Anemia Flashcards
Anemia
insufficient red cell mass to adequately deliver oxygen to peripheral tissues
measurements to define anemia (8)
hemoglobin concentration hematocrit red blood cell count MCV MCHC RDW WBC count and differential platelet count
percent volume of red cells in blood
hematocrit
variation in Hgb and Hct based on gender
higher than ever at birth
decrease to lower than adults in childhood
puberty go back to adult levels
menstruating women have lower values
How can we ID retics?
presence of mRNA
How are retics counted?
—as the percent of 1000 red cells counted (normal 0.4-1.7)
absolute retic count?
%retics x RBC count
reticulocyte index
ratio of how many fold beyond baseline the production of red cells is:
RI = Retic Count x (PatientHgb /Normal Hgb) x 1/stress factor
where 1.5 = mild
2 = moderate
2.5 = severe anemia
What should the RI be for a health individual?
1-2
2,3-DPG and anemia?
If develops over weeks, 2-3DPG compensatory mechanism will help O2 dissociate in tissue
If develops acutely, 2-3DPG does not have enough time to esatblish compensatory mechanism
Symptoms of anemia
shortness of breath fatigue rapid heart rate dizzy pain with exercise pallor
signs of anemia
tachycardia
tachpnea
dyspnea
pallor
Question one in the classification of anemias
Are there any additional hematologic abnormalities
If anemia is associated with additional hemotologic abnormalities (e.g., thrombocytopenia, leukopenia, neutropenia) what should you consider?
look for infiltrative and proliferative processes (e.g., leukemia, lymphoma, aplastic anemia)
If the only manifestation is anemia, what should be your next question?
Is there an appropriate reticulocyte response to anemia?
If the only manifestation is anemia and there is an increase in reticulocytes, what should you consider?
increased red cell destruction (hemolysis) or hemorrhage
If the only manifestation is anemia and the retic count is not increased and there is no other evidence for hemolysis, what should you consider?
the type of anemia based on the MCV and size…i.e., normocytic, macrocytic, or microcytic
in what form does iron exist?
Iron exists in two valence states, ferric and ferrous - activity may depend on specific state
iron in aqueous solution
in aqueous solutions, iron forms insoluble hydroxides unless bound to a specific protein or other compound
at what pH is iron more soluble?
low
how does the body control iron balance?
controlled by absorption
there is no active excretion mechanism
iron losses?
losses each day are small
- exfoliation of skin and mucosal surfaces (GI/skin)
- in urine or with menstruation
is iron ever free in the body?
no
majority of iron is contained?
hemoglobin (65%)
primary storage form of iron?
ferritin and hemosiderin are the primary storage forms of iron (25% of the total body iron, mostly intracellular)
in addition to hemoglobin, what other oxygen binding protein binds iron and how much?
myoglobin (6%)
In addition to ferritin and hemosiderin, plus the oxygen binding proteins, what transport protein binds iron?
transferrin
a very small amount of iron is bound to transferrin, the transport protein which moves the iron to the tissues requiring iron - particularly the developing erythroid precursors.
Aside from the major iron binding proteins, what is the remaining
a whole variety of enzymes, including catalases, peroxidases, cytochromes, and other proteins which a critical to basic metabolic processes of the cell
Where does the absorption of iron take place?
mucosal surface of the duodenum
Hemoglobin iron form
Fe2+ (ferrous)
myoglobin iron form
Fe2+ (ferrous)
transferrin iron form
Fe3+ (ferric)
transferrin iron form
Fe3+ (ferric)
Plasma Fe transporter?
transferrin
Intracellular Iron sotarage?
Ferritin and hemosiderin
How do we get iron into mucosal cell?
DCYTB converts Fe3+ to Fe2+ then comes into cell through DMT1
Once iron is inside mucosal cell what happens?
Can be stored as ferritin
Or
Can cross basolateral membrane through ferroportin (Haphaestin coverts back to Fe3+)
what compound forms pore in basolateral membrane of mucous cell to allow mobilization of iron from cells into blood stream?
ferroportin
What compound produced by the liver decreases ferroportin?
hepcidin
types of iron absorbed?
elemental adn heme bound
Intraluminal factors influencing iron absorption (5)
gastric (low pH / gastroferrin) presence of proteins / amino acids (more) vitamin c (more) phytates / oxalates (less) amount of iron ingested
Hephaestin
oxidizes Fe2+ to Fe3+ as it moves out of basolateral ferroportin to bind plasma transferrin
Extraluminal factors influencing iron absorption?
