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Lesson 9-3
Anemia as Categoized by Morphology

MACROCYTIC ANEMIAS

General lab findings – MCV > 100 fL, macrocytic RBCs. Macrocytic anemia may be either megaloblastic or non-megaloblastic (normoblastic) megaloblastic anemias.

Megaloblastic anemia results from deficiencies of vitamin B12 and folic acid that are necessary for DNA synthesis and subsequent cell division. General laboratory findings:

c. Vitamin B12 deficiencies can also result from inability of gastric mucosa to secrete intrinsic factor (IF) necessary for absorption of vitamin B12. Condition referred to as Pernicious anemia (pernicious = dangerous). Biological competition of vitamin B12 due to parasitic infections such as Diphyllobothrium latum (fish tapeworm), malabsorption syndrome due to gastric resection or gastric carcinoma, abnormal absorption due to celiac disease or sprue, or nutritional deficiency or diminished supply of vitamin B12. General laboratory findings of Pernicious anemia:

d. Folate (folic acid) deficiency anemia is abnormal absorption of folate due to celiac disease or sprue. There is increased utilization caused by pregnancy, dietary deficiency, drugs and alcohol, and/or malabsorption disorders. General laboratory findings for Folic Acid Deficiency:

e. Non-megaloblastic anemia (disease of the liver -- acanthocytes may be seen in patients with severe liver disease). General lab findings:

 

 

 


NORMOCYTIC ANEMIA

General lab findings

a. Aplastic anemia (pancytopenia) is the failure to produce RBCs, WBCs, and platelets. This form of anemia can be due to damage or destruction of hematopoietic stem cells in bone marrow. Hematopoietic cells are replaced with fat cells. The types of aplastic anemia are acquired (secondary) which is the result of exposure to chemical agents or drugs such as radiation, benzene, insecticides, antibiotics, viral infections. Idiopathic aplastic anemia occurs in patients with no history of chemical or drug exposure or viral infection.

b. There are two types of congenital (primary) aplastic anemia: Fanconi's anemia and Estren–Dameshek syndrome. Fanconi’s anemia is autosomal recessive, and characterized as having microencephaly, skin hyperpigmentation (brown), short stature, skeletal disorders, renal anomalies, and/or mental retardation Estren– Dameshek syndrome has the same hematologic features as Fanconi’s but without the physical abnormalities. General laboratory findings:

c. Pure red cell aplasia is characterized has having suppressed RBC production with normal WBC and platelet production. The types are congenital erythroid hypoplasia (Diamond-Blackfan anemia) defective erythroid stem cell; slow, progressive anemia. Acute acquired pure RBC aplasia occurs as a result of hemolytic anemia, infections, malnutrition, and drug therapy, and chronic acquired pure RBC aplasia, an autoimmune disease in which IgG antibody attacks erythroid precursors. Thymoma (tumor of the thymus gland) is a frequent finding. General laboratory findings:

d. Anemia of chronic disorders (ACD) is the term used for anemia associated with chronic infection, inflammation or malignancy. ACD is the second most common cause of anemia and may be the most common cause of anemia in hospitalized patients. The general causes are decreased erythropoietin level (cytokine produced by activated macrophages during the acute phase of inflammation inhibits erythropoietin), iron block (cytokine also stimulates neutrophils to release lactoferrin, which binds iron. This complex is phagocytized by marrow macrophages, which makes iron unavailable for hemoglobin synthesis.), shortened RBC survival (possibly due to increased activity of macrophages), and suppression of erythropoiesis. General laboratory findings:

e. Anemia of chronic renal disease is due to failure of kidneys to produce erythropoietin and decreased bone marrow response to erythropoietin. The severity of anemia directly related to level of blood urea nitrogen levels and uremic plasma is highly toxic to cells. General laboratory findings:

f. Anemia of endocrine disease is due to a deficiency of hormones that regulate erythropoiesis.

(1) Hypothyroidism - erythropoietin production by the kidney depends on the tissue oxygen tension, which is influenced by thyroid hormones. In a hypothyroid condition there will be a decreased tissue oxygen tension resulting in a decreased need for erythropoiesis. Hypothyroidism, when associated with a folic acid or vitamin B12 deficiency, may result in an anemia that is more macrocytic than normocytic such as adrenal abnormalities – Addison disease or Cushing’s disease.

