A 44-year old female with unremarkable past clinical history refers to the Hematology Clinic for persistent thrombocytosis (Hb = 15.2 g/dL; Hct = 44.8%; WBC = 12.65 × 109/L [N = 9.58 × 109/L]; Plt = 742 × 109/L). Epo levels are close to the lower limit of normal (4.29 mU/mL; range: 4.3–29), LDH is not increased (206 U/L, range: 135–214) and JAK2 mutation is detected (VAF = 5.5%). Splenomegaly is not documented at clinical examination and sonography. BM biopsy (d–f) discloses a hypercellular marrow with features of panmyelosis, maturing erythroid and myeloid lineages and polymorphous, and loosely clustering megakaryocytes with frequent giant hyperlobated forms. A minor increase in reticulin fibers is observed, consistent with MF-1 according to WHO criteria. This case displays borderline features between a pre-polycythemic phase of PV (highly supported by the very typical morphologic pattern) and pre-fibrotic PMF.\nA diagnosis of ET is ruled out by BM histology. In contrast to case 1, the still low JAK2 allele burden could be responsible for the blood count, which is not fully consistent with PV. In similar cases, concurrent hematopoiesis-modifying factors (e.g., thalassemic trait, vitamin deficiencies, malabsorption, etc.) should be investigated. In addition, a minor increase in fibrosis should warrant closer monitoring.
A 17-year-old Caucasian male, a high school student from Missouri was referred for evaluation of unexplained erythrocytosis. He reported a myriad of symptoms including nausea, vomiting, abdominal pain, weight loss, fatigue, headaches, cold hands and feet with numbness and tingling, hyperhidrosis, palpitations, and pruritus. He was a non-smoker without illicit drug or hormone use. Family history was unremarkable. On physical examination, no cutaneous, abdominal or neurological abnormalities were noted. A review of serial blood counts showed a consistent elevation in Hgb >16.5 g/dl, with peak Hgb/Hct of 18.3 g/dl/52.4% and normal leukocyte and platelet counts. PV was excluded with a negative JAK2V617F/exon 12 mutation screen and elevated EPO at 22.6 mIU/mL (normal range; 2.6–18.5 mIU/mL). Bone marrow aspirate/biopsy was without features of a MPN. Hereditary erythrocytosis evaluation did not reveal high-affinity Hgb variants or mutations in 2,3-Bisphosphoglycerate Mutase (BPGM)(exons 1–4), EPOR (exon 8), or oxygen-sensing pathway proteins, including hypoxia-inducible factor 2 α (HIF2A) encoded by endothelial PASS domain protein 1 (EPAS1) (exons 9 and 12), prolyl hydroxylase 2 (PHD2) encoded by egl-9 family hypoxia-inducible factor 1(EGLN1)(exons 1-5), von Hippel Lindau (VHL) (three coding exons and intron/exon boundaries). Chest/abdominal imaging, arterial blood gas, transthoracic echocardiogram with shunt study, urinary catecholamines/metanephrines were unremarkable. Interestingly, MRI brain/spine revealed multiple cerebrovascular malformations; both developmental venous anomalies and cavernous hemangiomas in the frontal and temporal regions. Accordingly, the cerebrovascular malformations were hypothesized to be a plausible link to the patient’s erythrocytosis. Surgical intervention was not feasible due to the presence of multiple anomalies. He was initiated on phlebotomies with marked improvement in symptoms; thereafter, need for periodic phlebotomies was determined by symptoms rather than a target Hct value. This previously published case underscores the importance of a systematic diagnostic approach to JAK2 unmutated erythrocytosis [].