Module 7.0 - Anemia's

Question 1

What are the normal hemoglobin levels for men & women?

Answer 1

• Men: (14.0-17.5)
• Women: (12.3-15.3)

Question 2

In which populations do the normal ranges for RBC parameters not apply?

Answer 2

• Athletes
• Living in a high altitude location – Hgb values will be higher
• Smokers – will have a higher HCT than nonsmokers
• African Americans – typically 0.5 -1 gm/dL lower than Caucasian populations
• Presence of a chronic disease – tend to be skewed towards anemic levels
• Older adults – anemia more common in elderly;

Question 3

What are the normal hematocrit levels for men & women?

Answer 3

• Men: 42-50
• Women: 36-45

Question 4

What is the normal mean corpuscular volume (MCV) and what is it a measure of?

Answer 4

• MCV range: 80-96
• It is the average volume (size) of the patient’s RBCs; anemia can be classified based on whether MCV is low, normal or elevated

Question 5

What is the normal mean cell hemoglobin (MCH) and what is it a measure of?

Answer 5

• MCH Range: 28-33
• It is a measure of the average Hgb content in a RBC; a low MCH indicates decreased Hgb content per cell and is referred to as hypochromic on the peripheral blood smear; low counts typically seen in iron deficiency anemia and thalassemias

Question 6

What is the normal mean cell hemoglobin concentration (MCHC) and what is it a measure of?

Answer 6

• MCHC range: 33-36
• It is the average Hgb concentration per RBC; very low MCHC values are typical in iron deficiency anemia and very high MCHC values typically reflect spherocytosis or RBC agglutination.

Question 7

What is the normal red cell distribution width (RDW) and what is it a measure of?

Answer 7

• RDW: 12-15
• It is a measure of the variation in RBC size; high RDW implies large variation of RBC sizes (anicytosis) and low RDW indicates more homogenous size of RBCs. A high RDW is seen in iron deficiency and myelodysplastic syndrome; as well as in patients you have received transfusions.

Question 8

Describe the red blood cell life cycle

Answer 8

• Erythropoiesis in the adult takes place within bone marrow under the influence of a stromal framework, cytokines, erythroid specific growth factor and erythropoietin (EPO)
• Erythropoietin (EPO) is a glycoprotein produced by the kidney; it enhances the growth and differentiation of erythroid progenitors (stem cells) necessary for reticulocyte development (RBC development)
• In the normal state- the rate of RBC production = the rate of RBC loss
• The survival of a mature RBC is 80-120 days

Question 9

How are Hgb, HCT, and RBC count levels related to each other?

Answer 9

• Hgb, HCT, and RBC count are dependent on the red blood cell mass (RCM) as well as the plasma volume.
• If plasma volume decreases, all three values (Hgb, HCT, RBC count) will increase.
• If plasma volume increases, all three values will be decreased.

Question 10

What are 3 common clinical examples of how volume status affects RBC values?

Answer 10

1. Acute bleeding – Patients with bleeding peptic ulcers may suffer postural hypotension from volume loss, but Hgb/HCT are normal initially; over the next 36-48 hours, the body will correct the blood volume deficit by movement of fluid from the extravascular into the intravascular space- this is when the Hgb/HCT will reflect the blood loss. If the total blood volume is not replaced and the patient remains hypovolemic- the Hgb/Hct will underestimate the degree of blood loss.
2. Late pregnancy – 3rd trimester of pregnancy the RBC mass and plasma volume expand by 25-50% resulting in reductions of Hgb, HCT and RBC count- this is ‘dilutional‘ anemia- they are not truly anemic
3. Volume depletion – anemic patients in a volume-depleted (hemoconcentrated) state may not show abnormally low Hgb/HCT initially- once volume is replaced the anemia will become apparent.

Question 11

What are the subjective and physical exam findings associated with anemia?

