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Flashcards in Approach to Anemias Deck (21):

What are reticulocytes? Describe their development.

  • Erythroid progenitors in the bone marrow: burst forming units-erythroid (BFU-E) and colony forming units-erythroid (CFU-E) develop into normoblasts
    • The normoblasts extrude their nucleus to form a red blood cell, which initially retains some of a ribosomal network capable of some protein/hemoglobin synthesis
  • These early red blood cells are called reticulocytes, and are larger than and lack the central pallor of a mature RBC (have a higher mean cell volume, MCV), and stain bluish on a standard Wright Giemsa peripheral blood smear
    • Under normal steady state conditions, the reticulocyte typically spends about 3 days in the marrow, and 1 day in the circulation, after which it loses its ribosomal network, gains central pallor, and becomes a mature RBC


How is anemia measured, and how are reticulocytes involved?

  • Measurement of the reticulocyte is automated, and can often help differentiate the underlying cause of anemia:
    • High reticulocyte count in anemia = adequate bone marrow response (eg, bleeding, hemolytic anemia)
    • Low reticulocyte count in anemia = inadequate bone marrow response (eg, aplastic anemia, iron deficiency) 
  • Mature RBCs circulate on average for approximately 110-120 days
  • Macrophages then remove them from the circulation upon detecting senescent signals on the membrane
  • The rate of production of RBC must equal the rate of loss; if production does not keep up with losses, the patient becomes anemic


What is the role of erythropoiten in RBC development?

  • The rate of RBC production is tightly regulated by erythropoiten (EPO), a hormone mainly produced by the kidney in response to oxygen tensions in the blood
    • EPO results in increased production of RBC in the bone marrow
  • The lower oxygen tensions seen with anemia are detected by cellular molecular sensors, resulting in production of hypoxia-induced transcription factor HIF
    • HIF results in upregulation of EPO production
    • As red blood cells decrease in number, there is a compensatory increase in EPO production
    • In turn resulting in an increase in RBC production by as much as 7-8x in children, and ~5x in adults
  • This is provided that other aspects of erythropoiesis are adequate, which may often not be the case with specific causes of anemia (eg, lack of RBC precursors in aplastic anemia)


What are the normal values for Hgb, Hct, RBC count, and MCV?

  • As previously stated, anemia is a reduction in the absolute number/mass of circulating red blood cells
    • Women on average have  ~10% lower values than men
  • Typical measurements and approximate normal ranges on a complete blood count (CBC) include:
    • Hemoglobin (Hgb): concentration of hemoglobin in whole blood (g/dL)
      • Men: 1.35-17.5
      • Women: 12.0-16.0
    • Hematocrit: percent of a sample of whole blood occupied by RBC
      • Men: 40-52%
      • Women: 36-48%
    • RBC count: number of red blood cells in a particular volume of whole blood (millions/microL)
      • Men: 4.5-6.0
      • Women: 4.0-5.4
    • Mean cell volume (MCV): average size of RBC (femtoliters, normally 80-100)


What is the definition of anemia? When is this definition not accurate?

  • The typical ways to evaluate RBC mass involves measuring the concentration of RBC in the blood volume
    • This assumes normal maintenance of the blood volume, which is often the case
  • Therefore, anemia can also be thought of as a decrease in concentration of the RBC in the circulating blood
  • There are times when this assumption is not accurate, however:
    • Decreased plasma volume (dehydration, vomiting/diarrhea, over-diuresis, severe burns, etc) can lead to an artificially increased RBC concentration
    • Increased plasma volume (pregnancy, congestive heart failure) can lead to an artificially low RBC concentration
    • Acute blood loss/hemorrhage may give false impression of normal or even high hemoglobin/hematocrit levels due to rapid loss of both RBC and plasma


What is the Fick equation?

  • Reduction of RBC lowers oxygen carrying capacity, reducing O2 delivery as indicated by the Fick equation:
    • O2 delivery = Blood Flow  x  Hgb concentration  x (Arterial O2 saturation – Venous O2 saturation)
  • The human body will attempt to preserve O2 delivery by augmenting the other variables listed above, and by attempting to correct the low RBC level itself


How does blood flow change in anemia?

