Week 1 Flashcards
Normal morphological maturation of granulocyte precursors
Blast (3-4%)–> promyelocyte (2-8%) –> myelocyte (10-13%) –> metamyelocyte (10-15%)–>bands and neutrophils (25-40%)
Which cells of granulocyte maturation form a mitotic pool in the marrow? Of those which is most common?
blast, promyelocyte, myelocyte (most common)
Which cell of granulocyte maturation has primary granules?
promyelocyte
Which cell of granulocyte maturation has secondary granules?
myelocyte
Which cell of granulocyte maturation has a bean shaped nucleus?
metamyelocyte
Which cell of granulocyte maturation has prominent hof?
myelocyte
What releases G-CSF?
bone marrow and stromal cells
% of bone marrow doing erythropoiesis
20-30%
% of bone marrow doing myelopoiesis
60-70%
What key growth factors can be mimicked by drugs and what do they stimulate?
EPO: BFUe–> CFUe
TPO: BFUemeg–> CFU meg
GM-CSF
G-CSF: CFUgm–> CFUg
Where does G-CSF act?
Blast–> promyelocyte–> myelocyte
What organ releases TPO and is it constiuitive or only when stimulated?
liver; constant
Describe the genetic material of megakaryocytes
polyploid: 16-32n
How are platelets formed?
proplatelets are extended into fenestrated blood vessels in bone marrow and get looped off
What 2 things does TPO bind?
platelets and megakaryocytes
In normal conditions, describe the function of TPO
binds mostly platelets, some goes to megakaryoctes (where it stimulates production of more megakaryocytes and platelet production).
In low platelet, describe the function of TPO?
more TPO binds megakaryocytes stimulating more thrombopoiesis
What is the cell lineage in normal maturation of erythropoiesis?
blast–> pronormoblast–> basophilic erythroblast–> polychomatophilic erythroblast–> normochromic erythroblast
How much of the bone marrow is cellular and active?
100%-age.
Heme synthesis requires:
Iron***, B6, succinyl CoA, glycine (B12+ folate(
globin synthesis requires:
normal globin genes, alpha, beta, amino acids
What usually causes globin problems in the US?
genetic problems rather than malnutrition
DNA synthesis requires:
deoxynucleoside triphosphates (ribonucleotide reductase, thymidine (B12, folate))
For which of the requirements for erythropoiesis is folate and B12 required?
DNA synthesis, Heme synthesis
Morphology of iron deficiency
microcytosis, hypochromia, anisocytosis (size distribution), poikilocytosis ( cell shape variation)
Dietary iron is in _____ state.
Oxidized: Fe3+, ferric
What has to happen for dietary iron to be absorbed?
It has to be reduced in the stomach to ferrous iron (Fe2+) before it can be taken up in the bowel.
What 2 factors affect the ability of dietary ferric iron to be reduced?
low pH, Vitamin C
What happens after iron is absorbed in the bowel?
It is oxidized to Fe3+ (ferric) by serum oxidases then bound to transferrin
Reduced transferrin levels can cause _____.
Low serum iron
What takes up transferrin-bound iron?
bone marrow macrophages via TfR1
How is TIBC calculated?
lab saturates transferrin with added iron.
What does TIBC tell you?
if serum iron is low due to reduced transferrin or not
What is % transferrin saturated?
serum iron concentration/ TIBC
What increases in iron deficiency?
serum transferrin and soluble transferrin receptors
What is reduced in iron deficiency?
serum iron, iron saturation, serum ferritin
Outside of red cells and transferrin, most of the body’s iron stores are bound to a protein called _____.
Ferritin
What morphology is seen with B thalassemia?
microcytosis (may be smaller than in iron def), hypochromia, target cells,
Target cells are not specific; they are commonly associated with ______.
liver disease
How can you tell if a pt has iron deficiency or thalassemia?
Number of red cells. In iron deficiency, the number goes down. In thalassemias, its normal or increased.
How can you confirm a thalassemia after seeing the right lab values?
Because Hb A2 is increased and it migrates differently during electrophoresis. Hb F may also be detected if the thalassemia is severe
Describe the beta globin locus.
It is on chromosome 11. There are 6 copies on each chromosome. 3 are expressed in utero (epsilon, g-gamma, a gamma), psi-beta does nothing, delta is in fetus and low amounts in adults, and finally beta is the form expressed in adults
If expression of beta globin allele is impaired, what may increase?
Hb A2, Hb F if severe
Decribe the alpha globin locus
Chromosome 16; 4 copies on each chromosome. zeta 1 and 2 are expressed in utero, alpha 1 and alpha 2 in adults
What happens when there is a mutation in one of the 4 alpha genes (2 on each chromosome)?
Alpha thalassemia 1 trait
What happens if there are 2 defective alpha alleles?
alpha thalassemia 2 trait
What RBC problems is expected with alpha thalassemia 2 trait
mild microcytic anemia, excess Hgb Barts (gamma 4 tetramer) at birth, normal electrophoresis as adult
how is alpha thalassemia 2 trait diagnosed?
PCR
What percent of population have alpha thalassemia 2 trait
3% of blacks
What happens if there are 3 defective alpha alleles?
