MEDSEM2LE4: Approach to Anemia

LE LE 4

Date @January 19, 2022

Status Ongoing

Approach to Anemia
Hematopoiesis

Site of Hematopoiesis

RBC Life Span:

Erythropoiesis

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 Bone Marrow— where the rbc or erthrocyte is produced, usually takes 7 days.

EPO is induced in episodes of hypoxia.

Reticulocyte— immature rbc

Erythropoietin
Protein hormone essential to production of red blood cells (physiologic regulator)

Small (~30 kDa) glycoprotein structurally similar to growth hormone

Produced by peritubular capillary lining of cells in kidney

In the fetus, starts to synthesize in the liver

When blood oxygen concentration is normal (normoxia), synthesis of erythropoietin occurs in scattered cells
located predominantly in the inner cortex, but under conditions when blood oxygen is deficient (hypoxia), interstitial
cells within almost all zones of the kidney begin to produce the hormone

Clearance of EPO is 69 hrs needs to be attached to specific receptors in the bone marrow

Eryptosis

Form of apoptosis

phagocytosis- spleen, liver and bone marrow

normally occurs at the same rate of the production of rbc

death is higher than production: hemolytic anemia, sepsis, malaria or abnormality in the process of increase in cellular
damage increase ROS

Cell death → broken down and circulated in the body

RBC → biliverdin

Anemia
→ Described as an absolute reduction in the proportion of the rbcs

Prevalence:
Increases with age

More common in women of reproductive age, pregnant women and the elderly

>85 yrs old → often due to poor nutrition, especially of iron and folic acid.

In another one-thurd of patients: renal failure or chronic inflammation

Incidence of anemia is 50-60% in the nursing home population

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 New-onset anemia, especially in those over 55 years of age, needs investigating and should be considered cancer
until proven otherwise

This is especially true in men of any age who present with anemia

WHO

Common Causes and Classification of Anemia

Obtaining the History

Some important questions to obtain in a history:

Obvious bleeding- per rectum or heavy menstrual bleeding, black tarry stools, hemorrhoids

History of any worm in stool

Thorough dietary history

Consumption of nonfood substances

History of Fever –can be seen in Infections, Malignancies and Connective tissue disorders

Bulky or fatty stools with foul odor to suggest malabsorption

Thorough surgical history, with a concentration on abdominal and gastric surgeries

Family history of hemoglobinopathies, cancer, bleeding disorders

Menstrual History (Defined as excessive flow –Duration exceeds 7 days, More than 12 pads used; Clots after 1st day
of menstruation)

Drugs that can cause Anemia

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 Consumption of non-food substances (pica)

Careful attention to the medications taken daily

Clinical Features
Depends on the maginitude and rate of reduction in oxygen carrying capacity of the blood

worst case scenario: irregular heartbeat and chest pain

Classically depends on the rate of blood loss (acute or chronic blood loss)

Adaptive response to Anemia

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 Physical Examination
HEENT:

Pallor of the conjunctiva

“Boxcars” or “sausaging” of retinal veins: suggestive of hyperviscosity which can be seen in myelofibrosis

Jaundice- elevated bilirubin is seen in several hemoglobinopathies, liver diseases and other forms of hemolysis

Lymphadenopathy: suggestive of lymphoma or leukemia

Glossitis (inflammation of the tongue) and cheilitis (swollen patches on the corners of the mouth): iron/folate
deficiency, alcoholism, pernicious anemia

ABDOMINAL EXAM:

Splenomegaly: hemolysis, lymphoma, leukemia, myelofibrosis

Hepatomegaly: alcohol, myelofibrosis

Scar from gastrectomy: decreased absorptive surface with the loss of the terminal ileum leads to vitamin B12
deficiency

Scar from cholecystectomy: Cholesterol and pigmented gallstones are commonly seen in sickle cell anemia are
hereditary spherocytosis

CARDIOVASCULAR:

Tachycardia

Systolic flow murmur

Severe anemia may lead to high output heart failure

NEUROLOGIC EXAM:

Decreased proprioception/vibration: vitamin B12 deficiency

SKIN:

Pallor of the mucous membranes/nail bed or palmar creases: suggests hemoglobin < 9 mg/dL

Petechiae: thrombocytopenia, vasculitis

Dermatitis herpetiformis (in iron deficiency due to malabsorption- Celiac disease)

Koilonychia (spooning of the nails): iron deficiency

Knuckle Hyperpigmentation –Megaloblastic anemia

RECTAL AND PELVIC EXAMS:

📌 These examinations are usually overlooked and underperformed in the evaluation of anemia.

