Which condition presents with a low red blood cell count and low hemoglobin combined with a high platelet count?

Iron Deficiency Anemia with Reactive Thrombocytosis

The combination of decreased red blood cell count, decreased hemoglobin, and increased platelet count most commonly indicates iron deficiency anemia with reactive thrombocytosis. 1, 2

Primary Pathophysiology

Iron deficiency anemia is the most common cause of this specific hematologic pattern, where severe anemia triggers a compensatory increase in platelet production. 1, 3 The mechanism involves:

• Erythropoietin (EPO) cross-reactivity: Elevated EPO levels in iron deficiency may stimulate megakaryocyte production through shared signaling pathways with thrombopoietin receptors, leading to thrombocytosis even as red blood cell production remains impaired. 1

• Severity correlation: Patients with iron deficiency anemia who develop thrombocytosis demonstrate more severe anemia, lower ferritin levels, and more advanced iron deficiency compared to those without elevated platelets. 2

• Prevalence: Approximately 8.1% of patients with iron deficiency anemia develop reactive thrombocytosis (platelet count >450 × 10⁹/L), though moderate platelet elevation is more common. 2

Diagnostic Laboratory Pattern

The characteristic findings include:

• Microcytic, hypochromic anemia: Low hemoglobin with mean corpuscular volume (MCV) <83 fL and reduced mean corpuscular hemoglobin concentration (MCHC). 4, 3

• Iron studies: Low serum ferritin (<30 ng/mL), low serum iron, elevated total iron-binding capacity (TIBC), and transferrin saturation <15%. 4, 2

• Platelet elevation: Counts typically range from 450-1000 × 10⁹/L, though extreme thrombocytosis can occasionally occur. 1, 2

• Low reticulocyte index: Indicates decreased red blood cell production despite anemia. 4

Alternative Diagnoses to Consider

Cyanotic Congenital Heart Disease with Iron Deficiency

Paradoxical presentation: Cyanotic heart disease causes polycythemia (increased red blood cells) as compensation for chronic hypoxemia, but concurrent iron deficiency leads to decreased hemoglobin within each cell. 4 However, this typically presents with:

• Elevated or normal red blood cell count despite low hemoglobin (microcytic cells). 4
• Thrombocytopenia (not thrombocytosis) due to hyperviscosity and consumption. 4
• Oxygen saturation <75% on room air. 4

This diagnosis is excluded when thrombocytosis is present rather than thrombocytopenia.

Myeloproliferative Neoplasms with Iron Deficiency

Polycythemia vera or essential thrombocythemia can present with elevated platelets, but these conditions typically show:

• Elevated red blood cell mass initially (hematocrit >49% in men, >48% in women for polycythemia vera). 4
• JAK2, CALR, or MPL mutations present. 4
• Splenomegaly in most cases. 4

Iron deficiency can develop secondarily in polycythemia vera from repeated phlebotomy, creating a mixed picture, but the primary presentation differs from isolated iron deficiency anemia. 4, 5

Cancer-Associated Anemia with Thrombocytosis

Malignancy can cause both anemia and reactive thrombocytosis, but:

• Anemia is typically normocytic (MCV 80-100 fL), not microcytic. 4
• Ferritin is often elevated due to chronic inflammation, not decreased. 4
• Constitutional symptoms (weight loss, fever, night sweats) are usually present. 4

Clinical Implications and Management

Thrombotic Risk Assessment

Critical consideration: While most cases of iron deficiency-related thrombocytosis are benign, extreme platelet elevation (>1000 × 10⁹/L) carries thrombotic risk. 1, 2 Patients require:

• Identification of bleeding source (menstruation, gastrointestinal bleeding). 6, 3
• Assessment for symptoms of thrombosis (chest pain, leg swelling, neurological changes). 2
• Increased monitoring frequency during treatment for those with platelet counts >600 × 10⁹/L. 2

Treatment Response Timeline

Iron supplementation rapidly corrects thrombocytosis: 2

• 50% of patients with thrombocytosis normalize platelet counts within 2 weeks of oral iron therapy. 2
• All patients resolve thrombocytosis within 6 weeks of adequate iron replacement. 2
• Hemoglobin improvement follows more gradually over 8-12 weeks. 6, 3

Iron Replacement Strategy

Oral iron is first-line: 6, 3

• Intermittent dosing (every other day) is as effective as daily dosing with fewer gastrointestinal side effects. 6
• Continue treatment until iron stores are fully repleted, not just until hemoglobin normalizes. 3

Intravenous iron indications: 6

• Intolerance to oral iron despite dosing adjustments. 6
• Malabsorption syndromes. 6
• Ongoing losses exceeding oral replacement capacity. 6
• Hemoglobin <7.0 g/dL requiring rapid correction. 6

Important Pitfalls

Persistent thrombocytosis after 6 weeks of adequate iron therapy mandates bone marrow evaluation to exclude an underlying myeloproliferative neoplasm, as iron deficiency can mask clonal disorders. 2

Chronic inflammatory states falsely elevate ferritin, potentially masking coexistent iron deficiency—use transferrin saturation <15% and low serum iron as more reliable markers in this context. 4, 5

Pregnancy-related iron deficiency requires screening at first prenatal visit and again at 24-28 weeks gestation, as maternal anemia increases transfusion risk at delivery. 6