Evaluating Anemia

Tabraiz Mohammed, DO, MS

Disclosures
None
Goals & Objectives
1. Develop a framework to assist in the initial evaluation of an anemia
2. Differentiate between common types of anemia based on routine lab
information
3. Initiate an appropriate evaluation for:
1. Microcytic anemia
2. Normocytic anemia
3. Macrocytic anemia
4. Brief overview of management of anemia
Taken from https://www.flickr.com/photos/paul_irish/6474235835 without modifications.
License at https://creativecommons.org/licenses/by/2.0/
Anemia
Hgb < 13.5 g/dl (Hct 41) in men or < 12 g/dl (Hct 36) in women
Case 1 56 yo patient who is referred to your office for evaluation of a
6 month history of anemia. The patient has a Hgb of 9.6 g/dl
Key features on history
Gender male vs female
Age
Duration of symptoms
MCV
Reticulocyte count
Evaluation of an Anemia
Is there an anemia?
What is the MCV?
Are other cell lines ok?
Wbc
platelets
What is the reticulocyte count?
Proxy for bone marrow function
Anemia
Microcytic
MCV less than 80
Normocytic
MCV between 80-100
Macrocytic
MCV above 100
Microcytic Anemia
MCV less than 80
Few causes
Iron deficiency
Anemia of chronic disease*
Thalassemias
Sideroblastic Anemia
Iron deficiency
Causes
Blood loss (physiologic vs pathologic)
Menstruation
Ulcer/diverticulosis
Malignancy
Nutritional deficiency
Rare
Pregnant women
Infants
Malabsorption (pathologic vs iatrogenic)
Gastric bypass
Celiacs disease
Check antibody panel
Biopsy is gold standard
Peripheral Smear

By Keith Chambers [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Iron deficiency

By Ed Uthman from Houston, TX, USA [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons
 Thalassemia
Alpha thalassemia
Epidemiology Asian populations, Middle Eastern, West Africa, African Americans
4 genes; 2 located on chromosome 16
1 gene mutation is silent (silent carrier)
2 genes mild anemia, microcytosis (alpha thal trait)
3 genes Hgb H hemolytic anemia (4 beta chains) (similar to beta intermedia)
4 genes Hgb Barts hydrops fetalis (4 gamma chains)

Beta thalassemia 0 or +
Epidemiology Mediterranean, African, Southeast Asian populations
2 genes; each located on chromosome 11
1 gene carrier Microcytosis, normal iron studies, low normal Hgb to mild anemia
Thalassemia intermedia variable course; non-transfusional anemia*
2 gene Cooleys anemia - transfusion dependent anemia
 Target cells

By Dr Graham Beards - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=20526635

Sideroblastic Anemia
Herediatary ALA deficiency
Acquired
B6 pyridoxine gastric bypass
Lead poisoning
Copper deficiency
Alcohol
Chloramphenicol
INH
MDS
 Sideroblastic anemia

By Herbert L. Fred, MD and Hendrik A. van Dijk - http://cnx.org/content/m15003/latest/, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=5038848

 Iron stain

By Paulo Henrique Orlandi Mourao (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via
Wikimedia Commons
How to Evaluate an Iron Deficiency
Anemia?
Check iron studies
Check reticulocyte count
Check for blood loss
Review medications and diet
If no obvious blood loss, it would be appropriate to check for celiacs
disease (antibody panel; *gold standard is endoscopic evaluation with
biopsy)
Men and non-menstruating females require endoscopic evaluation (GI
consultation)
Iron Studies
Iron deficiency
Low serum iron
High iron binding capacity
Low ferritin
Elevated platelets
High RDW
Anemia of chronic disease
Low serum iron
Low TIBC
Normal or elevated ferritin.
There may be iron deficiency with inflammation
RDW normal
Treatment
Oral iron
324 mg of iron sulfate
2-3 times a day
Take with vitamin C (some OJ would suffice)
Unless symptomatic and as long as anemia is not severe (ie less than
6.5 g/dl)
Do not transfuse
This will mask the problem and further evaluation
Blood transfusions deliver a significant iron load
Risk of transfusion reactions and alloimmunization which can complicate
matter down the line
Normocytic Anemia
These require additional evaluation
Important possibilities to consider
Hemolysis*
Immune mechanism
Autoimmune
Cold antibody
Drug
Abnormal hemoglobin Sickle cell disease
Abnormal enzymes G6PD
Abnormal membrane Hereditary spherecytosis
MAHA TTP/HUS, aortic valve
Blood loss
Bone marrow suppression
Myeloma
Anemia of chronic disease*
Chronic kidney disease
Hypothyroidism*
How to Evaluate a Normocytic
Anemia
Check for hemolysis
Reticulocyte count
LDH
Haptoglobin
DAT/Coombs test
Platelet count
Check renal function, serum calcium, liver function and TSH
Check iron, folate and B12 studies
Hemolysis requires urgent evaluation/hospitalization
Macrocytic Anemia
Vitamin B12
Dietary
Gastric bypass
Pancreatic insufficiency
Pernicious anemia
Tapeworm (diphyllobothrium latum)
Nitrous oxide abuse
Folate
Dietary
Pregnancy
Skin conditions
Hemolytic anemia
Alcohol (and liver disease)
Drugs/Medications (hydroxyurea)
MDS
Hypothyroidism
 Hypersegmented Neutrophils

