OBJECTIVES Define anemia and identify the appropriate diagnostic testing necessary to diagnose anemia Discuss various types and causes of anemia Discu

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1 ANEMIA Marjaana Krieger, MSN, RN, NP-C, AOCNP Advanced Oncology Certified Nurse Practitioner Department of Veterans Affairs/ VA Southern Nevada Healthcare System Hematology/Oncology/Infusion Clinic

2 OBJECTIVES Define anemia and identify the appropriate diagnostic testing necessary to diagnose anemia Discuss various types and causes of anemia Discuss intervention & rationale for the treatment of anemia Identify when it is appropriate to refer/consult specialists such as hematologists/oncologists

3 DEFINITION OF ANEMIA Anemia is defined as a reduction in the number of RBCs or quantity of Hgb. Normal red blood cell (RBC) level in men: ( million/ul) Normal red blood cell (RBC) level in women: (4.2 to 5.4 million/ul) Hemoglobin is the oxygen carrying component of the blood (molecular proteins with two alpha globulins and two beta globulins) Normal Hemoglobin (Hgb) levels in men: (14-18 g/dl) Normal Hemoglobin (Hgb) levels in women: (12-16 g/dl) Hematocrit (Hct ) % = 3 x Hgb

4 CLASSIFICATION Classified as microcytic, normocytic or macrocytic based on size of the RBC which is the MCV (mean corpuscular volume). MCV is a part of the complete blood count (CBC). Microcytic (MCV < 80) Normocytic (MCV ) Macrocytic (MCV > 100)

5 CAUSES OF ANEMIA Anemia can be due to a single cause or more than one cause (multifactorial) Causes include: iron deficiency, B12/folic acid deficiencies, chronic diseases/inflammation, autoimmune diseases, chronic kidney disease, medication-induced and hematologic/oncologic causes. Consider a hematology/oncology consult/referral for any unexplained anemia or multifactorial anemia as a bone marrow aspiration & biopsy procedure may be warranted.

6 MICROCYTIC ANEMIA Iron deficiency anemia is a microcytic anemia (MCV < 80) and Hgb/Hct below normal range. Ferritin is a blood cell protein containing iron and is referred to as the stored iron in the body. Serum ferritin levels are low or low normal in patients with iron deficiency anemia. Ferritin level range ( ng/ml). A level of at least 50 is an overall good ferritin level. A low ferritin level is indicative of iron deficiency (below 50 classifies patient as iron deficient). The lower the ferritin the more iron deficient. If the ferritin level < 10 the patient is severely iron deficient.

7 MICROCYTOSIS Also note patients with thalassemia trait have low MCV values and may not have IDA or require any treatment. Patients with lead poisoning/toxicity may present with microcytosis. Keep in mind that FERRITIN IS AN ACUTE PHASE REACTANT therefore the ferritin level may elevated due to acute illness/trauma, inflammation, infection, etc. The serum ferritin level may not reflect the patient's true stored iron level. Under steady state conditions the serum ferritin level correlates with the total body iron stores.

8 CAUSES OF IDA Bleeding such as menorrhagia in women whose menstrual cycles are heavy/ prolonged and/or passing clots and/or bleeding from fibroids. Bleeding from acute/overt blood loss such as in a trauma. Bleeding from a chronic/ occult GI bleeding such as ulceration or esophageal varices (chronic alcoholism). It can also be found in malignancies such as colon cancer (rectal bleeding), lung cancer (hemoptysis) and bladder or renal cell carcinoma (hematuria). Patients who are bleeding are losing iron and not able to balance the amount of iron intake with the loss and thus are in a deficient state. Malabsorption as seen in patients who have undergone abdominal surgery such as gastric bypass. They may be taking in adequate iron in their diets or even oral iron supplements but not absorbing it.

9 CAUSES OF IDA Patients with Celiac disease (gluten intolerance) may also have issues with iron absorption. Patients who repeatedly donate blood or have blood loss from major surgeries may have IDA. Pregnant women are usually iron deficient as well as those who may lose large amounts blood during delivery.

10 SIGNS/SYMPTOMS OF IDA Fatigue Dizziness SOB Pallor (skin, conjunctivae and palate) Poor appetite Tachycardia Possible systolic ejection murmur (SEM) Feeling cold Itchy PICA (cravings for dirt, clay, paper products) Pagophagia (craving for ice)

11 TREATMENT OF IDA WITH ORAL SUPPLEMENTATION The recommended oral daily dose of iron for the treatment of IDA in adults is in the range of mg po daily. Oral iron supplementation: ferrous sulfate 325 mg po TID. Each tablet has 65 mg elemental iron therefore a total of 195 mg elemental iron daily. Each tab of ferrous gluconate has g iron/tablet. Generally it is advised to take on an empty stomach but because of GI upset some patients will need to take it with food or they become noncompliant. Avoid taking it with antacids, PPIs, antibiotics (usually a 2-4 hr time frame). Side effects include GI upset: usually nausea/vomiting, constipation or diarrhea in some patients and dark stools. Consider prescribing a stool softener such as docusate sodium. Vitamin C (ascorbic acid) promotes absorption of oral iron. Iron is better absorbed in a mildly acidic environment. Advise patients to take with Vit C fluids/foods or Rx ascorbic acid 500 mg po daily.