If a patient has heavy rectal bleeding, one must evaluate for the presence of hemorrhoids or hard masses that
suggest neoplasm as causes of bleeding.

Evaluation

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 📌 Tests used in the initial workup of anemia. A routine complete blood count (CBC) is required as part of the
evaluation and includes the hemoglobin, hematocrit, and red cell indices: the mean cell volume (MCV) in
femtoliters, mean cell hemoglobin (MCH) in picograms per cell, and mean concentration of hemoglobin per
volume of red cells (MCHC) in grams per liter (non-SI: grams per deciliter). The MCH is the least useful of the
indi- ces; it tends to track with the MCV.

A. Complete blood Count

Hematocrit

Measures the volume of red blood cells compared to the total blood volume (red blood cells and plasma)

The normal hematocrit for men is 40 to 54%; for women it is 36 to 48%

Both the hemoglobin and the hematocrit are based on whole blood and are therefore dependent on plasma
volume

If a patient is severely dehydrated, the hemoglobin and hematocrit will appear higher than if the patient were
normovolemic;

if the patient is fluid overloaded, they will be lower than their actual level.

📌 HENCE, When first confronted with an abnormal hemoglobin or hematocrit level, the next step is to
assess the red cell indices, peripheral smear, and the reticulocyte count in light of the patient's
history and physical examination.

In anemia, where there are fewer RBCs in the circulating blood relative to the total volume of the blood, the HCT
decreases

PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS WHERE THE HCT MAY DEVIATE FROM ITS
NORMAL RANGE

Adult male shows higher HCT than an adult female

Pregnant women show lower HCT due to hemodilution

In high altitude, the number of RBC becomes high due to persistent hypoxia; hence, the inhabitant of high
altitude shows higher HCT

Blood collected from different sources may also show variation

Venous blood shows higher HCT than arterial blood

No difference in HCT between venous blood and finger prick blood.

Reticulocyte Count

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 Reticulocytes are immature red blood cells (RBCs) produced in the bone marrow and released into the peripheral
blood where they mature into RBCs within 1 to 2 days

Expressed as a percentage of the total number of RBCs

In the setting of a normal hemoglobin, the reticulocyte count ranges from 1 to 2% and reflects the daily
replacement of 0.8–1.0% of the circulating red cell population

Used as a marker of red cell production and helps in distinguishing hypo- and hyperproliferative anemias

In the initial classification of anemia, the patient’s reticulocyte count is compared with the expected reticulocyte
response

NORMAL RESPONSE:

if the EPO and erythroid marrow responses to moderate anemia

[hemoglobin <100 g/L (10 g/dL)] are intact, the red cell production
rate increases to 2-3X normal within 10 days following the onset of anemia

In the face of established anemia, a reticulocyte response < 2-3X

normal → inadequate marrow response

Must be corrected because in patients with moderate or severe anemia, the reticulocyte count may appear
elevated, but in absolute terms, it may be insufficient for the degree of anemia

Methods of Correcting the Reticulocyte Count for the Degree of Anemia

Reticulocyte count = % reticulocytes in RBC population

Corrected reticulocyte count = % reticulocytes x (patient Hct / 45) or

Corrected reticulocyte count = reticulocyte count x hgb/15

Reticulocyte production index = Corrected reticulocyte count /

maturation time in peripheral blood in days (NV: 0.5 - 1.5%)

A higher reticulocyte count may indicate:

Hemolytic anemia

GI bleeding

Blood disorder in a fetus or newborn

Kidney disease, with increased production of erythropoietin

Pregnancy

A lower reticulocytes count may indicate

Bone marrow failure (eg drug, tumor, radiation, infection)

Cirrhosis of the liver

Untreated pernicious or megaloblastic anemia

Chronic kidney disease

RBC Count

It is the total number of RBC uL or a liter of blood.

