Anemia Causes, Diagnosis, and Treatment: Understanding Iron Deficiency Anemia, Summaries of Hematology

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B. F. Rodak, J. H. Carr,

Clinical Hematology

Phaím Management of Anemia

Objectives : ● Compare and contrast IV oral iron supplementation ● Given a patient case, provide optimal pharmaceutical care Definition of anemia: ● Disorder resulting in reduced oxygen-carrying capacity of the blood ○ Inadequate RBC production ○ Increased RBC destruction ○ Blood loss ● World Health Organization criteria: ○ Hemoglobin <fi3 g/dL in men ○ Hemoglobin <fi2 g/dL in women RBC production regulated by feedback loop ● Decrease in tissue oxygen concentration, hormone EPO gets produced in the kidneys → EPO gets in plasma→ stimulates production of RBCs in bone marrow → stimulates RBC maturation RBC maturation Red circle: nucleus Erythrocyte: no nucleus 90% of cell is hemoglobin

Homocysteine & MMA are m measurement (intermediary s MCV Interpretation Evaluation of Iron Studies ● Serum iron: concentration of iron bound to transferrin ○ Diurnal (higher in morning) not clear if this has clinical significance ● Total Iron Binding Capacity (TIBC): indirect measurement of iron-binding capacity of serum transferrin (HIGH = bad) ● Transferring saturation (%) (TSAT): radio of serum iron to TIBC ○ Indicates amount of iron readily available for (low = bad) erythropoiesis as a % ● Serum ferritin: total iron storage ○ Low level is always iron deficiency ○ Acute phase reactant, so can be elevated in inflammation and mask iron deficiency Additional Laboratory Values Scaricato da giove novantanove ([email protected]) ore indirect methods of teps); signific. questionable Folic acid Decreased serum folic acid <4 ng/mL indicates deficiency Serum folic acid levels fluctuate more compared to erythrocyte folic acid levels Can check erythrocyte folate level is suspect deficiency & serum level is normal B12 Low serum vitamin B12 <200 pg/mL indicates deficiency Can be falsely low with folate deficiency and pregnancy (so check both levels) Schilling test – GOLD STANDARD for assessing Vitamin B12 (rarely used) Homocysteine Both B12 and folic acid are required for homocysteine to convery to methionine Increased levels may suggest B12 or folate deficiency Methylmalonic acid (MMA) B12 is needed to convery methylmalonyl coenzyme A to succinyl coenzyme A B12 deficiency can lead to increased MMA levels

Iron replacement strategies : dietary iron, oral iron supplementation, IV iron supplementation ➔ Iron important for development Contraindication for Fe supplementation: HEMOCHROMATOSIS (inability of liver to excrete iron stores) Dietary Iron: Recommended dietary intake: 8 mg iron daily in adults ➔ Menstruating women: 18 mg ➔ Children and pregnancy women require higher intake ➔ Best absorbed in Fe2+^ form (most Western diets contain Fe3+) ➔ Primary absorbed in duodenum, some in jejunum ◆ Gastric sleeve procedures often bypass the duodenum and jejunum ➔ Absorption is in relation to decreased levels, not intake

Oral Iron: Clinical Pearls ● Start low and slow ● Food can decrease absorption but help with tolerability ● Take 1 hour before eating or 2 hours after, if possible ● Every other day many improve absorption (long term studies needed) ● Store away from children/pets (can be toxic/fatal) ● Consider adding a stool softener to prevent constipation ● Take with orange juice or acidic drink to improve absorption ● Avoid milk and tea due to decreased absorption Indications for IV Iron Oral Iron DRUG INTERACTIONS DECREASED IRON ABSORPTION

IRON DECREASES THEIR

ABSORPTION

Antacids (Mg, Ca, Al) Levodopa Tetracyclines Methyldopa H2RA Levothyroxine PPI Penicillin Cholestyramine Fluoroquinolones Tetracyclines Mycophenolate There’s a lot of drug interactions related to Fe supplementation. Antacids and H2RA to the end – pH issues! On the right side, iron competes for Fe absorption with all the other medications on the side ➔ Not tolerating orals (or NPO), Malabsorption, Nonadherence, Significant blood loss (refusing blood products)

