Anemia

Microcytic (MCV < 80)

• Big picture: microcytic anemias arise from inability to effectively generate some element of hemoglobin, whether that be iron, the globin protein, or heme.
• IDA: low iron. 
• ACD: poor iron mobilization. 
• Thalassemia: globin chains imbalance. 
• Lead/ Congenital Sideroblastic: impaired heme synthesis. 
• Initial evaluation: Iron studies, hemolysis labs, retic count, blood smear. 
• Iron deficiency typically shows low RBC count and high RDW. 
• Thalassemia typically shows normal/high RBC count and normal RDW. 
• Basophilic stippling on peripheral smear: think lead poisoning or other cause of sideroblastic anemia.

Thalassemia

Alpha thalassemia: mostly gene deletions; 2 alpha globin genes on each copy of chromosome 16 

• alpha thal minima (one deletion, asymptomatic carrier). 
• alpha thal minor (2 deletions, mild anemia). 
• HbH disease (3 deletions, severe anemia with gamma [infant] and beta [adult] tetrameters that cause RBC fragility and hemolysis).
• hydrops fetalis (4 deletions, in utero hydrops fetalis and fetal demise).

Beta thalassemia: 1 beta globin gene on each copy of chromosome 11 

• Mostly splice site mutations, can result in residual partial function or complete loss of function. 
• Severity depends on severity of mutations and whether heterozygous or homozygous. 
• Clinical Findings: + family history, onset at birth or shortly thereafter. 
• RBC Indices: ↓ MCV (often less than 70), ↑ RBC count, Mentzer Index (MCV/RBC) < 13, 
• Target cells on smear. 
• Iron studies: either wnl or show evidence of Fe overload due to ineffective erythropoesis. 
• Definitive diagnosis: Hb electrophoresis (gamma or beta tetramers in alpha thal; HbF or HbA2 in beta thal), genetic testing. 
• Tx: per classical heme. In summary: transfusions, Fe chelators to control Fe overload; maybe luspatercept (increases production of mature RBCs).

Iron Deficiency Anemia

Etiologies include: 

• Poor Fe intake: malnutrition, heme-poor diets—vegetarian, vegan diets.
• Impaired Fe absorption: Gastric etiologies (related to decreased acidity): atrophic gastritis, H pylori, bariatric surgery, PPIs; Duodenal etiologies: Celiac disease vs inherited IRIDA/Iron Refractory Iron Deficiency Anemia. 
• Increased Fe demand: pregnancy and lactation, blood donation, recent initiation of EPO therapy. 
• Increased Fe demand from bleeding: Most common: GI bleeds (gastric ulcer/gastritis, parasites, GI telangiectasias, colorectal cancer), GU bleeds (heavy menstrual bleeding, heavy abnormal uterine bleeding 2/2 cervical or endometrial malignancy), iatrogenic (frequent blood draws, iHD, surgical).

Diagnosis: 

• Iron studies: ↓ Fe, ↑ TIBC, ↓ TSAT, ↓ Ferritin. 
• RBC Indices: MCV <80, ↓ MCHC, ↓ RBC count, Mentzer Index (MCV/RBC) >13, ↓ CHR (reticulocyte hgb content or “retic hgb equiv” in Epic). 
• Note: MCV may be normal in early iron deficiency. 
• Note: Should strongly consider colonoscopy + EGD in all adults with unexplained IDA in addition to celiac serologies, fecal H pylori antigen, pelvic ultrasound.

Treatment: 

