Silent Clonality Essential Thrombocythemia: High-Risk Thrombotic Presentation and the Diagnostic Role of Next-Generation Sequencing
Introduction/Background/Significance: Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by sustained thrombocytosis (platelet count ≥450 × 109/L), exclusion of reactive causes, and distinctive bone marrow findings—increased numbers of large, mature-appearing megakaryocytes in loose clusters. The median age at diagnosis is approximately 59 years, with a slight female predominance, but can occur at any age. Many patients are asymptomatic at diagnosis, while others present with microvascular symptoms, thrombosis, or hemorrhage. Genetically, ET is defined by mutually exclusive driver mutations in JAK2 (64%), CALR (23%), or MPL (4%). These mutations constitutively activate the JAK-STAT pathway, driving megakaryocyte proliferation. About 10% of cases are "triple-negative," lacking mutations in all three genes. Triple-negative ET is diagnostically challenging, as some cases may represent hereditary or reactive thrombocytosis rather than true clonal disease. Next-generation sequencing can identify noncanonical or rare mutations and additional somatic mutations (e.g., TET2, ASXL1, SF3B1, SRSF2, TP53), which may inform prognosis and clarify clonality, especially in triple-negative cases.The clinical significance of driver mutations includes a higher risk of thrombosis in JAK2-mutated ET and a greater risk of myelofibrotic transformation with certain CALR and MPL mutations. Prognostic models now increasingly incorporate both clinical and molecular features.
Materials and Methods/Case Presentation/Objective: A 48-year-old obese male with 25 pack year smoking history presented with intermittent, sharp left-sided chest pain radiating to the left arm, ongoing for one week, and associated with dyspnea. Laboratory evaluation revealed severe thrombocytosis (1.7 million/μL), mild normocytic anemia (H/H 12.1/39.3), and elevated troponin, consistent with NSTEMI. Reactive causes were excluded. Erythropoietin was within normal limits. Peripheral blood testing for JAK2 V617F, CALR exon 9, MPL, and BCR-ABL1 were negative. Flow cytometry showed no evidence of clonal lymphoid or aberrant myeloid populations. Bone marrow biopsy revealed normocellular marrow (~50%) with trilineage hematopoiesis and marked megakaryocytic hyperplasia with dysplastic clustering, without fibrosis. Iron stores were mildly decreased. Bone marrow flow cytometry was unremarkable. NGS identified a Variant of Uncertain Significance (VUS), while no definitive driver mutations were detected. There was no evidence of acquired von Willebrand disease. Despite negative molecular findings, the diagnosis of ET was made based on clinical presentation, bone marrow morphology, and exclusion of secondary causes. Given the thrombotic presentation, the patient was classified as high-risk ET and initiated on hydroxyurea for cytoreduction and aspirin.
Conclusions: This case highlights the diagnostic complexity of triple-negative ET, particularly in the setting of acute arterial thrombosis and absence of canonical mutations. The presence of a Variant of Uncertain Significance (VUS) underscores the growing role—and current limitations—of next-generation sequencing in evaluating atypical MPNs. While VUS findings may eventually be reclassified as pathogenic or benign, they presently offer limited clinical guidance. Nonetheless, meeting morphologic and clinical criteria remains sufficient for diagnosis, even in the absence of a definitive clonal marker. The case emphasizes the need for individualized risk assessment and treatment, as patients without known driver mutations may still present with high-risk complications requiring cytoreductive therapy. Ongoing molecular research is essential to better define the pathogenic significance of VUS and to refine classification and treatment strategies for triple-negative ET.