  • Cardiac output is increased in anemia, particularly if it develops relatively rapidly and/or the anemia is severe
    • Patients with severe anemia are therefore at risk for high-output cardiac failure, and this compensatory mechanism also explains why patients are often tachycardic & have impaired exercise tolerance
  • Blood will also flow preferentially to vital organs- heart, brain, liver, kidneys- at the expense of other such as the skin (in part explaining why patients can be pale)


How does erythropoietin levels change in anemia?

  • As previously stated, lower O2 delivery associated with anemia results in increased production of erythropoietin, sometimes by as much as 1000x normal
    • This can help maximize RBC production with some forms of anemia (eg, bleeding or hemolysis)
    • However, this is not as helpful with other causes, specifically those due to impaired red blood cell production, as the erythroid progenitors are unresponsive to EPO


WHow does the oxygen affinity of hemoglobin change in anemia?

  • The hemoglobin in anemic patients has a lower affinity for O2, due to increase in 2,3-diphosphglycerate (2,3-DPG) in RBC
    • This allows for a much higher fraction of O2 to be unloaded from RBC as they pass from the arterial to the venous system via capillary beds
  • This maximizes O2 delivery in situations of lower pO2
  • This is represented by the oxygen dissociation curve (see Goldman’s Cecil Medicine figure 161-2)


What are the physiological compensatory mechanisms for anemia?

  • Increased cardiac output
  • Altered blood flow
  • Increased EPO
  • Increased 2,3-DPG
  • Decreased RBC O2 affinity


What are the symptoms and physical exam findings of anemia?

  • Symptoms
    • Symptoms of anemia vary significantly based on:
      • rapidity of development
      • severity of anemia
      • comorbidities
    • Many symptoms are due to impaired O2 delivery
      • Common symptoms include fatigue and decreased exercise tolerance
    • Lightheadedness and dizziness can accompany severe anemia or when it develops rapidly
    • Shortness of breath, palpitations, and cold intolerance are also commonly experienced
  • Physical Exam
    • Pallor of skin and mucosal surfaces (eg, conjunctiva) is common due to preferential blood flow to vital organs
    • Tachycardia, wide pulse pressure, hypotension, and a systolic flow murmur can also be seen
    • With active bleeding, orthostatic hypotension (drop in blood pressure and increased heart rate with postural changes) can accompany anemia


What are the CBC findings in anemia?

  • Complete blood count (CBC), red blood cell indices, reticulocyte count, peripheral blood smear, and in some cases, a bone marrow examination are key laboratory studies in working up anemia
  • The CBC is automated in most US laboratories, and reports the:
    • hemoglobin concentration
    • hematocrit
    • white blood count (often with differential)
    • platelet count
  • Of the RBC indices, the MCV is often the most helpful in determining underlying cause of anemia
    • Microcytosis is <80 fL & macrocytosis >100 fL
    • Since this is a mean cell volume, mixed anemia with elements that could lead to microcytosis and separate ongoing processes that lead to macrocytosis can result in a “normal” MCV (eg, iron deficiency causing microcytosis and concomitant B12 deficiency leading to macrocytosis)
  • Mixed anemias such as this should have a high red cell distribution width (RDW), indicating a variation in sizes of the RBC being picked up by the automated counter


What is the role of a reticulocyte count and bone marrow evaluation in evaluating anemia?

  • The reticulocyte count is also helpful in working up anemia
    • If erythropoiesis is adequate, there should be a brisk increase in production and release of reticulocytes from the bone marrow (eg, if anemia is due to loss with bleeding)
    • However, a low reticulocyte count with anemia indicates impaired RBC production
  • A bone marrow biopsy can be helpful in situations where etiology of anemia is not clear through testing peripheral blood, and there is indication of impaired erythropoiesis


What is the role of a peripheral blood smear in diagnosing anemia? List the conditions associated with the following conditions: microcytes, macrocytes, spherocytes, schistocytes, tear drops, target cells, sickle cells, spur cells/acanthocytes.

  • Evaluation of a peripheral blood smear can reveal clues to cause of anemia, as there are changes in RBC size (anisocytosis) and/or shape (poikilocytosis) seen with specific etiologies, some examples:
    • microcytes - iron deficiency
    • macrocytes - B12, folate deficiencies
    • spherocytes - autoimmune hemolytic anemia
    • schistocytes - microangiopathic hemolytic anemias (eg. TTP)
    • tear drops - myeloplastic processes (replacement of bone marrow with fibrosis, tumor, etc.)
    • target cells - thalassemias
    • sickle cells - sickle cell anemia
    • spur cells/acanthocytes - cirrhosis


What are the ways of evaluating caues of anemia?

kinetic and morphologic approaches


What are the major categories in the kinetic approach of evaluating the cause of anemia?

