Heme Onc [APPROACH TO ANEMIA]
Fatigue, Malaise, SOB,
Pallor, Pale Conjunctivae,
Presyncope, MI, CVA
All causes of anemia have the same presentation that’s based on the severity and Ø etiology. There’s Ø point in
saying over and over again for each disease the symptomatology. Instead, knowing what’s unique in the history and
then the specific best diagnostic test for each one becomes most important.
The symptoms are listed in the chart at the bottom. The symptoms of anemia are vast - everything from a little fatigue, a
stroke acutely, high output cardiac failure chronically, even death as a result of myocardial infarction. While I have
them in a nice chart, remember that the symptoms are dependent on the severity and the patient’s tolerance. It all comes
down to the oxygen delivery. Oxygen delivery is based on three things: Hgb, %Saturation, and Cardiac Output. An
old man with COPD (↓%sat), MI and HF (↓CO), and on a Beta Blocker has a limited supply as is - any drop in the Hgb
significantly compromises him. Even a drop from 10 to 9 can be fatal. On the other hand, the 25 year old athlete can
tolerate Hgb that falls from 13 down to 7. He’ll experience only a little fatigue and will compensate with tachycardia.
Microcytic Anemia
Thalassemia
Iron Studies
Hgb Electrophoresis
Minor: Ø,
Major: Transfuse
Iron
Deficiency
Anemia of
Chronic Dz
BM Bx
Give Iron
BM Bx
Tx the disease
Hgb
>10
8-9
6-8
4-6
<4
Hct
>30
24-30
18-23
12-17
<12
Symptoms
Ø Symptoms
Tired, Fatigue, Malaise
Dyspnea on Exertion
Lightheaded, Presyncope, Syncope
Chest Pain, Stroke, High Output Failure
Anemia
MCV
↑Reticulocyte Count
↑ LDH ↑Bilirubin
↓Haptoglobin
Acute Blood
Loss
Confirmed Hemolysis
Paroxysmal
Nocturnal
Hematuria
Megaloblastic
G6PD Def
Hereditary
Spherocytosi
B12
Folate
Smear
G-6-PD Level
Avoid Triggers
Smear
Osmotic Fragility
Splenectomy
Autoimmune
Coombs
Steroids
Something Else
Macrocytic Anemia
Smear
5+ Lobes
PMNs
Plug Hole
Give Blood
BM Bx
Try B6
Smear, Hgb Electrophoresis
IVF, O2, Analgesia
Exchange Transfusion
Hydroxyurea, Vaccines
↓Hgb/Hct
Hgb/Hct
Normal
Normocytic Anemia
Sideroblastic
Sickle Cell
CBC
↓B12
Ø
Nonmegaloblastic
↓Folate
B12 Def.
Folate Def.
B12
Folate
Equivocal
DO2=
Old Man
Athlete
Hgb X
%Sat X
CO
↓
↓
↓
↓↓
No Compensation
Compensates
↑MMA
MMA
Normal
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Heme Onc [MACROCYTIC ANEMIA]
Introduction
Many people find heme confusing yet simplicity is key. In the
basic sciences most people assume that macrocytic (a large
MCV) is the same as megaloblastic (Hypersegmented
neutrophils). One implies big cells only while the other implies
impaired nuclear development. The first step in analyzing a
macrocytic anemia is to therefore view a smear looking for
Hypersegmented (5 or more lobes) neutrophils. In real life you’d
get a smear and a B12 & Folate level at the same time, but if
you had to say which came first it’s the smear.
CBC
Anemia
MCV
Macrocytosis
Megaloblastic Anemia
Both Folate and B12 deficiencies look the same and present the
same way except for one major difference: neuro symptoms
(B12 only). Look for both deficiencies at the same time, but
learning the specifics of each and how to tell them apart is
important.
i. Folate Deficiency
Folate comes from leafy greens and has Ø storage forms in the
body. Thus, it often presents with higher acuity than B12.
Malnutrition (Alcoholics) is the strongest risk factor. It presents
as an isolated megaloblastic anemia without any symptoms
other than anemia. A folate level will diagnose it and folate
supplementation is usually sufficient for treatment. On rare
occasions you may need to know that ↑ homocysteine and
normal methyl malonic acid levels separate Folate from B12
deficiency.
ii. B12 Deficiency
B12 comes from animal products and requires an intact gastric
mucosa (secretes Intrinsic Factor) to be absorbed. There are 310 years of stores in the body so B12 takes a long time to
develop. It occurs in strict vegans and in pernicious anemia
(↓Intrinsic Factor). It presents first with a megaloblastic anemia
and then, if left untreated, with subacute combined
degeneration of the cord. Diagnose it with a B12 level, and
supplement B12. Be cautious with Folate administration.
