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					Lecture Outline:     Anemia

1.    Definition - anemia is a symptom of an underlying disorder
                    and is characterized by a lower than normal
                    hemoglobin value or a low red count.

2.    Relative vs. Absolute Anemia:

             a.   relative anemia - seeming "anemia" due to increase
                                    in plasma volume; seen in:
                                    1) pregnancy
                                    2) macroglobulinemia
                                    3) multiple myeloma
             b.   absolute anemia - actual decrease in red cell mass
                                    due to:
                                         1)    blood loss
                                         2)    decreased production
                                         3)    elevated red cell

 3.    Physiological effects of anemia

      Tissue hypoxia ---------> Increased erythropoietin levels
      --------> Increased erythropoiesis

 4.    Clinical signs and symptoms

      a.   fatigue
      b.   headache
      c.   low blood pressure
      d.   pallor
      e.   rapid pulse

 5.    Diagnosis depends on determination of:

      a.   Evaluation of peripheral blood smear
      b.   Hct
      c.   Hgb
      d.   RBC count
      e.   Red Cell Indices
      f.   Retic count
      g.   Sometimes a BM smear
      h.   WBC and Plt count
6.    Classification:     There are two main ways to classify the

      a.    Morphologically (based on red cell size and hemoglobin

            (1) Microcytic hypochromic
            (2) Macrocytic
            (3) Normocytic normochromic
      b.    Pathophysiological (based on causative factors)

            (1)   Blood Loss
            (2)   Impaired RBC production
            (3)   Increased RBC destruction

             Pathophysiological Classification of Anemias

 I.    Blood Loss Anemia

       A.    Acute posthemorrhagic anemia
       B.    Chronic posthemorrhagic anemia

II.    Impaired RBC Production

       A.    Disturbance of the proliferation and differentiation of
             stem cells

             1.   Multipotential stem cells
                  a. Aplastic anemia

             2.   Unipotential stem cells
                  a. Pure red cell aplasia
                  b. Anemia of renal failure
                  c. Anemia of endocrine disease
       B.   Disturbance of the proliferation and maturation of
            differentiated stem cells

            1.   Defective DNA synthesis (megaloblastic anemia):
                 nuclear maturation defect

                 a.   Vitamin B12 deficiency
                 b.   Folic acid deficiency

            2.   Defective hemoglobin synthesis (hypochromic
                 anemias): cytoplasmic maturation defect

                 a.   Iron deficiency anemia (defective heme
                 b.   Thalassemia (defective globin synthesis)

            3.   Unknown or multiple mechanisms

                 a.   Anemia associated with bone marrow infiltration
                 b.   Anemia of chronic disease
                 c.   Lead poisoning
                 d.   Sideroblastic anemia

III.   Increased RBC Destruction (Hemolytic Anemias)

       A.   Intrinsic Disorders

            1.   Membrane Defects
                 a. Hereditary spherocytosis
                 b. Hereditary ovalocytosis
                 c. Hereditary acanthocytosis (rare)
                 d. Hereditary stomatocytosis (rare)
                 e. Paroxysmal nocturnal hemoglobinuria (PNH)

            2.   Metabolic Defects

                 a.   G6PD deficiency
                 b.   Pyruvate kinase deficiency
            3.   Hemoglobin Defects

                 a.   Hemoglobinopathies
                 b.   Thalassemia

       B.   Extrinsic Disorders

            1.   Chemical Agents
            2.   Vegetable and Animal Poisons
            3.   Infectious Agents
            4.   Physical Agents

                 a.  Heat
                 b.  Traumatic hemolysis (Red Cell Fragmentation
            5.   Immunologically Caused Hemolytic Anemias

Classification of Anemias

     Using the information obtained from the indices regarding
the red cells or the knowledge which has been used to derive the
indices, a discussion may now be made concerning the anemias
themselves. In general, anemia may result from loss of the
circulating blood cells at a rate greater than they are being
replaced from the marrow; interference with production of cells
in the marrow; or excessive destruction of the cells by the
reticuloendothelial system. These different types of anemia will
show various morphologic characteristics in the circulating
blood. Although, theoretically, the anemias can be neatly placed
in one or another of these categories, there are many occasions
in actual practice where there may be a combination of factors
acting at the same time so that it is not unusual to see one or
more etiologies combined in a given patient. In general, anemias
may be characterized by both cell size and hemoglobin content.
This consideration leads to the following classification:

