What is the differential diagnosis and management for a patient presenting with thrombocytosis and splenomegaly?

Differential Diagnosis of Thrombocytosis with Splenomegaly

When thrombocytosis presents with splenomegaly, you must immediately suspect a primary myeloproliferative neoplasm (MPN), particularly essential thrombocythemia (ET), polycythemia vera (PV), or primary myelofibrosis (PMF), as this combination is highly atypical for reactive thrombocytosis and demands urgent hematologic evaluation. 1, 2

Primary (Clonal) Causes - Most Likely Given Splenomegaly

Myeloproliferative Neoplasms

• Essential thrombocythemia (ET) requires sustained platelet count ≥450×10⁹/L, bone marrow biopsy showing megakaryocytic proliferation, exclusion of other myeloid neoplasms, and demonstration of JAK2V617F (present in 86% of cases) or other clonal markers (CALR or MPL mutations) 1, 2
• Polycythemia vera (PV) presents with elevated hemoglobin/hematocrit as the primary feature, JAK2V617F mutation in >90% of cases, and splenomegaly in 40-50% of patients at diagnosis 3, 1, 2
• Primary myelofibrosis (PMF) is associated with JAK2V617F mutation in nearly 50% of cases, characteristic bone marrow fibrosis, atypical megakaryocytes, and progressive splenomegaly 3, 1
• Chronic myeloid leukemia (CML) typically presents with marked leukocytosis (often >100×10⁹/L), splenomegaly in 40-50% of cases, and requires detection of Philadelphia chromosome t(9;22) or BCR-ABL1 transcripts 3

Critical Distinction

• Prefibrotic myelofibrosis must be excluded when evaluating suspected ET, as it carries a worse prognosis and different management approach 2

Secondary (Reactive) Causes - Less Likely with Splenomegaly

Conditions That Can Cause Both Features

• Chronic liver disease with portal hypertension causes splenic sequestration leading to thrombocytopenia in 76% of cases, making thrombocytosis with splenomegaly highly unusual in this context 4
• Chronic inflammatory disorders account for 11.7% of secondary thrombocytosis cases but rarely present with significant splenomegaly 1
• Tissue injury and infection account for 32.2% and 17.1% of secondary thrombocytosis respectively, but splenomegaly suggests a more serious underlying process 1

Rare Causes

• Isolated spleen agenesis can cause thrombocytosis mimicking ET, but obviously presents without splenomegaly and shows Howell-Jolly bodies on peripheral smear 5

Diagnostic Algorithm - Prioritizing Morbidity and Mortality

Step 1: Immediate Laboratory Evaluation

• Complete blood count with differential to assess for pancytopenia, leukocytosis, or isolated thrombocytosis 6, 1
• Peripheral blood smear examination is mandatory to identify immature myeloid cells, abnormal white cells, red cell fragments, and platelet morphology 6, 1
• JAK2V617F mutation testing should be performed immediately when primary thrombocytosis is suspected, as it is present in 86% of ET cases and >90% of PV cases 1, 2

Step 2: Exclude Pseudothrombocytosis

• Repeat platelet count in heparin or sodium citrate tubes to exclude EDTA-dependent platelet agglutination 6

Step 3: Assess for Secondary Causes

• Iron studies to detect iron deficiency, which can cause thrombocytosis even without anemia 1
• Inflammatory markers (ESR, CRP) to identify chronic inflammation 1
• Infectious disease screening including HIV, hepatitis C, and H. pylori in appropriate clinical contexts 6

Step 4: Bone Marrow Examination - Mandatory in This Presentation

• Bone marrow biopsy with aspirate is mandatory when thrombocytosis presents with splenomegaly, as this combination strongly suggests MPN 3, 1, 7
• Bone marrow examination is also required for patients >60 years or with systemic symptoms to exclude myelodysplastic syndromes, leukemias, or other malignancies 6, 1
• Both aspirate and biopsy should be obtained, with consideration for flow cytometry and cytogenetic testing 3
• Bone marrow histology remains the cornerstone of diagnosis and is essential for distinguishing between different MPNs 2, 7

Step 5: Additional Molecular Testing

• CALR and MPL mutation testing if JAK2V617F is negative, as approximately 90% of ET patients express mutually exclusive JAK2, CALR, or MPL mutations 2
• BCR-ABL1 testing by multiplex RT-PCR to exclude CML if leukocytosis is present 3
• Cytogenetic analysis to assess for abnormal karyotype, which might compromise survival in PV and ET 2

Red Flags Demanding Urgent Evaluation

• Splenomegaly with thrombocytosis is never normal and mandates immediate hematologic workup 3
• Constitutional symptoms (fever, weight loss, bone pain) suggest underlying malignancy or myelodysplasia 6
• Abnormal hemoglobin, white blood cell count, or white cell morphology beyond isolated thrombocytosis 6
• Immature myeloid cells on peripheral smear suggest accelerated phase or blast crisis 3

Clinical Significance and Thrombotic Risk

• Primary thrombocytosis carries significantly higher thrombotic risk than secondary thrombocytosis, making this distinction critical for mortality reduction 1, 7
• JAK2V617F mutation increases thrombotic risk in ET compared to CALR-mutated or triple-negative cases 2
• Risk stratification in ET includes four categories: very low (age ≤60 years, no thrombosis history, JAK2 wild-type), low (same but JAK2 mutated), intermediate (age >60 years, no thrombosis history, JAK2 wild-type), and high (thrombosis history or age >60 years with JAK2 mutation) 2

Common Pitfalls to Avoid

• Never assume reactive thrombocytosis when splenomegaly is present - this combination demands exclusion of MPN 1, 7
• Do not delay bone marrow examination in patients with thrombocytosis and splenomegaly, as missing MPN diagnosis has significant mortality implications 6, 1
• The presence of a reactive condition does not exclude ET if WHO criteria are otherwise met 1
• Failing to perform bone marrow histology leads to misdiagnosis, as molecular testing alone cannot distinguish between different MPNs 2, 7