12 TREATMENT OF IDA WITH IV IRON Consider IV iron replacement when patient is severely deficient generally with a ferritin <10 ng/ml, symptomatic, can't tolerate oral iron or are not absorbing oral iron. Generally you can correct IDA without PRBC transfusions by replacing iron with IV iron unless patient is losing blood volume as in acute bleeding episodes and requires transfusions. Example of IV iron: Ferrlecit (ferric gluconate)125 mg IV weekly to every 4 weeks to correct it. Infused IV over 1 hour and will improve ferritin and therefore increase ferritin and H/H more rapidly than oral iron. Side effects can include flu-like symptoms. Can pre-medicate but test dose and pre-meds generally not necessary. Less likely for patients to have anaphylactic reactions from Ferrlecit in comparison to iron dextran.

13 IRON DEFICIENCY ANEMIA (IDA) GI consult for evaluation of GI source of bleeding (EGD/colonoscopy) warranted in IDA. Consider Gyn consult for menstruating women. Consider Hematology/Oncology consult.

14 NORMOCYTIC ANEMIA Normocytic anemia is noted when the MCV is within the normal range (80-100) and decrease in Hgb/Hct. Normocytic anemia is seen in diseases of a chronic nature. These include chronic diseases such as hematologic/oncologic diseases, HIV/AIDS, autoimmune/inflammatory diseases, chronic kidney disease and/ or liver disease.

15 CAUSES OF NORMOCYTIC ANEMIA Anemia of neoplastic disease is caused by hematologic/oncologic diseases such as myelodysplastic syndrome (MDS), aplastic anemia, leukemias, lymphomas, multiple myeloma, solid tumors/malignancies ie. lung cancer, etc. In multiple myeloma patients may present with anemia as part of the CRAB criteria (hypercalcemia, renal insufficiency, anemia & bone lesions). Serum electrophoresis (SPEP) is tested to look for presence of a monoclonal protein and elevated free light chains (FLC). Anemia due to MDS can generally be diagnosed on a bone marrow aspiration & biopsy. Anemia of CKD is seen in patients with chronic kidney disease. HIV/AIDS patients also have anemia of chronic HIV disease.

16 CAUSES OF NORMOCYTIC ANEMIA Anemia of inflammation is seen in autoimmune/inflammatory diseases such as RA, lupus, psoriasis, gout, etc. Anemia of chronic disease is also seen in thyroid disease such as hypothyroidism, hyperthyroidism, etc. Anemia of chronic disease is found in patients with liver disease such as cirrhosis or Hep C.

17 CAUSES OF NORMOCYTIC ANEMIA Medications can also cause anemia. They include chemotherapy/biologic/immunologic therapies, HIV medications, Hep C medications, psychiatric medications, antibiotics as well as other drugs.

18 TREATMENT FOR NORMOCYTIC ANEMIA Erythropoetin is a hormone made primarily by the kidneys and involved in red blood cell production. Therefore if CKD disease exists then a decrease in production of erythropoetin occurs. Replacing with erythropoetin stimulating agents (ESAs) such as Epo, Procrit, Aranesp improve the anemia. Erythropoetin agents are commonly used to anemia of chronic kidney disease, MDS and sometimes chemotherapy-induced anemia. Treating the underlying disease can improve or even correct the anemia as in thyroid disease for example or in multiple myeloma. Removing the cause (ie. discontinuing the medication) can correct the anemia. PRBC transfusions are generally used if Hgb/Hct drop below 8 g/dl and/or patients are symptomatic. In anemic patients with cardiac disease they are often transfused even with a Hgb 8 g/dl.

19 MACROCYTIC ANEMIA & CAUSES Macrocytic anemia is noted when MCV > 100 and there is a decrease in hemoglobin/hematocrit. Patients with myelodysplastic syndrome may have macrocytic anemia. Medications such as hydroxyurea can cause macrocytosis. Macrocytic anemia includes deficiencies such as B12 (cobalamin) and folate. Vit B12 and folate deficiencies often coexist. Methylmalonic acid (MMA) and homocysteine (HC) appear to be sensitive for the diagnosis of B12 deficiency and are elevated in this deficiency. Normal MMA level= 70 to 270 nanomol/l. Normal HC level=5 to 14 micromol/l. Patients should be fasting when vit B12/folate levels are drawn as food or even blood transfusions can normalize serum concentration levels.