• Fe repletion indicated in all with IDA and those with Fe deficiency without anemia if no source control, goal ferritin >50 after repletion. Treat underlying cause. 
• PO Fe: Most common is FeSO4, 325 mg (65 mg elemental Fe) QOD for 6W (correct anemia) to 6M (replete Fe stores). Avoid enteric coated pills, take on empty stomach, consider vitamin C (not OJ which has Ca) to improve absorption; avoid Ca, antacids. 
• Note: QOD repletion has similar efficacy to QD. 
• IV Fe: Use Ganzoni Equation to calculate deficit, but usual clinical practice is to replete 1000 mg total. 
• VA: Iron sucrose 200 mg x5 doses over 14-day period or 300 mg x3 doses over 28-day period; can then give additional 200 mg doses q1-2 weeks until ferritin at goal. 
• VUMC: Ferric Gluconate 125-250 mg over 4-8 doses, doses QOD; can give additional doses afterwards as needed 
• SEs for IV iron include non-anaphylactic infusion reactions (less than 1%, self-limited urticaria, N/V, palpitations, dizziness; Fishbane reaction: facial flushing and myalgias of chest and back, but NO hypotension, wheezing, stridor, periorbital edema vs true anaphylactic reactions (exceedingly rare). 
• For non-anaphylactic reactions, allow symptoms to resolve then restart infusion at ½ the rate. Can consider 1x dose IV methylpred. 
• Note: Have anaphylaxis kit available at bedside.

Sideroblastic Anemia

• Ringed sideroblasts are erythroblasts with Fe rich mitochondria surrounding nucleus on marrow aspirate smears stained with Prussian blue 
• Pathophysiology: impaired maturation of erythroid precursor 2/2 altered heme production within mitochondria>>more Fe taken into precursors to compensate>>Fe overloaded precursors 

Etiologies: Congenital (often mutations in heme synthesis) vs acquired (clonal [MDS/MPN], ETOH, medication induced [isoniazid, chloramphenicol, linezolid], lead exposure, Cu deficiency

Diagnosis: 

• Consider lead levels if high clinical concern.
• RBC Indices: ↓ MCV, ↓ retic count, 
• Iron studies: ↑ Ferritin, nl or ↑ Fe, ↓/nl TIBC. 
• Smear: basophilic stippling of RBCs. 
• Definitive Diagnosis: marrow aspirate stained with Prussian blue, Genetic studies if c/f congenital (family history, young age of presentation, etc.). 
• Treatment: Address underlying cause if acquired: treat MDS/MPN, stop ETOH use, stop offending medication, eliminate lead exposure, replete Cu.

Normocytic (MCV 81-100)

• Common etiologies: hemolytic anemia, chronic kidney disease, anemia of chronic disease (normocytic ~75% of cases), acute blood loss anemia, aplastic anemia, pure red cell aplasia, other bone marrow failure, hypothyroidism, adrenal insufficiency.
• Normocytic anemia can also be the beginnings of a pure microcytic or macrocytic process or the combination of microcytic and macrocytic processes.
• Initial Evaluation: Reticulocyte Count 
  • High RPI: Often hemolysis. May also represent acute blood loss anemia. 
  • Low RPI: CKD, ACD, aplastic anemia, pure red cell aplasia, other bone marrow failure, hypothyroidism, adrenal insufficiency. Early iron, folate, or B12 deficiency.
• Additional Evaluation: Iron studies, B12, folate, hemolysis labs, blood smear.

Anemia of Chronic Disease/Inflammation

Etiology: infections, rheumatic dz, cancer, heart failure, COPD, obesity, CKD 

Diagnosis: 

• Iron studies: ↓-low nl MCV, ↓ Fe, ↓ Transferrin and TIBC, nl to ↑ Ferritin, Fe/TIBC >18% 
• Consider CRP/ESR 

Treatment: Address underlying cause. PO vs IV Fe if contribution of IDA (ferritin <100, TSAT<20%). ESAs if CKD or HIV on HAART

Anemia of Chronic Kidney Disease

Pathophysiology: EPO essential for survival or erythroid progenitors; ↓ renal function associated with ↓ renal interstitial cells that produce EPO, therefore ↓ terminal maturation of erythroid progenitors. Possible contributions of uremia-related hemolysis, ESRD related Burr cells with decreased half-life, iHD blood loss, decreased hepcidin clearance 

Diagnosis: Normocytic, normochromic RBCs, Fe studies similar to ACD/I, EPO ↑ 

Treatment: 