Throwing a lot of Folate at a B12 deficiency can overcome the
anemia but the irreversible neuro symptoms will set in. In B12
deficiency the homocysteine is elevated (just like Folate), but in
B12 deficiency only Methylmalonic Acid is also elevated. The
only time a Schilling’s test is done is when there’s uncertainty
about the etiology; it’s a test that is rarely used.
Nonmegaloblastic Dz
This isn’t that interesting. There’s just a list of things that cause
it. It’s important to first rule out a B12/Folate deficiency then
look for: Liver Disease, EtOH, Hypothyroid, Medications
(AZT, 5-FU, ARA-C) and metabolic conditions (Lesch-Nyhan,
Hereditary Orotic Aciduria).
Dx
Folate
Deficiency
B12
Deficiency
Presentation
Megaloblastic Anemia Only
Blood Smear
5+ Lobes PMN
Ø Hypersegmentation
Megaloblastic
NonMegaloblastic
B12 and
Folate
↑ Folate
B12 Deficiency
↓ Folate
Equivocal
Folate Deficiency
B12
Folate
Methyl
Malonic
Acid
↑ MMA
Nrml MMA
Subacute Combined Degeneration of the cord. The dorsal
columns (marked in red) are affected in B12 deficiency,
resulting in loss of proprioception and two point
discriminatory touch. The symptoms are permanent.
Eventually any and all neuro symptoms may present, but
it’s peripheral neuropathy that’s most common.
Pathology
Best Test
Homocysteine
Elevated
Alcoholic Malnutrition
↓Folate
Leafy Greens, 3 week stores
Normal B12
Megaloblastic Anemia and
Pernicious Anemia, vegans
Normal Folate
Elevated
Neuro Sxs (any), peripheral
Animal Products
↓B12
neuropathy (most common)
3-10 year stores
Nonmegaloblastic
after ruling out B12 and Folate look for Liver Dz / EtOH / Drugs / Metabolic
MMA
Normal
Tx
Folate
Follow-up
r/o B12
Elevated
B12
Schilling’s
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Heme Onc [MICROCYTIC ANEMIA]
Brief Introduction
So we know the patient is anemic; we saw the MCV was low. If
they were unstable we’d transfuse them. But we ought to get
some labs first because after transfusion the labs will be based
on the transfused blood only. The first step is to get Iron
Studies and go from there.
Iron Deficiency Anemia
The most common form of microcytic anemia is iron
deficiency. The normal requirement of iron is 1mg/day with a
maximum of 3mg/day. If the body starts to lose blood it may
begin using iron (to replace the lost hemoglobin) at a greater rate
than it can be absorbed. But this also means that it must be a
chronic source of blood loss. Potential causes are GI Bleeds
(slow, polyps, hemorrhoids, etc) or Gynecologic losses
(menorrhagia, cancer). Alternatively, decreased uptake of iron in
a non-bleeding person (as in a gastrectomy) is possible. In any
male or postmenopausal female with iron deficiency anemia
follow up with a colonoscopy to rule out cancer. The best test to
diagnose iron deficiency anemia is a Bone Marrow Biopsy. But
it’s rarely done because Iron studies are so good at diagnosing
Iron Deficiency Anemia. The most sensitive part of the Iron
studies is a low Ferritin (if Ferritin is low, it’s iron deficiency
anemia, period). That is, the iron stores are small. Low stores
means high capacity to bind, so there’ll be an elevated TIBC.
The low stores also means low serum iron. Stop the bleeding
then give iron. It takes 6 weeks to replace the serum iron and 6
months to replace iron stores.
Anemia of Chronic Disease
When there’s inflammation the body is trying to prevent
whatever it’s fighting from getting the iron it needs. If it’s only
an acute process, that helps fight infection. A side effect is that it
makes the iron unavailable even to the host! Great in fighting an
infection; awful in a chronic disease. Essentially, what happens
is the connection between the Iron stores and the blood is
severed. The body has a lot of iron stored so a low capacity to
bind but still has a low serum iron. Treating the underlying
disease will fix the anemia (the inflammation goes away, the
iron stores can be reconnected to the blood). Sometimes, that’s
not possible (Lupus, Rheumatoid Arthritis) so help the body
utilize iron stores with EPO.