The test can help diagnose anemia with low RBC and other conditions affecting RBCs

Normal RBC count:

Male: 4.3-5.9 (x10^12/L)

Female: 3.5-5 (x10^12/L)

Higher number of RBC may be due to:

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 Cigarette smoking

Cor pulmonale (R HF)

Dehydration

Renal Cell Carcinoma

Hypoxia

Polycythemia vera

Drugs

Lower number of RBCs may be due to:

Anemia

Bleeding

Bone marrow failure (from radiation, tumor, or toxins)

EPO deficiency

Hemolysis

Multiple myeloma

Over hydration

Pregnancy

Iron, folic Vit. B6 or Vit B12 deficiency

Polycythemia

General term for erythrocytosis resulting in an increase in both hemoglobin concentration and hematocrit →
increase in RBC mass

It can be due to an increase in number of RBC (”absolute polycthemia”) or to a decrease in the volume of plasma
(”relative polycthemia)

RBC indices

It is a quantitative measurement of RBC, and the amount and concentration of hemoglobin in them

Definitions:

Mean Cell Volume (MCV)- measure of average volume of rbcs

Mean Cell Hemoglobin (MCH)- measurement of the average weight of hemoglobin in individual erythrocytes

Mean Cell Hemoglobin Concentration (MCHC)- average concentration of hemoglobin in erythrocytes

Red Cell Distribution (RDW) measure of variability of erythrocyte size

Mean Cell Volume

Measures the average size of your RBCs

If RPI is <2.5%, Check for MCV (Mean Corpuscular Volume)

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 MCV (<80 fl)

Iron deficiency decreased serum iron, percent saturation of iron, with increased total iron-binding
capacity (TIBC), transferrin levels, and soluble transferrin receptor

Lead poisoning basophilic stippling on the peripheral blood smear, ringed sideroblasts in bone marrow,
elevated lead levels

AOCD may be normocytic

Thalassemia RBC count may be normal/high, low MCV, target cells, and basophilic stippling are on
peripheral smear. Alpha thalassemia is differentiated from beta-thalassemia by a normal Hgb
electrophoresis in alpha thalassemia. Elevated Hgb A2/HgbF is seen in the beta-thalassemia trait.

Sideroblastic anemia elevated serum iron and transferrin with ringed sideroblasts in the bone marrow

BASOPHILIC STIPPLING

Numerous small purplish inclusions which results from RNA and mitochondrial remnants

MCV (90-100fl)

Renal failure: BUN/Creatinine

Aplastic anemia ask for drug exposure, check for infections (EBV, hepatitis, CMV, HIV), test or
hematologic malignancies and paroxysmal nocturnal hemoglobinuria (PNH)

Myelofibrosis/myelophthisis check bone marrow biopsy

Multiple myeloma serum and urine electrophoresis

Pure red cell aplasia test for Parvovirus B19, exclude thymoma

MCV (>100 fl)

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 B12/folate levels B12 and folate deficiency can be differentiated by an elevated methylmalonic and
homocysteine level in B12 deficiency and only an elevated homocysteine level in folate deficiency.
Methylmalonic levels are relatively normal.

MDS hyposegmented PMNs on peripheral smear, bone marrow biopsy

HypothyroidismTSH, free T4

Liver disease check liver function

Alcohol assess alcohol intake

Drugs

Megaloblastic Anemia

A type of macrocytic anemia that results from inhibition of DNA synthesis (mitosis (M) stage) during red
blood cell production

Continuing cell growth without division (macrocytosis)

Often due to hypovitaminosis, specifically vitamin B12 deficiency or folate deficiency

Characterized by

Many large immature and dysfunctional red blood cells (megaloblasts) in the bone marrow

Hypersegmented neutrophils (defined as the presence of neutrophils with six or more lobes or the
presence of more than 3% of neutrophils with at least five lobes)

Drugs Causing Megaloblastic Anemia

Folate antagonists (e.g., methotrexate)

Purine antagonists (e.g., 6-mercaptopurine)

Pyrimidine antagonists (e.g., cytosine arabinoside)

