What is the likely diagnosis and recommended work‑up for a patient with marked leukocytosis, extreme thrombocytosis, mild conjugated hyperbilirubinemia, low serum iron, low transferrin saturation (TSAT), and low‑normal total iron‑binding capacity (TIBC)?

Likely Diagnosis: Myeloproliferative Neoplasm (Essential Thrombocythemia or Chronic Myeloid Leukemia)

This patient's extreme thrombocytosis (1,758 × 10⁹/L) combined with leukocytosis (19.7 × 10⁹/L) and functional iron deficiency strongly suggests a myeloproliferative neoplasm, most likely essential thrombocythemia (ET) or chronic myeloid leukemia (CML), and requires immediate peripheral blood smear examination followed by BCR-ABL testing and bone marrow biopsy. 1

Immediate Diagnostic Priorities

Peripheral Blood Smear Examination (Mandatory First Step)

• Examine for left shift, basophilia, immature granulocytes, and blast percentage to distinguish between CML (which shows myeloid hyperplasia with basophilia) and ET (which shows predominantly mature cells without significant left shift). 1, 2
• Look specifically for dysplastic features, as their presence would suggest myelodysplastic syndrome rather than a primary myeloproliferative neoplasm. 3
• Assess platelet morphology for large, mature-appearing forms typical of ET versus reactive changes. 3

BCR-ABL Testing (Urgent)

• Obtain Philadelphia chromosome testing via cytogenetics and/or BCR-ABL by RT-PCR or FISH from peripheral blood immediately if CML is suspected based on smear findings showing basophilia or left shift. 1
• CML is characterized by the Philadelphia chromosome t(9;22) or BCR-ABL fusion gene in almost all patients and classically presents with neutrophil leukocytosis, thrombocytosis, and basophilia. 1

Bone Marrow Aspiration and Biopsy (Required for Definitive Diagnosis)

• Bone marrow examination is mandatory to assess for proliferation patterns, blast percentage, megakaryocyte morphology, and fibrosis. 3
• For ET diagnosis, look for proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes with deeply lobulated and hyperlobulated nuclei. 3
• The marrow should be normally or only slightly hypercellular for age in ET, without the increased trilineage proliferation (panmyelosis) that characterizes polycythemia vera. 3

Diagnostic Algorithm

Step 1: Rule Out CML

• If BCR-ABL is positive, diagnose CML and initiate imatinib 400 mg daily as first-line therapy. 1
• If symptomatic leukocytosis or massive splenomegaly is present, start hydroxyurea for rapid cytoreduction before or concurrent with imatinib. 1, 4

Step 2: If BCR-ABL Negative, Evaluate for Essential Thrombocythemia

The revised WHO criteria for ET require all 4 of the following 3:

1. Sustained platelet count ≥450 × 10⁹/L (this patient meets criteria with 1,758)
2. Bone marrow biopsy showing megakaryocytic proliferation with enlarged, mature megakaryocytes; no significant increase or left-shift of neutrophil granulopoiesis
3. Not meeting WHO criteria for PV, PMF, CML, MDS, or other myeloid neoplasm
4. Demonstration of JAK2V617F or other clonal marker, or in absence of clonal marker, no evidence for reactive thrombocytosis

Step 3: Rule Out Reactive Thrombocytosis

• The low iron (33), low transferrin saturation (14%), and low-normal TIBC (228) indicate functional iron deficiency, which can cause reactive thrombocytosis. 3
• However, reactive thrombocytosis rarely exceeds 1,000 × 10⁹/L, making a primary myeloproliferative neoplasm much more likely at this platelet count. 3
• Other causes of reactive thrombocytosis include infection, inflammation, malignancy, and recent surgery—but the presence of a reactive condition does not exclude ET if the first three WHO criteria are met. 3

Understanding the Laboratory Pattern

Iron Studies Interpretation

• Low serum iron (33) with low transferrin saturation (14%) and low-normal TIBC (228) indicates functional iron deficiency (iron-restricted erythropoiesis despite adequate or increased iron stores). 3
• In the context of a myeloproliferative neoplasm, this pattern suggests either:
  • True iron deficiency from chronic occult bleeding
  • Anemia of chronic disease (functional iron deficiency from inflammatory cytokines)
  • Increased iron utilization by the expanded myeloid compartment 3

Hyperbilirubinemia Pattern

• Total bilirubin 2.8 with indirect bilirubin 2.0 indicates predominantly unconjugated hyperbilirubinemia (conjugated = 0.8), suggesting hemolysis or ineffective erythropoiesis. 3
• This pattern can occur in myeloproliferative neoplasms due to:
  • Ineffective erythropoiesis with intramedullary hemolysis
  • Increased red cell turnover from splenomegaly (if present)
  • Concurrent hemolytic process 3

Additional Required Workup

Complete Blood Count with Differential

• Obtain manual differential to confirm automated counts and assess for dysplasia, immature forms, and blast percentage. 3, 4, 2
• Document presence or absence of basophilia (favors CML) and eosinophilia. 1

JAK2V617F Mutation Testing

• Test for JAK2V617F mutation, which is present in approximately 50-60% of ET cases and supports clonal diagnosis. 3
• If JAK2V617F is negative, consider testing for CALR and MPL mutations, which account for most remaining ET cases. 3

Cytogenetic Analysis

• Perform cytogenetic studies on bone marrow to identify clonal abnormalities and exclude MDS-associated changes. 3
• Cytogenetic abnormalities including del(20q), del(5q), and unbalanced whole-arm translocation between 1q and 7p have been reported in ET and do not exclude the diagnosis unless accompanied by MDS features. 3

Assessment for Splenomegaly

• Physical examination for splenomegaly is essential, as approximately 50% of CML patients have splenomegaly at diagnosis. 1
• If splenomegaly is present with this degree of leukocytosis and thrombocytosis, CML becomes the leading diagnosis. 1

Critical Pitfalls to Avoid

• Do not assume reactive thrombocytosis with platelet counts >1,000 × 10⁹/L—this degree of elevation strongly suggests a myeloproliferative neoplasm and requires full hematologic workup. 3
• Do not delay bone marrow biopsy—peripheral blood testing alone cannot definitively diagnose ET or exclude other myeloid neoplasms. 3
• Do not treat iron deficiency empirically without establishing the underlying diagnosis first, as this may mask important diagnostic features and delay recognition of a myeloproliferative neoplasm. 3
• Do not overlook the need for BCR-ABL testing—CML can present with thrombocytosis and must be excluded before diagnosing ET. 3, 1