Thalassemia
Something different is going on in thalassemia. It’s not the iron
stores that are the problem - it’s the hemoglobin. There’s a
genetic disease (α, chromosome 16, frameshift and β,
chromosome 11, deletion) that leads to ↓ production of the
normal hemoglobin with 2α and 2β; HgbA1 α 2 β 2 . It doesn’t
matter which portion is broken - the patient is going to have
anemia with normal iron studies. The way to definitively
diagnose thalassemia is with a
CBC
Anemia
MCV
Microcytosis
Iron Deficiency Anemia
Anemia of Chronic Disease
Fe Studies
Thalassemias
Iron Stores
↑TIBC
(Available Storage)
Sideroblastic Anemia
↓Fe
(Iron in the Blood)
↓Ferritin
(Iron in the Stores)
Iron Deficiency Anemia. Iron stores are depleted, plenty of
storage availability. Iron is low. ↑TIBC, ↓Ferritin, ↓Fe.
Iron Stores
↓TIBC
(Available Storage)
↓Fe
(Iron in the Blood)
↑Ferritin
(Iron in the Stores)
Anemia of Chronic Disease. There’s a disconnect between
the blood and the iron stores, but iron absorption is intact.
↓TIBC, ↑Ferritin, ↓Fe
Asx
Minor
Major
β-Thal
N/A
1 Gene Deleted
2 Gene Deleted
α-Thal
1 Gene Deleted
2 Gene Deleted
3 Gene Deleted
Dead
N/A
4 Gene Deleted
HgbA1 α2β2
HgbA2 α2δ2
HgbF α2у 2
Barts
y4
HgbH β4
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Heme Onc [MICROCYTIC ANEMIA]
Hemoglobin Electrophoresis (α-thal is ‘normal’). Here’s the
kicker; because anemia is based on severity, not etiology,
definitive diagnosis is not required except for genetic
counseling. Think of ALL thalassemia patients as minor (do
nothing) and major (routine transfusion). The deal with which
hemoglobin it is, 1, 2, 3, 4 gene deleted is unnecessary and
bogus for the clinical rotations. Recognize the hemoglobins (A1,
A2, Fetal, Barts, HbH) but realize it’s either do nothing (minor)
vs transfuse (major). Each bag of blood has 350mg Fe - enough
supply for one year. Frequent transfusion leads to iron overload
treated with deferoxamine to prevent Hemosiderosis.
Deferasirox is an oral medication that might pop up on a test or
on the wards.
Fe Normal
(Iron in the Blood)
Ferritin Normal
(Iron in the Stores)
Thalassemia. The iron stories are normal. The more genes
deleted, the more severe the disease. Consider
Thalassemias as either minor or major only.
Iron Stores
Normal TIBC
(Available Storage)
Sideroblastic Anemia
Nobody likes Sideroblastic anemia because it’s “hard.” Really
it’s because it sounds terrifying and is named from what it looks
like on Bone Marrow Biopsy. It’s the only microcytic anemia
with elevated iron. Definitively diagnose it with a bone
marrow biopsy, which will show the ringed sideroblasts. It
has a number of causes (Lead, EtOH, Isoniazid, a pyridoxine
metabolic disease of B6, and Myelodysplasia / AML). Get the
pt away from lead, give him/her B6, and do a BM Bx for the
cancer (which, coincidentally, you just did for the diagnosis).
Anemia
Iron Deficiency
Anemia of
Chronic
Disease
Thalassemia
Sideroblastic
↑Fe
(Iron in the Blood)
Normal Ferritin
(Iron in the Stores)
Sideroblastic. Diagnosis of Exclusion confirmed on bone
marrow biopsy. The tipoff is an elevated iron despite an
anemia with small cells
Pathology
Blood Loss (Chronic)
GI, GYN
Any chronic
inflammatory disease
Ferritin
↓Ferritin
TIBC
↑TIBC
Iron
↓ Fe
Best Test
BM Bx
Tx
Iron
↑Ferritin
↓TIBC
↓ Fe
BM Bx
Treat the Dz (Steroids)
Try Epo
Chr 16, α, Frameshift
Chr 11, β, Deletion
Lead, B6, genetic Dz,
Myelodysplasia,
EtOH, ↓ Copper
Normal
Ferritin
Normal
Ferritin
Normal
TIBC
Normal
TIBC
Normal
Iron
↑ Fe
Hgb
Electrophoresis
BM Bx
(Ringed
Sideroblasts)
Minor: Ø
Major: Transfuse
Give B6, Look for
Cancer
f/u
Colonoscopy
-
Deferoxamine
(transfusions)
-
Iron Stores
TIBC Normal
(Available Storage)
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Heme Onc [NORMOCYTIC ANEMIA]
Introduction
When it comes to normal sized anemia there are generally two
things to consider: hemorrhage and hemolysis.