• If associated with Fe deficiency, treat with IV Fe. 
• If not on dialysis: ESAs when Hb < 10, goal Hb 10-11.5. 
• If 1) ferritin < 100 and TSAT <40% OR 2) ferritin 100-300 and TSAT <25%, will often trial IV iron before ESAs. If response to IV iron is appropriate, can defer ESAs 
• Once on ESAs, should give iron supplementation if 1) ferritin < 100 and TSAT <40% OR 2) ferritin 100-300 and TSAT <25% 
• On dialysis: ESAs for Hb < 10; trial IV iron in patients with TSAT <30% AND Ferritin <500 to see if Hb improves with iron alone. 
• If Hb <10 and TSAT >30% or no response to trial IV iron, use ESAs for Hb goal 10-11.5 
• IV iron monthly when on ESAs if TSAT <30% AND Ferritin <500 
• Note: Above ferritin and TSAT levels reflect 2026 KDIGO guidelines, though exact numbers are often attending-specific

Pure Red Cell Aplasia

Pathophysiology: absence or destruction of RBC precursors. Inherited causes like Diamond-Blackfin anemia. Destruction/acquired causes associated with thymoma; lymphoid malignancies/CLL; viruses like parvovirus B-19 (viral tropism for erythrocyte P antigen on erythroid progenitors), hepatitis, EBV; autoimmune diseases like SLE; drugs.

Diagnosis: Very ↓ retic index; BMBx that lacks erythroid progenitors, consider other marrow studies for heme malignancy, thoracic imaging for thymoma.

Treatment: transfusion support +/- pathology specific Tx>>thymectomy for thymoma; chemo for CLL; consider IVIG for parvo.

Anemia of Hypometabolism

• Hypothyroid: decreased TSH causes body-wide hypometabolism, decreased O2 consumption, hypo-proliferation of erythroid precursors, possible multifactorial etiology with pernicious anemia (if comorbid autoimmune diseases). 
• Addison’s disease: anemia possibly masked by plasma volume depletion. 
• Protein malnutrition: from impaired EPO production/release as well as decreased metabolic rate, likely multifactorial 2/2 concomitant nutritional deficiencies (folate, B12, Cu).

Macrocytic (MCV >100)

• Big picture: Macrocytic anemias arise from impaired nuclear cell cycle progression of erythroid +/- other bone marrow progenitors relative to cytoplasmic maturation. 
• Common etiologies: megaloblastic anemia (B12/folate/Cu deficiency, drugs), myelodysplastic syndrome, alcohol use, liver disease, reticulocytosis. 
• Additional evaluation: reticulocyte count, hemolysis labs, CMP, peripheral smear, B12, folate.

Megaloblastic

Folate Deficiency

• Folate is absorbed in jejunum. 
• Poor dietary intake: inadequate green leafy vegetables (if from a country where grains are not fortified with folate), anorexia, chronic excessive ETOH use. 
• Malabsorption: Celiac disease, IBD. 
• Increased usage: pregnancy, chronic hemolysis, other states of high cell turnover (malignancy). 
• Iatrogneic: meds (methotrexate, trimethoprim, ethanol, antiepileptics). 
• Dx: serum folate, consider MMA (nl) and homocysteine (↑) if folate borderline. 
• Tx: Folic acid 1 mg PO QD, may increase to 5 mg PO QD, treat for 1-5 months if reversible cause, if irreversible treat indefinitely.

B12 Deficiency

• B12 is absorbed in terminal ileum but absorption depends on salivary R-binder, gastric H+ and IF, pancreatic enzymes. 
• Prolonged poor intake (vegan or strict vegetarian diet as animal protein is primary source) versus prolonged poor absorption—bodily liver stores ~3Y. 
• Gastric: autoimmune gastritis (autoAbs to IF or parietal cells), H pylori gastritis, bariatric surgery 
• Meds: PPI and H2 blockers and metformin. 
• Small bowel: Crohn’s (terminally ilium involvement), ileal resection, competition (SIBO, fish tapeworm). 
• Pancreatic: pancreatic insufficiency 
• Dx: total B12, consider MMA (↑) and homocysteine (↑) if B12 borderline, IF Abs if c/f autoimmune gastritis. 
• Neurologic symptoms favor B12 deficiency > folate deficiency. May progress to subacute combined degeneration (dorsal columns: vibration/proprio and corticospinal tract: voluntary motor function) 
• Tx: Intramuscular: in patients with severe deficiency, adherence issues (lack of access, bad at taking pills): 1000 mcg IM QWeekly then monthly; Oral: 1000 mcg PO QD with nl absorption, 2000 mcg PO QD for impaired absorption 
• Note that treatment of B12 deficiency anemia with folate may transiently relieve hematologic effects of B12 deficiency but neurological symptoms persist