Alkylating agents (e.g., cyclophosphamide)

Zidovudine (AZT, Retrovir)

Trimethoprim

Oral contraceptives

Nitrous oxide

Arsenic

Mean Corpuscular Hemoglobin Concentration (MCHC)

Measure of the concentration in a given volume packed RBC

It is calculates by dividing the hemoglobin by the hematocrit

References ranges for blood tests are 32 to 36 g/dL (4.81 to 5.58 mmol/L)

MCHC= Hgb (d/dL) x 100/ Hct (L/L)

Normochromic: 32-36 g/dL

Hypochromic: <32 g/dL

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 If the area of central pallor is >1/3 of the cell size

Hyperchromic: >36 g/dL

The only erythrocyte that is hyperchromic with an MCHC of >36g/dL is the spherocyte

Apparent hyperchromacia (high MCHC) is usually due to an artifactural increase in the hemoglobin result due
to hemolysis, lipemia or large numbers of Heinz bodies

SPHEROCYTES

Round red blood cells that lack an are of central pallor

Occurs due to partial loss of the red blood cell membrane

Associated conditions

Hemolytic Anemia

G6PD deficiency

Mean Corpuscular Hemoglobin (MCH)

Measurement of the average weight of hemoglobin in individual erythrocytes

MCH= Hb(g/g/dL) x 10 / rbc x 10^12 /L

MCH varies in direct linear relationship with MCV. Cells with less volume contain less hemoglobin and vice versa

Normal: 28-34pg

Red Cell Distribution Width

RDW is used because MCV is less reliable in describinh the erythrocyte population when considerable variationin
erythrocyte size occured

RDW= Std deviation of mcv x 100 /MCV

Normal: 11.5 - 14.5%

Increased value indicates anisocytosis

Differential diagnosis of anemias based on MCV and RDW

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 B. Peripheral Blood Smears

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 C. Red Blood Cell Indices

D. Microcytic Anemia: Tests of Iron Supply and Storage

Serum iron

Measures the amount of circulating iron that is bound to transferrin (90%)

and serum ferritin (10%)

Normal serum iron ranges from 9 to 27 μmol/L (50–150 μg/dL)

Serum ferritin

Used to evaluate total body iron stores

Adult males have serum ferritin levels that average ∼100 μg/L, corresponding to iron stores of ∼ 1 g

Adult females have lower serum ferritin levels averaging 30 μg/L, reflecting lower iron stores (∼300 mg)

Acute phase reactant

TIBC

Measures the blood's capacity to bind iron with transferrin

Transferrin

Functions as the most critical ferric pool in the body

It transports iron through the blood to various tissues such as the liver, spleen and bone marrow

It is an essential biochemical marker of body iron status

The amount of transferrin in the blood indicates the amount of iron in the body

Produced in the liver → hence, alterations in function (such as cirrhosis, hepatitis, or liver failure) must be
considered

normal TIBC is 54–64 μmol/L (300–360 μg/dL)

Percent transferrin saturation

Serum iron/TIBC x 100

Normal transferrin saturation ranges from 25 to 50%

Iron Deficiency Anemia

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 May result from insufficient iron intake, decreased absorption, or blood loss

May also be seen with low dietary intake, increased systemic requirements for iron such as in pregnancy, and
decreased iron absorption such as in celiac disease

EVALUATION

Microcytosis, hypochromia, and anisocytosis

Serum levels of ferritin, iron, and transferrin saturation will be decreased but the total iron-binding capacity will be
increased

Stool for occult blood may reveal a gastrointestinal source of bleeding

Mentzer index (MCV/RBC) - help differentiate between IDA and thalassemia minor

An index greater than 15 suggests iron deficiency, while an index less than 11 suggests thalassemia minor

Thalassemia and other hemoglobinopathies --> Haemoglobin electrophoresis

📌 The standard for establishing iron deficiency is a bone marrow aspiration or biopsy followed by iron
staining since it is unaffected by inflammation

Sideroblastic Anemia
Form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells
(erythrocytes) hence the body has iron available but cannot incorporate it into hemoglobin, which red blood cells need
in order to transport oxygen efficiently

