2
nd
lecture in Hematology by Dr.Alaa Fadhil Alwan
Introduction and Approach to Anemia
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 persons who are presumed to be
without hematologic disease (in other words, normal). It is defined as the range of
values containing 95% of the population (two standard deviations above and below
the median value). 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). It
should also be adjusted for other factors, such as altitude (the normal range for
Basrah, muthana, would be different from that for Sulaymaniyah, Duhok).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.
It should always be kept in mind that anemia is not a diagnosis; it is a laboratory
abnormality that requires explanation.
CLASSIFICATION OF ANEMIA
Anemia can be approached from two ways: morphologic and pathophysiologic
Morphologic Approach
The morphologic approach to anemia begins with review of the CBC, particularly the
mean corpuscular volume (MCV), and the peripheral blood smear. The initial
distinction is based on the red cell size: anemias are classified as microcytic,
normocytic, or macrocytic. The presence of abnormally shaped erythrocytes
(poikilocytes) may suggest a specific disease or cause.
Classification of Anemia Based on Erythrocyte Size
1. Microcytic: e.g. IDA, Sideroblastic anemia, Thalassemia
2. Normocytic: e.g. Anemia of chronic disease, Anemia of renal disease,
3. Macrocytic: e.g Megaloblastic anemia due to folate or cobalamin, Hemolytic
anemia (reticulocytosis) Hypothyroidism , Myelodysplastic syndrome
Pathophysiologic (Functional or Kinetic) Approach
The pathophysiologic approach1 is based primarily on the reticulocyte count.
Anemias are classified into three broad categories: 1.hemorrhagic/hemolytic
(hyperproliferative) anemias, 2. hypoproliferative anemias, and 3. maturation defects,
1. hemorrhagic/hemolytic (hyperproliferative) anemias, there is increased
destruction or loss of erythrocytes. The bone marrow is attempting to respond
to the anemia and is producing mature erythrocytes but is unable to fully
compensate for the increased red cell loss. The reticulocyte production index
is high (>3) and the MCV is frequently high since reticulocytes are larger than
normal mature erythrocytes.e.g Acute blood loss, Acute hemolysis:
Intravascular or Extravascular, and Chronic hemolysis
2. Hypoproliferative anemias, the marrow fails to appropriately respond to the
anemia, but the cells that are produced are usually normal. The reticulocyte
count or reticulocyte production index is low; erythrocyte morphology is
unremarkable.e.g IDA , Chronic renal disease and Endocrine disorders
3. Maturation defect anemias, the bone marrow is attempting to respond to the
anemia, but the cells produced are unable to enter the circulation and most die
within the bone marrow (ineffective erythropoiesis). The reticulocyte count is
low, and, in contrast to the hypoproliferative anemias, erythrocyte morphology
is abnormal. The maturation defect anemias are sub classified into cytoplasmic
maturation defects, which are generally associated with microcytic
erythrocytes, and nuclear maturation defects, which are associated with
macrocytic erythrocytes.
SYMPTOMS AND SIGNS OF ANEMIA
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.
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.
GENERAL APPROACH TO A PATIENT WITH ANEMIA
Clinical History:
Questions significance
Onset of symptoms: insidious Nutritional deficiency likely to be insidious in
or abrupt onset; hemolysis more likely to be abrupt
Duration of symptoms Nutritional deficiency is likely to be of longer
duration; hemolysis is more likely to be rapid
Previous CBC? When and A previous normal CBC helps exclude an
What circumstances? Inherited disorder
Previous diagnosis of anemia? Possible recurrence of previous disease
When and what circumstances?
Family history of anemia? Possible inherited hemoglobinopathy,thalassemia,
membrane defect or enzyme deficiency
Change in bowel habits? Iron loss due to peptic ulcer disease, colon
Black or tarry stools? carcinoma, or other GI tract malignancy;
Hematochezia? malabsorption in folate or B12 deficiency
Diet: meats, dairy products, Does the patient have adequate intake of iron
fresh fruits and vegetables (meat), folic acid (fresh fruits and vegetables),
Medications Interference with folate metabolism (sulfa drugs,
trimethoprim, antiepileptic medications);
oxidant drugs causing hemolysis in enzyme deficiency;
blood loss from gastritis or peptic ulcer due to
nonsteroidal anti-inflammatory drugs
Past medical history Anemia of chronic disease due to inflammatory
diseases or malignancy; decreased
erythropoietin production in renal disease
Alcohol consumption Alcohol interferes with folate metabolism;
liver disease
Menstrual history (women) Iron loss in menorrhagia
Reproductive history (women) Iron loss in pregnancy
Occupational history Exposure to chemicals that are toxic to bone
marrow (organic solvents, hydrocarbons)
Jaundice or dark urine Hyperbilirubinemia could indicate hemolysis
or ineffective erythropoiesis
Weight loss Common with malignancies
Fevers, night sweats Common in malignancies; could indicate chronic
infection
Abdominal discomfort or Splenomegaly occurs with lymphoma, chronic
liver Fullness disease, myeloproliferative disorders
Sores in mouth or sore tongue Common in megaloblastic anemia; may also
occur in iron deficiency
Paresthesias, clumsiness, Neurologic disease due to B12 deficiency
weakness
Physical Examination
System Significance
General appearance pallor, Jaundice due to hemolysis or megaloblastic
anemia; cachexia; tremor or myxedema due to thyroid
disease;“spider” angiomata in liver disease; “spoon nails”
in iron deficiency
Eye examination pallor, Scleral icterus due to hemolysis; retinal hemorrhages
in iron deficiency and other anemias
Head and neck Glossitis or angular stomatitis in iron deficiency or
megaloblastic anemias
Cardiac Murmurs due to bacterial vegetations in endocarditis;
flow murmur in anemia
Abdomen Splenomegaly in chronic hemolytic anemias;
hepatosplenomegaly in lymphoma or myeloproliferative
disorder; mass due to intra-abdominal malignancy
Lymphatic system Lymphadenopathy in lymphoma
Nervous system Peripheral neuropathy, cerebellar or cortical dysfunction
due to cobalamin deficiency
Laboratory Tests
Important laboratory tests include a CBC with erythrocyte indices, white cell count
and leukocyte differential, and platelet count. 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) . 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.
