Anemia

Define Hemoglobin

signifies oxygen ­carrying capacity of the blood

• determines whether a patient is anemic

Define MCV

• A widely used laboratory value to measure RBC “size”

• higher values indicate macrocytosis and lower values indicate microcytosis

• Tends to be low in IDA and normal (rarely low) in ACD

Define Macrocytic

Abnormally large red blood cell

Define Normocytic

Normal-sized cell

Define Microcytic

Smaller than normal blood cell

• Does not have enough Hgb

Define TIBC

• Measures the capacity of transferrin to bind iron and carry it

• high in IDA and low in ACD

Define Transferrin

• a protein of the beta globulin group which binds and transports iron in blood serum

  • it is lower in IDA (Iron deficinecy anemia)

Define Serum iron

Amount of iron bound to transferrin

Define Serum ferritin

• the best indirect determinant of body iron stores

  • Decreased in IDA 

  • Elevated in ACD

Define EPO

• Hormone secreted by the kidney in response to cellular hypoxia

• Patients may benefit from EPO therapy if they are anemic & EPO levels are normal or mildly elevated

Define Hepcidin

• is an acute ­phase protein expressed in response to the upregulation of inflammatory cytokines

• Major iron regulator (high levels = lack of iron absorption through GIT)

Define Methylmalonic Acid

An organic acid that serves as a crucial biomarker for Vitamin B12 deficiency and certain metabolic disorders

Define Homocysteine

Amino acid that is broken down by vitamin B6, B9 (folate), B12 (cyanocobalamin)

• Elevations indicate a deficiency in B vitamin(s)

What are the common signs and symptoms of a patient with anemia?

• Fatigue, lethargy, dizziness

• Shortness of breath

• Headache

• Edema

• Tachycardia

What are other signs and symptoms seen in some patients with anemia?

• Dry skin, chapped lips

• Nail brittleness or spoon-shaped nails (iron deficiency)

• Hunger for ice, starch, or clay (termed pica) (iron deficiency)

• Cognitive impairment, gait abnormalities, irritability, peripheral neuropathy (vitamin B12 anemia)

True or False:

Signs and symptoms of anemia are usually specific

False

• the signs and symptoms of anemia are nonspecific/generalized

What other conditions must be discussed or ruled out when considering anemia?

• History of blood loss, such as hemorrhoids, melena, or menorrhagia (IDA)

• Dietary habits (vegan/vegetarian), malnourishment, or recent weight loss (vitamin B12 or folate deficiency)

• Recent GI surgeries (gastric bypass) (vitamin B12, folate, or copper deficiency)

• Alcoholism (folate deficiency), medications or supplements interfering with optimal nutrient absorption (zinc)

• Cancer or CKD

• Chronic autoimmune disorders or infections, such as HIV infection or rheumatoid arthritis that may impact nutritional absorption (anemia of chronic disease)

• Socioeconomic barriers (access to primary care, food security)

Which worldwide and US-based patient populations are most likely to be diagnosed with anemia?

Anemia is a common diagnosis with a prevalence that widely varies based on age, gender, race/ethnicity, underlying clinical diagnosis, and geographic location

• Age: 40% of young children less than 5 years old in US

• gender: 37% of pregnant women

• Underlying clinical diagnosis: CKD, cancer

• location: lower & middle income countries

What is erythropoiesis?

The process of red blood cell (RBC) production that begins in the bone marrow and results in mature RBCs entering the peripheral blood.

What hormone stimulates erythropoiesis?

Erythropoietin (EPO).

How does erythropoietin (EPO) stimulate RBC production?

By inducing differentiation of RBC precursors in the bone marrow.

Where is erythropoietin (EPO) produced?

In the kidneys

What triggers the release of erythropoietin (EPO)?

Cellular hypoxia.

What are reticulocytes?

Immature red blood cells found in peripheral circulation.

Do reticulocytes have oxygen-carrying capacity?

Yes, reticulocytes are capable of carrying oxygen.

How long do reticulocytes remain in the bloodstream before becoming erythrocytes?

Approximately 1–2 days.

What happens to reticulocytes as they mature?

They shrink in size and become mature erythrocytes.

What nutrients are required for reticulocyte maturation?

• Iron

• folic acid

• vitamin B12.

Describe copper’s role in nutrient absorption

essential micronutrient needed for proper functioning of organs and metabolic processes

• Ex: Hgb synthesis and Fe oxidation

T/F: Diets poor in nutritional supplements may slow erythrocyte production

True

↓ meat = ↑ risk of …

IDA (iron deficient anemia)

↓ animal products (eggs, dairy) = ↑ risk of…

B12 deficiency anemia

Bariatric surgery or colitis can cause nutritional deficiencies because of…

malabsorption

What happens as a result of ↓ folic acid and B12 (that can be caused by poor diet)

• hinders erythrocyte maturation

• ↓ DNA formation

• ↓ RBC production

• ↓ neurological fxn (B12 specific and may be irreversible) 

What type of anemia is caused by B12 deficiency induced by autoantibody production to intrinsic factor glycoprotein (needed for normal B12 absorption and made by gastric parietal cells)

Pernicious anemia

Who are at greater risk for nutritional deficiencies?