Answer 11

• Signs/symptoms are dependent upon the degree of anemia and the rate at which it has evolved, as well as the oxygen demands of the patient.
• Symptoms related to 2 factors:

1. Decreased oxygen delivery to tissues - if anemia has developed slowly the patient may be asymptomatic

• Dyspnea on exertion
• Headaches
• Tinnitus
• Syncope
• Dizziness
• Fatigue, weakness
• Impaired concentration
• Angina
• Hepatosplenomegaly
• Peripheral edema
• Systolic ejection murmurs
• Tachycardia
• Skin and mucous membrane pallor
• Arrhythmias

2. Hypovolemia - from acute or marked bleeding

Question 12

What lab tests are obtained to diagnose anemia?

Answer 12

• CBC with differential * The screening test for all anemias*
• Absolute reticulocyte count
• Platelet count
• Wright-stained blood smear
• Serum Ferritin, serum iron, and total iron-binding capacity (TIBC)

Question 13

What are the 8 steps to work-up a patient with anemia?

Answer 13

Step 1:

• It is preferable to diagnose the cause of anemia, prior to transfusion, when possible.

Step 2:

• Evaluate Hgb/HCT against normal reference values
• The hemoglobin value is the amount of hemoglobin in a volume of blood
• The hematocrit is the ratio of the volume of red cells to the volume of whole blood

Step 3:

• Evaluate Absolute Reticulocyte count:
  
  • If elevated, indicative of erythropoietic response to anemia and probably blood loss or hemolysis.
  • If low, indicative of anemia of chronic disease

Step 4:

• Evaluate peripheral blood smear for characteristics

Step 5:

• Classify RBC indices according to size (MCV) of erythrocytes:
• Microcytic – decreased MCV < 80
• Normocytic – normal MCV (80-100)
• Macrocytic – increased MCV > 100

Step 6:

• Classify RBC indices according to the average concentration of hemoglobin in a given volume of blood [Mean Cell Hemoglobin Concentration (MCHC)]
  
  • Hypochromic – red blood cells (erythrocytes) have increased pallor in the center from a decrease in hemoglobin
  • Normochromic – red blood cells have a normal area of pallor in the center and a biconcave disk shape
  • Hyperchromic – red blood cells have an increase in color; the only cells that are truly hyperchromic are spherocytes- they contain more hemoglobin that normal in relation to the cell volume

Step 7:

• Classify RBCs by RDW (variation in size)
• Consider bone marrow smear and biopsy.

Step 8:

• Specific studies as indicated:
  
  • Hgb electrophoresis (thalasemmia, hemoglobinopathies)
  • Antiglobulin testing (Hemolytic anemias)
  • Osmotic fragility test (hereditary spherocytosis)
  • Serum iron and iron binding capacity (iron deficiency anemias)
  • Folate and vitamin B12 measurements (megaloblastic anemias)
  • RBC enzyme testing ( G6PD deficiency, hemolytic anemias)

Question 14

What are the types of macrocytic anemias?

Answer 14

• B12 deficiency
• Folic acid deficiency
• Pernicious anemia

Question 15

What are the different microcytic anemias?

Answer 15

• Iron deficiency anemias
• Thalassemias
• Sideroblastic anemias
• Hemoglobinopathies

Question 16

What 2 diseases can cause normocytic anemia?

Answer 16

Anemia of chronic disease or inflammation

Question 17

What causes pernicious anemia and what type of anemia is it?

Answer 17

Cause:

• Due to a lack of intrinsic factor produced by parietal cells of gastric mucosa preventing vitamin B12 absorption, resulting in Vitamin B12 deficiency
• Autosomal recessive disorder, 50% of patients with antibodies to intrinsic factor.
• May be due to atrophic gastritis, or antibodies to gastric parietal cells

Type:

• A megaloblastic anemia: macrocytic, normochromic

Question 18

What are the subjective/physical exam findings associated with pernicious anemia?