Hgb H disease (beta 4)
What are the clinical findings associated with Hgb H disease?
variable degree of microcytic anemia,
What happens if all 4 alpha alleles are defective?
lethal in utero or soon after birth, Hgb H disease
UTP has to be methylated to TTP. Methylation requires what?
B12 and folate
What happens if DNA synthesis is impaired?
fewer cells produced, normal/enhanced maturaion of cytoplasm, impaired nuclear maturation
What are the causes of megaloblastic anemia?
Impaired B12 uptake (pernicious anemia); impaired folate uptake (malabsorption, malnutrition), drug effect (nucleoside analogs [HAART], ribonucleotide reductase inhibitors [hydroxyurea]), intrinsic bone marrow dysfunction (myelodysplastic function)
_____ can impair iron storage usage.
Hepcidin
Chronic inflammation conditions can induce ____ production that impairs utilization of bone marrow iron stores.
Hepcidin
What cytokine is produced in chronic inflamattion that causes production of hepcidin?
IL-6
Failure to use iron stores is seen in ______.
anemia of chronic inflammation
How do you confirm anemia of chronic inflammation?
bone marrow biopsy
Describe the clinical findings of anemia of chronic disease
normocytic anemia, increased ferritin, reduced or normal serum ion, increased bone marrow iron stores.
Define ferritin
stores iron; has apoferritin shell and hydroxide core. It is water soluble and easy to mobilize in deficiency
How is hemosiderin different from ferritin?
lacks apoferritin shell
Define labile iron pool. How many mg of iron?
iron leaving the plasma and entering the interstitial and intracellular fluid compartments. 80-90 mg
What makes up the smallest pool of iron?
Transferrin- 3mg
How many times a day does transferrin turn over?
10
Where is transferrin found and how much of it is saturated?
plasma; 1/3
How many mg of iron do youg/ pregnant women absorb?
2/3 mg
How many mg of iron do men absorb?
1 mg
____ allows export of iron from duodenal enterocyte into circulation.
ferreportin
What does hepcidin do to ferreportin?
degrades it
What does ferriportin regulate?
transfer of iron from mom to baby; iron absorption in intestines; iron export from macrophages
Hepcidin is a _____ regulator of iron uptake.
negative
_____ inhibites hepatocytes that store iron.
Hepcidin
What increases the absorption of non-heme iron?
low ph, ascorbic acid; Vitamin C
What decreases the absorption of non-heme iron?
insoluble complexes, chelating agents
What 3 major things can cause malabsorption of iron?
GI tract surgery, non-tropical sprue, picca
What is non-tropical sprue?
gluten induced damage to differentiated villus epithelial cells of the small intestines; stop all grains except rice and corn
What is tropical sprue?
overgrowth of coliforms in jejunum that results in malabsorption of folic acid, cobalamin, fat, folic acid
causes of GI bleeding in US adults
peptic ulcer disease, hiatal hernia, chronic gastritis, hemorrhoids, intermitant bleeding after surgery, neoplasms
Causes of GI bleeding in infants
milk allergy (boil milk), Meckel’s diverticulum
Most common cause of GI bleeding in underdeveloped countries
hook worm
Symptoms of iron deficiency
fatigue, headaches, irritability, decreased exercise tolerance, burning tongue, picca
physical findings in iron deficiency
pallor, glossitis, stomatitis, angular chelitis
What is koilonychia
spoon shaped nails associated with iron deficiency
How is iron deficiency treated orally?
Ferrous sulfate
What are the indications for parenteral iron therapy?
malabsorption, intolerance, uncooperativeness, inability of pt
What are some side affects associated with intravenous iron therapy?
thrombophlebitis, arthralgia, hypotension, bradycardia, nausea and vomiting, anaphylactic reactions
What does unbound iron due to iron overload do?
release hydroxyl radical, lipid peroxidation, fibrosis, carcinogenesis
____ occurs in 30% or chronic alcoholics
iron overload
How does alcohol lead to iron overload?
high iron content in red wines, folate def increases iron absorption
Clinical findings of iron overload due to alcohol
skin pigmentation, hypogonadism, glucose intolerance,
How is thalassemia related to iron overload?
need of transfusion can cause iron overload
What are the clinical findings of iron overload due to treatment of thalassemia?
1st decade: hepatomegally; lack of sexual development. 2nd decade: cardiomegally
What is the treatment of iron overload due to transfusions?
dextroferramine
____ is a group of diseases in which there is excessive absorption of iron from the gastrointestinal tract leading to iron overload of the parenchymal cells of the liver, endocrine organs, and in the heart.
hereditary hemochromatosis
Mode of inheritance of hereditary hemochromatosis
autosomal recessive with variable penetrance
What happens to hepcidin levels in hemachromatosis?
a mutation in the HFE gene occurs that results in low hepcidin levels. Iron can accumulate for years and the hepcidin levels remain low
Clinical symptoms of hemachromatosis
liver function abnormalities, weakness and lethargy, skin hyperpigmentation, diabetes, arthralgias, impotence, heptomas
Lab findings with hemachromatosis
high serum iron, low binding capacity, high saturation, high ferritin, increased iron in liver biopsy
Treatment for Hemachromatosis
phlebotomy
Why are patients with hereditary hemochromatosis told to avoid vitamin C?
