Farland Macrocytic Anemias

Front 1

Megaloblastic anemia cause and morphology

Back 1

Defect in DNA synthesis →
-unbalanced cell growth
-impaired division
-Most common causes are B12 and folate deficiency

Distinct morphologic pattern
-Immature-appearing nucleus
-mature cytoplasm
-hypersegmented neutrophils
-large cells

Front 2

Two cobalamin dependent mechanisms

Back 2

L-methylmalonyl-CoA to Succinyl CoA
-cobalamin as a cofactor
-if no B12, buildup of methylmalonic acid
Homocysteine to methionine
-cobalamin as a cofactor
-Demethylation of methyl-tetrahydrofolate (CH3-THF) to THF is a critical step in DNA synthesis because THF is the substrate for the enzyme that converts (THF)-1 to the polyglutamated form (THF)n. Only polyglutamated (THF)n participates in purine synthesis: convert deoxyuridylate to thymidylate.
-if no b12, buildup of homocysteine

Front 3

Cobalamin absorption

Back 3

Cobalamin bound to animal protein
Acidity of stomach dissociates cobalamin from animal protein
Salivary R protein grabs cobalamin and exits stomach
Intrinsic factor (unbound) goes with it into duodenum
Decreased acidity, R protein leaves and intrinsic factor binds
Absorption occurs in distal third of ileum
Enterocyte has cubulin which is receptor for intrinsic factor
Cobalamin dissociates from intrinsic factor and is transported to portal system by transcobalamin

Front 4

Pernicious anemia

Back 4

Pernicious anemia – autoimmune destruction of gastric parietal cells or intrinsic factor
Traditionally diagnosed by Schilling Test
Can now be diagnosed by detection of anti-IF or anti-parietal cell antibodies

Front 5

Folate dependent mechanisms

Back 5

If no folate, there is no methyltetrahydrofolate
-buildup of homocysteine

Front 6

Serum findings in megaloblastic anemias

Back 6

B12 deficiency:
cobalamin low
folate normal
methylmalonic acid high
homocysteine high

Folate deficiency:
cobalamin normal
folate low
methylmalonic acid normal
homocysteine high

Front 7

Megaloblastosis: not just blood cells

Back 7

All proliferating cells can exhibit megaloblastosis
-epithelial cells lining the gastrointestinal tract (buccal mucosa, tongue, small intestine)
-cervix, vagina, and uterus.
However, megaloblastic changes are most striking in the blood and bone marrow

Front 8

B12 deficiency neuropsychiatric manifestations

Back 8

Peripheral neuropathies
Dorsal column involvement (loss of position and vibratory sense, ataxia)
Subacute combined degeneration of spinal cord
Psychiatric symptoms (dementia, psychosis)

Front 9

Subacute combined degeneration of the spinal cord

Back 9

Largely due to demyelination
Posterior spinal tracts – diminished vibration and postion sense in the lower extremities
Lateral tract injury – impairment of motor function and spasticity

Front 10

Folate and B12 deficiency treatment

Back 10

1000 microg B12 weekly by IM injection x 8 weeks then monthly for life
Consider oral therapy with very high doses with close monitoring
Folate 1 mg po per day
Warning: Folate repletion without B12 repletion may normalize MCV and Hgb but allow neurologic manifestations to persist

Front 11

Causes of folate deficiency

Back 11

Diet lacking fruits and veggies
Alcoholism
Absorptive
Hemodialysis
Cellular proliferation
Drugs
-antifolates
-anticonvulsants

Front 12

Reticulocytes

Back 12

Occur after extrusion of nucleus from orthochromic normoblast
Remain in marrow for approx 3 days
Released into circulation – remodeled with loss of water and membrane
Normal retics are macrocytic
Shift to spend more time in peripheral blood when hematocrit drops

Front 13

Alcohol and macrocytosis

Back 13

Mechanism unknown
Acetaldehyde
-can induce membrane changes
-Interferes with cellular division

Front 14

Liver disease and macrocytosis

Back 14

Mechanism of macrocytosis unclear
May be caused by increased lipid deposition on red cell membranes
Target Cells

Front 15

Thyroid disease and macrocytosis

Back 15

Mechanism of macrocytosis unknown
Autoimmune thyroiditis associated with antiparietal cell antibodies

Front 16

Spurious macrocytosis

Back 16

Artifacts that can occur to normal sized RBCs
Clumps of RBCs counted as single cells by automated cell counters

Front 17

Myelodysplastic syndromes: definition, features

Back 17

Definition from National Cancer Institute
-A group of diseases in which the bone marrow does not make enough healthy blood cells. Also called preleukemia and smoldering leukemia.
Features
-Hypolobulated or hypogranular neutrophils
-Large and/or abnormally granulated platelets
-Monocytosis
-Occasional blast forms
-Macrocytosis is common
Largely irreversible (but treatable)