Anemia

Margaret Wheless

Michael Kaminski

  • First establish acuity: bleed or consumptive process vs slow onset anemia
  • Check vitals for hypotension, tachycardia.
  • Check Hgb trend from prior if available.
  • Examine patient for pallor, rapid onset fatigue, AMS, feeble pulses and any signs of bleeding.
  • Consider risk factors such as recent procedure, blood thinner use, falls, new medications.
  • STAT repeat CBC along with haptoglobin, LDH, HFP (bilirubin) to rule out hemolysis
  • If no sx/signs of acute bleeding, move onto general anemia eval below.
  • Note: CBC does not accurately reflect blood loss in acute rapid bleeding scenarios so do not be falsely reassured by normal hematocrit in GI bleeds/trauma patients.

Presentation 

  • Symptoms: fatigue/malaise, dyspnea on exertion, angina (if history of CAD)
  • Signs
    • Pallor, tachycardia, orthostatic hypotension, purpura, glossitis, koilonychia (in IDA)
    • Jaundice (if hemolysis)
    • Splenomegaly: suggests extramedullary hematopoiesis or sequestration
    • Neurologic symptoms: suggests B12 deficiency

Evaluation 

  • CBC w/diff, retic count, peripheral blood smear, iron studies (Fe, TIBC, ferritin), nutrient studies (folate, B12, Cu)
    • RI < 2%: hypoproliferative >> stratify based on RBC size
      • Microcytic (<80) vs. Normocytic (80-100) vs. Macrocytic (>100)
    • Reticulocyte index (RI) > 2%: blood loss vs hemolysis
      • Hemolysis labs: Bilirubin, LDH, hapto, DAT

Reticulocyte Index < 2%: Hypo-proliferative/Inadequate Marrow Response

Microcytic (MCV < 80) 

  • Big picture: microcytic anemias arise from inability to effectively generate hemoglobin

Thalassemia 

  • Alpha thalassemia: mostly gene deletions
    • 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: mostly splice site mutations, can be heterozygous (beta thal trait) or homozygous (more severe, alpha chains accumulate and precipitate, killing erythroid precursors and decreasing RBC survival)
  • Dx: + family history, onset at birth or shortly thereafter, ↓ MCV (often less than 70), ↑ RBC count, Mentzer Index (MCV/RBC) < 13, target cells on smear, Fe studies either wnl or show evidence of Fe overload, 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 (activin receptor IIB-Fc fusion protein)

Iron Deficiency Anemia 

  • Negative Fe balance>>Fe deficient erythropoiesis>>Fe deficiency anemia; Negative Fe balance >> Fe stores mobilized from RES, becoming depleted if cause not corrected. Erythroid progenitors can’t incorporate Fe into heme. 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 (though may be multifactorial with malabsorption of B12/ folate, Cu and anemia of chronic inflammation) vs inherited IRIDA/Iron Refractory Iron Deficiency Anemia
    • Increased Fe demand without bleeding: 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)
  • Dx: Labs: In negative Fe balance and Fe deficiency erythropoiesis: ↓ Fe, ↑ TIBC, ↓ TSAT, ↓ Ferritin. In IDA, MCV <80, ↓ MCHC, ↓ RBC count, Mentzer Index (MCV/RBC) >13, ↓ Ferritin (<30 highly specific, >15 means marrow Fe stores gone), Fe/TIBC <16%, soluble transferrin receptor (sTfR, receptor cleaved, helpful to differentiate IDA from ACD/I) increased and sTfR-ferritin index > 2-3. Consider Celiac serologies, fecal H pylori antigen, bidirectional GI scope, pelvic ultrasound
  • Tx:
    • 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.
    • In general, start with PO Fe unless: inability to attain source control, lack of response, intolerable side effects (primarily GI, nausea, diarrhea, constipation), severe anemia (Hb <7), need for fast response, bariatric surgery Hx, malabsorption condition, ESRD on iHD, CHF with Ferritin <100 OR TSAT <20 and Ferritin <300
    • PO Fe: Most common is FeSO4, 325 mg (65 mg elemental Fe) QD vs 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); avoid Ca, antacids
    • IV Fe: Calculate Fe deficit with Ganzoni equation (MDCalc). Typical total dosing is ~ 1 gram. Ferric gluconate/Ferrlecit at VUMC given in 125 or 250 mg doses. Fe sucrose at VA in 100-500 mg doses. SEs 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 nonanaphylactic reactions, allow symptoms to resolve then restart infusion at ½ the rate. Can consider 1x dose IV methylpred. Contraindications: true anaphylactic reaction in past, ongoing bacterial infection (though paucity of evidence)