Cu Deficiency

• Etiology: Dietary deficiency (rare), malabsorption: inherited syndromes (Menkes) versus acquired (excessive PO zinc, Celiac, CF, bariatric surgery). 
• Dx: serum Cu, MCV normocytic or macrocytic, may have bi-cytopenia (plt usually spared); Bone marrow biopsy may show dysplastic changes similar to MDS. 
• Tx: Address underlying cause. For repletion, per Uptodate: 8 mg elemental Cu PO QD x1W, 6 mg PO QD x1W, 4 mg PO QD x1W, 2 mg PO QD x1W then recheck.

Non-megaloblastic macrocytic anemia

• Reticulocytosis, cirrhosis, ETOH, hypothyroid, MDS.
• Drugs that interfere with hematopoiesis: Chemotherapies, hydroxyurea, immunosuppressants: methotrexate, leflunomide, 6-MP, MMF, ART/NNRTIs, AEDs/phenytoin/Valproic acid and Bactrim (impaired folate metabolism), Acid suppressants (reduced B12 absorption).

Hemolytic Anemias

• Intrinsic: issue is intrinsic to the RBC (issues with globin, RBC membrane, etc.). 
• Extrinsic: issue is extrinsic to RBC (antibodies, MAHA). 
• Intravascular: hemolysis occurs within bloodstream due to direct destruction (MAHA, mechanical hemolysis, PNH). Additional findings may include hemoglobinuria (positive blood on dipstick, no RBCs on micro), undetectable haptoglobin, DAT+.
• Extravascular: hemolysis occurs within the spleen due to damage incurred in the periphery (AIHA, spherocytosis, sickle cell, G6PD def, RBC infections, etc.). Haptoglobin remains low, but may still be detectable. 
• Additional lab findings for hemolytic anemias: elevated reticulocyte count, elevated LDH, low haptoglobin, elevated bilirubin (predominantly unconjugated). Peripheral smear findings differ by individual condition. 
• Folate supplementation can benefit many of these patients given their reliance on a constantly active bone marrow which can quickly deplete folate stores. 
• Though classically taught to be associated with sickle cell disease, all hemolytic anemias rely on over-active bone marrow. As such, parvovirus B19 infection can cause aplastic crisis in all hemolytic anemias, though severity may differ by condition. 
• Treat underlying cause.

