Anemia Correction Protocol
Initial Diagnostic Workup
When anemia is detected, immediately order a complete blood count with red cell indices (MCV, MCH, RDW), absolute reticulocyte count, serum ferritin, transferrin saturation (TSAT), and C-reactive protein (CRP) to classify the anemia and guide treatment decisions. 1, 2, 3
Hemoglobin Thresholds Defining Anemia
Additional Tests Based on Clinical Context
- Vitamin B12 and folate levels should be measured in all patients with anemia, particularly when MCV >100 fL or when initial iron studies are inconclusive 1, 3
- Serum creatinine and estimated GFR to evaluate for chronic kidney disease as a contributor 1, 4
- Thyroid function tests in patients with heart failure or unexplained anemia 1
Iron Deficiency Anemia: Diagnosis and Management
Diagnostic Criteria Without Inflammation (Normal CRP)
Ferritin <30 µg/L confirms absolute iron deficiency and warrants immediate treatment. 3
- Ferritin <15 µg/L has 99% specificity for iron deficiency 3, 5
- TSAT <20% is the primary confirmatory marker, especially when ferritin is 30-100 µg/L 1, 3
- Microcytosis (MCV <80 fL)** with **elevated RDW (>14%) strongly supports iron deficiency 3
- Low or normal reticulocyte count indicates inadequate bone marrow response consistent with iron deficiency 2, 3
Diagnostic Criteria With Inflammation (Elevated CRP/ESR)
In the presence of inflammation, ferritin up to 100 µg/L may still represent true iron deficiency; always calculate TSAT to confirm. 3
- Ferritin 30-100 µg/L + TSAT <20% + elevated CRP: Mixed picture of true iron deficiency plus anemia of chronic disease—treat both the iron deficiency and underlying inflammation 3
- Ferritin >100 µg/L + TSAT <20% + elevated CRP: Anemia of chronic disease with functional iron deficiency—prioritize aggressive management of the inflammatory condition 3
Treatment of Iron Deficiency
Start oral elemental iron 100-200 mg daily immediately upon diagnosis, regardless of hemoglobin level, and continue for 3-6 months after hemoglobin normalization to replenish stores (target ferritin >50 µg/L). 3, 5
Indications for Intravenous Iron
- Intolerance to oral iron with significant gastrointestinal side effects 3, 5
- Documented malabsorption (celiac disease, inflammatory bowel disease, gastric bypass) 3
- Failure to respond to oral iron after 4-6 weeks of adherent therapy 3, 5
- Chronic kidney disease patients (CKD-ND): Consider IV iron when TSAT ≤30% and ferritin ≤500 ng/mL if increase in hemoglobin without ESA therapy is desired 1
For CKD patients, IV iron can be given as 500 mg initially, followed by 500 mg four weeks later. 1
Investigation for Source of Blood Loss
In adult men and postmenopausal women with iron deficiency anemia, gastrointestinal bleeding from occult malignancy is the presumptive source until proven otherwise—perform bidirectional endoscopy (upper endoscopy + colonoscopy) promptly. 3
- Do not delay endoscopic evaluation even if hemoglobin is above fast-track referral thresholds; investigation is indicated at any anemia level when iron deficiency is present 3
- Stool guaiac testing should be performed if occult GI bleeding is suspected 2
- Do not attribute severe iron deficiency in perimenopausal adults solely to menstrual blood loss; GI pathology must still be investigated 3
Anemia of Chronic Disease
Diagnostic Criteria
Ferritin >100 µg/L + TSAT <20% + elevated CRP/ESR defines anemia of chronic disease with functional iron deficiency. 3
- Normocytic anemia (normal MCV) with normal or elevated ferritin points toward anemia of chronic disease 3
- Low or normal reticulocyte count indicates inadequate marrow response 2
Management
The primary intervention is aggressive management of the underlying inflammatory disease (rheumatoid arthritis, heart failure, inflammatory bowel disease, chronic infection). 3, 6
- IV iron may be beneficial in selected patients with chronic heart failure and functional iron deficiency (ferritin <100 ng/mL or ferritin 100-300 ng/mL with TSAT <20%) 1
- Blood transfusion is not appropriate treatment for chronic anemia as it does nothing to address the underlying disorder 6
Vitamin B12 Deficiency
Diagnostic Criteria
- Macrocytosis (MCV >100 fL) with low or normal reticulocyte count suggests B12 or folate deficiency 2, 3
- Measure serum B12 and folate levels in all patients with macrocytic anemia 1, 3
Management
- Treat confirmed B12 deficiency with appropriate replacement therapy (oral or parenteral depending on cause) 1
- Patients with extensive small-bowel resection, ileal Crohn's disease, or ileal-anal pouch should have B12 and folate monitored more frequently than annually 3
Folate Deficiency
