How should I evaluate and manage a patient with thrombocytosis?

Evaluation and Management of Thrombocytosis

Begin by confirming true thrombocytosis with a platelet count ≥450 × 10⁹/L on at least two separate samples, then immediately distinguish between primary (clonal) and secondary (reactive) causes through molecular testing for JAK2V617F, CALR, and MPL mutations. 1

Initial Diagnostic Steps

Confirm True Thrombocytosis

• Verify the sample does not contain clots and examine the peripheral smear to exclude platelet aggregates that may cause spurious elevation 1
• Confirm platelet count ≥450 × 10⁹/L on at least two separate samples 1
• Perform complete blood count with peripheral smear to evaluate platelet morphology and identify other cellular abnormalities 1

Immediate Molecular Testing

Request JAK2V617F, CALR (exon 9), and MPL mutation testing on whole blood or purified granulocytes as the first essential diagnostic step 1. Approximately 80% of patients with essential thrombocythemia harbor at least one of these driver mutations in a mutually exclusive pattern 1. This molecular testing has revolutionized the diagnostic approach and should not be delayed 2.

Distinguishing Primary from Secondary Thrombocytosis

Primary (Clonal) Thrombocytosis

Primary thrombocytosis accounts for approximately 12.5% of cases and is characterized by:

• Presence of JAK2V617F, CALR, or MPL mutations (found in ~86% of primary cases) 3
• Higher median platelet counts compared to secondary causes 3
• Significantly increased incidence of thrombotic complications 3
• Bone marrow biopsy showing features consistent with myeloproliferative neoplasm 4

Secondary (Reactive) Thrombocytosis

Secondary thrombocytosis represents 83% of cases, with major causes including 3:

• Tissue injury (32.2%) - including post-surgical states and trauma
• Infection (17.1%) - acute or chronic infectious processes
• Chronic inflammatory disorders (11.7%) - autoimmune conditions, inflammatory bowel disease
• Iron deficiency anemia (11.1%) - check ferritin and iron studies
• Malignancy - solid tumors or hematologic conditions 5
• Post-splenectomy - occurs in 75-82% of cases 6

Consider extended mutational panel testing for TET2, ASXL1, DNMT3A, and SF3B1 if initial driver mutations are negative but clinical suspicion for myeloproliferative neoplasm remains high 1.

Risk Stratification for Primary Thrombocytosis

The American Society of Hematology recommends a two-variable risk stratification system based on age and history of thrombosis 1:

Risk Categories

• High-risk: Age >60 years OR history of thrombosis
• Intermediate-risk: Age <60 years with cardiovascular risk factors
• Low-risk: Age <60 years without thrombosis history or cardiovascular risk factors

Apply the Triple A survival risk model (Age, Absolute neutrophil count, Absolute lymphocyte count) to further stratify patients into high, intermediate-1, intermediate-2, and low-risk categories 1.

Screening for Complications

Thrombotic Complications

• Perform Doppler ultrasound of lower limbs in all patients with primary thrombocytosis to identify asymptomatic thrombosis 1
• Consider abdominal imaging (ultrasound or venography) to exclude splenic or portal vein thrombosis 1
• CT angiography of lungs if respiratory symptoms present 1

Splanchnic vein thrombosis is frequently encountered in myeloproliferative neoplasms, with JAK2V617F mutation found in approximately 45% of Budd-Chiari syndrome patients and 34% of portal vein thrombosis patients 4.

Bleeding Risk Assessment

• In extreme thrombocytosis (>1,000 × 10⁹/L), evaluate for acquired von Willebrand syndrome 1
• Perform platelet function tests if history of bleeding despite elevated platelet count 1
• Platelet count >1,500 × 10⁹/L is a risk factor for bleeding and requires cytoreductive therapy 4

Management of Primary Thrombocytosis (Essential Thrombocythemia)

Low-Risk Patients

All patients should receive low-dose aspirin (75-100 mg daily) if microvascular disturbances are present 4. Cytoreduction is generally not indicated in low-risk patients with well-controlled cardiovascular risk factors 4.

Common pitfall: Do not use cytoreductive drugs in otherwise low-risk patients having well-controlled cardiovascular risk factors, as this exposes them to unnecessary toxicity 4.

High-Risk Patients

First-Line Therapy

Hydroxyurea is the first-line cytoreductive therapy at any age; in young patients (<40 years old), its use should be carefully considered due to potential leukemogenic risk 4. The goal is to restore platelet counts to <400 × 10⁹/L 4.

Add low-dose aspirin to hydroxyurea unless contraindicated by major bleeding history 4. The PT-1 trial demonstrated that hydroxyurea plus aspirin reduced the composite endpoint of arterial/venous thrombosis, major bleeding, or death compared to anagrelide plus aspirin 4.

Special Situations

• Pregnancy (high-risk features): Use low molecular weight heparin throughout pregnancy and stop aspirin if bleeding occurs 4
• Platelet count ≥1,500 × 10⁹/L: Consider interferon alfa 4
• Previous major bleeding: Avoid aspirin and consider interferon alfa to reduce thrombocytosis 4

Second-Line Therapy

For patients intolerant or resistant to hydroxyurea, use anagrelide as the recommended second-line therapy 4. Interferon-α is reserved for selected patients such as young females or those with contraindications to anagrelide 4.

Avoid sequential use of multiple cytotoxic agents, as this significantly increases the risk of acute myeloid leukemia/myelodysplastic syndromes 4.

Monitoring Response

• Evaluate response by normalization of blood counts and disappearance of signs/symptoms 4
• No indication to routinely monitor bone marrow response for clinical follow-up 4
• No strict indication to routinely monitor JAK2V617F allele burden 4

Management of Secondary Thrombocytosis

Secondary thrombocytosis is generally benign and self-limiting, requiring treatment of the underlying cause rather than the elevated platelet count itself 5, 3.

When to Treat Secondary Thrombocytosis

• Extreme thrombocytosis (>1,000 × 10⁹/L) with thrombotic complications: Consider short-term cytoreduction 7
• Post-splenectomy thrombocytosis with thrombotic events: Thrombosis occurs in approximately 5% of post-splenectomy patients 6
• Chronic inflammation or malignancy with high thrombotic risk: Consider individualized antiplatelet therapy 7

Most patients with secondary thrombocytosis do not require specific treatment for the elevated platelet count if the underlying condition is addressed 5.

Specialist Referral Criteria

Immediate hematology referral is recommended if 1:

• Platelet count >1,000 × 10⁹/L
• Presence of driver mutations (JAK2, CALR, MPL)
• History of thrombosis or unexplained bleeding
• Splenomegaly

Critical Pitfalls to Avoid

• Do not assume reactive thrombocytosis without molecular testing - 12.5% of thrombocytosis cases are primary, and these patients have significantly higher thrombotic risk 3
• Do not overlook splanchnic vein thrombosis - perform abdominal imaging in all primary thrombocytosis patients 4, 1
• Do not use aspirin in patients with platelet count >1,000 × 10⁹/L without first reducing the count - extreme thrombocytosis paradoxically increases bleeding risk 4, 1
• Do not delay cytoreduction in high-risk patients - thrombotic complications are the predominant cause of morbidity and mortality 2
• Do not use multiple sequential cytotoxic agents - this dramatically increases leukemia risk 4