By Bobjgalindo (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC BY-SA 4.0-3.0-2.5-2.0-1.0 (http://creativecommons.org/licenses/by-sa/4.0-3.0-2.5-2.0-1.0)],

via Wikimedia Commons
Anemia Evaluation (summary)
Start with an MCV
Check iron studies including serum iron, TIBC and ferritin
Check folate and B12
Obtain a smear (helpful for the hematologist)
If elevated reticulocyte count (>75K) the body is responding
Check for hemolysis
Check TSH
Liver and renal function
Screen for alcohol use
Macrocytic Anemia - Treatment
Replace appropriate vitamin B12 or folate
B12
Pernicious anemia IM injection, a nasal formulation is available
100-1000 mcg daily for a week
Then weekly for 3 weeks
Then monthly (as long as response is adequate)
Other B12 deficiency oral route may suffice. 1000-2000 mcg daily. 1000 mcg might be
sufficient
Give concomitant folic acid 1 mg
Folic acid
1 mg a day should suffice
Alcoholic patients
Thiamine
Vitamin B6
B12 and folate
Alcohol cessation
Questions
Question # 1: Does the reticulocyte count comes along with a CBC or we need to order a separate
test from the lab?
Answer: It actually depends on the lab. Some labs mention the reticulocyte count as part of CBC
profile. For others it needs to be ordered as a separate test from the lab. Reticulocyte count > 75,000
indicates that the bone marrow trying to compensate for the anemia by increasing its red blood
cells production. Reticulocyte count < 75,000 indicates that the bone marrow is producing red
blood cells, but it isn't exactly responding to anemia.
Question # 2: Does the reticulocyte count helps one differentiate what kind of an anemia it is?
Answer: In the whole scheme of things, after it has been established that the patient is suffering
from an anemia, the reticulocye count helps differentiate whether the body is responding
appropriately in case of an anemia. So, a low reticulocye count (less than 75,000) should make you
question that what's wrong within the bone marrow that it isn't responding to an anemia. On the
other hand if the reticulocyte count is increased (more than 75,000), this suggests that the bone
marrow is responding appropriately to the situation, but what's wrong within the blood which is
actually causing the anemia.
 Questions
Question # 3: So, as part of the work up, is this how it should be done: First, order the the CBC and
check if there's something wrong, if yes, only then order the reticulocyte count? Or should I order the
reticulocyte count as part of the initial CBC?
Answer: If you already know that the patient you're seeing is anemic, its better to get it done upfront as
part of the CBC. On the other hand, if you're evaluating a patient and you don't know yet that the patient
has anemia, then only CBC needs to be ordered and you can skip the reticulocyte count for later in case
the anemia is confirmed by the CBC. Most labs usually have enough blood sample left over from the
initial CBC that was ordered, hence if a reticulocyte count is required later, there's no need to send in a
new blood sample.
Question # 4: Is reticulocyte count part of a blood smear, or is it something different?
Answer: Blood smear involves taking a drop of the sample blood on to a glass side and literally smearing
it across the slide, so that blood cells could be analyzed under the microscope. Reticulocytes can be seen
as part of a blood smear and an estimate number could be determined, but blood smearing doesn't
inherently gives the value of the reticulocyte count that we are looking for. Reticulocytes are newly
formed RBCs released from the bone marrow to replace worn out mature RBCs in the circulation. On a
blood smear the reticulocytes appear as slightly larger cells compared to normal RBCs and they tend to
present with a bluish tinge to their cytoplasm. This bluish tinge comes from the residual RNA within the
reticulocytes.
 Questions
Question # 5: Iron has an affinity for acidic environment, so do you recommend that when patient takes
an iron supplement, it should be accompanied with Vitamin C?
Answer: Absolutely, Vitamin C is ascorbic acid and it tends to reduce normal dietary iron from its Fe3+
state to an Fe2+ state which is more readily absorbed. So, the best way to take ron supplementation is on
an empty stomach and it should be twice a day. It could be taken with an orange juice which is rich in
Vitamin C that acts as a cofactor for reducing dietary iron and subsequently enhances iron absorption in
the duodenum. The issue with most patients who take iron supplementation on an empty stomach is that
they have to face a lot of GI distress (including belly pain, constipation & diarrhea) and tend to be
noncompliant. In that case they're recommended to take it with meals but they have to take it three times
per day in order to compensate for the decreased absorption which accompanies food intake. However, it
takes 6 to 8 weeks for iron supplementation to show a meaningful change on the CBC. Reticulocyte count
is however, the first index to show a change on the CBC, and the other indices might take some more time
to show improvement.
Question # 6: So, do you think that (in case of anemia) its useful to treat patient for inflammation
(chronic) before initiating the treatment for anemia?
