Nonregenerative Anemia Clinical Approach in the Dog and Cat Mathematical Gamesmanship
World Small Animal Veterinary Association World Congress Proceedings, 2003
Bernard F. Feldman, DVM, PhD
Virginia-Maryland Regional College of Veterinary Medicine Virginia Polytechnic Institute and State University
Blacksburg, VA, USA

CASE EXAMINATION

A nine month old West Highland White Terrier was presented for elective castration but, during physical examination, the mucous membranes were noted to be pale. Despite this the patient was bright, alert, responsive and afebrile. A biochemical profile was essentially unremarkable but the hemogram had some unusual findings:

WBC/µL

14,400 (12,400 neuts; 500 monos; 1000 lymphs; 500 eos)

RBC/µL

2,400,000 (MCV 79; MCHC 34; MCH 27)

PCV%

19

Hbg/dL

6.5

T.P.g/dL

6.1

NRBCs

5/100 wbcs

Retics%

10

Icterus Index-normal
ESR (corrected) - negative 12
Polychromasia ++++, Anisocytosis +++++, Poik +, Target ++, Lepto ++
Spherocytes-, Stomatocytes-, Bowls-, Knizocytes-, Schisto-.

Abnormal test(s)?_______________________________________________

Diagnosis?____________________________________________________

Why? _______________________________________________________

ANEMIA

1.  Hypoproliferative (nonresponsive anemia)

2.  Hyperproliferative (responsive anemia)

3.  Variable response anemia

Anemia is NOT a disease, simply a sign of disease. The evaluation of the patient with anemia requires the usual careful history and physical examination, followed by laboratory screening that provides a complete hemogram:

Examination of red blood cells

1.  Red blood count

2.  Hemoglobin (Hc) concentration

3.  Packed cell volume or hematocrit

4.  Mean cell volume

5.  Mean cell hemoglobin

6.  Mean cell Hb concentration

7.  Reticulocytes

8.  Reticulocyte production index

9.  Metarubricytes and other NRBCs

10. Red cell morphology and cytograms

11. Histogram of RBC vol. distribution

12. Total protein

Determining inflammation (other than the leukogram)

1.  Fibrinogen

2.  Sedimentation rate

Examination of platelets

1.  Platelet count

2.  Mean platelet volume

3.  Platelet morphology

Examination of leucocytes

1.  White blood cell count corrected for metarubricytes

2.  Differential white blood cell count in absolute values Immature forms, neutrophils, lymphocytes, monocytes, eosinophils, basophils, degenerated cells, unidentifiable cells

3.  White blood cell morphology

4.  Leucocyte cytogram

Red Cell Indices

While the red cell indices reflect abnormalities in red blood cell production, changes in the indices are slow to occur (remember, they are mean values!) and often lag behind the pathologic process. Despite the fact that most clinical anemias are normocytic and normochromic, macrocytic normochromic anemias usually reflect maturation abnormalities (vitamin B12, folate, myeloproliferative disease), microcytic hypochromic anemias specifically suggest iron deficiency in small animals, and macrocytic hypochromic anemias are associated with intense red cell regeneration.

Reticulocyte Count

The percentage reticulocyte count requires, at least, conversion to absolute values. The reticulocyte count in the dog requires several conversions to account for the "normal" bone marrow response to erythropoietin, and the length of time of bone marrow reticulocyte maturation which is correlated with the degree of anemia. These two conversions are often called the reticulocyte production index (RPI).

Hypoproliferative (nonresponsive) anemia

Anemia as a disease sign is placed into one of several categories. Anemia of inflammatory disease is modest, often undetectable, and clinically insignificant. Anemia associated with acute hemorrhage presents little diagnostic challenge and in the early stages is characterized as nonresponsive. Anemia associated with chronic hemorrhage is associated, in general, with parasitism in young animals and ulceration of bleeding neoplasms in older animals and in the early stages is characterized as nonresponsive. Microcytosis and hypochromasia, however, are slow to occur. Anemia associated with decreased erythropoietin production suggests the clinician examine renal function, thyroid function or adrenal function. Production deficits, manifested by anemia and or bicytopenia or pancytopenia suggests anemia associated with bone marrow disease.

Hyperproliferative (responsive) anemia--Hemolysis or Hemorrhage

Hemolytic Anemia is caused by fragmentation, phagocytosis, or intravascular lysis. The most common canine hemolytic anemia is immune-mediated hemolytic anemia (IHA), which may be defined as a premature breakdown of red cells and in the case of immune-mediation, premature breakdown of red cells associated with antibodies. Among the implicated antibodies are immunoglobulin G (IgG) and IgM. When associated with the red cell at 37 degrees they are considered warm reacting. When temperatures are below 35 degrees and antibody is associated with red cell membranes, the reaction is considered cold reacting. Both of the aforementioned immunoglobulins, and especially IgM, can fix complement. Complement-- and/or phagocyte-mediated red cell membrane damage result in swelling (spherocytosis) or lysis (hemoglobinemia). When hemolysis is active the erythroid marrow becomes responsive in three to five days. Anemia of hemorrhage also becomes responsive in three to five days. Variable response anemia, anemia which is unpredictable in terms of its reticulocyte response is a maturation abnormality due, most often, to vitamin B12 or folate deficiency. Intrinsic marrow disease, also potentially a maturation abnormality may also present similarly in the early stages.