IV IRON SUPPLEMENTATION

Generic name Brand name Dose Ranges Pearls Reading Notes Iron dextran Infed 25 - 1000 mg (100 mg QD or 1000 mg single dose) Must do 25 mg test dose and observe for 1 hour Anaphylactic reactions (BBW) Requires test dose Immune-mediate diseases highest risk Long half life (~40- 60 hrs) CKD [-] HD [-] Total dose infusions Higher risk of ADE: arthralgias, myalgias, flushing, malaise, fever, staining of skin, pain @ injection site, allergic reactions, anaphylaxis Lupus+RA pts higher risk because of hyperreactice immune response Sodium ferric gluconate Ferrlecit HD: 125 mg each HD session, total up to 1000 mg Short half life (~1 hr) CKD [X] HD [X] ADE : cramps, nausea, vomiting, flushing, hypotension, intense upper gastric pain, rash, pruritis Off-label (not studied) in non-HD patients (same dose) MOA: complex of iron bound to one gluconate + 4 sucrose molecules; taken up by mononuclear phagocytic system Iron sucrose MC Venofer Non-HD: 100- 200 mg daily HD: 100 mg each HD session (total up to 1000 mg for HD/Non-HD) Short half life (~6 hrs) Do not give with oral iron; will DECREASE absorption CKD [X] HD [X] ADE : leg cramps, hypotension MOA: polynuclear iron III hydroxide in sucrose complex; Fe released from circulating iron sucrose to transferrin → taken up by mononuclear phagocytic system → metabolized Ferumoxytol Feraheme 510 mg IV single dose, may repeat dose in 3 - 8 days BBW for allergic reactions No test dose but need to observe after for 30 mins Longer half life (~15 hrs) CKD [X] HD [X] FDA approved for IDA pts + CKD on HD + unresponsive to oral iron ADE: NOT be used in pts with allergic rx to other iron preps Ferric carboxymaltose Injectafer (^) ≥50 kg : 750 mg, repeat dose in 7 days (total 1500 mg) <50 kg : 15 mg/kg, repeat dose 7 days Longer half life (~12 hrs) CKD [X] HD [-] ADE : hypophosphatemia CKD = chronic kidney disease; HD = hemodialysis ● Iron dextran needs a test dose aka subcutaneous/subdermal test to avoid downstream anaphylactic reactions ● Venofer is most prevalent due to BBW associated with iron dextran and ferumoxytol; but because of their short half life pts needs 3-5 doses before they are adequately supplemented Calculating Iron Deficit Ganzoni Equation : weight (kg) x [target Hb (g/dL) – actual Hb (g/dL)] x 2.4 + iron stores (mg) Normal iron stores: ~500 mg

Synthetic folic acid does not need cobalamin to convert active form Non-pharmacologic Beef liver, lentils, green leafy vegetables Fortified cereals, orange juice, rice

Picclass Rcadi⭲o Notcs Iron Supplementation B12 supplementation IDA Tx : Most cases: oral admin. Iron therapy&soluble Fe2+ iron salts are appropriate. IDA pts rec. Dose fi50-200mg elemental iron daily in 2 - 3 divided doses to maximize tolerability. Tx should continue for 3 - 6 mo after anemia is resolved to allow repletion of Fe stores & prevent relapse Effective for pernicious anemia ; should be continued for LIFE in patients with this condition ADE: GI (dose related and similar among iron salts) in nature → dark discoloration of feces, constipation or diarrhea, nausea, vomiting. Impaired absorption: H2A or PPI reduce gastric acidity, previous gastrectomy (gastric bypass surgery or celiac disease) ADE: very rare; uncommon side effects hyperuricemia & hypokalemia CKD/HD: Ferric citrate FDA approved for IDA Tx in CKD patients who are not on dialysis; parenteral iron therapy indicated Folic acid Absorption : IRON BEST ABSORBED IN REDUCED FE2+ FORM; MAX ABSORPTION IN DUODENUM (acidic medium of stomach); slow release may not be dissolved until they reach SMALL INTESTINE – and they tend to form insoluble complexes due to alkaline environment in small intestine (reduces absorption)

N/A

Hepcidin : protein that helps regulate iron absorption may play role in iron dosing. Large dose iron in morning→elevated hepcidin levels → prevent absorption for rest of day- 48 hours later Parenteral iron : indications: oral Fe intolerance, malabsorption, nonadherence, significant blood loss/transfusions/can’t take PO. fist line in IBD + gastric bypass/resection pts , CKD undergoing HD, cancer pts w/ chemo+EPO tx.

1. Iron dextran needs test dose BBW anaphylactic rxn
2. Sodium ferric gluconate
3. Iron sucrose
4. Ferumoxytol
5. Ferric carboxymaltose Additional Fe to replenish stores should be added: 600 mg women, 1000 mg men

Casc Applicatio⭲

CC: “I’ve been feeling really tired lately, and it’s making it difficult to study for my pharmacy school exams.” HPI: JD is a 23 - year-old female presenting to her PCP today for her annual checkup, and she mentions that she has been feeling more tired than usual and very fatigued lately. She states she has been getting enough sleep (about 7 - 8 hours per night) and eating healthy, reporting that she is a vegetarian. JD also mentions that recently she has been eating ice chips. Her fatigue is negatively impacting her ability to concentrate during lectures and studying in the evenings. PMH: None, first period at age 12 FH: Mother: hypothyroidism Father: hypertension, hyperlipidemia SH: Pharmacy intern at a local community pharmacy (+) EtOH: drinks socially, about once per week (-) Tobacco (-) Illicit drug use Allergies: PCN (rash) Home medications: Acetaminophen 500mg 1 - 2 tablets Q6h PRN for headache (uses 1 - 2 times/week) ROS: Reports regular periods (occasionally heavy); normal bowel movements; no report of blood in stool PE: Ht: 5’4” Wt: 120lbs Vitals: 112/68 mm Hg; HR 80 BPM; RR 14; afebrile General: pleasant, well-nourished female Skin: pale-appearing, hands cold to touch HEENT: (-) Chest: Clear to auscultation Cardio: Regular rate and rhythm GI: (+) bowel sounds Laboratory Tests: WBC 4 x 103 /mL (WNL) RBC 3.8 x 1012 /mL (Low) Hgb 10.5 g/dL (Low) MCV 70 fL (Low) Hct 30% (Low) MCH 22 pg (Low) Plt 275 x 103 /mL (WNL) MCHC 33/100 mL (WNL) Serum Fe 45 ug/dL (Low) Fe Saturation 15% (Low) Ferritin 10 ug/L (Low) TIBC 524 mg/dL (High) Questions: fi. What signs and symptoms of iron deficiency anemia does KC have?