(2) Hypogonadism – androgens (testosterone) promote erythropoiesis: by increasing the production of erythropoietin by the kidney and by directly stimulating the marrow in conjunction with erythropoietin.

(3) Hypopituitarism - pituitary gland is responsible for secretion of TSH and gonadotropins, which control the production androgens. General laboratory findings:

g. Myelophthisic anemia (leukoerythroblastosis) is characterized as having abnormal cells, (e.g., leukemia, replaced bone marrow). General laboratory findings:

h. Anemia caused by acute blood loss is usually associated with traumatic conditions such as accident or severe injury. It does not produce an immediate anemia which means there is no change in hematocrit and hemoglobin during the first hours after blood loss due to vasoconstriction. However, severe hemorrhage reduces an individual's total blood volume and produces a condition of shock. The body then adjusts itself by expanding the circulatory volume (fluid from the extravascular spaces enters the blood circulation and has a diluting effect on the remaining cells) which produces the subsequent anemia. General laboratory findings:

i. Anemia caused by chronic blood loss is indicative in situations where blood loss of small amounts occurs over an extended period of time -- usually after several months. Instead of a dilution problem as with acute blood loss, chronic blood loss results in an iron deficiency anemia. This type is frequently associated with disorders of the gastrointestinal (GI) tract (bleeding ulcer), or extremely heavy menstrual flow. General laboratory findings:

j. Hemolytic anemia- caused by an increase in RBC destruction and/or a decrease in the normal average life span of the RBC.

k. RBC membrane defects are discussed below.

(1) Hereditary spherocytosis (HS) characterized by a defect in RBC membrane protein (spectrin) composition. It results in weakening of the membrane skeleton and loss of membrane surface area. This is an autosomal dominant trait. The spherocytic cells are abnormally permeable to sodium ion (Na+) causing an influx of sodium at 10 times the normal rate. The cells have reduced cellular flexibility (less deformable than normal) and have shortened survival time due to destruction by the spleen. Some patients compensate and have only slight symptoms while others may be severely anemic. General laboratory findings:

(2) Hereditary elliptocytosis (HE) exists where there is an abnormality in the red cell structural membrane protein spectrin. This is an autosomal dominant trait. The mechanism of hemolysis involves membrane loss, decreased RBC deformability and shortened RBC survival due to splenic destruction. General laboratory findings:

(3) Hereditary stomatocytosis is characterized as having an increased permeability of RBC membrane to sodium and potassium ions. RBCs have increased inflow of sodium and decreased outflow of potassium resulting in a net increase in cellular cation concentration that allows increased water content and swollen cells (stomatocytes). The cells have increased volume with a decreased surface-to-volume ratio, which leads to decreased ability to deform, and increased splenic destruction. General laboratory findings:

(4) Hereditary xerocytosis (more common than stomatocytosis) also has a permeability disorder where the outflow of K+ is greater than inflow of Na+. The net decrease in cellular cation concentration results in movement of water out of the cell and dehydrated cells (xerocytes). Therefore the cells have increased surface-to-volume ratio - leads to cells with decreased ability to deform and increased splenic destruction. General laboratory findings:

(5) Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, acquired, hemolytic disease found in young to middle aged adults. There is an abnormal clone of bone marrow stem cells. White blood cells and platelets are also affected. The defect in RBC membrane makes cells highly sensitive to lysis by heat labile serum factors (complement). It is characterized by intravascular hemolysis and hemoglobinuria during and following sleep in less than 25 percent of patients. General laboratory findings:

NOTES:
  • Sugar Water screening test: Whole blood is incubated in low ionic strength solution, which promotes binding of complement components, particularly C3 to the erythrocyte surface. This environment strains the ability of the erythrocytes to remain intact. Normal RBCs do not hemolyze under these conditions, but RBCs from individuals with Paroxysmal Nocturnal Hemoglobinuria (PNH), which are extremely sensitive to complement- mediated lysis, do hemolyze.
  • Ham’s acidified serum test: (A confirmatory test for PNH) Ham’s test is used to confirm the diagnosis of PNH. A positive Ham’s test is confirmed when it is shown that the patient’s own serum is capable of lysing his own cells; this means that PNH is present.

l. RBC enzyme deficiencies are discussed below.

