Clinical presentation in chronic phase and relationship to phenotypic driver mutation. PV and ET are modeled as a disease spectrum along a biological continuum where different genetic lesions skew the clinical phenotype from that of thrombocytosis to that of additional erythrocytosis (±leukocytosis). CALR mutations result in excessive MPL signaling, in a manner similar to that resulting from MPL mutations. JAK2 mutations signal downstream of multiple cell surface receptors, including MPL, and are thus associated with thrombocytosis but also erythrocytosis and leukocytosis. The exact nature of the phenotypic driver mutation, germline genetic background, and additional somatic mutations influence disease phenotype. *In the context of JAK2^V617F, several factors modulate the balance between erythrocytosis and thrombocytosis, including sex, mutation homozygosity, and patient-specific factors such as erythropoietin (EPO) levels, renal function, and iron status.