Fatigue, pagophagia (eating ice chips), pale skin, cool to touch, low Hgb and Hct, Low MVC/MCH, TIBC is high. Serum ferritin levels are low.

2. Which of KC’s lifestyle and demographic factors can contribute to iron deficiency anemia? She’s vegan, additionally, she’s actively menstruating from blood loss. The labs don’t seem to be acute phase, so they are more likely due to their dietary choices. 3. What, if any, lifestyle changes can KC make to improve her symptoms? Consider adding iron-rich vegetables like chickpeas, pinto beans, kale, and broccoli. 4. What is KC’s iron deficit? Round to the nearest whole number. Ganzoni equation: 54.4 kg x (12-10.5)*2.5 + 500 = **696 mg

5. What drug therapy would you prescribe for KC?** Ferrous sulfate 325 mg po BID (any iron supplementation answer is acceptable) 6. How would you educate KC on her drug therapy? Possible constipation and dark stools. Food can help with tolerability but decrease absorption, take with orange juice or acidic drink to improve absorption, and avoid milk and tea that would increase pH in stomach (antacids too like oral tums, H2blockers, or PPI avoid 2 hours before and 2 hours after dose). 7. What monitoring parameters do you have for KC? When would you anticipate scheduling a follow-up appointment to monitor KC’s iron deficiency anemia? CBC, RBC studies, iron studies. Come back around 4 weeks to check initially to see if supplementation would work, and then 3 months after that.

Casc Applicatio⭲

HPI : JV is a 67 year old male patient presenting to the cancer clinic. Today in office, he reports feeling very weak and tired. He explains to you he was noticed bruising on his arms and legs, and that now there is a “funny looking color” beneath the bruising. Now there is a “green looking glob” in his right eye that has been bothering him. Over the last month, JV also has lost 20 pounds. JV remembers his father experiencing similar symptoms right before his cancer diagnosis; because of this, he has came into the clinic for evaluation. His recent labs and bone marrow biopsy results have been updated to his profile. After reviewing his chart, it has been updated to include a diagnosis of AML, and Azacitidine has been ordered for the patient PMH : Type 2 Diabetes HTN FH : Mother- deceased age 87; natural causes Father-deceased age 70; AML Sister- A&W age 60 SH: retired construction foreman; lives alone since wife passed 2 years ago; has three adult children who visit him frequently; never smoked; reports having 1-2 Busch Lights a week during football season Allergies : penicillin (hives) Medications : Multivitamin po daily Metformin 1,000 mg BID Trulicity 0.75 mg SubQ weekly Losartan 50 mg daily Vitals: BP: 127/79 HR: 54 RR: 16 T: 98.3 F Wt: 150 lbs (down 20 pounds in last month) Ht: 5’10’’ Laboratory Test: Date Lab Panel Specific Lab Value 10/13/30 Comprehensive metabolic Panel Glucose 124 (high) BUN 14(normal) Creatinine 0.94 (normal) Sodium 137 (normal) Potassium 4.0 (normal) Chloride 102 (normal) CO2 27 (normal) Calcium 9.3 (normal) Total bilirubin 0.5 (normal) AST (SGOT) 14 (normal) ALT (SGPT) 13 (normal) Albumin 3.8 (normal) 10/13/30 CBC with diff WBC 2.01 (low) Hct 37.4 (low) HGB 10.2 (low) Platelets 303 (normal) Bone Marrow Biopsy (10- 13 - 30) % Presence of Blasts: 35% a. Bone marrow biopsy blasts 35%

b. Petechiae, generalized malaise, weakness, and fatigue c. Pancytopenia on CBC

2. Based on the choice of therapy, what intensity is his therapy? a. High intensity
3. What class of agents does Azacitidine belong to? What other options could be considered for JV? a. Hypomethylating agent
4. What dose of azacitidine needs to be ordered for this patient? Calculate BSA. i. 75 mg/m^2 QD subcutaneously x 7 days and then 21 days for 28 day cycle
5. What toxicities need to be monitored for with the use of azacytidine? Pancytopenia: Febrile neutropenia, neutropenia, thrombocytopenia, pneumonia, anemia
6. What monitoring needs to be ordered for the patient i. Labs: CBC needs to be ordered to see the pancytopenia