  I.   Macrocytic Anemia

       These anemias are usually normochromic but, on the smear,
       may actually appear "hyperchromic". Hyperchromia,
       however is not considered an acceptable term to describe
       the color of a macrocyte. They should be characterized as
       normochromic. The MCV is usually greater than 94 cu.
microns and the MCHC is greater than 30%. This type of
anemia is seen where there is a disturbance in the
formation of the stroma of the red cell without definite
evidence of disturbance in the hemoglobin formation.
Generally this occurs in deficiencies of vitamin B12 or
folic acid. In the bone marrow the red cells mature
abnormally in the so-called megaloblastic series rather
than in the normal line of development. This gives rise to
large red cells well filled with hemoglobin. Normally,
vitamin B12 is taken into the stomach in the form of
various foods. Here it comes in contact with an "intrinsic
factor" secreted by gastric parietal cells which apparently
leads to the increased absorption of the vitamin B12 by the
mucous membrane of the duodenum and jejunum. This type of
anemia may result from any disturbance in the absorption or
utilization of vitamin B12. In some areas such as the
tropics (not usually in the U.S.) it is seen as a
nutritional deficiency where the diet is lacking in vitamin

If intrinsic factor is not being properly produced by the
stomach then absorption of vitamin B12 is decreased as is
seen in the disease pernicious anemia. Secretion of
intrinsic factor seems to be related to the secretion of
gastric acid and therefore, we see a lack of acid secretion
accompanying this condition. Diarrhea with excessive loss
of vitamin B12 as is found in certain types of bowel and
pancreatic diseases may also produce this picture. It is
characteristically also seen in sprue, both tropical and
non-tropical, and in certain types of fatty diarrhea called
steatorrhea. Following gastric resection, this type of
anemia may result later in life.

Occasionally a macrocytic anemia may be seen during
pregnancy, during infancy, or in cases of infestation with
the fish tapeworm, Diphyllobothrium latum. This type of
macrocytic anemia must be differentiated from the
"macrocytic" anemia seen in states of intense activity of
the bone marrow. Reticulocytes are usually macrocytic when
they are released into the blood stream. If these
reticulocytes are significantly increased, the indices may
suggest a macrocytic anemia, but the stained smear would
show polychromasia instead of a truly macrocytic blood
      In addition to the defect in red cell production in this
      group of anemias there are usually associated disturbances
      of a greater or less extent seen in the white cells and
      platelets. The white cells may show a "double shift"
      meaning that immature granulocytes as well as hypermature
      or multilobed granulocytes may be seen. The platelets may
      be reduced due to reduction in the megakaryocytes in the
      bone marrow. The treatment of this type of anemia usually
      consists in supplying the missing factor by injection or in
      such a form that absorption will definitely take place.

II.   Normocytic, Normochromic Anemia

      This type of anemia results from sudden loss of blood from
      the peripheral blood stream, from cessation of manufacture
      in the bone marrow or from excessive destruction in the
      reticuloendothelial system. This type of anemia is
      usually normochromic. The MCV falls between 82 and 92 cu.
      microns and the MCHC is approximately 33%. A sudden loss
      of blood either from trauma or from giving blood as a blood
      donor, results for the first 1 to 2 hours in merely an
      acute normocytic anemia. Then the white cells are
      increased (leukocytosis) followed by an increase in
      platelets (thrombocytosis). Later there is evidence of
      bone marrow regeneration (reticulocytosis). If the blood
      loss is chronic, there may eventually result a depletion of
      iron stores in the patient with a picture resembling the
      iron deficiency type of anemia.

      The normocytic anemia seen as a result of impaired
      formation in the bone marrow is known as hypoplastic or
      aplastic depending upon the degree. The red cells which
      are present appear to be normal but there is no replacement
      coming from the marrow as the cells expire normally. This
      is indicated by a lack of reticulocytes in the peripheral
      blood and the bone marrow shows evidence of lack of
      formation. Often, the white cells and platelets are
      similarly affected.

      The normocytic anemias due to hemolysis (excessive
      destruction by the reticuloendothelial system) usually
      indicate evidence in the peripheral blood of extreme bone
      marrow activity as contrasted to the aplastic group. The
hemolysis may be due to defects in the red cell itself
(intrinsic hemolytic disease) or due to abnormal influences
on the normal cell as it comes from the bone marrow into
the peripheral blood where it is acted upon by various
noxious agents which lead to its early destruction
(extrinsic type of hemolytic disease). Examples of the
intrinsic type of hemolytic anemia include: 1) congenital
spherocytosis where the red cell is abnormally formed in
the bone marrow so that instead of being a biconcave disk
it is spherical and (2) the abnormal hemoglobin diseases
such as sickle cell anemia. Hemolytic anemias of the
extrinsic type include those in which there is hemolysis
due to chemicals or physical agents in the peripheral blood
or due to various types of antibodies which may be
encountered in immunohematology or which may arise
abnormally as part of certain disease processes. The signs
of excessive marrow activity normally found in the blood in
the course of hemolysis are increased "indirect" type or
bilirubin and urinary urobilinogen; reticulocytosis;
sometimes leukocytosis and thrombocytosis; shortened
half-life of the red cells when tagged with radio-active
chromium; and often disturbances in the fragility tests and
autohemolysis technique.