Answer 18

• Positive Babinski/Romberg signs
• Abnormal DTRs
• Vibratory sensation and proprioception are lost or decreased in lower extremities
• Gradual onset of symmetrical paresthesia and numbness of extremities – Stocking-glove neuropathy
• Ataxia (positive Romberg test)
• Loss of sense of smell
• Loss of glossal papillae with tenderness (smooth tongue)
• Difficulty maintaining balance

If neurological alterations are present for longer than 6 months**, may potentially be permanent.

Question 19

What lab/diagnostic tests are done to diagnose pernicious anemia?

Answer 19

1. Blood cell changes( megaloblastic anemia):

• Macrocytic- MCV > 110-140
• RDW increased

2. Decreased Vitamin B12 levels

• < 200pg/ml: low, deficiency likely

Question 20

How do you manage a patient with perncious anemia?

Answer 20

• Parenteral vitamin B12- titrate from daily SQ injection to monthly for life.
• Folic acid should not be given without vitamin B12 due to potential for fulminant neurologic deficit
• Monitor for hypokalemia during first week of B12 replacement
• CNS signs/symptoms may not be reversible if not caught early.

Question 21

What can cause a vitamin B12 deficiency?

Answer 21

• Deficiency of hydrochloric acid or pancreatic enzymes causing an inability to metabolize vitamin B12; also from malabsorption syndromes of ileum or enteritis
• Vegetarians at risk
• Some mediations can predispose: metformin, alcohol, anesthetics
• Roux-en-Y gastric bypass
• Nutritional B12 deficiency rare in U.S

Question 22

What causes folic acid deficiency and what type of anemia is associated with it?

Answer 22

Cause:

• deficiency in folic acid (folate) causes decreased RBCs and Hgb due to impaired production
• Increased requirements due to pregnancy, hemolytic anemia
• Decreased intake, especially in alcoholics; strict vegan diet without supplementation
• Decreased absorption due to gastric bypass surgery, celiac disease
• Loss during hemodialysis
• Medications that interfere with metabolism (methotrexate, sulfasalazine, phenytoin, isoniazid)
• Rare genetic disorders

Type:

• A megaloblastic anemia: macrocytic, normochromic​

Question 23

What are the subjective/physical exam findings associated with a folic acid deficiency?

Answer 23

• Fatigue, pallor
• Symptoms not evident until stores are depleted and anemia severe
• Signs of malnutrition
• Glossitis/Stomatitis
• Hyperpigmentation
• Infertility
• Weight loss
• Neurologic symptoms- less common

Question 24

What lab/diagnostic tests are done to diagnose a folic acid deficiency?

Answer 24

Serum folate concentration:

• If > 4 nl/mL can rule out folate deficiency
• If < 2 ng/mL diagnostic of folate deficiency

RBC folate levels:

• provides information about folate status over lifetime of RBCs; BEST INDICATOR of folate deficiency; < 150ng/mL is diagnostic; test used when serum folate is borderline or not in line with clinical picture

Other Labs:

MCV usually > 100fl

Serum Homocysteine level will be elevated

Question 25

How do you manage a patient with a folic acid deficiency?

Answer 25

• Administration of folate can exacerbate neurologic symptoms of untreated B12 deficiency
• Oral folate, 1-5mg daily for 3-4 months
• After initiation of supplements, total correction of anemia should be seen within 2 months.

Question 26

What causes beta thalassemia major and what type of anemia is it?

Answer 26

Cause:

• It is an inherited disorder leading to the impaired production of beta globin chains, leading to a relative excess of alpha globin chains which are unstable
• The degree of alpha globin chain excess determines the severity of clinical manifestations
• Signs/symptoms emerge during the second 6 months of life when gamma globin chain production decreases and normally is replaced by beta globin to form adult hemoglobin A.
• 80% of children die within first 5 years of life

Type:

• hypochromic and microcytic anemia

Question 27

What are the physical exam findings associated with beta-thalassemia major?