Women>men

Describe examples of Anemia of Chronic Disease (ACD)

• Infection

• Autoimmune diseases

• CKD

• Cancers

What are some causes of Anemia of Chronic Disease (ACD)?

• Disturbance of Fe homeostasis (related to immune system)

• Hepcidin (acute-phase protein) in response to upregulation of inflammatory cytokines. 

  • When ↑ = ↓ Fe absorption from GIT and ↓ Fe release for splenic macrophages

• Immune activation = upregulation of cytokines that ↓ proliferation/differentiation of erythroid precursors

• ↓ EPO (esp in CKD)

• Disrupted erythropoiesis

What laboratory test evaluates red blood cell characteristics to determine the cause and treatment of anemia?

Complete blood count (CBC)

What is the first step in the diagnostic approach to anemia?

Evaluate mean corpuscular volume (MCV)

How is macrocytic anemia (high MCV) evaluated?

• Check vitamin B12 and folate

  • low folate = folate deficiency

  • low B12 = B12 deficiency →

    • Schilling test:

      • ↓ intrinsic factor = pernicious anemia

      • normal intrinsic factor → Investigate GI pathology

  • Normal b12 & folate = consider: hepatic disease, drug-induced anemia, hypothyroidism, reticulocytosis

How is microcytic anemia (low MCV) evaluated?

Check ferritin

• low = iron deficiency anemia

• if normal/high → check TIBC

  • low = anemia of chronic disease

  • normal/high:

    • hemoglobin electrophoresis for thalassemia)

      • Increased A2, F —> B Thalassemia

      • Normal = Bone marro evaluatoin

        • Ring sideroblasts = sideroblastic anemia

        • Normal = alpha thalassemia

    • consider lead toxicity based on history

How is normocytic anemia evaluated?

Check reticulocyte count

What do reticulocyte count results indicate in normocytic anemia?

High = blood loss

• Consider Acute blood loss, hemolysis, splenic sequestration

Low → check WBC/platelets

• low = bone marrow failure (aplastic anemia, leukemia)

• normal/high = chronic infection, inflammation, malignancy, or chronic kidney disease

What food sources are high in iron?

• Red meat

• Organ meats

• Seafood

• Wheat grains

• Egg yolks

• White beans

• Lentils

• Kidney beans

• Nuts and dried frurit

• Fortified cereals/breads

What food sources are high in Vitamin B12?

• Eggs

• Milk

• Yogurt

• Fish/seafood

• Poulty

• Meat

• Fortified cereals

What food sources are high in Folic acid?

• Dark Green Vegetables (Spinach, asparagus, brussel sprouds, broccoli)

• Liver

• Peanuts

• Beans (Kidney)

• Fruits

• Fortified cereals

• Chickpeas

• Enriched pasta/breads/rice

What food sources are high in Copper?

• Vegetables

• Mushrooms

• Legumes

• Whole grains

• Barley

• Nuts

• Seeds

• Milk

• Liver

• Beef

• Crustaceans

• Chocolates

What two non-pharmacologic therapies are used to treat anemia?

1. Transfusions of RBCs (trigger = 7 g/dL, for patients w/o CVD)

2. Diet focusing on sources of iron, folic acid, and B12 (encouraged but should not be the sole modality)

What is the hemoglobin trigger to use Transfusions of RBCs?

7 g/dL

• for patients without cardiovascular disease

What is the cell size of Iron deficiency?

Microcytic

Is HGB incresed or decreased in Iron deficiency?

Decreased

Is MCV high or low in Iron deficiency?

low

Is TIBC and Transferrin high or low in Iron deficiency?

high

Is MMA (methylmalonic acid) level high or low in iron deficiency?

Slightly high

T/F:

Folate and Vitamin B12 deficiency is Microcytic

False

• Macrocytic

HBG is high or low in Folate and Vitamin B12 deficiency?

Low

MVC is high or low in Folate and Vitamin B12 deficiency?

High

What is the cell size of anemia of chronic diseaes (ACD)?

Microcytic

Anemia of chronic disease (ACD) has a high or low:

• HGB

• MCV

• TIBS

• Trasnferrin

• Iron

Low for all

Anemia of chronic disease (ACD) has a high or low Ferritin?

High

• the body has iron in storage, but it’s locked away and not available for erythropoiesis.

Anemia of chronic kidney disease (ACKD) has a cell size of…

Normo/Microcytic

HGB in Anemia of chronic kidney disease (ACKD) is high or low?

low

MCV in Anemia of chronic kidney disease (ACKD) is high or low?

Normal/micro

TIBC in Anemia of chronic kidney disease (ACKD) is high or low?

High

Transferrin and Iron in Anemia of chronic kidney disease (ACKD) is high or low?

Low

Ferritin in Anemia of chronic kidney disease (ACKD) is high or low?

Normal/High

What is the dosing regimen of PO Iron?

50-65 mg 2-3x daily (on empty stomach)

What are common adverse effects of PO iron?

