Introduction to Anemia

1. Introduction to Anemia Prof. Dr. S. Sami Kartı

2. Definition • Anemia is defined clinically as a blood hemoglobin or hematocrit value that is below the appropriate reference range for that patient • The reference range is derived from the hemoglobin or hematocrit values of a group of normal persons • The reference range needs to be adjusted for the age and sex of the patient since the hemoglobin and hematocrit vary with age and sex (in adults) • However, for general purposes, anemia can be defined as hemoglobin values less than 14 g/dL (140 g/L) in adult men and less than 12 g/dL (120 g/L) in adult women • Normal hemoglobin values for children vary with age; values begin to reach the adult range after puberty

3. Problems with the Definition of Anemia (I) • Of the normal population, 2.5% will have hemoglobin values below the defined reference range and will therefore be considered anemic • Another 2.5% of the normal range will have hemoglobin values above the upper limit of the reference range and will be considered polycythemic • Anemia, thus defined, ignores physiologic factors; for example, a person with a hemoglobin variant that has a low oxygen affinity will have a low blood hemoglobin but he or she is physiologically normal

4. Problems with the Definition of Anemia (II) • The hemoglobin value does not change with acute blood loss; this is not really a problem since the bleeding is usually clinically apparent • The blood hemoglobin does not always reflect the true red cell mass. A patient with expanded plasma volume may have a low hemoglobin, although his or her red cell mass may be perfectly normal • Anemia is not a diagnosis; it is a laboratory abnormality that requires explanation. After you identify the presence of anemia, your job is not finished until you have also identified the cause of the anemia

5. Symptoms and Signs of Anemia (I) • Common symptoms of anemia include decreased work capacity, fatigue, weakness, dizziness, palpitations, and dyspnea on exertion. The severity of symptoms may vary widely depending on the degree of anemia, the time period over which anemia developed, the age of the patient, and other medical conditions that are present. • If the anemia developed gradually (months or years), compensatory mechanisms such as an expanded plasma volume and increased 2, 3-diphosphoglycerate (2,3-DPG) have time to take effect. Consequently, the patient may not experience any symptoms with a hemoglobin level down to 8 g/dL, or even lower. If the anemia developed more rapidly, the patient may note symptoms with a hemoglobin level as high as 10 g/dL.

6. Symptoms and Signs of Anemia (II) • Children may tolerate remarkably low hemoglobin levels with few symptoms, whereas older patients with cardiovascular or pulmonary disease tolerate even mild anemia poorly. Angina pectoris may be the initial symptom of anemia in patients with coronary atherosclerosis • Physical signs of anemia include pallor, tachycardia, increased cardiac impulse on palpation, systolic “flow” murmur heard at the apex and along the left sternal border, and a widened pulse pressure (increased systolic blood pressure with a decreased diastolic blood pressure). Pallor is best noted in the conjunctiva, mucous membranes, palmar creases, and nail beds, especially in people with darkly pigmented skin

7. GENERAL APPROACH TO A PATIENT WITH ANEMIA

12. Laboratory Tests (I) • Important laboratory tests include a CBC with erythrocyte indices, white cell count and leukocyte differential, and platelet count • Examination of a well-made peripheral blood smear is critical and may be diagnostic • Important chemistries include serum creatinine, calcium, liver profile including total and direct bilirubin, lactic dehydrogenase, total protein, and albumin • A reticulocyte count (corrected for anemia) and RPI should be performed • After the initial laboratory studies have been performed, a selection of additional tests should be performed based on the clinical situation and the results of initial studies

13. Laboratory Tests (II) • These additional tests could include iron indices (serum ferritin or serum iron/transferrin/saturation), folic acid and cobalamin (vitamin B12) levels, hemoglobin electrophoresis, and direct antiglobulin (Coombs’) test, among others • A general approach to the laboratory diagnosis of the anemic patient will be given, based largely on erythrocyte size (MCV) • Naturally, the approach for each individual case will be modified by the history, physical examination, and other clinical and laboratory information for that specific patient

14. RETICULOCYTE COUNT • The reticulocyte count is the proportion (percent) of young erythrocytes containing ribonucleic acid (RNA), which can be visually identified as reticulin using a special stain such as new methylene blue • Under normal conditions, approximately 1% of red blood cells (RBCs) are turned over each day; an erythrocyte contains RNA for approximately one day after leaving the marrow, so the normal reticulocyte count is approximately 1% • The reticulocyte count increases if RBC production by the marrow increases, so an increased reticulocyte count is the primary indicator of increased RBC production • However, in order to be useful in an anemic patient, the reticulocyte count must be corrected to take into account both the anemia and the possibility of premature release of reticulocytes from the marrow under the stimulus of increased erythropoietin

15. CORRECTED RETICULOCYTE COUNT • Since the reticulocyte count represents a ratio (number of reticulocytes divided by the total number of erythrocytes), a decrease in the total RBC count may result in an increase in the reticulocyte count even if reticulocyte production by the marrow is not increased • In order to correct for this, the reticulocyte count is multiplied by the patient’s hematocrit divided by a normal hematocrit (45%) Corrected reticulocyte count = reticulocyte count x (patient hematocrit /45)

16. The Reticulocyte Production Index (RPI) • Under severe erythropoietin stimulus, reticulocytes may be released from the bone marrow prematurely and must finish their maturation in the peripheral blood (shift reticulocytes) • Since these prematurely released cells exist as reticulocytes for more than 1 day, they are, in effect, “counted” more than once in the reticulocyte count (remember: the normal reticulocyte count presumes that the cells exist as reticulocytes for only 1 day, rather than 2 or more days). In order to correct for these shift reticulocytes, the corrected reticulocyte count has to be divided by a correction factor, giving the RPI (RPI = corrected reticulocyte count /correction factor). The correctionfactor varies depending on the severity of the anemia Reticulocyte Production Index Correction Factors Hematocrit Correction Factor 40 1,0 35 1,5 25 2,0 15 2,5

17. RPI • The RPI can be used to indicate whether the marrow is successfully responding to the anemia: RPI > 3: Good marrow response (hyperproliferative) RPI < 2: Inadequate response (hypoproliferative) RPI > 2 but < 3: Appropriate for mild anemia (hemoglobin >10–11 g/dL) but borderline for more severe anemia • A healthy marrow with adequate nutrition (iron, vitamin B12, and folate) should be able to increase RBC production four to fivefold (RPI = 4 to 5). • Under prolonged stress (for example, a chronic hemolytic anemia such as sickle cell anemia), the marrow can increase RBC production seven to eightfold. • An alternative to calculating the RPI is to determine the absolute reticulocyte count, which can be done by many modern hematology analyzers. • A value >100 x10E9 cells/L indicates that the marrow is responding to the anemia with increased erythrocyte production.

18. RPI (Example) • A patient is found to have a hematocrit of 15% and reticulocyte count of 10%. Is this an appropriate reticulocyte response for this degree of anemia? • First, calculate the corrected reticulocyte count: • Corrected reticulocyte count = 10 X(15/45) = 3.3% • 3.3% is increased, but is it increased enough for the degree of anemia? • Second, calculate the RPI: • RPI = 3.3 /2.5 = 1.3 • An RPI of 1.3 is too low for this severe degree of anemia and indicates that the marrow is not appropriately responding to the anemia. This would be consistent with a hypoproliferative anemia.