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
  • Dx: ↓ MCV, ↓ retic count, ↑ Ferritin, nl or ↑ Fe, ↓/nl TIBC, smear: basophilic stippling of RBCs, marrow aspirate stained with Prussian blue, Genetic studies if c/f congenital (family history, young age of presentation, etc.)
  • Tx: Address underlying cause if acquired: treat MDS/MPN, stop ETOH use, stop offending medication, eliminate lead exposure, replete Cu

Normocytic (MCV 81-100) 

  • Normocytic anemia can be the beginnings of a pure microcytic or macrocytic process or the combination of microcytic and macrocytic processes that negate one another

Anemia of Chronic Disease/Inflammation

  • Etiology: infections, rheumatologic disorders (RA, SLE, Systemic Sclerosis, vasculitis, IBD), cancer, heart failure, COPD, obesity, CKD
  • Pathophysiology: inflammation >> IL-1, IL-6 from macrophages >> hepcidin from liver that 1. In macrophages: suppresses Fe2+ release and stimulates ferritin expression that sequesters Fe intracellularly. 2. In enterocytes: suppresses Fe absorption from GI. Cytokines also reduce EPO, impair erythroid progenitor differentiation/proliferation, and shorten RBC half-life.
  • Dx: ↓-low nl MCV, ↓ Fe, ↓ Transferrin and TIBC, nl to ↑ Ferritin, Fe/TIBC >18%; if uncertain if concomitant IDA can order soluble transferrin receptor (sTfR) elevated in IDA and nl or ↓ in ACD; consider CRP/ESR
  • Tx: 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 terminal maturation of erythroid cells; ↓ 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
  • Dx: Normocytic, normochromic RBCs, Fe studies similar to ACD/I, EPO ↑
  • Tx: With nephro. If Fe deficiency, treat with IV Fe. If not on dialysis: ESAs when Hb < 10 so long as TSAT >20 and Ferritin <500 (numbers approximate and attending specific), goal Hb 10-11.5. On dialysis: ESAs preferred over HIF PHIs

Pure Red Cell Aplasia

  • Pathophysiology: absence or destruction of RBC precursors. Inherited causes like Diamond-Blackfan 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
  • Dx: Very ↓ retic index; BMBx that lacks erthroid progenitors, consider other marrow studies for heme malignancy, thoracic imaging for thymoma
  • Tx: 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: Megaloblastic anemias arise from impaired nuclear cell cycle progression of erythroid +/- other bone marrow progenitors relative to cytoplasmic maturation. ]
  • Retics are larger than mature RBCs so in reticulocytosis you may see macrocytosis (ie brisk reticulocytosis follow Fe repletion in Fe deficiency anemia)