Answer 27

• Hepatosplenomegaly
• Cardiac failure/dilatation
• Jaundice
• Marked osteoporosis and cortical thinning
• Growth retardation- delayed secondary sex characteristics
• Pallor
• Fatigue
• Failure to thrive

Question 28

What lab/diagnostic tests are used to diagnose beta thalassemia major?

Answer 28

• Hallmark is microcytic and hypochromic anemia
• Decreased Hgb, HCT, MCH, MCH, reticulocyte count
• Normal to mildly decreased MCHC
• Normal RDW
• Diagnosis confirmed with hemoglobin electrophoresis *(Gold Standard for diagnosis) – Hemoglobin A is absent or severely reduced, only hemoglobins F and A2 are present.

Question 29

Describe the incidence of iron deficiency anemia

Answer 29

• Affects over 12% of world’s population *Most common anemia worldwide*
• Women with higher incidence than men 11% females: 1% males
• Pregnant women with a 25% rate of iron deficiency
• Elderly patients – 12% incidence at > 65 years of age.

Question 30

What are the 4 causes of iron deficiency anemia and what type of anemia is associated with it?

Answer 30

Causes:

1. Blood loss – *Most common cause- either occult or overt

2. Iron Loss – pregnancy/lactation, hemodialysis, menstrual blood loss

3. Reduced Iron absorption – uncommon cause- duodenum is the site of maximum absorption

• Celiac disease: contributes by several mechanisms- iron def., reduced absorption, malabsorption of other nutrients
• Atrophic Gastritis and H. Pylori
• Bariatric surgery: limits gastric reservoir capacity, shortens length of functional small intestine causing malabsorption

4. Redistribution after erythropoietin – after treatment with erythropoietin for anemia of chronic renal failure, often leads to absolute or functional iron deficiency

• Absolute iron deficiency- refers to the absence or severely reduced storage of iron in bone marrow, liver and spleen
• Functional iron deficiency –when there is adequate stores of iron for hematopoiesis, but the iron is not available for RBC production due to anemia of chronic inflammation a

Type:

• Hypochromic/Microcytic anemia

Question 31

What are the symptoms and physical exam findings associated with iron deficiency anemia?

Answer 31

• Refer to initial workup of anemia physical findings/symptoms
• In addition, may have Pica- ice craving
• Restless leg syndrome
• May have hearing loss
• Pallor, rough dry skin, blue sclera, cheilosis (cracking at corner of mouth), koilonychias (spoon shapedand brittle nails)
• Glossitis- sore and shiny red tongue

Question 32

What labs/diagnostic tests are used to diagnosed iron deficiency anemia?

Answer 32

1. Peripheral Smear (4 stages):

• Stage 1: body stores depleted, lab tests normal
• Stage 2: Hgb normal, but iron stores depleted by lab test values
• Stage 3: iron depletion, slight anemia, normal MCV
• Stage 4: severe iron deficiency, hypochromic RBCs and low MCV with marked anemia
  
  • Microcytosis, poikilocytosis and hypochromia appear as deficiency worsens

2. Elevated RDW in the absence of any other RBC abnormalities – MAJOR DIAGNOSTIC INDICATOR
3. Reticulocyte count is markedly decreased in relation to the degree of anemia
4. Ferritin level less than 10-12 mcg/dl; TIBC increased by more than 300mcg/dl
5. Serum Iron usually low (< 50mg/dl)
6. Consider stool guaiac, send for ova and parasites; GI endoscopy and clotting studies.

Question 33

How do you manage a patient with iron deficiency anemia?

Answer 33

1. Determine cause and treat underlying disorder
2. Therapeutic trial of oral iron supplementation. The dose of oral iron depends on patient age, estimated iron deficit and the rapidity with which it needs to be corrected, and side effects.
3. Follow up in 3 weeks for CBC - (Hgb and reticulocyte count) should be normalized at 2 months. Takes 6 months to rebuild iron stores.
4. If symptomatic- transfusion may be necessary
5. IV iron – Sodium ferric gluconate complex (Ferrlecit) - watch for anaphylaxis. Observe for hypotension and flushing; keep resuscitation equipment nearby. Administer test dose initially.
6. Within 7-10 days a reticulocyte response and increase in HCT should occur with parenteral iron.
7. Iron supplementation in the absence of a documented deficiency may lead to iatrogenic iron overload!