CBC
Anemia of Acute Blood Loss
When the blood loss is acute there’s an acute drop in H/H. This
generally has an obvious source (trauma, GI, GYN) and is not
the slow chronic onset iron deficiency stuff. An underlying
anemia can be exposed with dilution, but you can’t dilute a
normal person’s H/H to anemia. If a Normocytic anemia is
revealed, look for the source of the loss. Fix this by plugging
the hole and/or giving blood.
Hemolytic Anemia
Red blood cells last 120 days. When they die they release iron
and hemoglobin into the blood. Haptoglobin binds up
hemoglobin for transport to the liver. Because it’s bound to
hemoglobin (“used up”) it’ll be ↓ in hemolysis. There will be an
overwhelming of the conjugation system so there will also be an
indirect hyperbilirubinemia causing jaundice, icterus, and
pruritus. There can be a lot of talk of intravascular vs
extravascular hemolysis but let’s focus on identifying the
diagnosis and management rather than the basic science details.
i. Sickle Cell Anemia
This is a long one with plenty of details - all of which are
important. It’s caused by an Autosomal Recessive mutation in
the β-Globin and commonly seen in African Americans. When
the patient undergoes an oxidant stress (hypoxia, infection,
DKA, or dehydration) the hemoglobin, termed Hemoglobin S,
polymerizes inducing sickling. This creates a non-deforming
cell that gets trapped in capillaries causing hemolysis and
microvascular occlusion. There are many consequences of this.
One is a chronic anemia, usually with sufficient reticulocytosis.
If the retic is low, consider either an acute aplastic crisis
(parvovirus 19) or a folate deficiency. For this reason HbSS
patients should be on daily folate + Fe. Another is the
vasoocclusive crisis. Microvascular occlusion causes infarction.
Infarction hurts. These people will be on chronic pain
management because their joints hurt all the time.
Occasionally, they’ll suffer an acute crisis where they need IVF,
O 2 , and Analgesia to ride out the attack. If the patient develops
an acute chest (ARDS picture) or priapism, he/she needs an
exchange transfusion to get over the severe crisis. But
infarction costs him/her more than that. Splenic Autoinfarction
increases risk for infection by encapsulated organisms,
requiring annual vaccinations (PCV, Meningococcus, H. Flu,
HBV). Aseptic Necrosis of the hip/femur requires dexa scan
screening. Finally, these patients are at ↑Risk for salmonella
osteomyelitis. Decrease the amount of bad hemoglobin (HbSS)
by giving Hydroxyurea (induces fetal hemoglobin, which does
not sickle). Prevent sickling by avoiding stressors and staying
hydrated. Control the pain with analgesia chronically and
reduce the anemia with Iron and Folate. But how do we know
who has sickle cell disease? Seeing sickled cells on a blood
smear is sufficient for the diagnosis. Definitive diagnosis of the
disease or of the carrier state may be confirmed by Hemoglobin
Electrophoresis. Finally, the carrier state
Anemia
MCV
Normocytic
↓Haptoglobin
↑Bilirubin
↑LDH
Retic Count
Acute Blood
Loss
Plug the Hole
Give Blood
G-6-PD
G-6-PD Levels
Avoid Triggers
Hemolysis
Sickle Cell
Hgb Electrophoresis
Folate, Fe,
Hydroxyurea
IVF, O2, Analgesia
Exchange Transfuse
Spherocytosis
Osmotic Fragility
Splenectomy
PNH
Flow Cytometry
Autoimmune Steroids, Eculizumab
Coomb’s
Steroids
IVIg
Splenectomy
Hgb SS Disease
Oxidant Stress
Sickling
Hemolysis
Splenic
Autoinfarcts
Osteomyelitis
Anemia
Folate, Fe
Hydroxyurea
Encapsulated
PPx Abx PCN
Vaccines
S. Aureus
Salmonella
Vasoocclusive
Crisis
Priapism
Acute Chest
Exchange Transfusions
IVF, O2,
Analgesia
Pain
Avascular
Necrosis
Analgesia
DEXA Scans
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Heme Onc [NORMOCYTIC ANEMIA]
almost never sickles unless under extreme conditions (such as
climbing mount Everest) and in the renal vein (↑ risk for renal
vein thrombosis).