Megaloblastic 

  • Folate Deficiency
    • Etiology: Folate absorbed in jejunum. Poor dietary intake: inadequate green leafy vegetables (if from 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)
    • Pathophysiology: Folate involved in DNA/RNA synthesis>>deficiency impairs nucleotide synthesis and impairs nuclear cell cycle progression
    • 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
    • Etiology: B12 absorbed in terminal ileum but absorption depends on salivary Rbinder, 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
    • Pathophysiology: B12 is involved in DNA/RNA synthesis >> deficiency impairs nucleotide synthesis and impairs nuclear cell cycle progression
    • Dx: total B12, consider MMA (↑) and homocysteine (↑) if B12 borderline, IF Abs if c/f autoimmune gastritis. Maybe subacute combined degeneration (dorsal columns: vibration/proprio and corticospinal tract: voluntary motor function) if severe
    • 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 o Note that treatment of B12 deficiency anemia with folate may transiently relieve hematologic effects of B12 deficiency but neurological symptoms persist
  • Cu Deficiency o Etiology: Dietary deficiency (rare), malabsorption: inherited syndromes (Menkes) versus acquired (excessive PO zinc, Celiac, CF, bariatric surgery) HEMATOLOGY-ONCOLOGY 183
    • Pathophysiology: Cu necessary for enzymatic functions including ETC, collagen crosslinking, neurotransmitter synthesis, free radical scavenging
    • Dx: serum Cu, MCV normocytic or macrocytic, may have bi-cytopenia; 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)

Reticulocyte Index > 2%: Hyper-proliferative/Adequate Marrow Response

Intrinsic, Hereditary

Sickle Cell Disease

  • Etiology: autosomal recessive HBB gene mutation glu6val. Sickle cell disease is HbS/S; Heterozygosity causes sickle cell trait.
  • Pathophysiology: HbS valines interact hydrophobically>>Hbs self-assemble in T conformation >> parallel bundles “stretch” RBCs; ↓ pH, ↓ pO2, ↑ pCO2, ↑ 2,3-BPG promote T state >> promote polymerization/sickling; R state, ↑ HbF and HbA2 impair polymerization
  • Dx: ↑ LDH, ↓ Hapto, ↑ indirect bili; smear: sickled cells; electrophoresis
  • Tx: Hydroxyurea (increases HbF), folate/multivitamin (↑ RBC turnover/metabolic need), possibly L-glutamine or crizanlizumab (anti-P selectin); RHM includes vaccines for encapsulated bacteria (Mengococcal, 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

Thalassemia

  • see hypo-proliferative anemia section

G6PD deficiency

  • Etiology: X-linked, missense mutations in G6PD gene >> decreased enzyme function
  • Pathophysiology: ↓ G6PD activity >> ↓ glutathione >> ↓ protection against oxidants >> oxidized Hb and other proteins; worsened by any insult that increases oxidant stress (infection [immune effectors generate oxidants], drugs with high redox potential [dapsone, primaquine, rasburicase, nitrofurantoin, more], foods [fava beans])
  • Dx: test prior to treating with oxidizing medication; functional assay of G6PD activity in RBCs-do not test during flair (cells with faulty G6PD function die first > false negative)
  • Tx: remove inciting event (infection, med, food); supportive care with transfusions

Pyruvate kinase deficiency

  • PKLR mutations, rare, Dx: enzyme function assay

Hereditary Spherocytosis/Elliptocytosis 

  • Pathophysiology: 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
  • Dx: family Hx; mild to severe hemolytic anemia depending on mutation; ↑ MCHC; smear: spherocytes or elliptocytes; DAT negative; positive osmotic fragility test, EMA binding test; genotyping
  • 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.
  • Dx: ↑ LDH, ↓ hapto, ↑ indirect bili, flow cytometry with ↓ or absent CD55/59, 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

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)
    • Dx: Cold induced Sxs (acrocyanosis), ↑ retic count, ↑ LDH, ↓ hapto, ↑ indirect bili; DAT + C3d, - IgG; Cold agglutinin titer > 1:64; smear: aggregating RBCs
    • Tx: Treat underlying condition, avoid cold; if symptomatic: WARMED RBC transfusion, plasmapheresis or IVIG; possibly rituximab or B cell targeting therapy if lymphoproliferative disorder; C1 inhibitor sutimlimab approved 2022

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 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
    • 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
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