Answer: The bigger question is what's driving the inflammation here. However, it's sufficient to say that I
won't necessarily give them an NSAID per se to correct the inflammation. In some instances, that's pretty
obvious if people have inflammatory arthritis. Or it can be more subtle if people have a bad reflux disease
that's causing esophagitis or gastritis resulting in some low level inflammation. So, the issue of what's
causing the inflammation is a pretty broad question that needs to be investigated. But, if you do treat the
underlying cause of a chronic inflammation then the anemia should improve. A good example of that is
with patients of rheumatoid arthritis, who present with an exacerbation of their joint symptoms and with
an anemia that has worsened. However, if the joint symptoms are addressed and aprropriately treated, the
anemia tends to improve.
Questions
Question # 7: Why will an infant develop an anemia?
Answer: The most important reason is that iron content of the breast milk isn't that great. Also, it needs to be
considered that during pregnancy the women tend to develop iron deficiency, particularly during the 3rd
trimester. Subsequently, when these women tend to breast feed their child, the infant receives even lower amounts
of iron via the breast milk. As for the infants, supplementary iron drops can be started for the period they're being
breastfed. Also it needs to be considered that, the pregnant women tend to develop a fluid overload state which
can lead to a dilutional anemia as well. So, it hard to differentiate whether the woman has an iron deficiency or a
dilutional anemia. In pregnant women its important to regularly monitor the MCV, and if there's a significant
derangement, then iron studies need to be conducted to determine if she has developed an iron deficiency
anemia.
Question # 8: Does the size and shape alteration on a peripheral smear should alert that its a case of microcytic
anemia?
Answer: No, not necessarily. If its mentioned in the differential that the peripheral smear shows anisocytosis
(RBCs are of unequal sizes) and poikilocytosis (abnormally shaped cells), all that its supposed to convey is that
there's alot of variation in what red blood cells look like.
Questions
Question # 9: When should we suspect that patient is presenting with thalassemia? Once confirmed what should
be the next step in management?
Answer: Thalassemia should be suspected when you find microcytosis which is much more pronounced than the
degree of anemia with which the patient is presenting. For instance, when the Hb level = 9-11, but the MCV = 60.
In such a situation, when iron studies are conducted and they turn out to be normal. Such a situation points out
that you're dealing with a thalassemia. These are more common in patients of African American, Inidan,
Pakistani and South Asian backgrounds. As for what needs to be done for a case of thalassemia, the severe cases
involving 3 to 4 gene deletions are established with the hematologist and there's already a plan of action. As for
the milder cases, they don't need any intervention. One thing to make sure is that they're not given iron
unnecessarily, which will create an iron overload state.
Question # 10: Do we need to prepare ourselves to read peripheral smears, or this is done by someone else?
Answer: The short answer is that you don't need to be able to read peripheral smears. Depending on the
institution you're at, ordering a smear actually generates a counsel for a pathologist to review the smear. But a
hematologist can also thoroughly review the smear findings.
Questions
Question # 11: How to evaluate a microcytic anemia?
Answer:
(a) Check iron studies: 1. Serum Iron
2. TIBC (Total Iron binding capacity)
3. Transferrin Saturation
4. Serum Ferritin ( >100, very unlikely that patient has iron deficiency)
(b) Check reticulocye count: In a microcytic anemia, a low reticulocyte count indicates that there's some anomaly
at the bone marrow level which is suppressing its function, and therefore resulting in a hypo-proliferative state.
This anomaly can be a nutritional anomaly such as iron deficiency.
(c) Check for blood loss: Obtain menstrual history from a female patient.
(d) Review medication history and diet: Its important in certain groups of patients such as pure vegetarians and
vegans who tend to avoid eating me at. Also people who are already on iron supplements but their serum iron has
shown any improvements. Patients who are simultaneously on proton pump inhibitors and iron supplements
should be taken of PPIs in order to ensure their serum iron goes up. Menstruating females who are on plan
dietary plan needs to get it reviewed.
(e) If no obvious blood loss, check for celiac disease using an antibody panel. Gold standard however, is endoscopic
evaluation with biopsy
(f) Men and menstruating women who have an iron deficiency anemia require endoscopic evaluation.
Questions
Question # 12: If a patient with thalassemia receives iron supplementation, but the iron studies are normal, will
this contribute to hemochromatosis?
Answer: It truly depends what kind of thalassemia is the patient suffering from. People who have transfusional
thalassemias then it can be related to iron overload syndromes and can contribute to hemosiderosis and or