CAUSES OF ANEMIA--A SUMMARY

1.  Iron deficiency--always nonresponsive

2.  Inflammation--always nonresponsive

3.  Marrow damage--always nonresponsive

4.  Decreased erythropoietin--always nonresponsive

5.  Hemorrhage--nonresponsive early; responsive later

6.  Hemolysis--nonresponsive early; responsive later

7.  Maturation abnormality-- usually nonresponsive but unpredictable

LABORATORY EVALUATION OF ANEMIA

The laboratory evaluation of anemia is initiated by examination of the red cell indices--MCV, MCHC, and MCH. If these indices are abnormal, this is essentially free information and gives specific direction. Examples are macrocytic hypochromic anemia which invariably suggests red cell response and microcytic hypochromic anemia which suggests (at least) iron deficiency. However if the indices are normal, normocytic and normochromic, examination of the degree of red cell response specifically the appropriateness of the reticulocyte response must be considered.

INITIAL APPROACH TO THE ANEMIC PATIENT

The reticulocyte count is the only index of effective erythropoiesis. Proper usage requires: 1) conversion to an absolute quantity; 2) adjustment for the reduced hematocrit; and 3) correction for the effect of erythropoietin on marrow reticulocyte release. These adjustments result in calculation of the adjusted reticulocyte numbers or the reticulocyte production index (RPI).

First: figure out the absolute quantity of reticulocytes. If the canine mean red cell count is seven million, one percent reticulocytes is seventy thousand reticulocytes--the reference interval would be thirty-five thousand to one hundred five thousand reticulocytes per microliter.

Second: correct for the reduced hematocrit. Multiply the absolute reticulocyte count by the patient's hematocrit and divide the result by the mean species hematocrit.

Third: correct for the effect of erythropoietin on reticulocyte release:

Erythropoietin--Erythropoietin (Epo) is inversely correlated with the red cell count (or hematocrit). The lower the hematocrit the higher the concentration of erythropoietin (except in renal failure). The effects of erythropoietin include:

1.  commits uncommitted stem cells to the erythroid line

2.  decreases the marrow maturation time for red cell development

3.  increases individual cell hemoglobin synthesis

4.  causes premature release of reticulocytes from bone marrow

ADJUSTING THE RETICULOCYTE NUMBERS--THE RETICULOCYTE PRODUCTION INDEX (RPI)

The average time for reticulocytes to mature in the dog or cat is four and one half days, three days occur in the marrow and one day in peripheral blood if the hematocrit is appropriate:

In the dog:

Hematocrit

Development in Marrow

in Peripheral Blood

45

3.5 days

0.5 days

35

3.0 days

1.5 days

25

2.5 days

2.0 days

15

1.5 days

2.5 days

In the cat:

32

3.5 days

1.0 days

24

3.0 days

1.5 days

16

2.5 days

2.0 days

10

1.5 days

2.5 days

To correct for the effect of erythropoietin on reticulocyte release, after converting reticulocytes to absolute values and adjusting for the reduced hematocrit, divide the final figure by the number of days the average reticulocyte will live as a reticulocyte based on the patient's hematocrit (see charts above).

For example, to determine red cell production over basal rate:

If a canine patient's hematocrit is 22 percent (mean normal is 45 percent) and the patient's reticulocyte percentage is 5 percent, is this patient responding appropriately to the reduced hematocrit? 5% X 22% (patient's Hct)/ 45% (mean canine Hct) = 2.5/2.0 = 1.27 basal rate If 1.0 is basal rate, 1.27 over basal rate is nonresponsive! Only patients with a corrected reticulocyte count over 2.0 are considered responsive, i.e., are responding from either hemorrhage or hemolysis

For example, to determine corrected absolute reticulocyte counts:

If the reticulocyte count is 5 percent of a red cell count of 3.5 million/ul, the absolute value is approximately 170,000/ul. 170,000 X 22% (patient's Hct)/ 45% (mean canine Hct) = 85,000/2.0 = 42,500. This corrected absolute reticulocyte number is within the reference interval observed for dogs with appropriate hematocrits. Thus, this patient must be considered nonresponsive

Initial characterization of anemia--is it responsive? nonresponsive?

A RPI less than 2.0 = nonresponsive anemia.

A RPI greater than 2.0 = responsive anemia i.e., hemorrhage or hemolysis.

References

References are available upon request

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Bernard F. Feldman, DVM, PhD
Virginia-Maryland Regional College of Veterinary Medicine
Virginia Polytechnic Institute and State University
Blacksburg, VA, USA


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