Microcytic, Macrocytic And Aplastic Anemias

Question 1

How is iron transported in plasma?

Answer 1

By a glycoprotein called transferrin synthesized in the liver

• normally 1/3 saturated which makes average serum levels in men and women 120 and 100/dL respectively

Question 2

Ferritin

Answer 2

Protein-iron complex that is found in spleen, bone marrow and skeletal muscles via macrophages
Due to macrophages breaking down RBCs

High levels of ferritin in serum implies RBC damage

Question 3

How large is the normal zone of pallor in normal RBCs?

Answer 3

1/3 cell diameter

Question 4

What are the 3 ways to classify anemia’s?

Answer 4

• amount of hematocrit in the blood (%)
• alterations in the RBC morphology/size
  (Normocytic, microcytic and macrocytic)
• degree of reflective color (normochromic or hypochromic)

Question 5

What are the most useful measurements for red blood cells?

Answer 5

Mean cell volume (MCV)
- normal = 82-96

Mean Cell Hemoglobin (MCH)
- normal = 27-33

Mean cell hemoglobin concentration
- normal = 33-37

Question 6

Microcytic hypochromic anemia’s

Answer 6

Caused by disorders of hemoglobin synthesis, usually due to iron deficiencies

Requires at least 1 of 3 components in sufficient amounts

• iron
• protoporphyrin
• globin
• decrease in any 3 causes microcytic anemia’s*

Most common form of anemia in hospitalized patients

Question 7

Macrocytic anemia’s

Answer 7

Usually stem from abnormalities that impair Maturation of erythroid precursors in bone marrow
- usually folate or Vit B12 deficiencies

• both folate and Vit. B12 are required for DNA synthesis and hemopoiesis by enabling methionine and thymidylate synthase enzymes

Question 8

Normochromic, normocytic anemia’s

Answer 8

Diverse etiologies and have a wide variety of specific abnormalities to the share of RBCs

Question 9

Iron deficiency anemia

Answer 9

• Deficiency of iron is the most common deficiency in the Underdeveloped world and the most common reason for anemia*
• chronic blood loss it the most common cause of iron deficiency in the developed world*
• it is assumed, until proven otherwise, that if a patient in the developed world has iron deficiency, it must be attributed to GI blood*

Can be caused by 1 of 4 causes

• dietary lack
• impaired absorption
• increased requirement
• chronic blood loss

ALWAYS PRODUCES HYPOCHROMIC MICROCYTIC ANEMIA

Question 10

What is the recommended daily iron requirement for men and women?

Answer 10

7-10 mg =. Men

7-20 mg = women
- these values are due to only 10-15% of ingested iron is absorbed properly

• at least 1 mg must be absorbed from the diet/day*
• increased requirement in premenopausal/ pregnant women, growing infants and children*

Question 11

Organic vs inorganic iron

Answer 11

Red meat = organic form and is easily absorbed in diet (its in heme form)

Plant iron = inorganic form and is poorly absorbed in diet (in non heme form)

• populations that eat more plants than meat are at risk for anemia*

Question 12

What are possible causes of impaired absorption of iron

Answer 12

Spure

Chronic diarrhea

Gastrectomy

Celiac disease

Question 13

What is the most diagnostically significant finding for iron deficiency?

Answer 13

Disappearance of stainable iron in macrophages in the bone marrow

• RBCs being destroyed dont have iron so the macrophages wont stain either in iron deficiencies

Question 14

Poikilocytosis

Answer 14

Small elongated red blood cells that are also called “pencil cells”

• seen in iron deficiencies and thalassemias

Question 15

Clinical features of acute iron deficient anemia

Answer 15

Weakness

Malaise

Easily fatiguable

Dyspnea

• also present with symptoms based on the underlying causes of the anemia (i.e GI bleeds)*

Question 16

Clinical features of chronic iron deficiency anemia

Answer 16

Koilonychia (brittle concaved looking nails)