It increases absorption of iron
How is hemachromatosis diagnosed?
HFE gene mutation analysis
What is the common, Type 1 hemochromatosis mutation in the HFE gene?
C282Y
What are the main foods containing folate?
liver, greens, yeast
What are the body stores of folate?
10-12 mg, 4 months worth
When is there an increased demand for folic acid?
pregnancy, RBC turnover in hemolytic diseases, dermatitis, certain drugs
What causes impaired absorption of folic acid?
tropical sprue, regional enteritis, resection of small intestines
Who is at risk for inadequate dietary intake of folate?
elderly, poor, alcoholics
Clinical features of megaloblastic anemias
insidious onset, mild jaundice, glossitis, angular stomatitis, weight loss, purpura
How do the neutrophils appear with megaloblastic anemia?
hypersegmented
Treatment of folate deficiency
1mg a day of folic acid supplemented with B12 if unsure of diagnosis to avoid neuropathy due to B12 deficiency
What are some important factors to absoprtion of B12?
R-B12 complex, IF-B12 complex, cubilin and amnion in transportation into enterocyte
Sources of B12
animal products, milk, eggs, cheese
Gastric disorders leading to B12 deficiency
total gastrectomy, blind loop syndrome, zollinger ellison syndrome; gastric producing tumors in pancrease secreting lots of HCL so B12 doesnt bind to IF, Ileal resection, malabsorption from hypothyroidism or drugs, tropical sprue, pancreatic insufficiency, vegans
What neurologic disorder is associated with B12 deficiency?
Early: parathesias, somulence and demetia, decreased vibratory and proprioreception
Late: paralysis from demyelination of dorsal and lateral columns, combined systemic disease
A lack of IF leads to _____.
pernicious anemia
____ is an autoimmune disease with insidious onset due to failure of IF secretion because of gastric mucosal atrophy.
pernicous anemia
Describe the pathogenesis of pernicous anemia.
CD4 T cells recognize receptors in secretory membrane. Antiparietal cell Ab in 90% of cases; IF Ab found in 50-70%
What test is performed when pernicious anemia is suspected?
schilling test
how is B12 deficiency treated?
give IM B12 for 2 wks
What type of sprue is associated with iron deficiency?
non-tropical
What type of sprue is associated with malabsorption of B12 and folate?
tropical
Hb ____ doesn’t give up oxygen as easily.
fetal
What happens if there are no functional alpha globin chains?
death
What unique Hb are seen with Beta-Thal?
increased F and A2
What unique Hb are seen with alpha-thal?
Hb H, Bart’s
Why are patients with B thalassemia anemic?
RBC die because of lack of Beta globin, causing hemolytic anemia and short-lived RBC. Blood transfusions can then cause iron overload.
Why do patients with T. major have distorted bones?
Bone marrow is extremely expanded and working super hard.
What clinical findings are seen the B-thalassemia major?
distorted bones, hepatomegaly, splenomegaly, hyperpigmentation, ulcers, cirrhosis of the liver, hepatocellular carcinoma
Why are pt with thalassemia hypercoaguable?
Membranes are damaged by alpha hemichromes and oxidative stress so that phosphotidlyserine is expressed on outer leaflet, targeting cell for apoptosis. This increases platelet activaion, hgb levels, and thrombin production.
Why do pt with thalassemia have endocrine and bone diseases?
hypogonadism, pituitary insuffieciency, osteopenia
Where is basophilic stippling seen?
thalassemia trait and major, hemolytic anemia, megaloblastic anemia,
Describe the diagnostic process for thalassemia?
family history, CBC, blood smear, physical exam (maybe normal), HPLC, PCR for alpha thal
What is hereditary persistence of fetal hemoglobin?
marked decrease in beta globin sytnthesis compensated by an increase in gamma chain synthesis.
_____ occurs 1%, as often as SS, and produces a favorable sickle syndrome.
S/HPFH
What is Hgb E disease?
Hgb E has a point mutation on beta globin that produces an unstable mRNA and beta-thal minor picture in homozygotes.
What is E/Beta- thal?
more common, 1 beta gene has mild-severe mutation and one has Hbg E mutation. Causes Thal minot to intermediate.
What is hemoglobin lepore?
normal alpha chains, a delta/beta fusion leads to thalassemia int. or major.
What kind of mutation usually causes beta thalassemia? Alpha?
Beta= point, alpha=deletion
Loss of 4 alpha genes=
gamma4. Bart’s –> fetal death, hydrops fetalis
Loos of 3 alpha genes=
Hb H disease (Beta4)
Loss of 2 alpha genes=
trait
Loss of 1 alpha gene-
carrier
What is hemoglobin spring constant?
single base substitution in the terminal codon of alpha chain so that mRNA copies another 31 amino acids, making an unstable mRNA leading to market decrease in translation of alpha globin gene to protein. Moderately severe alpha thal clinical picture.