hemochromatosis.
Question # 13: Do you think its jumping the gun to order iron studies and reticulocyte count alongwith the
CBCs, if you're suspecting an anemia?
Answer: Anytime I see an anemia patient, getting a workup for reticulocyte count, iron studies, folate and
Vitamin B12 levels is part of my reflexes. If you're referring a patient to a hematologist, it is really worth
sending these indices along with the CBC because they'll be using that stuff to establish a diagnosis and taking
the next step in management.
Question # 14: What do you recommend as part of iron supplementation: elemental iron or ferrous sulphate?
Answer: Ferrous sulphate is what I prescribe, but you can also use elemental iron. The issue to consider is that,
the higher the iron content of the supplementation, the more likely it's to cause some form of GI distress. So
ferrous sulphate is more preferred as iron replacement product.
Questions
Question # 15: What's the pathophysiology behind anemias associated with COPD?
Answer: Well technically, if its only COPD you really shouldn't be seeing an anemia. COPD is a state of chronic
hypoxia so you should expect to see a polycythemia. The body tries to compensate in response to chronic hypoxia
by making more red blood cells, resulting in a polycythemia. So, if you see an anemia with a COPD, it's most likely
because there's something else going on like an inflammatory state or a nutritional deficiency which is giving rise to
an anemic state.
Question # 16: Direct admission, what diagnosis?
Answer: So if you find hemolysis, then hemolytic anemia alone is a sufficient diagnosis.
Question # 17: If the patient has MDS (myelodysplastic syndrome) and gets multiple transfusions, and as a result
the WBC number starts to go up. Would you recommend checking Vitamin B12 levels, folate deficiency etc. or
recommend giving supplemental Vitamin B12?
Answer: Well, if they have MDS and you're treating them with transufusion, and the WBC count is going up then
the question should be WHY is that? If all the cell lines are correct, then particularly for MDS, the bigger question is
that what the underlying problem is?Can there be a situation where there is MDS along with a folate and vitamin
B12 deficiency? Absolutely yes, and sometimes just correcting these can temporize a myelodysplatic syndrome.
However, at times its not sufficient enough and you need to do more.
Questions
Question # 18: For pernicious anemia, do we refer the patient to a hematologist?
Answer: It depends on your comfort level. If you have found the parietal cell antibodies, the treatment simply is
Vitamin B12 replacement therapy. I think the thing that I would like you to consider is that, pernicious anemia
sometimes tends to fall into a cluster of autoimmune disorder disorders (such as Vitamin D deficiency, thyroid
deficiency or vertiligo). So you can confirm the diagnosis with a hematology consult, otherwise if you feel
comfortable with your diagnosis, then there's no need to.
Question # 19: So if there is a patient who has hemochromatosis, this means there will be a need for frequent
blood draw, is that right?
Answer: Hemochromatosis is a state of elevated iron stores and your tip for that would be to send off the iron
studies. If the transferrin saturation comes out to be higher than 50%, that's the first clue that you're dealing with
a patient of Hemochromatosis. Now, the treatment for some forms of polycythemia (elevated hemoglobin due to
increased RBC count as result of JAK2 mutation) or hemochromatosis is in fact a phlebotomy. In particularly
with polycythemia vera where there's a constant signalling to the bone marrow to increase RBC production, the
treatment involves periodic blood letting from the patient. Usually a hematologist is involved but if its too
frequent then some medication to supress RBC production is added. The same concept applies to
hemochromatosis, since you can't get rid of excess iron from the body so phlebotomy or blood letting has to be
added as part of the treatment plan. Phlebotomy tends to bring down the elevated iron stores within the body as
long as the individuals hemoglobin levels can tolerate this.
Questions
Question # 20: I work with several different doctors who work in a different way (when delaing with patients with
hemochromatosis). One sends patients to periodically donate blood, and the other one sends patients to a
hematologist. Is one correct over the other?
Answer: I think its purely based on comfort level. Most blood banks, if they know the donor has hemochromatosis,
tend to discard the blood and dont use it for transfusions. From the standpoint of the patient, it is to get the blood
off the patient. On the other hand, the standpoint of the blood bank is more protocol driven; they just don't want
blood taken out for a pathological condition to be infused to other people. But, I don't think if there's anything
wrong in doing it one way or the other. The point should be that with patients of hemochromatosis, the serum
ferritin level should be 50 or lower and you ought to be able to maintain a normal hemoglobin levels with this. As
long as these two parameters are under control, you can phlebotomize a patient with hemochromatosis.