Differential diagnosis

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Anemia

Definition

Hematocrite = 42%, Hemoglobin = 14 in males and

Hematocrite = 37% Hemoglobin 12 in females

Types
The normal physiological reaction to anemia is to increase bone marrow production of red cells. This is manifested by an increased reticulocytic count (a normal reaction).

In its simplest form anemia is ether:

1. Anemia without an increase in absolute reticulocyte count

This means that the bone marrow is not reacting as it should. This is the case when anemia is caused by bone marrow dysfunction or inability to produce red cells due to inadequate resources (e.g. iron).

2. Anemia with increased absolute reticulocyte count

This means that the patient has a healthy bone marrow which is reacting to the anemia as it should but not able to compensate it. Anemia here is caused by factors outside the bone marrow such as blood loss or destruction (hemolysis).

Absolute reticulocyte count = % of reticulocytes x RBC count and should be </= 100,000.

Anemia causes

1. Anemia without increased reticulocytes

Decreased MCV

Iron deficiency anemia
Clinical suspicion: Microcytic hypochromic anemia.

Thalasthemia

Clinical suspicion: microcytic hypochromic anemia without increase in reticulocyte count not caused by iron deficiency with morphological abnormalities in peripheral blood smear. In severe cases bone abnormalities & splenomegaly.

Normal MCV

Myelodysplastic syndrome
Clinical suspicion: Normocytic anemia & reticulocytopenia not diagnosed conventionally will require a bone marrow aspirate and subsequently a bone marrow biopsy OR macrocytic anemia not found to be due to folate or B12 deficiencies. More advanced cases may present with evidence of myelodysplasia.

Aplastic
Clinical suspicion: Anemia with thrombocytopenia or pancytopenia with reticulocytopenia. Bone marrow aspirate often shows dry tap.

Anemia of chronic diseases.

Increased MCV

Is almost always due to

B12 or

folate deficiencies.

Clinical suspicion: Macrocytic anemia with absolute reticulocytopenia.

Diagnosis: Serum B12 and RBC folate are measured.

If results of above are equivocal then both methylmalonic acid and homocysteine are measured. Both are elevated in B12 deficiency whilst only homocysteine is elevated in folate deficiency.

2. Anemia & increased reticulocytes

Is either due to hemorrhage or hemolysis (increased peripheral loss)

Blood Loss
History

2. Hemolytic anemia
Elevated indirect bilirubin and LDH


Hemolysis is the rapid breakdown of RBCs which manifests itself with jaundice and anemia. Hemolytic anemia is diagnosed by the presence of elevated indirect bilirubin and LDH in addition to anemia with increased retics.

Once hemolysis is established, the cause is determined using the clinical history, Coombs' test and red cell morphology on blood smear.

The history determines whether the hemolytic anemia is congenital or acquired.

Acquired hemolytic anemias result from immune or non-immune causes which can be easily determined by a direct (antiglobulin) Coomb test.


Intravascular hemolysis is hemolysis of RBCs inside the vascular system and
Extravascular hemolysis is RBC destruction in the reticuloendothelial system particularly the spleen.
Haptoglobin is a protein that removes free Hgb, hence it decreases in cases of intravascular hemolysis but remains normal in cases of extravascular hemolysis.

i. Acquired hemolysis History suggestive of acquired hemolysis

acquired hemolysis is either of immune cause or non-immune cause.

a. autoimmune hemolysis : Direct Coombs test positive


The direct Coombs' (antiglobulin) reaction is used to detect the presence of immunoglobulin or complement on the red-cell membrane and to determine the specific class of immunoglobulin or complement present.

1. Warm antibody hemolytic anemia (IgG): Direct Coombs test IgG / IgG & C3


Antibodies interact best with RBCs at 37º C. Hemolysis is primarily extravascular (serum haptoglobin normal).

Drug induced:
Clinical suspicion: Once the diagnosis of hemolytic anemia is established drug intake must be excluded.

Underlying hematological malignancy
Collagen vascular disorders
Infections
Idiopathic

1. Cold antibody hemolytic anemia (IgM): Direct Coombs test C3 only

Cold antibody hemolytic anemia:
Antibodies interact best with RBCs at 4º C. Hemolysis is mainly in the liver but maybe intravascular (serum haptoglobin decreased).

Paroxysmal cold hemoglobinuria
Cold agglutinin disease
Mycoplasma and viral infections
idiopathic

b. non-immune hemolysis : Direct Coombs test negative

Hypersplenism
Microangiopathic
Chemical agents
Physical agents
Lipid abnormalities
Infectious agents

ii. Congenital hemolysis : History suggestive of congenital hemolysis


Diagnosis is suggested by blood smear examination.

Secondary to Membrane Abnormalities
Hereditary spherocytosis
Hereditary elliptocytosis
Secondary to Abnormal Hemoglobin (Hemoglobinopathies)
Sickle cell anemia
Hemoglobin C and SC disease
Congenital Heinz body hemolytic anemias
Thalassemia
Secondary to Disturbed Metabolism (Enzymopathies)
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Glycolytic pathway enzyme deficiency (pyruvate kinase, hexokinase)