A general approach to the laboratory diagnosis of the anemic patient is 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.
Evaluation of a Microcytic Anemia (MCV < 80 fL)
The key initial steps in the evaluation of a microcytic anemia are iron indices and
examination of a blood smear. The most common cause of microcytic anemia is iron
deficiency. If the iron indices confirm the presence of an iron deficiency, the next step
is to discover the cause (blood loss, insufficient dietary iron) and begin replacement
therapy. If the iron studies do not suggest iron deficiency, the next step is to order a
hemoglobin electrophoresis to diagnose thalassemia. Consider the ethnic origin and
family history of the patient. A blood smear could be done to check for target cells
and basophilic stippling. Complete blood counts and blood smears from relatives
might be helpful in this circumstance. Consider the possibility of a chronic
inflammatory process that might be causing anemia of chronic disease. If none of
these appear to be responsible for the anemia, a bone marrow examination with an
iron stain to look for ringed sideroblasts might be required.
Evaluation of a Macrocytic Anemia (MCV > 100 fL)
The most important initial step in the evaluation of an anemia with an increased MCV
is to differentiate megaloblastic anemia from macrocytic, non-megaloblastic anemia.
Examine a blood smear for hypersegmented neutrophils and oval macrocytes, which
would suggest a megaloblastic anemia. The first laboratory studies should be serum
cobalamin, serum folate, and red cell folate levels. If these are all normal, a
reticulocyte count should be done to check for a hemorrhagic or hemolytic process. A
careful examination of the blood smear may also be helpful; for example, the presence
of polychromasia would indicate reticulocytosis, and the presence of target cells
would suggest liver disease. If reticulocytosis is confirmed, the underlying hemolytic
or hemorrhagic process should be determined. Tests that might be helpful in this
circumstance include a direct antiglobulin (Coombs’) test, a hemoglobin
electrophoresis, and a screen for glucose-6- phosphate dehydrogenase (G6PD)
deficiency.
Evaluation of a Normocytic Anemia (MCV 80–100 fL)
The first step in the evaluation of a normocytic anemia is to assess the clinical history.
Does the patient have some process that would cause an anemia of chronic disease?
Does the patient have renal insufficiency, thyroid disease, or another endocrine
disease? Check iron studies and folate/vitamin B12 levels to look for early iron
deficiency or combined nutritional deficiency. If the reticulocyte count is increased,
follow with hemoglobin electrophoresis to look for a hemoglobinopathy, a screen for
G6PD deficiency, and, possibly, a direct antiglobulin test. If the reticulocyte count is
low, consider anemia of chronic disease, chronic renal insufficiency, thyroid disease,
or marrow damage. If the cause is not apparent, a bone marrow aspirate and biopsy
should be done.
Anemia with Increased Reticulocyte Production Index
Anemia in the presence of increased reticulocyte production suggests blood loss
(hemorrhage) or increased erythrocyte destruction (hemolysis).
Anemia due to acute or recent hemorrhage will usually be apparent on clinical history
and physical examination. Hemolytic anemias will usually fall into one of the
following general groups:
• Obvious exposure to infectious, chemical, or physical agents
• Positive direct antiglobulin (Coombs’) test (immune hemolytic anemia)
• Spherocytic anemia, but with a negative antiglobulin test (most likely hereditary
spherocytosis)
• Hemolytic anemia with specific morphologic abnormalities on blood smear (sickle
cells, elliptocytes, schistocytes)
• Miscellaneous conditions including hemoglobinopathies, thalassemias, enzyme
defects, metabolic abnormalities, and paroxysmal nocturnal hemoglobinuria