(1) Glucose-6-phosphate dehydrogenase (G6PD) deficiency is Sex linked. There is a deficiency of enzyme present in RBC, which protects hemoglobin from oxidation. The absence of G6PD is harmless unless the RBCs are exposed to oxidative stress. Hemolytic anemia related to drug intake (redox compounds, i.e. primaquine, sulfonamides, etc.), oxidant stress. Primaquine can induce a hemolytic episode in about 10% of African-American males. Their Hemoglobin is oxidized to methemoglobin, which denatures and precipitates as Heinz bodies. Hemolysis of RBCs results from increased RBC rigidity caused by Heinz bodies and membrane damage from oxidants. General laboratory findings: positive autohemolysis test result.

(2) Pyruvate kinase deficiency is an autosomal recessive trait. Pyruvate kinase catalyzes the formation of pyruvate with subsequent conversion of ADP and ATP (Embden-Meyerhof pathway) - ATP provides the energy required for normal RBC membrane formation and other glycolytic reactions. RBCs have decreased life span due to lack of ATP and their inability to utilize glucose. Potassium and water are lost from cells resulting in cell shrinkage, distortion of shape, and speculation. RBCs removed from circulation by the spleen and liver. General laboratory findings: DAT negative.

m. Physical trauma -- disorders causing RBC fragmentation.

(1) Burns. Damage to RBCs results in fragmentation and membrane loss. General laboratory findings: Hemoglobinemia and hemoglobinuria are common first day after thermal injury.

(2) Cardiac replacement valves. Malfunctioning valves mechanically damage RBCs. General laboratory findings.

(3) Microangiopathic hemolytic anemia (MAHA). Occurs when fibrin strands within the small blood vessels shear RBCs as they flow through the vessels.

(4) Disseminated intravascular coagulation (DIC). Associated with over- activation of the clotting system. General laboratory findings:

(5) Thrombotic thrombocytopenic purpura (TTP). Characterized as aggregation of platelets and occlusion of blood vessels. This is most often seen in young adults although, it may occur secondarily to infections and connective tissue disease. General lab findings:

(6) Hemolytic uremic syndrome (HUS). Associated with acute intravascular hemolysis and renal failure following systemic illness. It is usually in infants and young children. General laboratory findings:

(7) Immune hemolytic anemia. Results from the removal of RBCs sensitized by antibody with or without complement.

(8) Alloimmune hemolytic anemia. Occurs when alloantibodies are produced when an individual is exposed to antigens of another individual of the same species that are not already present on the exposed individual’s cells.

(9) Hemolytic transfusion reaction. Occurs when donor red blood cells bear antigens foreign to recipient's immune system. The recipient's antibodies attach to donor cells and the cells hemolyze in the vascular system or antibody-coated cells are removed by the mononuclear phagocytic system (MPS). General lab findings: positive DAT.

(10) Hemolytic disease of the newborn (HDN). Occurs when antibodies from mother combine with antigens on fetal RBCs. The fetal RBCs coated with maternal antibody are removed from circulation by the infant's liver and spleen. General laboratory findings: positive DAT.

(11) Autoimmune hemolytic anemia. Occurs when individuals destroy their own RBCs by producing autoantibodies.

(a) Warm reacting. Reacts best at 37oC. Lab findings: positive DAT. Anisocytosis; Polychromasia; Spherocytes. Some macrocytes and NRBCs. Increased retics.

(b) Cold reacting. Reacts best at 10 to 30oC. Lab findings: positive DAT. Polychromasia and agglutination of RBCs. Increased cold agglutinin titer. Drug induced - patient forms antibody due to presence of drugs which results in lysis of RBC.

(12) Anemia of liver disease. Characterized as having a decreased RBC survival as a result of altered lipid production that leads to the production of targets cells, macrocytes, and acanthocytes. General laboratory findings:

(a) Hypersplenism - RBCs are destroyed by an enlarged spleen.

(b) Deficiencies of folate, protein, iron and vitamins as a result of poor nutrition.