Intrinsic, Hereditary

Sickle Cell Disease 

• Etiology: autosomal recessive HBB gene mutation Glu6Val. Sickle cell disease is HbS/S; Heterozygosity causes sickle cell trait. 
• Dx: ↑ LDH, ↓ Hapto, ↑ indirect bili; electrophoresis is definitive - Smear: Sickle Cells, Howel-Jolly Bodies (most pts become functionally asplenic in childhood) 
• Tx: Hydroxyurea (increases HbF), folate/multivitamin (↑ RBC turnover/metabolic need), possibly L-glutamine or crizanlizumab (anti-P selectin); management includes vaccines for encapsulated bacteria (Meningococcal, Hflu, Pneumococcus), Hep B, Flu, COVID; possibly alloSCT; 2 gene therapies with CRISPR-Cas9 approved in 2023; see Sickle cell crisis chapter for acute sickle complication management 
  • Hb C: HBB mutation Glu6Lys; heterozygotes are asymptomatic carriers, homozygosity causes mild hemolytic anemia; Dxed with electrophoresis. Smear: HbC Crystals 
  • Hb SC: Hb C mutation on 1 copy of beta globin, Hb S mutation on other copy. More common than homozygous Hb C disease. Similar manifestations to sickle cell disease, though with lower complication rates 
  • Thalassemia: see hypo-proliferative anemia section 
  • G6PD Deficiency: 
• Etiology: X-linked, missense mutations in G6PD gene >> decreased enzyme function >> RBC vulnerability to hemolysis with any insult that worsens oxidative stress 
• Potential triggers: infection (immune effectors generate oxidant), drugs with high redox potential (dapsone, primaquine, rasburicase, nitrofurantoin, more), foods (fava beans)  
• Dx: Functional assay of G6PD activity in RBCs-do not test during flare (cells with faulty G6PD function die first > false negative) 
• Smear: Bite Cells, Heinz Bodies 
• Note: Should test all patients, regardless of level of suspicion, prior to treating with oxidizing medication that are high risk for inducing flare (such as rasburicase) 
• Tx: remove inciting event (infection, med, food); supportive care with transfusions
  • Pyruvate Kinase Deficiency: PKLR mutations, rare, Dx: enzyme function assay 
  • Hereditary Spherocytosis/Elliptocytosis 
• Etiology: recessive or dominant mutations in RBC membrane proteins (Band 3 [anion transporter]), cytoskeletal proteins (a and b spectrin), and connector proteins (ankyrin, band 4.1, band 4.2) >> malformed and round membrane >> more prone to lysing 
• Clinical Features: family Hx; mild to severe hemolytic anemia depending on mutation; ↑ MCHC; DAT negative 
• Diagnosis: positive osmotic fragility test, EMA binding test; genotyping 
• Smear: Spherocytes/Elliptocytes 
• Tx: transfusion support, prevention of Fe overload for severe disease; possibly splenectomy, RHM with vaccinations

Intrinsic Acquired

Paroxysmal Nocturnal Hemolytic Anemia

• Pathophysiology: HSC PIGA mutation (anchors the complement inhibitors CD55 and CD59) >> complement on RBC membranes >> RBCs lysed. Clonal expansion of mutated HSC due to overlap with aplastic anemia. 
• Free hemoglobin binds nitric oxide, leading to increase smooth muscle tone and classic complications of ED, abdominal pain, dysphagia 
• Free hemoglobin and complement mediated platelet activation lead to increased thrombosis risk, often in abnormal vascular beds (hepatic veins, portal veins, cerebral veins, mesenteric veins) 
• Dx: ↑ LDH, ↓ hapto, ↑ indirect bili. Flow cytometry with ↓ or absent CD55/59 very important to diagnosis, possibly BMBx if concern for bone marrow failure/aplastic anemia 
• Tx: heme consult, complement inhibitor and depending on severity and complications possibly allogeneic SCT vs long term immunosuppressive therapy 
• Spur Cell Anemia/Anemia in Liver Disease 
• Pathophysiology: Liver disease >> dysregulated lipid metabolism >> excess cholesterol in RBC membranes>> spur cells more fragile and have ↓ half-life; likely multifactorial with concomitant nutritional deficiencies (folate, B12, Fe, Cu, protein), Hb loss (GI bleeds from EVs), mild hemolysis (Spur cells, mild DIC), sequestration (hypersplenism) 
• Dx: smear with spur cells, ↓ hapto (caution as hapto is synthesized in liver) 
• Tx: cessation of alcohol, banding of varices, liver transplantation is only cure 
• Note: Carries a very poor prognosis – most patients die within one year without liver transplant