Alopecia (paleness)

Atrophied changes in tongue and gastric mucosa

Intestinal malabsorption

Question 17

Diagnostic criteria for iron deficiency anemias

Answer 17

Hypochromic and microcytic RBCs

Low MCV

Low serum ferritin

Low serum iron levels

Low transferrin saturation ( will lower before symptoms arise)

Elevated platelet count (not completely understood why)

responses to iron therapy

Question 18

Anemia’s of chronic disease

Answer 18

Anemia’s that resemble iron deficiencies but are actually caused by suppression of erythropoiesis sue to systemic inflammation 
examples:
- chronic microbial infections 
- chronic immune disorders 
- neoplasms 

Stem from high levels of plasma hepcidin (blocks transfer of iron to erythroid precursors by down regulating ferroportin in macrophages)
- this is caused due to high IL-6 levels seen in inflammatory states

• Most common in hospitalized patients*

Question 19

Clinical features of anemias of chronic disease

Answer 19

Serum iron levels are low

Plasma hepcidin are high

RBCs slightly hypochromic and microcytic

Storage levels of iron in bone marrow and ferritin are high, but overall decrease in measured iron-binding capacity

• treatment of anemia of chronic disease is commonly done via administration of erythropoietin, however the only way to reverse it is to cure the underlying cause*

Question 20

Megaloblastic anemia

Answer 20

Type of macrocytic anemia caused by a deficiency in thmidylate synthatase enzymes which lowers the free amount of thymidine and thymidylate (building block of DNA)

• shows nuclear-cytoplasmic asynchrony disorder and causes premature apoptosis of RBCs in red bone marrow
  (Ineffective hematopoiesis)

Question 21

Clinical features of macrocytic anemias

Answer 21

Pancytopenia (low granulocyte and platelet precursors)

Hypercellular megaloblastic erythroid progenitors

RBCs appear ‘egg shaped”

Presence of hyper-segmented neutrophils in blood (5-6)

MCV = > 110 fL.

Question 22

Folate deficiency anemia

Answer 22

Almost always results from Inadequate dietary intake
- most common in elderly, vegans, Pregnant women

Can results from absorption/ metabolism dysfunction

• high acidic foods in diets can causes an absorption disorder
• Drugs can as well such as methotrexate and phenytoin
• celiac disease and tropical sprue are the most common absorption issues

Question 23

Function of folate

Answer 23

Converts dihydrofolate -> tetrahydrofolate via dihydrofolate reductase

Tetrahydrofolate acts and an acceptor and donor for synthesis of dTMP
-dTMP is required to synthesize hemoglobin and membrane proteins in RBCs as well as DNA replication

Question 24

Clinical features of folate deficiency anemia

Answer 24

Insidious onset w/ weakness and easily fatigued

Often seen in alcoholics

GI symptoms (upset stomach, sore tongue/throat, diarrhea etc.)

• NO neurological abnormalities occur (unlike Vit. B12 deficiencies*

Only way to really make the diagnosis is blood smears showing megaloblastic cells and measuring serum folate/ B12 levels.

Question 25

Vit B12 (cobalamin) deficiency anemia

Answer 25

Caused by Vit. B12 deficiencies usually via absorption/metabolic disorders - almost never found in low dietary intake, except for vegans (avoiding milk and eggs) Takes years form the beginning of onset to diagnose. (Due to very large stores of Vit B12 in the liver)

Question 26

Pernicious anemia

Answer 26

*Most common cause of vitamin B12 deficiency anemia* Caused by an autoimmune attack on gastric mucosa that suppresses intrinsic factor production. ( assumed to be T-cell initiated) - histologically shows chronic atrophic gastritis and a loss of parietal cells and marked increases in lymphocytes in the mucosa Antibodies in the serum block binding of Vit B12 to intrinsic factor/ cubilin