• Nausea

• vomiting

• abdominal pain

• heartburn

• constipation

• dark stools

• Intolerable GI effects → take with meal or use EC

What is the dosing regimen of IV Iron?

100mg (aliquots daily until dose is achieved) over 4-6 hours on day 1

• Used when pts cannot tolerate oral, have decreased absorption, or are non-compliant

What are common adverse effects of IV iron?

• Anaphylaxis

  • Need to do a test dose due to anaphylaxis risk**

• Injection site pain/irritation

• arthralgias

• myalgias

• flushing

• malaise

• fever

What is the typical dosing for oral vitamin B12 replacement?

1000–2000 mcg daily

• with similar doses used for maintenance if GI absorption is adequate

What factors affect the effectiveness of oral vitamin B12 therapy?

Requires intact GI absorption and intrinsic factor

• Conditions like gastritis or chronic proton-pump inhibitor use can slow absorption

How quickly does anemia correct with oral vitamin B12 therapy?

Correction may be slower and less predictable, especially in patients with impaired absorption

Which patients are best suited for oral vitamin B12 therapy?

Patients with dietary deficiency or reversible malabsorption syndromes

What is the typical IV vitamin B12 replacement?

• 1000 mcg daily for 1 week → then 1000 mcg weekly for ~1 month or until hemoglobin normalizes

  • followed by 1000 mcg monthly for maintenance in patients with pernicious anemia or a history of gastric bypass

How quickly does anemia correct with parenteral vitamin B12 therapy?

Rapid response with improvement in RBCs and hemoglobin typically within one week

Which patients should preferentially receive parenteral vitamin B12 therapy?

Patients with

• severe deficiency

• neurologic symptoms

• pernicious anemia

• gastric bypass

• impaired GI absorption

What is the recommended replacement regimen for folic acid deficiency anemia?

1 mg by mouth daily

When are higher doses of folic acid required in deficiency anemia?

Up to 5 mg daily + longer therapy durations

• in patients with malabsorption syndromes or short gut syndrome

What is the expected timeline for hemoglobin response to folic acid therapy?

Hemoglobin rises after ~2 weeks and normalizes within 2–4 months

How well is folic acid therapy tolerated?

well tolerated

What formulations are available for vitamin B12 anemia vs folic acid anemia?

Vitamin B12:

• PO (≈ parenteral efficacy)

• sublingual

• intranasal

Folic acid:

• PO only

Compare absorption and kinetics of vitamin B12 vs folic acid therapy.

Vitamin B12:

• complete absorption with parenteral dosing but rapidly cleared by plasma esterases (no IV)

Folic acid:

• rapid and complete absorption unless malabsorption or short gut

Compare standard dosing regimens for vitamin B12 anemia vs folic acid anemia.

Vitamin B12:

• IM 1000 mcg daily ×1 week → weekly ×1 month → monthly for maintenance (im 1000 mcg/month lifelong if pernicious anemia/gastric bypass)

• PO 1000–2000 mcg/day may be used if absorption adequate

• Intranasal if impaired GI absorption

• Dietary deficiency or or Reversible Malabsorption Syndrome → use PO and then D/C when cause is corrected

• Bridge therapy: IM → PO for maintainance

Folic acid:

• PO 1 mg/day

• up to 5 mg/day if malabsorption/short gut

Explain interactions and contraindications of vitamin B12

• Impacted by atrophic gastritis and chronic PPI usage

• Do not use PO for severe neurological/CNS S/S

Exlpain adverse effects of vitamin B12

• Well tolerated, but injection-site pain, pruritis, and rash are possible

Exlpain adverse effects Follic acid anemia therapy

Well tolerated, but allergic rxn, flushing, and rash are possible

What is the goal of ESA therapy in chemotherapy-induced anemia vs anemia of CKD?

Both to reduce or avoid transfusions

Why are ESAs used in chemotherapy-induced anemia?

EPO binds to RBC precursors to increase RBC production

Why are ESAs used in anemia of CKD?

• EPO deficiency due to kidney disease 

• When HGB< 10 g/dL and other causes of anemia have been ruled out

At what HGB level would you initiate ESA use in chemotherapy?

when HGB levels are <10 g/dL

At what HGB level would you initiate ESA use in Anemia of CKD?

• HD (hemodialysis): 9.0 – 10.0 g/dL 

• Non-HD: <10 g/dL

What additional evaluations are required before or during ESA therapy in CKD?

• Assess iron status

• check vitamin B12 and folate

• evaluate for bleeding or hemolysis

What additional evaluations are required before ESA therapy in chemotherapy?

Assess iron status/need

What is the goal of therapy of anemia of chronic disease?

decreased RBC transfusion requirements with the EPO-stimulating agents (ESAs)

Epoetin alfa (EPO): generation type?

First-generation ESA

Darbepoetin alfa: generation type?

Second-generation ESA

Methoxy PEG epoetin beta (CERA): generation type?

Third-generation (continuous ESA)

Is a biosimilar available for epoetin alfa?

Yes