A variant of the aplastic group of anemias is known as
myelophthisic anemia and is a disturbance in blood
formation apparently due to "crowding out" of the marrow by
foreign cells. Many cell types may get to the marrow by
way of the blood stream and begin dividing there. A cancer
in any part of the body as well as certain of the lymphomas
such as Hodgkin's disease may give rise to these foreign
cells. Various types of replacement of the marrow by
fibrous tissue or bone can occur in certain pathological

Treatment for this group of anemias usually consists in
removing the cause of hemolysis if known. In certain
cases, the use of the cortisone group of drugs is helpful.
In other cases, splenectomy in order to remove a large
portion of the reticuloendothelial system is required. In
the aplastic group of anemias the marrow depressing agent
is removed if known, or the patient may have to be
maintained continually on transfusions.
III.   Microcytic Anemias

       This group of anemias is usually either normochromic or
       hypochromic. The MCV is usually less than 82 cu. microns
       and the MCHC less than 30%. This type of anemia is
       generally seen accompanying a disturbance in hemoglobin
       formation, during the maturation of the red cells. The two
       main components which are usually disturbed are iron and
       protein. Iron loss may be due to chronic slow bleeding
       such as from the gastro-intestinal tract in adults. In
       adults a diet deficient in iron-containing foods is very
       commonly seen. The iron may not be absorbed adequately in
       certain gastro-intestinal disorders or the gross
       requirements for iron may be increased as during childhood
       and in repeated pregnancies. The same factors may apply to
       protein. Usually the white cells and platelets are not
       disturbed in this group of anemias. In subacute and
       chronic inflammatory diseases and in certain chronic
       non-inflammatory diseases, such as uremia and chronic liver
       disease, the red cells may be microcytic but relatively
       normochromic. In chronic infections a microcytic,
       normochromic anemia may result apparently from decreased
       iron utilization with a maturation arrest of the red cells
       at the rubricyte stage so that few reticulocytes are seen
       in the peripheral blood. Treatment of this group of
       anemias usually consists of removing the cause of decreased
       iron absorption; replenishing the diet in iron and/or
       protein, or in determining and correcting the cause of
       chronic blood loss. The latter may be very important.
       Chronic blood loss from the bowel may be the earliest sign
       in some cancers of the gastro-intestinal tract which,
       otherwise, do not cause any discomfort. Unless this early
       sign of disease is carefully investigated, the cancer may
       have a chance to grow to the point of inoperability so that
       early diagnosis and treatment is essential to the
       well-being of the patient.
       Careful inspection of a blood smear with calculation of the
       red cell indices may help the clinician greatly in
       determining the subsequent investigation of a given patient
       with regard to an anemia which has been detected. Since
       the three main groups of anemia come about in different
       ways and since their treatment main groups of anemia come
       about in different ways and since their treatment is
       radically different, accurate diagnosis and treatment can
       only be accomplished by careful investigation leading to
       the diagnosis. Unless an orderly approach is used in the
       investigation of an anemia state, much useless laboratory
       work and time may be used up before the cause of the anemia
       is accurately determined. There has historically been a
       tendency to treat all anemias with "shotgun mixtures" of
       various iron, vitamin B12, folic acid, vitamins and other
       forms of hematinic therapy. It should be pointed out that
       a great deal of harm can result to the patient by using
       this approach. An anemia state, once discovered, should
       suggest serious disease until proved otherwise. In this
       way tragic mistakes in overlooking early cancers or other
       forms of serious disease will be avoided to the greatest
       possible extent. An anemia may be regarded as a symptom
       like headache. The headache can be relieved by aspirin but
       this does not diagnose the cause of the headache.
       Similarly the continued use of aspirin cannot hope to cure.
       Likewise, treatment of an anemia may be overlooking a more
       serious underlying process. For this reason careful smear
       inspection with ability to differentiate the variations
       from the normal in the red cells is very important to the
       laboratory technologist in order to give the clinician
       every possible aid in helping the patient.

              Morphological Classification of Anemias

Hypochromic*, microcytic anemias -          one common cause, iron

           infant - lack of sufficient intake
           adult - chronic blood loss

Uncommon causes:

 1.   thalassemia syndromes - hereditary inability to make normal
      amounts of one of the polypeptide chains of globin impairs
      hemoglobin synthesis
 2.    hypochromic iron loading anemias - due to failure to
       synthesize heme despite an excess of iron. Some are called
       pyridoxine responsive anemias.

Slight hypochromia is sometimes noted in non-hematologic
disorders and probably reflects impaired release of iron
reticuloendothelial cells.