Question 27

Vitamin B12 deficiency causes for malabsorption specifically

Answer 27

Gastrectomy Ileal resection ( loss of intrinsic factor) Chronic disease Tropical sprue and whipped disease Gastric atrophy achlorhydria (low hydrochloride acid in the stomach)

Question 28

Function of Vit B12 in blood

Answer 28

Recycles tetrahydrofolate ( form that is needed for DNA synthesis) *deficiencies can show demyelination and degeneration of the posterior/lateral columns of the spinal cord*

Question 29

Clinical features of Vit. B12 deficiencies

Answer 29

Pallor Easy fatiguable Dyspnea red tongue Symmetric numbness, tingling burning feet or hands Unsteady gait/ loss of position of sense

Question 30

4 laboratory findings of vitamin B12 deficiencies

Answer 30

1) low serum, Vit B12 levels 2) normal/ slightly elevated serum folate levels 3) moderate to serve macrocytic anemia 4) leukopenia with hypersegmented granulocytes * show pernicious anemia with serum antibodies to intrinsic factor*

Question 31

Normochromic/ normocytic anemia

Answer 31

Normal MCV Increased reticulocyte counts for hemolytic anemia Decrease reticulocyte counts for aplastic anemia

Question 32

Aplastic anemia

Answer 32

Multipotent myeloid stem cells are suppressed which leads to bone marrow failure and pancytopenia - bone marrow has high levels of fat and low red bone marrow Most aplastic anemia is idiopathic but drug induced is common when exposed to cancer chemo/whole body irradiation,or hypersensitivity reactions Viral hepatitis is a rare cause but possible as well

Question 33

Specific inherited abnormalities that underlie aplastic aplasia

Answer 33

Fanconi anemia: rare autosomal disorder caused by defects in a multi-protein complex that is required for DNA repair Marrow hypofunction: becomes evident early in life and is often seen via hypoplasia of kidney, spleen and bone marrow Telomerase defects (always abnormally short telomeres in 510%)

Question 34

Two mechanisms possibly invoked during aplastic anemia

Answer 34

Extrinsic immune-mediated suppression of marrow progenitors - stem cells are first antigenically altered by drugs, infectious agents or environmental issues - promotes cellular immune response (TH1) that promotes IFN-y and TNF that suppress and kill hematopoietic progenitors - treated via immunosuppressive therapy against T cells Intrinsic abnormality of stem cells with telomerase - 5-10% of patients - leads to premature senescence of hematopoietic stem cells

Question 35

Neoantigens

Answer 35

Genetically altered stem cells via intrinsic pathway in aplastic anemia release neoantigens which attach T cells and cause them to release TNF and IFN-y *shows connection between intrinsic and extrinsic pathways*

Question 36

Clinical features of aplastic anemia

Answer 36

Can occur any age or any sex equally - insidious onset Pancytopenia and reticulocytopenia occurs with anemia induced weakness, pallor and dyspena Thrombocytopenia induced petechiae and ecchymoses Sudden random onset of chills and fevers *bone marrow biopsy is the only way to confirm*

Question 37

Prognosis and treatment of aplastic anemia

Answer 37

Prognosis varies however all treatment usually requires bone marrow transplantation (75% survival) Older patients or no donor = immunosuppressive therapy but this doesn’t cure, only prevents further damage

Question 38

Pure red cell aplasia

Answer 38

Only erythroid progenitors are completely absent from marrow Often presents with cancers, autoimmune disorders and parvovirus B19 infections - all of these will also produce autoimmune issues except parvovirus B19

Question 39

Parvovirus B19 in pure red cell aplasia

Answer 39

Initially attacks red cell progenitors, resulting in pure red cell aplasia. - usually clears up within 1-2 weeks and because of this is temporary Moderate to severe hemolytic anemias sickle cell anemia and hereditary spherocytosis will produce aplastic crisis - if compounded with autoimmunity, will produce chronic red cell aplasia