A 60-year-old man presented with acute right-sided weakness and dysarthria. His NIHSS was 10. Noncontrast head computed tomography (CT) showed no hemorrhage or acute ischemia, and computed tomography angiography (CTA) showed no vessel pathology. He received tenecteplase (TNK). Following TNK, brain magnetic resonance imaging (MRI) revealed an acute infarct in the posterior left basal ganglia.

Further workup revealed anemia (11 g/dL) and thrombocytosis (691 × 10³/µL), which were trending up. Splenic ultrasound showed splenomegaly. Due to concern for essential thrombocytosis and a CBC consistently showing elevation in thrombocytes (as high as 933 × 10³/µL), a bone marrow biopsy was performed and revealed increased cellularity, clustered megakaryocytes, and grade 2/3 fibrosis. Mutation testing demonstrated CALR exon 9 and MPL exon 10 mutations and was negative for JAK2 mutation.

Treatment with hydroxyurea and allopurinol was initiated, resulting in improved platelet counts. He received dual antiplatelet therapy with aspirin and clopidogrel for 21 days, followed by aspirin monotherapy for secondary stroke prevention. The patient was subsequently discharged home without complications.

This case underscores the importance of considering a broader spectrum of molecular drivers in ET beyond JAK2 when evaluating stroke etiology. Furthermore, it highlights the need to refine current risk stratification models and to pursue advanced diagnostic workups in patients presenting with hematologic causes of stroke. Early recognition can guide cytoreductive and antiplatelet strategies tailored to individual genetic profiles.