Extrinsic Acquired

Immune-Mediated (DAT-positive) Hemolytic Anemia

Warm AIHA

• Etiology: Idiopathic; lymphoproliferative disorders including CLL, MGUS, lymphomas; autoimmune disorders including SLE, RA, etc; infections including HIV, EBV, Hep C, Babesiosis; drugs; Evans Syndrome: warm AIHA with ITP 
• Pathophysiology: IgG (less common IgA, IgM) autoAbs against Rh complex or glycophorin A or B that bind best at 37C; extravascular hemolysis in RES via Fc receptors on Macrophages >> spherocytes; intravascular if severe/tons of complement fixation 
• Dx: ↑ retics; ↑ LDH, ↓ hapto, ↑ indirect bili; positive DAT IgG +/- C3d; smear: spherocytes; UA: urobilinogen, hemoglobinuria; maybe LE DVT USs as increased risk clots; may pursue lymphoproliferative, autoimmune, infectious workup 
• Tx: Transfusion support: if severe on presentation (Hb <7) contact blood bank immediately; 1st line: glucocorticoids (ie pred 1-2 mg/kg PO daily vs methylpred IV) +/- rituximab; 2nd line immunosuppressants like MMF, cyclophosphamide, etc; 3rd line splenectomy; Folic acid 1-5 mg PO QD during hemolysis; recovery after 2-3 weeks (existing Abs need to wash out); treat underlying etiology if identified

Cold AIHA / Cold Agglutinin Disease

• Etiology: Idiopathic vs Secondary to: Lymphoproliferative disorders: Waldenstrom, MGUS, CLL, lymphomas; infections: Mycoplasma and EBV; autoimmune like SLE 
• Pathophysiology: IgM autoAbs bind RBC I or i antigens at temps below 37C >> fix complement >> extra>intravascular hemolysis; different from Paroxysmal Cold Hemoglobinuria (Donath- Landsteiner Abs cause intra>extravascular hemolysis; mostly in peds, in adults a/w syphilis infection) 
• Dx: Cold-induced Sxs (acrocyanosis), ↑ retic count, ↑ LDH, ↓ hapto, ↑ indirect bili; DAT + C3d, - IgG; Cold agglutinin titer > 1:64; smear: agglutinated RBCs (clusters) 
• Tx: Treat underlying condition, avoid cold; if symptomatic: WARMED RBC transfusion, plasmapheresis or IVIG; possibly rituximab or B cell targeting therapy, esp if lymphoproliferative disorder; C1 inhibitor sutimlimab approved 2022, highly effective in refractory cases

Drug-induced Hemolytic Anemia

• Etiology: abx especially penicillins and cephalosporins, sulfa drugs, NSAIDs, chemotherapies and immunotherapies; may be immune or non-immune mediated 
• Pathophysiology: Immune-mediated: IgG binds drug-RBC membrane protein conjugate >> macrophage phagocytosis in RES. Non-Immune-mediated: oxidative injury in G6PD deficiency; methemoglobinemia 2/2 anesthetics, antimicrobials; TMA 2/2 medications 
• Dx: ↑ retic count, ↑ LDH, ↓ hapto, ↑ indirect bili; DAT IgG +/- C3d; smear with spherocytes or bite cells or schistocytes (depending on Pathophysiology) 
• Tx: stop possible offending medications, transfusion support

Non-immune (DAT-negative) hemolytic anemia

Microangiopathic Hemolytic Anemia/Thrombotic Microangiopathies

• Pathophysiology: TTP, Complement mediated TMA, Drug/malignancy induced TMA, Shiga toxin-induced HUS, DIC, HELLP, catastrophic APS, malignant HTN
•  Dx: concurrent thrombocytopenia, Smear: schistocytes, other markers of hemolysis (↓ hapto, ↑ LDH); 
• TTP: ADAMTS13 very ↓ (<10%); 
• In complement-mediated TMA severely ↑ Creat from renal failure; 
• In DIC, ↑ PT and PTT and ↓ fibrinogen 
• Tx: Heme consult; treat underlying cause (see Thrombocytopenia section)

Macroangiopathic Hemolytic Anemia

• Pathophysiology: sharp edges of calcium/metal/plastic lyses RBC membranes, including ECMO, prosthetic heart valve, severely sclerotic native heart valve; “March hemolysis” from repetitive trauma to the limbs 
• Dx: Blood smear with schistocytes, other markers of hemolysis (↓ hapto, ↑ LDH) 
• Tx: treat underlying cause if possible - Infections: Malaria, Babesia, C perfringens 
• Medications: Primaquine, dapsone, Rasburicase, sulfonylureas