Can polycythemia vera (PV) be diagnosed years after a thrombotic event in a patient with a history of unexplained or recurrent thrombosis?

Can Polycythemia Vera Be Diagnosed Years After a Thrombotic Event?

Yes, polycythemia vera (PV) can absolutely be diagnosed years after a thrombotic event, and clinicians should maintain a high index of suspicion for underlying myeloproliferative neoplasms in patients with unexplained or recurrent thrombosis, particularly when thrombosis occurs at unusual sites such as splanchnic veins.

Clinical Context and Epidemiology

The temporal relationship between thrombosis and PV diagnosis is well-established in the literature:

• Thrombosis frequently precedes PV diagnosis: Among patients with PV, arterial thrombosis occurs in approximately 16% and venous thrombotic events in 7% of patients either prior to or at the time of diagnosis 1
• Unusual thrombotic presentations are particularly suggestive: Thrombotic events involving unusual sites, such as splanchnic veins, should prompt evaluation for underlying PV even years after the initial event 1
• History of thrombosis is a major risk stratification factor: The NCCN guidelines and multiple studies identify prior thrombosis history as one of the two most important prognostic factors (along with age >60 years) for defining high-risk disease 2

Why Delayed Diagnosis Occurs

Several factors contribute to PV being diagnosed years after an initial thrombotic event:

• Insidious disease progression: PV can present with subtle hematologic abnormalities that may not meet diagnostic thresholds at the time of the initial thrombotic event 3
• Evolving diagnostic criteria: The 2016 WHO criteria lowered hemoglobin thresholds to 16.5 g/dL in males and 16.0 g/dL in females, allowing earlier diagnosis of cases that previously would have been missed 3
• Initial misattribution: Thrombotic events may initially be attributed to other risk factors (cardiovascular disease, thrombophilia, etc.) without comprehensive evaluation for myeloproliferative neoplasms 2

Diagnostic Approach for Patients with Remote Thrombosis

When evaluating a patient with a history of unexplained thrombosis for possible PV:

Essential Diagnostic Criteria

• JAK2 mutation testing is critical: More than 95% of PV patients harbor a JAK2 gene variant, which helps distinguish PV from secondary causes of erythrocytosis 1
• Current hemoglobin/hematocrit levels: Erythrocytosis with hemoglobin >16.5 g/dL in men or >16.0 g/dL in women, or hematocrit ≥49% in males and ≥48% in females 3
• Serum erythropoietin level: Normal or increased levels combined with absence of JAK2 mutation makes PV diagnosis unlikely 4, 5

Additional Supportive Findings

• Thrombocytosis (present in 53% of patients) and leukocytosis (present in 49% of patients) are common but not required 1
• Splenomegaly (present in 36% of patients) may be detected on physical examination or imaging 1
• Bone marrow biopsy showing hypercellularity with trilineage growth confirms diagnosis in equivocal cases 6

Clinical Implications of Delayed Diagnosis

The recognition of PV years after thrombosis has critical therapeutic implications:

Immediate Management Priorities

• All patients require phlebotomy: Target hematocrit strictly <45% based on the CYTO-PV trial, which demonstrated significant reduction in thrombotic events with this strict target 6, 1
• Low-dose aspirin therapy: 81-100 mg daily for all patients without contraindications, which significantly reduces cardiovascular death, myocardial infarction, stroke, and venous thromboembolism 6, 1

Risk Stratification Based on Thrombosis History

• Patients with prior thrombosis are automatically classified as high-risk: This classification applies regardless of age, based on NCCN guidelines and the ECLAP trial data 2
• High-risk patients require cytoreductive therapy: In addition to phlebotomy and aspirin, these patients should receive hydroxyurea as first-line cytoreductive therapy (Level II, A evidence) or interferon-α as an alternative (Level III, B evidence) 6, 5

Important Caveats and Pitfalls

Screening Considerations

• Do not rely solely on thrombophilia testing: Testing for heritable thrombophilic defects does not usefully predict likelihood of thrombosis recurrence and should not replace evaluation for myeloproliferative neoplasms in patients with unexplained thrombosis 2
• Consider PV even with "normal" blood counts: The prothrombotic state in PV involves multiple mechanisms beyond elevated hematocrit, including qualitative platelet abnormalities, widespread activation of coagulation proteins, and reduced levels of physiologic anticoagulants 7, 8

Bleeding Risk Assessment

• Screen for acquired von Willebrand disease: This occurs in more than one-third of PV patients and is particularly important in those with extreme thrombocytosis (platelet count ≥1000 × 10⁹/L) before administering aspirin 8, 4, 5

Long-term Monitoring

• Recognize transformation risks: Approximately 10% risk of transformation to myelofibrosis in the first decade and 6.8% risk of acute myeloid leukemia development, with 20-year cumulative risks of 16% and 4% respectively 8, 9
• Median survival is 14-27 years from diagnosis: In younger patients (<60 years), median survival extends to 24-33 years, emphasizing the importance of early diagnosis and appropriate management 5, 9

Anticoagulation Decisions

• Balance thrombosis and bleeding risks: The case-fatality of recurrent VTE in patients off anticoagulation is 5%, while the case-fatality of anticoagulant-associated bleeding is 9% 2
• Consider long-term anticoagulation carefully: Patients with PV and prior unprovoked thrombosis may benefit from extended anticoagulation, but this must be weighed against bleeding risk, particularly in those with acquired von Willebrand disease 2