Normochromic, normocytic anemias

Two types:

 1.    without poikilocytes (abnormally shaped red cells) or
       polychromatophilic macrocytes.
       a. Lack of poikilocytes rules out disordered red blood cell
       b. Lack of polychromatophilic erythrocytes indicates no
           stimulation of erythropoiesis

       Disorders include:
            a. chronic infectious and inflammatory states
            b. malignancies
            c. renal disease
            d. endocrine hypofunction

 2a.   with poikilocytes and polychromatophilic erythrocytes

       Disorders include:
            a. Leukemia
            b. Myelofibrosis
            c. Carcinoma of bone marrow
            d. Refractory normoblastic anemia

 2b.   with numerous polychromatophilic erythrocytes

*hypochromia - Red blood cells cannot make a normal amount of
Macrocytic anemia

Two categories:

 1.   with oval macrocytes and teardrop cells

      a.   megaloblastic anemias - also will find hypersegmented
      b.   Myelofibrosis in which one also finds nucleated red
           blood cells, immature white blood cells, and large

2.    without oval macrocytes and teardrop cells
      a. nonmegaloblastic macrocytosis

           1.     Alcoholism
           2.     Liver Disease
           3.     Hemolysis/Post-hemorrhagic anemia
           4.     Hypothyroidism
           5.     Aplastic Anemia
           6.     Artifactual (Cold agglutinins, RBC clumping)

                     Laboratory Investigation of Anemia

 1.   Blood count - red blood cell count

 2.   Study of Peripheral blood Smear

 3.   Reticulocyte count

 4.   Evaluation of Plasma pigments

Purposes of the initial examination includes classifying the
anemia on the basis of red blood cell morphology, finding other
morphological clues to the diagnosis, and identifying the kinetic
basis of the anemia as excess destruction, underproduction or
blood loss.
The Peripheral Blood Smear

A.   Morphology of red blood cell may yield important clues

     1.   size
     2.   chromia, or color
     3.   poikilocytosis - abnormally shaped cells due to either
          premature aging or abnormal maturation.

          a.   Crenated cell - artifact of slide preparation. From
                               use of a hypertonic staining fluid -
                               draws water out of the cell.
          b.   Burr cell -     cell has blunt horns seen in anemias
                               associated with chromic kidney
                               i.e. uremia
          c.   Acanthocytes - due to error of lipoprotein
                            metabolism/rare. Associated with
                               mental retardation.

          d.   Elliptocytosis - cells oval in shape. May be a
                                genetic defect. Homozygous - causes
                                hemolytic anemia
                                May also be seen in cases of severe
          e.   Sickle cells -   contain abnormal Hgb. Upon oxygen
                                deprivation, the cells form a sickle
          f.   Howell - Jolly bodies - remnant of DNA or RNA.
                                       Commonly seen in splenectomy
          g.   Cabot rings -    similar to Howell Jolly bodies
          h.   Basophilic stippling - due to poisoning by heavy
                                       metals, especially lead.

          i.   Pappenheimer bodies -     also called Siderocytes. Can
                                         get them in small numbers in
                                         all anemias except Fe
                                         deficiency. Must be specially
                                         stained. Maturation defect.
          j.   Schistocytes -   irregularly shaped fragments of red
                                cells which may be seen in hemolytic
      4.    Polychromasia - (Reticulocytosis)
            Polychromatophilic erythrocytes are newly released red
            cells, lilac in color and contain residual RNA which can
            be stained with a supravital stain such as New Methylene
            Blue. Levels of 5-1.5% are usually considered normal. A
            lot of polychromasia indicates increased cell production,
            usually hemolysis. Lots of new cells have to be produced
            to keep up with the loss.

B.    The slide should be examined at a point where red blood cells
      just touch each other. Fields in the feather edge or the
      thick portion of the smear are unsatisfactory.

C.    Determine size and Hgb content of red blood cell.

D.    Are frequent polychromatophilic macrocytes seen? This
      indicates increased red blood cell production and increased
      amounts of erythropoietin.

E.    Are there large numbers of nucleated red blood cells and only
      a few reticulocytes? This usually indicates disorders in
      which immature red blood cells are allowed to escape into the
      peripheral blood in the absence of increased production rate.

F.    Are there morphologic changes signifying hemolysis?

      1.    spherocytes
      2.    agglutination
      3.    fragmented red blood cells/ghost cells
      4.    sickle cells

G.    Are there morphologic changes signifying disordered red blood
      cell production?

      1.    Ovalocytes and teardrop forms
      2.    Siderocytes - imply Hgb synthesis impairment not due to
                          iron deficiency
      3.    Target cells - cells whose membranes are too large for
                           the cell's internal constituents
      4.    Punctate Basophilic Stippling - results from
                           precipitation of ribosomal material within
                           the red cell

Thursday, December 08, 2011

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