Erythropoietic activity (up)
Transferrin
main transport protein for iron (Fe3+)
binds 2 moles / mole
Where does transferrin go?
finds its way to the bone marrow and the maturing normoblasts where it binds transferrin receptors on the surface of cells where it is directed into cell and incorporated into hemoglobin
Who turns over erythrocytes?
macrophages in the spleen
what do macrophages do with the iron?
macrophages sequester iron in ferritin stores
is there extracellular ferritin?
only small amount
what happens to the ferritin bound iron in macrophages
evenutally iron from the storage pool may be released from teh cell and bound by transferrin again
what is the difference between ferritin and hemosiderin
in hemosiderin the iron is not completely soluble and bioavailble
what is hepcidin
25 aa antibacterial peptide produced by hepatocyte
negative regulator of iron absorption / transport / release
When do we make hepcidin
inflammation / infection / iron overload
hepcidin implication for hemochromatosis
deficiency of hepcidin
how does hepcidin increase iron retention in macrophage?
inhibits ferroportin - causes increase in macrophage retention - contributing to anemia
how does hepcidin influence iron resistant iron deficiency anemia?
implicated because iron won’t help if iron won’t be released
what is a negative regulator of iron absorption / transport / and release
hepcidin
Hepcidin release from hepatic cells during infection/inflammation –>
increased accumulation in macrophagic ferritin
splenic macrophage and iron?
stores Fe3+ in ferritin
Development of iron deficiency… first thing we see?
depletion of iron stores –> increase in iron absorption
Initial stage of iron deficiency, what is going on with transferrin?
should be the same saturation initially because we have only depleted stores - we are still going to be able to make normal amount of hemoglobin
Moderate stage of iron deficiency
We start to see a decrease in the serum as well as stores - then we see increase in iron binding capacity of transferrin and an incrase in iron absorption - start to see porphyrin rings that don’t have any iron in them (Protoporphyrin)
State of things when anemia sets in
our iron binding capacity will be elevated our ferritin will be low saturation we will have increased absorption decreased serum iron increased protoporphyrin micro/hypo erythrocytes
Hepcidin and ferroportin?
Hepcidin causes inhibtioion of ferroportin - leading to increased retention in macrophages contributing to anemia
Hepcidin is associated with which biological process?
inflammation/infeciton or iron overload
iron deficiency anemia is which kind?
micro/hypo
In addition to hematopoietic anemia, which other systems are affected?
neuromuscular epithelial upper GI Lower GI Immune
IMicrocytic Iron deficiency anemia is most commonly seeni in?
Infants / Teen grils
Etiology of iron deficiency anemia (microcytic?)
decreased intake
increased loss
increased need
Iron deficiency anemia
Oxygen carrying capacity?
Hemoglobin and Hematocrit are down
Iron deficiency anemia
reticulocytes?
Decreased production :(
Iron deficiency anemia
MCV?
Microcytosis
Decrased MCV
Iron deficiency anemia
MCHC
Decrased
Iron Defieicney anemia
RDW
Increased
Iron deficiency anemia
Serum Fe?
Down
Iron deficiency anemia
TIBC
Increased
Iron deficiency anemia
ferritin level?
decreased
iron deficiency anemia
free erythrocyte proprophyrin (FEP)
Increased
Treatment of iron deficiency anemia
Oral iron
Normalization cascade iron deficiency anemia?
