The Erythrocyte Count on Top of Bone Marrow Histology Discriminates Essential Thrombocythemia and Polycythemia Vera in JAK2v617f Mutated Prefibrotic Myeloproliferative Neoplasm with No or Minor Splenomegaly

Abstract

Blood and bone features in JAK2 V617F mutated prefibrotic essential thrombocythemia (ET) and polycythemia vera (PV) are overlapping in terms of increased cellularity due to increased erythropoiesis and pleomorphic megakaryocytes indicating the need to measure red cell mass (RCM) according to PVSG and WHO criteria. The JAK2 V617F mutated myeloproliferative neoplasms (MPN) appeared to be a broad biological continuum of normocellular ET, ET with features of polycythemia vera (prodromal PV), classical PV, advanced PV, Inapparent PV (IPV) with splenomegly, masked PV or hypercellular ET due to megakaryocytic granulocytic myeloproliferation (ET.MGM) when the 2013 WHO and European Clinical, Molecular and Pathological (WHO-CMP) criteria are applied. The megakaryocytes morphology may change from pleomorphic to dysmorphic in advanced PV, in IPV and in masked PV (ET.MGM) as bone marrow cellularity, the degree myelofibrosis and the JAK2 V617F mutation load increase during long-term follow-up. Erythrocytes above the upper limit of normal (5.8×10 12 /L), but not hemoglobin and hematocrit is clearly correlated with increased red cell mass (RCM) above (30) ml/kg) and therefore diagnostic for PV and idiopathic erythrocythemia (IE) on top of pathognomonic MPN bone marrow histology in newly diagnosed PV patients with normal mean cell volume (MCV) of erythrocytes and no or minor of splenomegaly. Erythrocyte count remain above the upper limit of normal in PV and IE in complete hematological remission by phlebotomy alone as the consequence of iron deficiency induced microcytic erythrocytes that correct the blood volume (RCM), hemoglobin and hematocrit to normal. The combination of increased RCM, increased plasma volume, and normal or low erythrocyte counts is characteristic for IPV with significant splenomegaly as the only cause of increased blood volume without symptoms of hypervolumemia.

The red blood cell count and the erythrocyte sedimentation rate in the diagnosis of polycythaemia vera

“…Our ET and PV study cohorts displayed similar biochemical profiles as previously described but being put in perspective in this report when compared with the MPN suspect group. First, we found significantly lower ratios of MCV <82 and ferritin <15 μg/L in the PV group compared to the MPN suspects group.…”

“…Indeed, one might argue, that the new disease entity—“masked“ PV has been born due to the inconvenient consensus in the international MPN—scientific community that RCM estimations in patients suspected of PV are too “time‐consuming” and accordingly are not being performed at several leading MPN centres of excellence worldwide. However, our results together with similar recent results from other studies unravel and substantiate the urgent need to revive RCM estimations to prohibit misclassification of an increasing number of JAK2V617F positive ET patients as “ET” albeit having a diagnosis of PV and to prohibit the misterm “masked “ PV to be consolidated in the future MPN literature …”

“…This highly important issue on the association between the HCT, the MCV and the RBC has most recently been addressed by Silver et al 18 and Michiels et al, 19 both studies concluding that the RBC is superior to the HCT in the diagnosis of PV. 18,19 However, the WHO criteria 2016 for PV do not take notice of these highly important observations, implying that the Hb concentration is still included although with minor modifications. 3,4 The aim of the present study of a larger series of Danish patients with essential thrombocythemia (ET) and PV is to confirm and substantiate the observations of a poor correlation between the HCT value and RBC when microcytosis is present.…”

System dynamics of cancer in erythropoiesis with multiple EPO feedbacks

“…The model predictions are shown as full curves for the erythrocyte count and as dashed curves for the JAK2V617F allele burden decay. The data shown in the first two panels are from Michiels et al (2014). The data shown in the last panel is from the clinical trial "DALIAH" (EudraCT number: 2011-001919-31) dimensional analysis reduced the number of parameters from 23 to 15.…”

“…The data shown in the first two panels are from Michiels et al . (2014). The data shown in the last panel is from the clinical trial “DALIAH” (EudraCT number: 2011‐001919‐31)…”