What is the appropriate management for a patient with a history of thrombocytosis and leukocytosis, positive antinuclear antibody (ANA), elevated erythrocyte sedimentation rate (ESR), thrombocytosis, and iron deficiency anemia?

Management of Thrombocytosis, Leukocytosis, and Iron Deficiency Anemia

This patient requires immediate iron replacement therapy, as the severe iron deficiency (iron 28 µg/dL, saturation 9%) is the most likely cause of the reactive thrombocytosis and leukocytosis, and treatment will resolve both hematologic abnormalities while preventing thrombotic complications. 1, 2, 3

Immediate Diagnostic Priorities

Confirm Iron Deficiency as Primary Etiology

• The combination of severe iron deficiency (saturation <10%) with marked thrombocytosis (496 × 10⁹/L) and leukocytosis strongly suggests reactive thrombocytosis rather than essential thrombocythemia (ET). 2, 3
• Iron deficiency can cause extreme thrombocytosis (even >1000 × 10⁹/L) and associated leukocytosis, both of which resolve rapidly with iron supplementation. 3, 4
• The low-titer ANA (1:80) and mildly elevated ESR (34 mm/hr) are likely reactive inflammatory markers secondary to iron deficiency rather than indicating autoimmune disease. 1

Exclude Myeloproliferative Neoplasm

• Clinical factors favoring secondary thrombocytosis over ET include: presence of iron deficiency, absence of arterial thrombosis history, and the constellation of findings. 2
• Active malignancy, chronic inflammatory disease, splenectomy, and iron deficiency are all associated with secondary thrombocytosis rather than ET. 2
• Molecular testing (JAK2, CALR, MPL mutations) should be deferred initially if iron deficiency adequately explains the findings, as the yield is low when clear secondary causes exist. 5, 2
• If thrombocytosis persists after 2-3 months of iron repletion, then proceed with JAK2 mutation testing and consider bone marrow examination. 5, 2

Essential Additional Workup

Identify Source of Iron Loss

• Obtain detailed menstrual history (menorrhagia is a common cause in women), gastrointestinal symptoms, dietary history, and history of bariatric surgery. 3, 6
• Consider gastrointestinal evaluation if no obvious source identified, as occult GI bleeding must be excluded. 2
• Check for malabsorption syndromes, particularly if history of bariatric surgery exists. 3

Complete Blood Count Analysis

• Obtain peripheral blood smear to assess for microcytic hypochromic cells, platelet morphology, and exclude abnormal/immature cells. 7, 2
• Check mean corpuscular volume (MCV), red cell distribution width (RDW), and mean platelet volume (MPV)—iron deficiency typically shows low MCV, elevated RDW. 2, 6
• Measure reticulocyte count to assess bone marrow response (should be appropriately elevated if marrow is responding to anemia). 7

Rule Out Concurrent Conditions

• The mildly positive ANA (1:80) does not warrant extensive autoimmune workup unless clinical symptoms suggest systemic lupus erythematosus or other connective tissue disease. 1
• Consider testing for Helicobacter pylori if refractory to iron therapy, as it can cause iron deficiency. 1
• Exclude infectious causes of elevated inflammatory markers if clinically indicated. 1

Treatment Algorithm

Iron Replacement Strategy

• Initiate oral iron supplementation (or intravenous iron if malabsorption, intolerance, or need for rapid repletion). 1, 6
• The American Society of Anesthesiologists recommends administering iron to patients with iron deficiency anemia when time permits. 1
• Monitor complete blood count weekly initially, then every 2-4 weeks to document resolution of thrombocytosis and leukocytosis. 3, 6
• Both thrombocytosis and leukocytosis should resolve within 2 months of adequate iron replacement. 3, 6, 4

Thrombotic Risk Management

• Low-dose aspirin is NOT routinely indicated for reactive thrombocytosis unless there are additional cardiovascular risk factors or history of thrombosis. 5
• The platelet count of 496 × 10⁹/L does not reach extreme thrombocytosis (>1000 × 10⁹/L) where acquired von Willebrand syndrome screening would be warranted. 5
• Monitor for thrombotic symptoms but avoid cytoreductive therapy, as this is reactive thrombocytosis. 3

Critical Pitfalls to Avoid

Do Not Initiate Cytoreductive Therapy Prematurely

• Hydroxyurea or other cytoreductive agents should NOT be started until myeloproliferative neoplasm is confirmed, as reactive thrombocytosis resolves with treatment of underlying cause. 5, 3
• One case report describes inappropriate initiation of cytoreductive therapy for extreme thrombocytosis that was ultimately due to iron deficiency. 3

Do Not Overlook Severe Iron Deficiency

• Iron saturation of 9% represents severe iron deficiency requiring aggressive replacement. 1, 2
• Failure to treat iron deficiency can lead to persistent thrombocytosis and potential thrombotic complications. 3, 6

Reassess if No Response to Iron

• If thrombocytosis and leukocytosis persist after 2-3 months of documented iron repletion (ferritin >50 ng/mL, saturation >20%), then proceed with JAK2 mutation testing and hematology referral for possible bone marrow biopsy. 5, 2
• Persistent cytopenias despite treatment would warrant evaluation for primary bone marrow disorders including myelodysplastic syndrome. 7