ii. G6PD Deficiency
An X-linked genetic disorder prevalent in Mediterranean
ancestry presenting with a hemolytic anemia after exposure to
oxidant stress: drugs (dapsone, primaquine), infection, DKA, or
foods (fava beans). Diagnose it with a smear showing Heinz
Bodies and Bite Cells. Confirm the diagnosis with a G-6-PD
level but do it weeks after the attack (doing so too soon may be
artificially normal).
The Greek man eating dapsone for breakfast, primaquine
for a lunch, fava beans for dinner, and a bucket of sugar
for desert (to go into DKA) might have a G6PD deficiency
iii. Hereditary Spherocytosis
The cytoskeleton of the RBC is missing a piece (usually
spectrin or ankyrin, band 3.1 or pallidin). This presents just
like a hemolytic anemia. The spherocytes can be seen on a
smear, though they are not pathognomonic. Confirm the
diagnosis with an osmotic fragility test. Because the big bad
spleen beats up on the little spherocytes a splenectomy will stop
the anemia. However, the cells will persist as spheres.
Splenectomy has its own problems so stick with Folate
supplements unless it’s really severe.
iv Autoimmune Hemolytic Anemia
As the name implies, it’s an autoimmune disease that attacks
RBC. There can be cold AIHA caused by Mycoplasma and
Mono, which produces IgM against RBC at cold temperatures.
Avoid the cold and it’s not a problem. Warm AIHA is caused
by autoimmune disease (any Rheum disease), drugs (PCN,
Sulfa, Rifampin), and Cancer, producing IgG against RBC @
warm temps. Treat this like any autoimmune disease by giving
steroids, IVIg when acute, and splenectomy if refractory. The
smear is non-diagnostic while the Coomb’s test is diagnostic.
v. Paroxysmal Nocturnal Hematuria
Caused by a mutation in the PIG-A gene the red blood cells
have no GPI-Anchor, so cannot inhibit complement fixation.
Fixation occurs all the time, but is accelerated by hypoxia
(when you sleep). So, while these patients sleep complement
fixes, cells lyse, and they wake up with hematuria. They can
also get venous thrombosis in intra-abdominal veins causing
abdominal pain. Confirm the diagnosis with a flow cytometry
and treat with Anti-Ab Drugs (eculizumab).
Disease
G-6-PD
Deficiency
Hereditary
Spherocytosis
Autoimmune
Hemolysis
Paroxysmal
Nocturnal
Hematuria
Sickle Cell
Disease
Patient
Mediterranean man who eats
dapsone, primaquine, fava
beans, and goes DKA
Enlarged Spleen
IgG: Drugs, Cancer, Rheum
IgM: Mycoplasma, Mono
Irregular bouts of morning
hematuria and abdominal
pain
African American, chronic
pain, acute chest, priapism
Path
G6PD Deficiency, cannot
tolerate oxidative stress
X-Linked
Defective RBC structural
proteins, Splenic Destruction
Autoimmune Antibodies
PIG-A gene mutation, failure
to inhibit compliment on RBC
Hgb S polymerizes in
response to stress
Smear = Schistocytes, Helmet cells (not pathognomonic)
Flow cytometry shows absence of CD55 + CD59
1st Test
Smear
Heinz Bodies
Bite Cells
Smear
(Spherocytes)
Smear
(Spherocytes)
Smear
(Sickles)
Best Test
G-6-PD Levels
weeks after the attack
Treatment
Avoid Oxidant Stress
Osmotic Fragility
Splenectomy
(Spherocytes Remain)
Steroids, IVIg,
Splenectomy
Coomb’s Test
Flow Cytometry
Steroids, Eculizumab
Hgb Electrophoresis
IVF, O2, Analgesia,
Exchange Transfusion
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