20 B12/FOLATE DEFICIENCIES Vitamin B12 deficiency as well as folate deficiency are commonly found in alcoholics, older adults and patients with malnutrition. Strict vegans/vegetarians are also at risk. All of these patients lack dietary intake of sufficient B12 and folate therefore are at risk for macrocytic anemia. Pernicious anemia (PA) is a type of B12 anemia in which the stomach doesn t make enough intrinstic factor and the intestine cannot properly absorb Vit B12. Intrinsic factor is a protein that helps intestines absorb vitamin B12. This protein is released by cells in the stomach. Therefore these patients with pernicious anemia require lifelong B12 treatment with injections. Anti-intrinsic factor antibody testing is very helpful in diagnosing pernicious anemia. In addition suspect B12/folate deficiencies in patients with unexplained pancytopenia or unexplained neurologic signs or symptoms. Patients who have undergone bariatric surgery/gastric bypass are also at risk of developing B12/folate deficiencies.

21 B12/FOLATE DEFICIENCIES Note that nitrous oxide inactivates cobalamin and its use in anesthesia can precipitate neurologic deterioration in B12 deficient patients. Pregnancy, alcohol intake, anticonvulsants can lower these serum levels.

22 TREATMENT FOR MACROCYTIC B12/FOLATE ANEMIA To correct anemia of folate deficiency prescribe folic acid 1 mg po daily until hematologic recovery. Watch for rise H/H. Normal folate level > 5 ng/ml although you can certainly treat for levels < 10 ng/ml. To correct anemia of B12 deficiency in levels less than 200 pg/ml or low 200s prescribe Vit B mcg IM or SQ daily x 1 week, weekly x 4 weeks then monthly. You can switch to oral after at least 6 months unless patient has pernicious anemia or absorption issues such as in gastric bypass patients. Vit B12 is water soluble. There are sublingual as well as nasal formulations (spray/ gel) but these routes are not adequately studied. Rx cyanocobalamin (B12) 1000 mcg po daily for B12 levels in the 300s. Normal levels approx Patients should generally remain on supplementation lifelong especially in the high risk groups.

23 OVERALL WORK-UP FOR ANEMIA CBC with reticulocytes, ferritin, iron panel, epo level, B12/folate, MMA, HC, antiintrinsic factor antibody, CMP, TSH, RF, ANA, HIV, Hep ABC panel, Hgb electrophoresis and sometimes peripheral blood smear (heme path review). Sometimes SPEP (serum electrophoresis) and free light chains are ordered if concerned about possible multiple myeloma. Also Coomb s and LDH if hemolysis suspected. Investigate the possible causes of the anemia and treat as indicated and/or consult Hematology/Oncology, Gynecology, GI, Rheumatology, etc. Consider GI work-up (EGD/colonoscopy) to try to locate a source of bleeding especially in IDA. Sometimes GI will order a capsule endoscopy. In IDA, consider a pelvic/transvaginal US in menstruating women to evaluate for abnormalities causing heavy bleeding such as fibroids. Bone marrow aspiration & biopsy procedure & imaging (CT scans/pet-ct scans) may be indicated if concern for hematologic/oncologic malignancies. Consult a dietician as well.

24 CASE STUDY #1 A 43 year old African American female presents to the clinic with c/o fatigue, SOB, dizziness. She reports a decreased appetite but does crave and crunches on ice. CBC shows Hgb =7.8 g/dl, Hct= 23.4 %, MCV= 68, Plts=600,000. Ferritin = < 5, transferrin 460 (normal ), iron sat 12% (normal 20%-50%). BUN 20, creatinine 0.9. She reports her menstrual cycles Q 28 days and last 5-7 days with heavy flow. Uses approx. 16 super absorbency pads in an 8 hr day and at least a few tampons at night. Last gyn visit was 2 years ago and she was told she has fibroids. Your diagnosis is: A. MDS (myelodysplastic syndrome) B. Anemia of CKD C. Iron deficiency anemia

25 CASE STUDY # 2 78 year old Caucasian male presents for an annual visit to his PCP. PMHx includes DM, CHF, peripheral neuropathy, alcohol abuse and PTSD. Specimen Collection Date: Feb 28, 2017@07:37 Test name Result units Ref. range WBC 5.6 K/mcL RBC 2.34 L M/mcL HGB 10.4 L g/dl HCT 31.2 L % MCV H fl PLT 181 K/mcL

26 CASE STUDY # 2 What are your differential diagnoses? What further work-up would you recommend at this time? A. B12/folate deficiencies B. MDS C. Multiple myeloma D. Multifactorial anemia E. All of the above

27 REFERENCES 1. Approach to the Adult Patient with Anemia 2. Causes and Diagnosis of Iron Deficiency Anemia in the Adult 3. Treatment of the Adult with Iron Deficiency Anemia 4. Diagnosis and Treatment of Vitamin B12 and Folate Deficiency