What are the next steps for a patient with thrombocytosis (high platelets), elevated hemoglobin, hyperferremia (high iron), and hypoferritinemia (low ferritin)?

Diagnostic Workup for Thrombocytosis with Elevated Hemoglobin, High Iron, and Low Ferritin

This constellation of findings—high platelets, high hemoglobin, high serum iron, and low ferritin—strongly suggests iron deficiency with reactive thrombocytosis, and the immediate next step is to measure transferrin saturation (TSAT) to confirm iron deficiency and rule out iron overload disorders before initiating treatment. 1

Initial Laboratory Assessment

The combination of low ferritin with elevated hemoglobin and platelets is paradoxical and requires systematic evaluation:

• Measure fasting transferrin saturation immediately alongside a complete iron panel (serum iron, TIBC, TSAT) to distinguish true iron deficiency from other causes 1, 2
• Obtain inflammatory markers (CRP, ESR) because ferritin is an acute phase reactant—inflammation can falsely elevate ferritin levels, masking iron deficiency, or falsely lower them in the context of iron overload 1, 3
• Complete blood count with red cell indices including mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and percentage of hypochromic erythrocytes to assess for microcytosis or hypochromia 2
• Reticulocyte count to evaluate bone marrow response and rule out hemolysis 2

Interpretation of Iron Parameters

If TSAT <45% with Low Ferritin (Most Likely Scenario)

This pattern confirms iron deficiency without anemia (also termed hypoferritinemia without anemia or HWA), which can present with reactive thrombocytosis:

• Iron-depleted patients have significantly higher platelet counts than those with adequate iron stores (mean difference approximately 18,000-24,000/µL higher in iron-depleted individuals) 4
• Thrombocytosis occurs in 4.4% of iron-depleted patients versus 2.0% in those with normal ferritin 4
• The elevated hemoglobin may represent hemoconcentration or a compensatory polycythemic response rather than true polycythemia 5

Treatment approach:

• Oral iron supplementation with 28-50 mg elemental iron daily (higher doses increase side effects without improving absorption) 3
• Dietary counseling to increase heme iron intake and avoid inhibitors of iron absorption 3
• Recheck CBC and iron panel in 8-10 weeks to confirm response—expect platelet counts to decrease by approximately 20,000/µL with iron repletion 4
• Target ferritin level ≥30 µg/L for adults over 15 years 3

If TSAT ≥45% with Low Ferritin (Less Common but Critical)

This pattern suggests a primary iron overload disorder (such as hereditary hemochromatosis) with paradoxically low ferritin, which can occur early in disease or with concomitant inflammation:

• Proceed immediately to HFE genotype testing for C282Y and H63D mutations 1, 2
• Assess liver enzymes (ALT, AST) and hepatomegaly to evaluate for organ damage 1, 2
• If C282Y homozygous and age <40 years with normal liver enzymes and ferritin <1000 µg/L, proceed directly to therapeutic phlebotomy without liver biopsy, targeting ferritin 50-100 µg/L 1
• If ferritin >1000 µg/L or elevated liver enzymes, consider liver biopsy to assess for cirrhosis 2

Evaluation for Secondary Causes

Before attributing findings solely to iron status, exclude:

• Chronic inflammatory conditions (rheumatologic diseases, chronic infections) that can cause reactive thrombocytosis and alter iron parameters 1, 2
• Occult blood loss via stool guaiac testing, as gastrointestinal bleeding is the most common cause of iron deficiency 2
• Metabolic syndrome/NAFLD which commonly causes hyperferritinemia, though less likely given low ferritin here 2, 1
• Myeloproliferative disorders if thrombocytosis is marked (>600,000/µL) or persistent after iron repletion—check JAK2 mutation 2
• Chronic kidney disease by measuring serum creatinine and eGFR, as CKD alters iron metabolism 2

Common Pitfalls to Avoid

• Do not assume low ferritin always means simple iron deficiency—the combination with high hemoglobin and high serum iron requires TSAT measurement to rule out hemochromatosis 1, 6
• Do not supplement iron without confirming TSAT <45%—iron supplementation in undiagnosed hemochromatosis can cause severe organ damage 2, 1
• Do not ignore reactive thrombocytosis—while usually benign in iron deficiency, persistent thrombocytosis after iron repletion warrants hematologic evaluation 4
• Do not use ferritin alone to diagnose iron status—always interpret in context of TSAT and inflammatory markers 1, 3

Monitoring and Follow-up

• If iron deficiency confirmed and treated: Recheck CBC and ferritin at 8-10 weeks, expecting normalization of platelet count and rise in ferritin 3, 4
• If hemochromatosis diagnosed: Initiate phlebotomy 500 mL weekly/biweekly, checking hemoglobin before each session, and ferritin every 10-12 phlebotomies 1
• Long-term: Patients with recurrent iron deficiency benefit from monitoring every 6-12 months and intermittent oral supplementation to maintain ferritin ≥30 µg/L 3