Serum iron –> Hbg/rectic –> ferritin –> MCV/FEP/RDW
Too much iron =
hemachromatosis
Etiology of hemachromatosis
too much in diet
too much absorption (HLA-H)
Repeat transfusions
Dangers of hemachromatosis
cardiac
liver
pancreas
serum iron
ferritin
liver iron
in hemachromatosis
all will be increased
treatment
hemochromatosis
therapeutic phleb
treatment
hemosiderosis
iron chelators
anemia of chronic disease (6) associated conditions
chronic infection chronic inflammation malignant disease lead intoxication renal insufficiency endocrine issues
pathophysiology of anemia in neoplasms and sepsis
increased TNF leads to decreased iron and EPO
increased INF-B
both lead to inhibition of erythroid proliferation and decreased RBC production
pathophysiology of anemia in chronic infeciton and inflammation
increased IL1 release leads to decrease iron and decrease EPO
Increased INF-gamma
both lead to inhibition of erythroid proliferation and decreased RBC production
pathophysiology of lead intoxication anemia
lead inhibits enzyme that puts iron on prophyrin ring and inhibits protoporphyrin synthesis
this lead to decreased heme + globin
pathophysiology of renal insufficiency anemai
decreased EPO –> decreased erythroid proliferation
We have a patient who comes in with fever, arthalgias, and fatigue…
Mild to moderate anemia (Hgb 8/12)
Normochromic, normocytic or microcytic with some hypochromia
They have decreased serum Fe Decreased TIBC normal to increased ferritin decreased EPO for Hct Decreased Rectic
What do you think they have?
Anemia due to chronic inflammation or infeciton
What are distinguishing features of chronic inflammaiton or infeciton anemia?
Unlike iron deficiency, they will have decreased TIBC and normal to increased ferritin
Chronic inflammation usually which type?
Normocytic or microcytic
Chronic inflammation serum Fe?
down
Chronic inflammation TIBC?
down
Chronic inflammation ferritin
normal to increased
chonic inflammation EPO?
down for Hct
chronic inflammation retic count?
down
Personality changes / irritaiblity / weight loss/ nausea etc are clinical features of which anemia?
lead toxicity
lead toxicity anemia usually which type?
microcytosis and hypochromia
what distinguishing features might we see with lead intoxciation anemia
increased zinc protoporphyrin
basophilic stippling
what distinguishing features will we see in renal insufficiency anemia?
what type?
EPO deficiency
Normocytic
Hypothyroidism, type?
most normochromic and normocytic, may be micro or macro
Hyperthryoidism, type?
normo, may be micro
When should we transfuse?
only transfuse red cells when the severity of anemia has potenital for cardiovascula decompensation
when should we use EPO? (2)
an absolute deficiency
or
a decrease our of proportion to Hct, for which a response has been documented
Sideroblastic anemia
underproduction
impaired protoporphyrin production or incorporation of iron
accumulation of iron in mitochondria characteristic of
sideroblastic
Folic acid and B12 are critical for synthesis of
methionine from homocystiene which is needed for purine and pyrimidine biosynthesis which are needed for thymodylate for DNA synthesis
what happens with Folate and B12 deficiencies (to cells)
Fucks with maturation
Cells increase in size and arrest in S phase –> destroyed –> ineffective erythropoiesis
in addition to anemia, what else might we see with folate / B12 deficiency?
neutropenia
thrombocytopenia
where is B12 absorbed?
terminal ileum
what does B12 absorption require?
IF from gut
What is the carrier of B12?
TC-II
Where is folic acid absorbed?
jejunum
What happens once folic acid is absorbed?
reduced/methylated
Do B12 of folic acid stores last longer?
B12
Causes of B12 deficiency? (5)
Autoimmune IF deficiency Malabsorption Defective transport / Storage Metabolic defect
Causes of folate deficiency? (6)
dietary insufficiency malabsorption drugs and toxins inborn error of metabolism increased demand (hemolysis/pregnancy/psoriasis) increased loss or metabolism
what type of anemia results from folate and vitamin b12 deficiencies
megaloblastic
does folate or b12 deficiency develop more rapidly
folate
is folate or b12 more likely to be associated with alcohol abuse / poor nutrition
folate
is folate or b12 more likely to be associated with malabsorption
B12
In folate and b12 deficiency what happens in bone marrow?
megaloblastic changes seen in both red cell and white cell precursors - at any stage, large, more immature nuclei
In folate and b12 deficiency what happens with erythrocytes in bone marrow?
erythroid hyperplasia
What happens with cytoplasmic maturation in folate and b12 deficiency?
normal
in folate and b12 deficiency whats up with the peripheral blood?