  • Evaluates reasons for decrease in hemoglobin as either:
    • Decreased RBC production
    • Increase RBC destruction
    • Blood loss


In the kinetic approach to anemia evaluation, the components of evaluating decreased RBC production?

  • Nutritional:
    • Iron
    • B12
    • folate deficiencies
  • Suppression of bone marrow:
    • specific drugs (chemotherapy)
    • radiation
  • Hormonal:
    • low EPO (kidney disease)
    • hypothyroidism
    • hypogonadism
  • Primary bone marrow disorders:
    • aplastic anemia
    • myelodysplastic syndrome
    • myelophthisic processes
    • pure red blood cell aplasia
  • Chronic inflammatory conditions:
    • can lead to impaired iron regulation
    • with decreased gastrointestinal absorption
    • decreased iron release from stores by macrophages
    • relatively reduced EPO level
    • mild reduction in RBC lifespan


In the kinetic approach to anemia evaluation, what are the components of evaluating increased RBC destruction?

  • Specific diseases can result in drastic reduction in the RBC survival from a typical of 110-120 days
    • Anemia will result when the bone marrow can no longer keep up with production to equal the decline in RBC
  • Acquired hemolytic anemias
    • Autoimmune hemolysis: Coomb’s positive hemolytic anemia (warm IgG or cold IgM antibody-mediated RBC destructive process)
    • Microangiopathic hemolysis: Disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP)
    • Infections:
      • babesiosis
      • malaria
    • Paroxysmal nocturnal hemoglobinuria (PNH)
    • Anatomic issues: RBC shearing across mechanical heart valves
  • Inherited hemolytic anemias
    • Membrane defects:
      • Elliptocytosis
      • Spherocytosis
    • Hemoglobinopathies:
      • thalassemia major
      • sickle cell anemia
    • Enzyme deficiencies: glucose 6 phosphate dehydrogenase (G6PD) deficiency


In the kinetic approach of anemia evaluation, what are the components of evaluating blood loss?

  • Menorrhagia is relatively common among menstruating females
  • Bleeding may not be as clinically apparent as one would expect to cause significant anemia
  • A large amount of blood can collect in spaces such as the retroperitoneum & upper thigh
  • Occult gastrointestinal losses are common, and are often associated with iron deficiency as well


Describe the morphologic approach of evaluating the cause of anemia.

  • Morphologic approach
    • Cause of anemia can also be classified based on RBC size reported on the CBC
    • As previously mentioned, since these are automated, evaluation of the peripheral blood smear is important to confirm automated reports, and to investigate whether a “mixed” micro- and macrocytic process is present, resulting in a “normal” MCV reported by the lab
    • Microcytic anemia (MCV <80 fL)
      • decreased iron availability: iron deficiency, anemia of inflammation, copper deficiency
      • decreased globin synthesis: hemoglobinopathies (eg, alpha thalassemia)
      • decreased heme synthesis: lead poisoning
    • Macrocytic anemia
      • Brisk reticulocytosis (Reticulocytes are larger than mature RBC)
      • Abnormal RBC maturation: primary bone marrow processes such as myelodysplastic syndrome, leukemias
      • Abnromal nucleic acid metabolism: seen with common nutritional deficiencies (B12, folic acid), and certain medications (Zidovuidine for HIV, hydroxyurea for myeloproliferative neoplasms)
      • Associated with other diseases: liver disease, hypothyroidims
      • Toxicities: Excessive/chronic alcohol consumption
    • Normocytic anemia: Can be seen with primary bone marrow failure (aplastic anemia, pure RBC aplasia)
      • Anemia associated with chronic inflammatory conditions may be microcytic as above, but can also present as a normocytic process


What is the treatment of anemia?

  • Treatment of anemia should target the underlying cause
    • For example, recommending iron supplementation to a patient with anemia due to a hemolytic process will not help
  • Acutely, transfusion of red blood cells will temporarily help, but work up to find the root cause is imperative