What is the differential diagnosis (ddx) for thrombocytosis?

Differential Diagnosis of Thrombocytosis

Thrombocytosis (platelet count ≥450×10⁹/L) is divided into primary (clonal) and secondary (reactive) causes, with secondary thrombocytosis accounting for approximately 83-88% of cases and primary thrombocytosis representing 12-13% of cases. 1, 2

Primary (Clonal) Thrombocytosis

Myeloproliferative Neoplasms (MPNs)

• Essential thrombocythemia (ET) is the most common primary cause, present in 45-86% of primary thrombocytosis cases, and requires sustained platelet count ≥450×10⁹/L, bone marrow biopsy showing megakaryocytic proliferation with enlarged mature megakaryocytes, exclusion of other myeloid neoplasms (PV, PMF, CML, MDS), and demonstration of JAK2V617F (present in 86% of ET cases) or other clonal markers (CALR or MPL mutations). 3, 4, 5

• 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. 4, 5

• Primary myelofibrosis (PMF) is characterized by JAK2V617F mutation in nearly 50% of cases, characteristic bone marrow fibrosis with atypical megakaryocytes (small to large with aberrant nuclear/cytoplasmic ratio, hyperchromatic, bulbous or irregularly folded nuclei, and dense clustering), and progressive splenomegaly. 3, 4, 5

• Chronic myeloid leukemia (CML) typically presents with marked leukocytosis, splenomegaly in 40-50% of cases, and requires detection of Philadelphia chromosome t(9;22) or BCR-ABL1 fusion gene for diagnosis. 3, 4

Other Myeloid Neoplasms

• Myelodysplastic syndromes (MDS) can present with thrombocytosis, particularly those with del(5q), t(3;3)(q21;q26), or inv(3)(q21q26), and are characterized by significant granulocytic dysplasia and micromegakaryocytes. 3

Secondary (Reactive) Thrombocytosis

Most Common Causes

• Tissue injury/damage accounts for 32-42% of secondary thrombocytosis cases and includes surgery, trauma, burns, and tissue necrosis. 1, 2

• Infection represents 17-24% of secondary thrombocytosis cases, including acute and chronic bacterial, viral, and fungal infections. 1, 2

• Chronic inflammatory disorders account for 10-12% of cases, including connective tissue diseases, inflammatory bowel disease, and rheumatologic conditions. 3, 1

• Iron deficiency anemia causes 11% of secondary thrombocytosis cases and can produce thrombocytosis even without overt anemia. 3, 5, 1

Other Secondary Causes

• Malignancy accounts for 13% of secondary thrombocytosis, particularly metastatic cancer and lymphoproliferative disorders. 3, 2

• Post-splenectomy thrombocytosis occurs due to loss of platelet sequestration and removal. 3

• Hemolytic anemia can cause reactive thrombocytosis through increased bone marrow stimulation. 2

• Rebound thrombocytosis follows recovery from bone marrow suppression, chemotherapy, or alcohol cessation. 2

Critical Distinguishing Features

Clinical Characteristics Favoring Primary Thrombocytosis

• History of arterial thrombosis is significantly associated with primary thrombocytosis (p<0.05). 6

• Higher median platelet count is characteristic of primary thrombocytosis compared to secondary causes. 1, 2

• Splenomegaly with thrombocytosis is never normal and mandates immediate hematologic workup for MPN. 4

• Constitutional symptoms (fever, weight loss, night sweats) suggest underlying malignancy or myeloproliferative disorder. 4

Clinical Characteristics Favoring Secondary Thrombocytosis

• Active malignancy is strongly associated with secondary thrombocytosis (p<0.05). 6

• Chronic inflammatory disease predicts secondary thrombocytosis (p<0.05). 6

• History of splenectomy indicates secondary thrombocytosis (p<0.05). 6

• Iron deficiency (with or without anemia) is associated with secondary thrombocytosis (p<0.05). 6

Laboratory Parameters Distinguishing Primary from Secondary

• Higher hemoglobin, MCV, RDW, and MPV are associated with ET (p<0.01). 6

• Higher white blood cell count and neutrophil count favor secondary thrombocytosis (p<0.01). 6

• Elevated hematocrit, serum potassium, and lactate dehydrogenase are significantly different in primary versus secondary thrombocytosis. 2

• Elevated ESR and fibrinogen suggest secondary thrombocytosis due to inflammation. 2

Diagnostic Algorithm

Step 1: Confirm True Thrombocytosis

• Exclude pseudothrombocytosis through peripheral blood smear examination to identify platelet clumping. 4, 5

Step 2: Assess Clinical Context

• Identify presence of active malignancy, chronic inflammatory disease, recent surgery/trauma, infection, splenectomy, or iron deficiency—all strongly suggest secondary thrombocytosis. 6

• Assess for splenomegaly, hepatomegaly, or constitutional symptoms—these mandate workup for primary thrombocytosis. 4

Step 3: Laboratory Evaluation

• Obtain complete blood count with differential to assess for pancytopenia, leukocytosis, or isolated thrombocytosis. 4, 5

• Perform peripheral blood smear examination to identify immature myeloid cells, abnormal white cells, red cell fragments, and platelet morphology. 4

• Measure inflammatory markers (ESR, CRP) and iron studies (ferritin, serum iron, TIBC) to identify chronic inflammation or iron deficiency. 5, 6

Step 4: Molecular Testing (When Primary Thrombocytosis Suspected)

• JAK2V617F mutation testing should be performed immediately when primary thrombocytosis is suspected, as it is present in 86% of ET cases, >90% of PV cases, and nearly 50% of PMF cases. 4, 5, 7

• If JAK2V617F is negative, test for CALR and MPL mutations, as 86-92% of primary thrombocytosis cases have at least one molecular marker. 1

Step 5: Bone Marrow Examination (Mandatory in Specific Situations)

• Age ≥60 years requires bone marrow examination to exclude myelodysplastic syndromes, leukemias, or other malignancies. 5

• Systemic symptoms (fever, weight loss, bone pain) mandate bone marrow examination. 5

• Splenomegaly with thrombocytosis requires bone marrow biopsy, as this combination strongly suggests MPN. 4

• Abnormal blood count parameters beyond isolated thrombocytosis (anemia, leukocyte abnormalities) necessitate bone marrow examination. 5

• JAK2V617F-negative patients with suspected primary thrombocytosis require bone marrow biopsy to differentiate ET from reactive thrombocytosis and to exclude cellular phase/prefibrotic PMF or MDS. 3

Clinical Significance and Thrombotic Risk

• Primary thrombocytosis carries significantly higher thrombotic risk than secondary thrombocytosis, with both arterial and venous thromboembolic complications occurring more frequently. 1, 2

• Secondary thrombocytosis has thromboembolic events restricted to the venous system and occurring only in the presence of other risk factors. 2

• The distinction between primary and secondary thrombocytosis is critical for mortality reduction, as primary thrombocytosis requires aggressive thrombotic risk stratification and management. 4, 5

Common Pitfalls to Avoid

• Do not assume secondary thrombocytosis based solely on presence of a reactive condition, as the presence of a condition associated with reactive thrombocytosis does not exclude ET if WHO criteria are otherwise met. 3, 5

• Do not skip bone marrow examination in patients ≥60 years, regardless of clinical presentation, as this age group requires exclusion of myelodysplastic syndromes and other malignancies. 5

• Do not overlook occult PV in iron-deficient patients—a trial of iron replacement therapy is necessary to exclude PV before diagnosing ET. 3

• Do not diagnose ET without careful bone marrow histologic assessment to exclude cellular phase/prefibrotic PMF, which has different prognosis and treatment implications. 3