MCV>97 - macrocytosis
ovalocytes
hypersegmented nuclei of neutrophils
As anemia progresses in severity in folate and b12 deficient anemia what happens in peripheral blood?
nuetropenia thrombocytopenia increased bilirubin LDH RI
Which anemia manifests neurologically
B12
Good way to distinguish Folate vs B12?
A reaction involving vitamin
B12 but not folate is the synthesis of succinyl CoA from methylmalonyl CoA. Thus, in B12 but
not folate deficiency, methylmalonic acid levels are increased, making measurement of
methylmalonic acid a good way to distinguish the two.
What fraction of B12 deficiency arise from GI?
95%
Management of B12 deficiency?
1 mg injections weekly for first few weeks…then monthly
How do we manage B12 if absorption not issue?
orally 2x/day
How do we manage folate?
orally
Folate / B12 anemia response to treatment?
reverses quickly
nuerological slower
what is hemolysis?
decrease in red cell survival or increase in turnover beyond normal range
how long do RBC take to develop in BM
10-14
How long are reticulocytes in marrow?
3
How long are retic in peripheral blood
1
How long do RBC survive
120 +/- 20
During stress what may happen to the time frame of reticulocyte release?
decrease BM maturation time to
5-7 days rather than 10-14
Normal production of RBC (% red cell mass / day)
1
How much may RBC production increase?
6-8 fold
where does most RBC turnover take place?
spleen (extravascular 90%)
where does minor RBC turnover take place?
intravascular 10%
do we see changes in RBC enzyme activity with age?
yes this is normal
do we see oxidative injury with RBC over time?
yes normal
do we see changes in calcium balance?
yes normal
do we see changes in carbohydrates and surface constituents?
yes, normal
do we see antibodies to RBC surface constituents
apparently, but that’s weird
extravascular RBC destruction is mediated by?
macrophages of the reticuloendothelial system
in which type of hemolysis do red cells release hemoglobin into the circulation
intravascular
what happens when hemoglobin is released into the circulation in intravascular hemolysis?
dissociates into dimer which may immediately bind to haptoglobin
haptoglobin is removed from circulation by liver
iron can be oxidized to form methemoglobin…dissociation of globin releases metheme which may bind to albumin or hemopexin - these can be taken up by parenchymal cells and converted to bilirubin
if not dissociated to yield bilirubin, what alternative pathway may dimeric forms of methemoglobin / hemoglobin take in intravascular hemolysis?
filtered and not reabsorbed by kidney and appear in urine
in which process are red cells ingestested by macrophages of the RE system
extravascular hemolysis
what happens when RBC is ingested by macrophages in EVH?
the heme is separated from the globin, iron removed and stored in ferritin, and the porphyrin ring converted to bilirubin and released from the cell
what happens to bilirubin that is released by macrophages?
taken up by transport system in the liver and converted to water soluble compound via conjugation of glucouronic acid
what happens once glucouronic acid is conjugated to bilirubin in liver parenchymal cells?
secreted into the biliary tract and small bowel - the glucouronic acid is removed and bilirubin converted to urobilinogen and other water soluble pigments
what happen with urobilinogen?
may cycle between teh gut and liver (entero-hepatic circulation) or excreted by the kidney into the urine…
decrease in serum haptoglobin
hemoglobin in urin or plasma
increase in metheme / methemalubin
suugests?
intravascular hemolysis
spectrin deficiency is most common abnormality seen in
hereditary spherocytosis
hallmark of hereditary spherocytosis
loss of plasma membrane and formation of microspherocyte
basic pathophysiology of hereditary spherocytosis
spectrin, ankyrin, or band 3 defects weaken the cytoskeleton and destabilize the lipid bilayer
consequence of spherocyte formation?
decreased RBC deformability and entrapment in the spleen
ultimate fate of RBC in hereditary spherocytosis
removal by macrophage
clinical presentation of hereditary spherocytosis
variable degree of anemia as well as jaundice and splenomegaly -
1/3 has hyperbilirubinemia as neonates
hereditary spherocytosis genetics
25% autosomal recessive
75% autosomal dominant
splenectomy usually resolves clinical manifestations of which condition?
