What is the best approach to manage an adult patient with a history of cardiovascular disease presenting with anemia, leukocytosis (elevated white blood cell count) with neutrophilic predominance?

Management of Anemia with Leukocytosis and Neutrophilic Predominance in Cardiovascular Disease

In an adult patient with cardiovascular disease presenting with anemia and neutrophilic leukocytosis, prioritize identifying the underlying cause through targeted diagnostic workup while implementing a restrictive transfusion strategy (hemoglobin threshold 7-8 g/dL) and avoiding erythropoiesis-stimulating agents. 1, 2

Immediate Diagnostic Priorities

The combination of anemia with neutrophilic leukocytosis suggests an inflammatory or infectious process rather than simple anemia of chronic disease. This pattern warrants urgent evaluation:

Rule Out Life-Threatening Conditions First

• Assess for infection or sepsis - neutrophilic leukocytosis (often >15,000 cells/L) with anemia suggests active infection requiring immediate treatment 1
• Evaluate for occult malignancy - new-onset anemia in cardiovascular patients is associated with 3.4-fold increased cancer risk 3
• Screen for bleeding sources - perform urinalysis, stool occult blood testing, and consider colonoscopy/esophagogastroduodenoscopy if clinically indicated 4, 3
• Consider Adult-Onset Still's Disease (AOSD) if patient presents with fever, rash, arthralgia, or sore throat - this condition characteristically causes marked neutrophilia (50% have WBC >15×10⁹/L, 37% have WBC >20×10⁹/L) with anemia of chronic disease 1

Essential Laboratory Workup

• Complete iron panel: ferritin, serum iron, total iron-binding capacity, and transferrin saturation - though only 44% of anemic heart failure patients receive this testing in routine practice 3
• Inflammatory markers: ESR and CRP to assess for inflammatory conditions like AOSD, where ESR is elevated in virtually all cases 1
• Liver enzymes and creatinine: performed in >90% of cases to identify contributing factors 3
• Peripheral blood smear: essential to confirm neutrophilic predominance and rule out hematologic malignancy 4, 5
• Reticulocyte count: distinguishes between production defects versus hemolysis/bleeding 5

Critical caveat: In routine practice, iron testing is suboptimal with only 65% of severe anemia cases receiving ferritin and transferrin saturation within 6 months of diagnosis 3

Management Algorithm Based on Iron Status

If Iron Deficiency Identified (Ferritin <100 ng/mL or Ferritin 100-300 ng/mL with Transferrin Saturation <20%)

Intravenous iron is the preferred treatment in cardiovascular disease patients - the European Society of Cardiology provides Class IIA recommendation for IV iron in heart failure with reduced ejection fraction 6

• Administer ferric carboxymaltose 200 mg weekly until ferritin >500 ng/mL, then 200 mg monthly for maintenance 4, 6
• IV iron bypasses hepcidin-mediated blockade of intestinal absorption, making it superior to oral supplementation in inflammatory states 4
• Benefits include improved exercise capacity, NYHA functional class, quality of life scores, and reduced cardiovascular events 6, 7
• Approximately 50% of patients report moderate-to-marked improvement versus 28% with placebo 4

Oral iron has minimal benefit in anemia of chronic disease with cardiovascular comorbidity due to hepcidin-mediated absorption blockade 4

If No Iron Deficiency Present

Focus on treating the underlying inflammatory/infectious cause driving both the anemia and leukocytosis:

• For AOSD: Prompt immunosuppressive treatment is necessary, particularly if pancytopenia develops (indicating haemophagocytic syndrome) 1
• For infection: Appropriate antimicrobial therapy
• For malignancy: Oncologic consultation and treatment

Transfusion Strategy

Use restrictive transfusion thresholds exclusively - the American College of Physicians recommends transfusing only when hemoglobin falls to 7-8 g/dL in hospitalized patients with coronary heart disease 1, 2, 6

• Liberal transfusion strategies provide no mortality or hospitalization benefit and may cause harm including transfusion-related acute lung injury, worsening heart failure, and fever 6
• Reserve transfusion for severe symptomatic anemia or when rapid correction is needed 4

What NOT to Do

Strongly avoid erythropoiesis-stimulating agents (ESAs) - the American College of Physicians provides a strong recommendation against ESAs in mild-to-moderate anemia with heart failure or coronary heart disease 1, 2, 6

• ESAs provide no mortality or hospitalization benefit 6
• Significant harms include hypertension, venous thromboembolism, and increased cardiovascular events 2, 6
• This prohibition applies even if anemia is symptomatic 6

Monitoring Protocol

• Recheck hemoglobin after 4 weeks of iron therapy 4, 6
• Monitor hemoglobin and red blood cell indices every 3 months for the first year, then annually 4, 6
• Reassess iron parameters (ferritin, transferrin saturation) to guide ongoing IV iron maintenance 6
• Track inflammatory markers if AOSD or other inflammatory condition suspected, as ferritin levels can reach extreme values (4,000-250,000 ng/mL) in AOSD and correlate with disease activity 1

Common Pitfalls to Avoid

• Under-recognition: Only 16% of anemia cases receive an ICD diagnosis code, leading to inadequate treatment 3
• Inadequate invasive workup: Colonoscopy and esophagogastroduodenoscopy performed in only 2-10% of cases despite bleeding being a common cause 3
• Overlooking the leukocytosis: The neutrophilic predominance suggests active inflammation/infection requiring specific treatment beyond anemia management alone 1, 8
• Assuming anemia is solely from heart disease: New-onset anemia is associated with 3.4-fold increased cancer risk and requires thorough evaluation 3