What is the most likely cause of a platelet count of 668 × 10⁹/L in a 67‑year‑old woman with chronic iron‑deficiency anemia and a newly discovered breast mass presenting with symptomatic anemia (hemoglobin 5.8 g/dL)?

Reactive Thrombocytosis Secondary to Severe Iron Deficiency Anemia

The platelet count of 668 × 10⁹/L in this patient is almost certainly reactive thrombocytosis caused by her severe chronic iron deficiency anemia (hemoglobin 5.8 g/dL), which is the most common hematologic cause of secondary thrombocytosis and frequently produces platelet elevations in this range.

Pathophysiology of Iron Deficiency–Induced Thrombocytosis

• Iron deficiency anemia is one of the four most common causes of secondary thrombocytosis, accounting for approximately 11% of all thrombocytosis cases in large retrospective series 1.

• The degree of thrombocytosis correlates directly with the severity of iron deficiency—patients with profound anemia (hemoglobin <6 g/dL) commonly develop platelet counts between 600–1,000 × 10⁹/L, and extreme thrombocytosis exceeding 1,000 × 10⁹/L can occur when iron stores are completely depleted 2.

• Elevated erythropoietin (EPO) levels in severe anemia may cross-stimulate megakaryocyte production, as EPO receptors are present on platelet precursors; however, the exact mechanism remains incompletely understood because thrombopoietin and other cytokine levels do not consistently correlate with platelet elevation 3.

• Reactive thrombocytosis typically resolves within 1–3 months of initiating iron replacement therapy, with platelet counts normalizing as hemoglobin rises and iron stores are replenished 3, 4.

Differential Diagnosis: Distinguishing Reactive from Primary Thrombocytosis

Key Clinical and Laboratory Features Favoring Reactive Thrombocytosis

• The presence of severe microcytic hypochromic anemia (hemoglobin 5.8 g/dL) with confirmed iron deficiency (ferritin <30 µg/L and transferrin saturation <16%) strongly points to reactive thrombocytosis rather than a primary myeloproliferative neoplasm 5, 6.

• Median platelet counts in secondary thrombocytosis (typically 500–700 × 10⁹/L) are significantly lower than in primary thrombocytosis (often >1,000 × 10⁹/L), and the thrombotic risk is markedly lower in reactive cases 1.

• The newly discovered breast mass raises concern for malignancy-associated thrombocytosis; however, cancer-related thrombocytosis usually occurs via chronic inflammation (elevated C-reactive protein) rather than through iron deficiency, and tissue injury from malignancy accounts for 32% of secondary thrombocytosis cases 5, 1.

When to Suspect Primary Thrombocythemia

• Primary thrombocytosis (essential thrombocythemia or other myeloproliferative neoplasms) should be considered if:

  • Platelet count exceeds 1,000 × 10⁹/L without an obvious secondary cause 2, 6
  • Iron studies are normal (ferritin >100 µg/L, transferrin saturation >20%) 5, 6
  • Thrombocytosis persists after 3 months of adequate iron replacement therapy 3, 6
  • The patient has splenomegaly, constitutional symptoms, or a history of unexplained thrombosis 6, 1

• Testing for JAK2, CALR, and MPL mutations is indicated only after excluding secondary causes; 86% of patients with primary thrombocytosis harbor at least one of these driver mutations 1.

Immediate Management Priorities

1. Investigate the Source of Iron Loss

• All adult women with confirmed iron deficiency anemia require gastrointestinal evaluation (upper endoscopy with duodenal biopsies and colonoscopy) unless menstrual blood loss fully accounts for the anemia, because occult GI bleeding—particularly from malignancy—is the most common etiology in this age group 5, 7.

• The newly discovered breast mass mandates urgent oncologic evaluation, as malignancy can cause anemia through multiple mechanisms: bone marrow infiltration, cytokine-mediated iron sequestration, chronic blood loss at tumor sites, and nutritional deficiencies 5.

• Upper endoscopy with duodenal biopsies is mandatory to exclude celiac disease (present in 2–3% of iron deficiency anemia cases), gastric cancer, NSAID-induced gastropathy, and peptic ulcer disease 5, 7.

• Colonoscopy is high-yield in a 67-year-old woman for detecting colonic carcinoma, adenomatous polyps, and angiodysplasia, all of which are common sources of occult bleeding in this demographic 5, 7.

2. Initiate Iron Replacement Therapy

• Begin oral iron supplementation with ferrous sulfate 325 mg once to three times daily immediately; a hemoglobin rise ≥10 g/L within 2 weeks confirms iron deficiency even when initial iron studies are equivocal 7.

• Intravenous iron (iron sucrose or ferric carboxymaltose) should be considered if:

  • Oral iron is not tolerated or causes significant gastrointestinal side effects 5, 7
  • Malabsorption is present (e.g., celiac disease, prior bariatric surgery, inflammatory bowel disease) 5, 2
  • Hemoglobin fails to increase by ≥2 g/dL within 4 weeks of adequate oral therapy 7

• Continue iron supplementation for at least 3 months after hemoglobin normalization to replenish iron stores (target ferritin >50 µg/L), and monitor hemoglobin and platelet counts at 3-month intervals for one year 7.

3. Assess Thrombotic Risk and Consider Antiplatelet Therapy

• Reactive thrombocytosis from iron deficiency carries an increased thromboembolic risk in both arterial and venous systems, particularly when platelet counts exceed 600 × 10⁹/L 4.

• Low-dose aspirin (75–100 mg daily) should be considered in patients with:

  • Platelet counts >600 × 10⁹/L and cardiovascular risk factors (age >60 years, hypertension, diabetes, smoking) 6, 4
  • A history of prior thrombotic events 6, 4
  • Concurrent malignancy, which independently raises thrombotic risk 4, 1

• Cytoreductive therapy (hydroxyurea) is not indicated for reactive thrombocytosis, even when platelet counts are markedly elevated, because the thrombotic risk is substantially lower than in primary thrombocythemia and platelets normalize with iron replacement 2, 6.

4. Transfusion Considerations

• Red blood cell transfusion is indicated for symptomatic anemia with hemoglobin 5.8 g/dL, targeting a post-transfusion hemoglobin of 7–9 g/dL in elderly patients with cardiac symptoms 8.

• Platelet transfusion is not indicated; a platelet count of 668 × 10⁹/L poses no bleeding risk and does not require intervention 8.

Common Pitfalls to Avoid

• Do not attribute the thrombocytosis to the breast mass alone without confirming iron deficiency as the primary driver; tissue injury from malignancy typically produces only mild thrombocytosis (450–600 × 10⁹/L) unless accompanied by severe iron deficiency 5, 1.

• Do not delay gastrointestinal investigation while awaiting oncologic work-up; dual pathology (both GI bleeding and malignancy) is present in 10–15% of patients with iron deficiency anemia 7.

• Do not order JAK2, CALR, or MPL mutation testing in the initial evaluation; these tests are only indicated if thrombocytosis persists after 3 months of adequate iron replacement or if iron studies are normal 6, 1.

• Do not assume ferritin alone excludes iron deficiency in the setting of inflammation or malignancy; ferritin can be falsely elevated by the acute-phase response, and a transferrin saturation <16–20% confirms iron deficiency even when ferritin appears borderline 5, 7.

• Do not overlook combined nutrient deficiencies; iron deficiency can coexist with vitamin B12 or folate deficiency, recognizable by an elevated red cell distribution width (RDW) 5, 7.