What are the causes of thrombocytosis and leukocytosis in a 55‑year‑old woman with low testosterone, normal pituitary function, normal C‑reactive protein, normal glycated hemoglobin, and dyslipidemia?

Differential Diagnosis: Combined Thrombocytosis and Leukocytosis

In this 55-year-old woman with combined thrombocytosis and leukocytosis, normal CRP, and absence of inflammatory markers, you must first exclude a myeloproliferative neoplasm (MPN)—specifically essential thrombocythemia (ET) or early polycythemia vera (PV)—before considering reactive causes.

Primary (Clonal) vs. Secondary (Reactive) Causes

The normal CRP is a critical discriminating feature here. A normal or minimally elevated CRP (<40 mg/L) strongly suggests primary thrombocytosis rather than reactive thrombocytosis 1, 2. In secondary thrombocytosis, CRP levels typically exceed 40 mg/L in 65% of cases, whereas no patients with primary thrombocytosis reach this threshold 3.

Most Likely Primary Causes to Investigate:

1. Essential Thrombocythemia (ET)

• Requires sustained platelet count ≥450 × 10⁹/L 1, 2
• JAK2 V617F mutation present in ~50% of ET cases 1
• Can present with concurrent leukocytosis
• Critical next step: Order JAK2 V617F mutation testing immediately 1, 2

2. Early/Masked Polycythemia Vera (PV)

• This is particularly important given the testosterone level of 1.6 (assuming ng/mL, which is elevated for a female)
• PV can present with thrombocytosis and leukocytosis BEFORE overt erythrocytosis becomes apparent 4
• Thrombocytosis may precede PV diagnosis by 24-46 months 4
• JAK2 V617F mutation present in >90% of PV cases 1
• Check: Hemoglobin, hematocrit, and iron studies with ferritin—iron deficiency can mask PV by preventing the characteristic erythrocytosis 1, 2

3. Primary Myelofibrosis (PMF) - Prefibrotic Phase

• Can present with both thrombocytosis and leukocytosis 1
• JAK2 V617F positive in ~50% of cases 1
• May show leukoerythroblastosis and elevated LDH 1

Secondary (Reactive) Causes to Consider:

Given the normal CRP, these are less likely but must be excluded:

1. Iron Deficiency Anemia

• Most common cause of reactive thrombocytosis 2, 5
• Can cause extreme thrombocytosis (>2000 × 10⁹/L) and leukocytosis 5
• Check: Complete iron panel (serum iron, TIBC, ferritin, transferrin saturation)
• Resolves rapidly with iron supplementation 5

2. Occult Malignancy

• Metastatic cancer or lymphoproliferative disorders 2
• Usually accompanied by elevated CRP, but not always
• Check: Age-appropriate cancer screening, CT chest/abdomen/pelvis if clinically indicated

3. Smoking

• Can cause persistent leukocytosis 6
• Less commonly associated with significant thrombocytosis

Algorithmic Workup

Immediate Laboratory Tests:

1. Repeat CBC with differential to confirm sustained thrombocytosis and characterize leukocytosis
2. Peripheral blood smear looking for:
   • Immature white cells (left shift, blasts)
   • Abnormal platelet morphology
   • Leukoerythroblastosis (nucleated RBCs, immature granulocytes)
3. JAK2 V617F mutation testing 1, 2
4. Complete iron studies (ferritin, serum iron, TIBC, transferrin saturation)
5. Hemoglobin/hematocrit with attention to gender-specific thresholds
6. LDH and uric acid (elevated in MPNs)

If JAK2 V617F is Positive:

• Proceed directly to bone marrow biopsy to distinguish between ET, PV, and PMF 1, 2
• Refer to hematology/oncology

If JAK2 V617F is Negative:

• Test for CALR and MPL mutations 1, 7
• If iron deficiency identified, trial of iron replacement and recheck counts in 4-6 weeks 2
• If no secondary cause identified and counts remain elevated, bone marrow biopsy is mandatory to exclude MPN 2, 7

Critical Pitfalls to Avoid

1. Do not dismiss this as "reactive" based solely on normal CRP—approximately 17% of secondary thrombocytosis cases have normal CRP 3, and MPNs typically have normal or only mildly elevated CRP 1

2. Do not overlook masked PV—iron deficiency can suppress hemoglobin elevation, masking the diagnosis 1, 2. Always check iron studies and consider iron replacement trial before excluding PV 2

3. The elevated testosterone (1.6) is a red flag—while the question states "H testosterone," this is abnormal for a 55-year-old woman and could indicate:

   • Polycythemia vera (which can cause secondary hormonal changes)
   • Concurrent androgen-secreting tumor
   • This requires endocrine evaluation alongside hematologic workup

4. Thrombotic events may precede MPN diagnosis by years—ask specifically about prior unexplained thrombosis, erythromelalgia, aquagenic pruritus, or microvascular symptoms 4

5. Dyslipidemia and normal A1C do not explain the blood count abnormalities—these are likely coincidental findings or cardiovascular risk factors that need separate management

Bottom Line

This patient requires urgent hematology referral and JAK2 mutation testing. The combination of sustained thrombocytosis, leukocytosis, normal inflammatory markers, and elevated testosterone in a middle-aged woman creates high suspicion for a myeloproliferative neoplasm, particularly early/masked polycythemia vera or essential thrombocythemia 1, 2, 7. Do not delay molecular testing and bone marrow evaluation—these conditions carry significant thrombotic risk and require specific management to prevent morbidity and mortality.