What is the likely cause and recommended work‑up and treatment for a patient with thrombocytosis, microcytic anemia, and a hemoglobin of 8 g/dL?

Thrombocytosis & Microcytic Anemia with Hemoglobin 8 g/dL

This presentation is iron-deficiency anemia with reactive thrombocytosis until proven otherwise, and the immediate priority is to identify the source of iron loss—most commonly gastrointestinal bleeding—while simultaneously initiating oral iron replacement.

Diagnostic Confirmation

Iron Studies (First-Line)

• Serum ferritin <15 µg/L is 99% specific for iron deficiency and confirms the diagnosis. 1
• Ferritin <30 µg/L indicates depleted iron stores consistent with iron-deficiency anemia. 1
• Transferrin saturation <16–20% confirms iron deficiency, particularly when ferritin may be falsely elevated by inflammation. 1
• A ferritin cut-off of 45 µg/L provides optimal sensitivity and specificity for iron deficiency in routine practice. 1
• If C-reactive protein is elevated, ferritin up to 100 µg/L may still represent iron deficiency because ferritin is an acute-phase reactant. 1

Red Cell Indices

• Low MCV with RDW >14% strongly suggests iron-deficiency anemia, whereas RDW ≤14% favors thalassemia minor. 1
• Mean corpuscular hemoglobin (MCH) is more reliable than MCV for detecting iron deficiency because it is less affected by specimen storage conditions. 1

Thrombocytosis Mechanism

• Reactive thrombocytosis occurs in approximately 8.1% of patients with iron-deficiency anemia, with platelet counts typically <700 × 10⁹/L, though extreme elevations (>1000 × 10⁹/L) can occur in severe iron deficiency. 2, 3
• Thrombocytosis peaks in the third week of iron deficiency and serves as a reactive marker; its presence strongly favors iron deficiency over anemia of chronic disease. 1
• Half of patients with iron-deficiency-induced thrombocytosis resolve their elevated platelet count within 2 weeks of iron supplementation, and all resolve within 6 weeks. 2

Mandatory Investigation for Source of Iron Loss

Gastrointestinal Evaluation (Highest Priority)

• Adult patients with confirmed iron-deficiency anemia require urgent upper endoscopy with duodenal biopsies AND colonoscopy to exclude gastrointestinal malignancy, which is the most common cause of iron loss in adults. 1
• Men with hemoglobin <110 g/L or non-menstruating women with hemoglobin <100 g/L warrant fast-track gastrointestinal referral. 1
• Upper endoscopy with duodenal biopsies is mandatory to screen for celiac disease, which accounts for 2–3% of iron-deficiency anemia cases and can present with extreme thrombocytosis. 1, 3
• Colonoscopy is essential to detect colonic carcinoma, adenomatous polyps, and angiodysplasia, particularly in older adults. 1
• Stool guaiac testing for occult blood should be performed immediately. 1

Additional Investigations

• Assess for heavy menstrual bleeding in premenopausal women, though gastrointestinal evaluation is still required even when menstrual loss appears explanatory. 1
• Evaluate for malabsorption disorders (celiac disease, H. pylori infection, autoimmune atrophic gastritis) if there is treatment failure or history of bariatric surgery. 1, 4

Immediate Treatment

Oral Iron Replacement (First-Line)

• Initiate ferrous sulfate 200 mg three times daily for at least three months after correction of anemia to replenish iron stores. 1
• Alternative formulations include ferrous gluconate or ferrous fumarate if ferrous sulfate is not tolerated, and ascorbic acid can be added to enhance absorption. 1
• A hemoglobin rise ≥10 g/L within 2 weeks confirms iron deficiency even when iron studies are equivocal. 1
• Expected hemoglobin increase is at least 2 g/dL within 4 weeks of starting treatment. 1

Intravenous Iron (Second-Line)

• Consider intravenous iron (iron sucrose or ferric carboxymaltose) if malabsorption is present, oral iron fails despite good compliance, or losses exceed maximal oral replacement capacity. 1, 5
• Expected hemoglobin increase is at least 2 g/dL within 4 weeks of IV iron administration. 1

Transfusion Indications

• Packed red blood cell transfusion is indicated only if hemoglobin falls below 7–8 g/dL OR the patient develops severe symptoms (chest pain, resting dyspnea, hemodynamic instability), regardless of the numeric hemoglobin value. 6

Monitoring & Follow-Up

• Monitor hemoglobin concentration and red cell indices at three-monthly intervals for one year, then after a further year. 1
• Platelet counts should normalize within 2–6 weeks of iron replacement; persistent thrombocytosis after 6 weeks warrants evaluation for a concomitant clonal myeloproliferative disorder. 2
• Provide additional oral iron if hemoglobin or MCV falls below normal during follow-up. 1

Critical Pitfalls to Avoid

• Do not attribute thrombocytosis to a primary myeloproliferative disorder (essential thrombocythemia) without first excluding iron deficiency, as reactive thrombocytosis can produce platelet counts exceeding 1000 × 10⁹/L in severe iron deficiency. 3, 4
• Do not delay gastrointestinal investigation to "optimize" the patient with iron therapy alone; the bleeding source must be identified promptly to prevent recurrent hemorrhage. 1
• Do not assume all microcytic anemia is iron deficiency; if iron studies are normal or borderline, order hemoglobin electrophoresis to exclude thalassemia trait. 1, 7
• Do not rely on ferritin alone in inflammatory states; add transferrin saturation to accurately diagnose iron deficiency when CRP is elevated. 1
• Do not overlook combined deficiencies; iron deficiency can coexist with vitamin B12 or folate deficiency, recognizable by elevated RDW. 1
• Do not attribute iron-deficiency anemia in adults solely to inadequate dietary intake; occult gastrointestinal blood loss, especially from malignancy, must be excluded. 1

Differential Diagnosis Considerations

When to Consider Alternatives

• If hemoglobin electrophoresis shows elevated hemoglobin A2 levels, diagnose beta-thalassemia trait. 7
• If ferritin is >100 µg/L with transferrin saturation <20% and elevated inflammatory markers, consider anemia of chronic disease. 1, 7
• If bone marrow examination shows ring sideroblasts, diagnose sideroblastic anemia and consider pyridoxine (vitamin B6) 50–200 mg daily. 1
• If remarkably low transferrin saturation with low-to-normal ferritin and failure to respond to oral iron, consider iron-refractory iron deficiency anemia (IRIDA), which requires intravenous iron. 1