(c) Inability of bone marrow to respond to anemia-toxic effects of alcohol or viral suppression of erythropoiesis.

n. Infectious agents.

(1) Malaria-Parasites infect and rupture RBCs. General laboratory findings:

(2) Hemolytic episodes also associated with other infectious agents - babesia, bartonella, clostridium, staphylococcus, streptococcus, gram- negative bacilli, viruses, and fungi.


MICROCYTIC ANEMIA

a. Iron Deficiency Anemia. Deficiency with iron storage and turnover. This is the most common type of anemia. Approximately 3/5 of iron in the body is present in hemoglobin and iron storage pools are present in bone marrow, spleen, and liver. 20 to 25 mL of RBCs are broken down each day as a result of normal aging therefore, approximately 1 mg of iron is lost and excreted by the body whereas the remaining iron is reused for hemoglobin production. The average adult absorbs 1 - 2 mg iron per day through his/her diet. An iron deficiency may result from one or more of the following four conditions:

(1) Nutritional deficiency where not enough iron is consumed to meet the daily requirement of iron.

(2) Faulty or incomplete iron absorption.

(3) Increased demand for iron that is not met, such as during pregnancy.

(4) Excessive loss of iron.

(5) General laboratory findings:

b. Sideroblastic Anemia. Anemia of abnormal iron metabolism and/or absorption. This anemia Characterized by iron loading as a result of a defect in heme synthesis or due to a variety of causes: drugs, hematological, neoplastic and inflammatory diseases, or hereditary factors. The body has adequate iron but is unable to incorporate it into heme synthesis. Iron enters the developing RBC but then accumulates in the perinuclear mitochondria of normoblasts to form iron deposits around the nucleus (ringed sideroblasts).

c. Hereditary Sideroblastic Anemia. Decreased d-aminolevulinic acid activity (the first enzyme in the heme synthesis pathway). General lab findings:

d. Primary Idiopathic Sideroblastic Anemia (Refractory Anemia) With Ringed Sideroblasts, Idiopathic Acquired Sideroblastic Anemia. Low d- aminolevulinic acid synthesis or heme synthase (ferrochetalase) activity. General lab findings:

POLYCYTHEMIA

a. Absolute Polycythemia. Signifies an above normal hemoglobin, hematocrit (greater than 50 percent) and RBC count.

(1) Polycythemia vera is a stem cell disorder characterized by excessive proliferation of the erythroid, granulocytic, and megakaryocytic cells - distribution, morphology, and maturation of marrow cells is normal polycythemia. It is characterized by an increased platelet count along with increased blood viscosity which may cause clot formation. Individuals may develop bleeding problems due to abnormal platelet function. It is usually treated with therapeutic phlebotomy - patients develop a mild iron deficiency anemia, which later becomes marked and may terminate into acute leukemia. There are significantly increased hemoglobin, hematocrit, RBC count, WBC count, and platelet count. General laboratory findings:

Peripheral Blood Smear – Normocytic/normochromic RBCs. Moderate anisocytosis. Slight polychromasia. Occasional NRBCs. Teardrop cells in long-term disease. Giant and atypical platelets and megakaryocyte fragments may be seen. May see megaloblastoid changes due to drug therapy. Left shift (immature granulocytes) with increased basophils and eosinophils

Increased ­

RBC; WBC; Plts; Hgb; Hct; Retics; LAP;

Normal

Decreased ¯

ESR; Decreased erythropoietin

 

(2) Secondary polycythemia is caused by an increase in erythropoietin levels that is due to appropriate (compensatory) response to hypoxia in which decreased amount of oxygen delivered to the tissue stimulates erythropoietin production - may result from living at high altitudes, cardiovascular or pulmonary disease, heavy smoking, and high oxygen-affinity hemoglobin. It is also due to inappropriate erythropoietin production associated with some kidney diseases, erythropoietin- producing renal tumors, and tumors of the brain, liver, adrenal and pituitary glands. General laboratory findings:

Relative Polycythemia. Caused by a decrease in the fluid (plasma) portion of the blood. It is seen in patients suffering from dehydration, burns, and those undergoing aggressive diuretic therapy. General laboratory findings:

 

David L. Heiserman, Editor

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Revised: June 06, 2015