > 42 fL is considered increased and is consistent with anisocytosis.

Which smear is most likely to resemble the patient’s?

a
A
b
B
c
Hard to know
While the reticulocytosis is sufficient, in itself, to increase the RDW, we cannot rule out anisocytosis among the mature red cell population.

With rare exceptions, there are two broad causes of reticulocytosis.

There is no reason to suspect that this 29 year-old outpatient with a history of congenital anemia is suddenly bleeding. It is much more likely that the patient has a type of congenital hemolytic anemia. We can divide these into three groups.

Let’s consider each of these categories in turn.

Hemoglobinopathy

ConditionComments
Sickle cell diseaseNot ruled out so far.
ThalassemiaThe anemia is too low for thalassemia minor and the mean cell volume (MCV) too high for any type of thalassemia.

The following are schematics of peripheral blood smears. Schematic A is the one we arrived at after considering the patient’s red cell indices and reticulocyte count.

Which statement(s) is/are true?

a
B represents sickle cell disease
Two sickle forms are seen, as well as a nucleated red cell at 5 PM. The average red cell size is similar to that of the lymphocyte nucleus.
b
B represents thalassemia
c
C represents thalassemia
Correct. Well hemoglobinized small mature red cells (low MCV, normal MCHC), relative to the size of the lymphocyte nucleus.
d
C represents sickle cell disease

Membranopathy

ConditionComments
Hereditary spherocytosisNot ruled out so far, though the mean corpuscular hemoglobin concentration tends to be high in this condition.
Hereditary elliptocytosisNot ruled out so far.
Hereditary pyropoikilocytosisNot ruled out so far.

The following are schematics of peripheral blood smears. Schematic A is the one we arrived at after considering the patients red cell indices and reticulocyte count.

Which statement(s) is/are true?

a
B represents elliptocytosis
b
B represents spherocytosis
Correct. Note the loss of central pallor, which is typical of a spherocyte and often associated with an elevated mean corpuscular hemoglobin concentration (MCHC).
c
C represents elliptocytosis
d
C represents spherocytosis

Enzymopathy

ConditionComments
G6PD deficiencyNot ruled out so far, though the patient’s current labs would be more consistent with an acute hemolytic crisis.
Hereditary pyruvate kinase deficiencyNot ruled out so far.

The following are schematics of peripheral blood smears. Schematic A is the one we arrived at after considering the patients red cell indices and reticulocyte count.

Which statement(s) is/are true?

a
B is G6PD deficiency
Shown at 12 o’clock is a pitted red cell, characteristic of a red cell that has been culled of a Heinz body. Heinz bodies can only be seen on special stains.
b
B is pyruvate kinase (PK) deficiency
c
C is B is pyruvate kinase (PK) deficiency
Yes. The peripheral smear can be normal in patients with PK deficiency, but it often shows the presence of spiculated red cells that have a similar appearance to acanthocytes. However, they are not called acanthocytes because they arise from ATP depletion, not from a change in the lipid components of the cell membrane (the latter being characteristic of an acanthocyte).
d
C is G6PD deficiency

Before moving on, what do you expect to find in the patient’s serum chemistry:

a
Low haptoglobin
b
Elevated haptoglobin
c
Elevated LDH
d
Low ferritin
e
High ferritin
Iron overload is common in patients with congenital hemolytic anemia.

With these considerations mind, let’s move on to the patient encounter.

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