Hereditary

X-linked - ALA synthetase deficiency

Autosomal –Disorder in Glycine transport to Mitochondria

Acquired

Primary sideroblastic anemia (refractory)

Secondary sideroblastic anemias caused by drugs and bone marrow toxins, Pyridoxine deficiency and Zinc excess

Isoniazid

Chloramphenicol

Alcohol

Lead

Chemotherapeutic agents

E. Normocytic Anemia

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 Anemia of Chronic Disease

Anemia due to Impaired Bone Marrow Response

Red blood cell aplasia

Aplastic anemia

Myelodysplasia

Leukemias

Myelophthisic anemia

Marrow infiltration

Myeloma

Congenital Dyserythropoietic Anemias

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 Aplastic Anemia

Hemolytic Anemias

Steps to evaluate for hemolytic anemia

1. Confirm the presence of hemolysis- elevated LDH, corrected reticulocyte count >2%,elevated indirect bilirubin and
decreased/low haptoglobin

2. Determine extra vs. intravascular hemolysis-

Extravascular

Spherocytes present

Urine hemosiderin negative

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 Urine hemoglobin negative

Intravascular

Urine hemosiderin elevated

Urine hemoglobin elevated

3. Examine the peripheral blood smear

Spherocytes: immune hemolytic anemia (Direct antiglobulin test DAT+) vs. hereditary spherocytosis (DAT-)

Bite cells: G6PD deficiency

Target cells: hemoglobinopathy or liver disease

Schistocytes: TTP/HUS, DIC, prosthetic valve, malignant HTN

Acanthocytes: liver disease

Parasitic inclusions: malaria, babesiosis, bartonellosis

4. If spherocytes, check if DAT is

DAT(+): Immune hemolytic anemia (AIHA)

DAT (-): Hereditary spherocytosis

📌 Other investigations that might be warranted include esophagogastro-duodenoscopy for the determination of an
upper GI bleed, colonoscopy for the determination of a lower GI bleed, and imaging studies if malignancy, or
internal hemorrhage is suspected. If a menstruating woman has heavy vaginal bleeding, evaluate the presence
of fibroids with a pelvic ultrasound.

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 F. Macrocytic Anemia

Treatment and Evaluation

1. Anemia due to acute blood loss

Treat with IV fluids, crossmatched packed red blood cells, oxygen

Always remember to obtain at least two large-bore IV lines for the administration of fluid and blood products

Maintain hemoglobin of > 7 g/dL in a majority of patients

Those with cardiovascular disease require a higher hemoglobin goal of > 8 g/dL.

2. Anemia due to nutritional deficiencies: Oral/IV iron, B12, and folate.

Oral supplementation of iron is by far the most common method of iron repletion

should be taken without food to increase absorption

The most common side effects include metallic taste and gastrointestinal side effects such as constipation and
black tarry stools

Iron supplementation is needed for at least three months to replenish tissue iron stores and should proceed for at
least a month even after hemoglobin has returned to normal levels

For such individuals, they are advised to take oral iron every other day, in order to aid in improved GI absorption.
The hemoglobin will usually normalize in 6-8 weeks, with an increase in reticulocyte count in just 7-10 days.

Intravenous iron may be required if the patient is intolerant to oral iron, has malabsorption such as celiac disease,
post-gastrectomy, or achlorhydria, or the losses are too high for oral therapy

3. Anemia due to defects in the bone marrow and stem cells: Conditions such as aplastic anemia require bone
marrow transplantation.

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 4. Anemia due to chronic disease: Anemia in the setting of renal failure, responds to erythropoietin. Autoimmune and
rheumatological conditions causing anemia require treatment of the underlying disease.

5. Anemia due to increased red blood cell destruction:

Hemolytic anemia caused by faulty mechanical valves will need replacement.

Hemolytic anemia due to medications requires the removal of the offending drug.

Persistent hemolytic anemia requires splenectomy.

Hemoglobinopathies such as sickle anemia require blood transfusions, exchange transfusions, and even
hydroxyurea to decrease the incidence of sickling.

DIC, which is characterized by uncontrolled coagulation and thrombosis, requires the removal of the offending
stimulus. Patients with life-threatening bleeding require the use of antifibrinolytic agents.

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