Diagnostic Criteria
- Macrocytosis (MCV >100 fL) with low serum folate level 1, 3
- Low or normal reticulocyte count indicates inadequate marrow response 2
Management
Folate supplementation: 5 mg/day for 2 weeks, then 5 mg/week for another 6 weeks. 1
Anemia in Chronic Kidney Disease
Diagnostic Thresholds
- Anemia is diagnosed when hemoglobin is <12 g/dL in men or postmenopausal women, or <11 g/dL in premenopausal women, in the setting of GFR <60 mL/min/1.73 m². 4
- Check hemoglobin if GFR is <60 mL/min/1.73 m², as serum creatinine may appear normal despite significant renal impairment, especially in elderly patients with poor nutrition and muscle mass 4
Iron Status Assessment in CKD
Absolute iron deficiency in CKD is defined as ferritin <100 ng/mL and TSAT <20%. 3, 4
- Functional iron deficiency can occur despite normal or elevated ferritin levels, particularly in patients receiving erythropoiesis-stimulating agents 3
- Target iron parameters before initiating ESA therapy: TSAT >20% and ferritin >100 ng/mL 4
Iron Replacement in CKD
For CKD non-dialysis patients with anemia not on ESA therapy, consider a trial of IV iron (or alternatively a 1-3 month trial of oral iron) if TSAT ≤30% and ferritin ≤500 ng/mL and an increase in hemoglobin without starting ESA treatment is desired. 1
- Select the route of iron administration based on severity of iron deficiency, availability of venous access, response to prior oral iron therapy, side effects with prior therapy, patient compliance, and cost 1
Erythropoiesis-Stimulating Agents (ESAs)
Initiate ESA therapy only after correcting iron deficiency and excluding other reversible causes of anemia (B12/folate deficiency, blood loss, inflammation, malignancy, aluminum intoxication). 1, 4
- Balance potential benefits of avoiding blood transfusions, ESA therapy, and anemia-related symptoms against risks of harm (anaphylactoid reactions, unknown long-term risks) 1
- Poor response to ESA can be due to iron deficiency, inflammation, continued blood loss, or hemoglobinopathy 4
Blood Transfusion Indications
Blood transfusion is not an appropriate treatment for chronic anemia as it elevates hemoglobin only in the short term without addressing the underlying disorder. 6
Appropriate Transfusion Scenarios
- Acute symptomatic anemia with hemodynamic instability 6
- Severe anemia with cardiac ischemia or decompensation 6
- Failure of other therapies in life-threatening anemia 6
Special Populations
Inflammatory Bowel Disease
- In remission: Ferritin <30 µg/L reliably indicates iron deficiency 3
- During active inflammation: Use ferritin <100 µg/L as screening threshold and confirm with TSAT <20% 3
- Monitor iron status: Every 6-12 months in remission or mild disease, at least every 3 months in active disease 3
Chronic Heart Failure
Evaluate for iron deficiency with serum iron, iron binding capacity, and ferritin in all patients with chronic heart failure (NYHA II-IV), regardless of anemia status. 1
- Iron deficiency criteria in CHF: Ferritin <100 ng/mL OR ferritin 100-300 ng/mL with TSAT <20% 1
- IV iron therapy (ferric carboxymaltose or iron sucrose) improves functional capacity, quality of life, and NYHA class in iron-deficient CHF patients 1
Advanced Diagnostic Parameters
Reticulocyte Hemoglobin Content (CHr)
CHr <30 pg predicts favorable response to IV iron therapy in functional iron-deficiency states and is an early marker of iron-deficient erythropoiesis. 2, 7
- CHr is less affected by inflammation than serum iron, TSAT, and ferritin 7
- CHr increases within days of initiating iron therapy, making it useful for early measurement of treatment response 7
Soluble Transferrin Receptor (sTfR)
Measure sTfR when ferritin and TSAT provide conflicting information; elevated sTfR confirms true iron deficiency even in the setting of inflammation because sTfR is not an acute-phase reactant. 3, 5
Critical Pitfalls to Avoid
- Do not rely on ferritin alone when inflammation is present; always calculate TSAT because functional iron deficiency can exist with high ferritin but low TSAT 3
- Do not discontinue iron supplementation once hemoglobin normalizes; iron stores must be restored (target ferritin >50 µg/L) to prevent rapid recurrence 3
- Do not diagnose thalassemia trait without first correcting iron deficiency, as the two conditions can coexist and iron deficiency can mask electrophoretic findings 3
- Do not postpone endoscopic investigation while awaiting response to iron therapy; malignancy work-up should proceed in parallel 3
- Mild anemia is not less indicative of serious underlying disease; no evidence supports down-ranking its clinical significance 3