hereditary spherocytosis
hereditary spherocytosis lab features
variable Hct and Hgb increased retic decreased MCV spherocytes on smear unconjugated hyperhiliruinemia
clinical complications of herediatry spherocytosis
aplastic crisis
bilirubin stones
enzyme disorder anemias
G6PD
PK
G6PD deficiency presents with
presents with hemolytic anemia
G6PD genetics
X linked recessive
G6PD enzyme
important enzyme in the pathway which provides protection again oxidant stress - loss of the enzyme actitvity in the red cells results in inability to restore reduced glutathione - with oxidant stress
G6PD and oxidant stress –>
denatured hemoglobin attaches to the membrane and spectrin may be damaged - decreased deformability
G6PD clinical presentation
intermittent episodes of acute hemolytic anemia and hyperbilirubinemia associated wtih oxidant stress
G6PD characteristic cells
blister bite
Pyruvate Kinase deficiency
decrease in converting phosphoenolpyruvate to pyruvate results in decreased ATP, increased 2,3-DPG, loss of membrane plasticity and increase in rigidity and destruction in the spleen
PK deficiency clinical presentation
variable chronic anemia, hemolysis, increased reticulocytes, and no specific morphology
Cold antibodies
activate complement
Warm antibodies
incite splenic macrophage to antibody mediated phagocytosis through Fc receptor
Warm or cold antibodies act via intravascular hemolysis?
cold
warm or cold antibodies act via extravascular hemolysis?
warm
direct antiglobulin test
evaluates for presence of IgG c3d or c4d on the surface of the patients red cells by addition of Coombs reagnet which has antibodies for IgG, C3d, and C4d causing agglutination
indirect antiglobulin test
detect the ability of patient’s serum to bind IgG and or complement to test (normal) red blood cells - by definition, autoimmune hemolytic anemia should have a positive DAT
Clinical characteristics of AIHA
acute or chronic onset anemia pallor jaundice dark urine splenomegaly may occur
retic count in AIHA?
increased
bilirubin in AIHA
increased
is there hemoglobin in urine in AIHA?
Depends on the extent of intravascular hemolysis
Which AIHA will exhibit psotiive DAT (strong IgG with weak complement)
warm
which AIHA will exhibit positive DAT (complement only no IgG)
cold
spleen is critical for
clearnace of intravascular microbes
spleen important in children for development of
humoral response and is the origin of IgM agglutinins
most significant complication of splenectomy?
bacterial sepsis associated with S pneumoniae
risk of sepsis following splenectomy greatest in who
children under 5
increased mortality from sepsis if splenectomy
200x
pre-surgical splenectomy protocal
vaccination against
H influenza
S pneumoniae
meningococcus
after splenectomy give?
penicllin
most RBC turnover is extravascular occuring in the
spleen
where does met-heme come from?
during intravascular hemolysis, iron is released from cell - converts to ferric form and yield met-heme which then binds albumin –> methemalbumin which is pulled out by the liver
hemolytic anemia
RBC morphology
spherocytes / fragments
hemolytic anemia
retic
increased
bilirubin in hemolytic anemia
up because more Hgb is present to RE system - most unconjugated
Hemolytic anemia
Hbg?
up
hemolytic anemia
haptoglobin
low
hemolytic anemia
methemalubin
up
hemolytic anemia
housekeepign enzymes
up
familial hereditary disorder characterized by anemia, intermittent jaundice, splenomegaly, and responsiveness to removal of spleen
herediatry spherocytosis
most common molecular abnormality in Hereditary spherocytossi
spectrin
we see abnormal response to hypotonic stress (osmotic fragility) in what disorder?
hereditary spherocytosis
what is destablized in HS?
Lipid bilayer –> mkcrospherocytosis
the loss of membrane surface area and subsequent microspherocytosis in HS leads to what consequence?
decreased RBC deformabiltiy and incrased entrapment in the splenic cords –> macrophage removal
lab features of HS Hct? Hgb? Retic? Mchc? mcv?
vatiation in Hct and Hgb
retic up
mchc up
mcv down
also see spherocytes
unconjucated hyperbilirubinemia
increased osmotic fragility
