Paroxysmal nocturnal hemoglobinuria and concurrent JAK2V617F mutation

Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic and pro-thrombotic disorder associated with the clonal expansion of hematopoietic stem cells harboring somatic mutations in the PIG-A gene. Mutations in PIG-A result in a lack of surface expression of all glycosylphosphatidylinositol (GPI)-anchored proteins, including the complement inhibitors CD55 and CD59, which is responsible for the hemolytic (and probably also the pro-thrombotic) phenotype. However, long-term colony-forming assays and in vivo murine models have failed to show that PIG-A mutations are alone sufficient to drive clonal expansion. There are two leading hypotheses to account for clonal expansion of PIG-A-null stem cells: (i) clonal selection and (ii) second mutations. The first model posits that aplastic anemia--which is epidemiologically associated with PNH---results in an immune-mediated marrow injury that selectively spares PNH stem cells. The second hypothesis is borrowed from models of oncogenesis and may be supported by the observation that patients with PNH can harbor clonal cytogenetic abnormalities. However, no specific gene mutations other than PIG-A have been reported in patients with PNH---with one exception. In two patients, a rearrangement of chromosome 12 with a break in the 30-untranslated region of the HMGA2 gene has been reported. Overexpression of an HMGA2 truncated protein recapitulates an myeloproliferative neoplasms (MPN)-like phenotype in a murine model and could theoretically contribute to clonal expansion in PNH. Interestingly, literature from the 1970’s has reported several cases of PNH in association with myelofibrosis and other MPNs. Here we report on three index cases of PNH with myeloproliferative features harboring a JAK2 mutation, which is now understood to drive clonal expansion in many MPNs. The first case is a 51-year-old male, presenting with right hemiparesis and dysarthria secondary to a stroke, followed by multiple thrombotic events, including the Budd Chiari Syndrome (BCS). A hypercoagulable workup revealed the presence of the JAK2 mutation in the peripheral blood. Upon referral to us, a complete