What are the causes of anemia in sepsis?

Causes of Anemia in Sepsis

Anemia in sepsis results from multiple overlapping mechanisms: inflammation-induced suppression of erythropoiesis through cytokine-mediated hepcidin elevation and erythropoietin blunting, reduced red blood cell lifespan, functional iron sequestration despite adequate total body iron stores, and iatrogenic blood loss from phlebotomy and procedures. 1, 2

Primary Pathophysiologic Mechanisms

Inflammation-Driven Erythropoiesis Suppression

• Pro-inflammatory cytokines (TNF, IL-1, IL-6) directly suppress bone marrow erythropoiesis and blunt the normal erythropoietin response to low hemoglobin levels. 1, 3

• Elevated IL-6 levels correlate directly with hepcidin elevation and inversely with hemoglobin concentration in septic patients. 2, 4

• Persistent elevation of inflammatory cytokines (IL-6, IL-8, G-CSF) beyond day 14 is independently associated with progressive anemia even after accounting for blood loss and transfusions. 3

Hepcidin-Mediated Iron Sequestration

• Hepcidin-25, an IL-6-induced acute phase reactant, reaches peak levels at sepsis onset (median 17.9 nmol/L) and causes functional iron restriction by sequestering iron in macrophages and hepatocytes. 4

• Hepcidin levels increase proportionally with the number of SIRS criteria present (p = 0.0005), demonstrating direct correlation with sepsis severity. 4

• Higher hepcidin levels on days 2-3 of ICU admission correlate significantly with the rate of hemoglobin decrease (Spearman's r = -0.32 to -0.37, p < 0.03), independent of blood loss. 4

• This creates a state of functional iron deficiency where total body iron is adequate but unavailable for erythropoiesis—oral or intravenous iron supplementation does not improve anemia because iron is sequestered rather than truly deficient. 1

Blunted Erythropoietin Response

• Septic patients demonstrate inadequate erythropoietin production relative to the degree of anemia, with inflammation suppressing the normal compensatory EPO rise. 1, 5

• Non-survivors of sepsis have significantly lower plasma EPO levels compared to survivors on days 1,3, and 7 of ICU admission, despite similar or lower hemoglobin levels. 2

Reduced Red Blood Cell Lifespan

• Critically ill septic patients experience shortened erythrocyte survival due to oxidative stress and inflammatory damage to red cell membranes. 1, 5

• Mean corpuscular volume (MCV) progressively decreases in septic patients with persistent anemia (89.6 vs 93.2 fL on day 4, p = 0.04), indicating iron-restricted erythropoiesis despite normal serum transferrin receptor levels. 3

Secondary Contributing Factors

Iatrogenic Blood Loss

• Phlebotomy for diagnostic testing represents a major contributor to anemia in ICU patients, with hemoglobin dropping by a mean of 0.52 g/L per day. 1

• Blood loss from renal replacement therapies, surgical interventions, occult gastrointestinal bleeding, and traumatic injuries compounds the anemia. 5

Fluid Administration Effects

• The reduction in hemoglobin concentration from emergency department presentation to ICU admission is significantly greater in septic patients (median 1.0 mmol/L) compared to non-septic controls (0.5 mmol/L, p < 0.001), even before "sepsis-related anemia" mechanisms fully develop. 6

• This early hemoglobin drop correlates with both the volume of intravenous fluids administered (Spearman rho = 0.3, p < 0.001) and baseline creatinine levels (rho = 0.4, p < 0.001), reflecting hemodilution and fluid sequestration. 6

• Importantly, hemoglobin levels at initial hospital presentation do not differ between septic and non-septic patients (8.8 vs 8.9 mmol/L, p = 0.07), indicating that true "sepsis-related anemia" develops over hours to days rather than being present at onset. 6

Nutritional Deficiencies

• Folate and vitamin B12 deficiencies may contribute to impaired erythropoiesis in prolonged critical illness, though these are not primary mechanisms in acute sepsis. 5

Clinical Implications for Anemia Management

• The most effective intervention for correcting sepsis-associated anemia is achieving complete control of the infectious process—anemia-directed therapies are generally unnecessary and ineffective. 1

• A restrictive transfusion threshold of hemoglobin < 7 g/dL (target 7-9 g/dL) is recommended once tissue hypoperfusion resolves, as this reduces mortality, morbidity, and infection risk compared to liberal transfusion strategies. 1, 7

• Erythropoietin should not be used for sepsis-associated anemia, as randomized controlled trials demonstrate no mortality benefit or improvement in clinical outcomes. 7

• Iron supplementation (oral or IV) provides no benefit in sepsis-related anemia because the iron is functionally sequestered by hepcidin rather than truly deficient. 1

Prognostic Markers

• Plasma hepcidin demonstrates superior predictive value for 28-day mortality (AUC 0.808, specificity 87.3%) compared to other inflammatory anemia parameters. 2

• Lower sTfR/log ferritin ratios, higher ferritin levels, and elevated IL-6 on days 1,3, and 7 are significantly associated with 28-day mortality in septic ICU patients. 2