Question 34

How should iron replacement be prescribed for a patient with iron deficiency anemia?

Answer 34

• Recommended daily dose for an iron deficient adult is in the range of 150-200mg elemental iron daily.
• There is new evidence suggesting alternate-day dosing may result in better iron absorption than daily dosing with a reduction in common side effects (Schrier, S. & Auerbach, M., 2018).
• Ferrous sulfate preparations has the lowest amount of side effects (30%) compared to other oral preparations.

Question 35

What should you advise/warn patients when prescribing iron replacement therapy?

Answer 35

• Avoid enteric coated and sustained release preparations- not well absorbed.
• Advise patient to take supplements on an empty stomach for enhanced absorption.
• Iron should be taken separately from calcium containing foods (milk, calcium supplements, dietary fiber, tee, coffeeandeggs)
• Iron should not be taken with ant-acids, histamine receptor blockers, proton pump inhibitors- these impair its absorption.
• Normally, you should co-administer either a 250mg ascorbic acid tablet or a half-glass of orange juice with the dose of oral iron to enhance its absorption. (it is best absorbed in a mildly ascitic environment)

Question 36

What are the side effects associated with iron replacement therapy?

Answer 36

oral metallic taste, nausea, flatulence, constipation, epigastric distress, black/green tarry stools. Ferrous sulfate iron preparations had the least side effects (30%) of all preparations.

Question 37

What causes anemia of chronic disease and what type of anemia is associated with it?

Answer 37

Cause:

• Associated disorders include infections, inflammatory disorders, malignancy, trauma, aging (due to concomitant inflammatory conditions or chronic kidney disease) and acute or chronic immune activation.
• Gradual in onset
• Resolves when therapy for the underlying disorder is instituted

Type:

• Typically normochromic, normocytic, hypoproliferative and mild in degree of severity
• 2nd most common cause of anemia worldwide, after Iron deficiency anemia*

Question 38

What are some lab/diagnostic tests used to diagnose anemia of chronic disease?

Answer 38

• Hgb < 10 gm/dL unusually; mostly mild to moderate anemia (Hgb 10-11g/dL)
• RBCs normochromic and normocytic
• Reticulocytecount is < 1% or a low absolute number
• High serum ferritin (>100ng/ml); TIBC is usually low in ACD (< 250microgm/ml)
• RDW usually normal in ACD
• Consider obtained Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) to assess severity of inflammation from underlying disease

Question 39

How do you diagnose anemia of chronic disease?

Answer 39

ACD is most likely when all of the following are present:

1. Low serum iron
2. Normal to low serum transferrin (TIBC)
3. Normal to increased serum ferritin
4. Elevated ESR and/or CRP

Question 40

What are the treatment options for patients with anemia of chronic disease?

Answer 40

• Primary management: Identify underlying disease and institute treatment
• No specific therapy exists; Oral iron alone is of no benefit in ACD and must be used in combination with other measures.
• Patients may require red blood cell transfusions or erythropoiesis stimulating agent.

Question 41

What are some gerontologic considerations with anemia?

Answer 41

• Common in the older adult, typically mild with Hgb > 10gms/dL
• Prevalence is up to 25% in the elderly U.S population
• Nursing home residents at increased risk
• Associated with substantial morbidity and mortality if Hgb < 12gms/dL
• Racial and ethnic considerations are considered due to anemia being 3-fold higher in elderly African Americans relative to elderly Caucasians
• Multifactorial causes: underlying renal insufficiency, myelodysplasia, nutritional deficiencies, etc.
• Regardless, should undergo standard evaluation for anemia and identification of underlying cause.