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Editorials
botomies. Additionally, these patients will then also have the opportunity to be treated with IFN in cases in which the institution does not include ET patients as an indica- tion for being treated with IFN but does so if the patient has PV. This will be even more important when the new IFN-drug, ropeginterferon α-2b, has been licensed for use in newly diagnosed PV in Europe, and hopefully soon in the US as well.47 Based upon the above considerations, the paper by Silver et al. is also of utmost importance since by diagnosing many more JAK2V617F ET patients correctly as PV, their findings may offer more patients the opportunity to be treated with IFN, which is the only agent that has shown to be disease modifying. In fact, in a subset of patients with early MPN disease (ET and PV), after approximately five years of IFN therapy it was seen that this approach may induce minimal residual disease (MRD), with normal cell counts, normal spleen size, a normal BM, and no detectable JAK2V617F mutation, rep- resenting an MRD stage that may even be sustained after interrupting IFN for up to three years.48
Considering the findings by Silver et al. and Michiels et al., in some of their previous papers the RBC count is the most valuable parameter and is better than Hb-concentra- tion and hematocrit when considering the equation: HCT= RBC count x MCV, and taking into account that several PV patients have lowered MCV which according- ly lowers the HCT and wrongly dictates that a phleboto- my is not needed, irrespective of the fact that the RBC count is increased49 (Figure 1). In this context, it is also important to note that erythrocytosis in PV usually induces plasma volume expansion4,16,50 which may mask the true HCT, implying that the HCT in many PV patients, especially women, appears to be normal.2,4,16,41,50
These considerations are not only relevant at the time of diagnosis but also during the course of PV when sever- al patients may not be phlebotomized when only using HCT and elevated RBC count is not taken into consider- ation (Figure 1). On the contrary, hydroxyurea (HU)-treat- ed patients may be unnecessarily phlebotomized due to an HU-induced increase in MCV and accordingly also an increase in the HCT, although the RBC count is normal.
Hopefully, based upon previous reports on the need of
the RCM in the diagnosis of MPN,2-7,10,11,16,49,50 and the most
recent studies by Silver et al. and the French study dis-
cussed above, consideration of the RCM will be revived
at many more MPN centers worldwide. Such efforts are
not only expected to improve quality of life of the large
proportion of undiagnosed PV patients amongst
JAK2V617F positive ET patients, but likely prognosis as
well, since they will be correctly diagnosed as PV and
accordingly receive the cornerstone treatment of PV
(phlebotomy) to reduce the HCT <0.42 in women and <0.45 in men.2-4,11,16,50-53
The important distinction between different HCT lev- els for women and men when deciding the need for phle- botomies has been addressed in several papers.2,4,16,50-53 The rationales for this distinction are several and obvious, including the simple fact that women and men have dif- ferent red blood cell volumes as reflected in different ranges for red cell indices. This common knowledge dic- tates that a woman’s normal RCM is approximately 600 mL lower than that for men.4,53 Accordingly, a female
patient with a hematocrit of 45% has at least an excess of approximately 600 mL blood4 which associates with an increased risk of major thrombosis.54 Indeed, the study by Marchioli et al. clearly showed that allowing HCT between 0.45 and 0.50 is associated with a significant risk of death from cardiovascular causes or major thrombotic events54 - also in the general population.55 These are les- sons that we learnt from Pearson 30 years ago51,52 and which have been repeated since then in several other studies: an elevated HCT is associated with an increased risk of thrombosis. In fact, in the general population the risk of thrombosis at elevated HCT values has previously been reported to be driven by smoking,56 which has recently been associated with an increased risk of MPN.57
The excess blood volume is even larger in PV-patients with hepatic vein thrombosis,16 who often have a normal HCT due to an expanded plasma volume.4 Importantly, the thrombosis risk in JAK2V617F positive “ET” patients will likely be markedly reduced simply due to normaliza- tion of the expanded RCM by phlebotomies. Additionally, without a RCM estimation, some patients with JAK2V617F positive “ET” may be erroneously classi- fied as “early prefibrotic myelofibrosis” while actually having undiagnosed PV for several years and then being referred with an enlarged spleen, a normal Hb-concentra- tion and a normal HCT, red cell values that are in the nor- mal range due to hemodilution consequent to the expanded plasma volume associated with the enlarged spleen. Accordingly, in such patients, a RCM estimation may reveal an expanded RCM requiring phlebotomies to omit thrombotic complications, often at unusual sites such as portal thrombosis, mesenteric thrombosis and thrombosis of hepatic veins.58 Indeed, similar to mPV as a transitional stage in the biological continuum from ET to overt PV, one might speculate as to whether a proportion of JAK2V617F positive patients with a normal Hb /HCT and splenomegaly classified as “early prefibrotic myelofi- brosis” may actually have PV with an expanded RCM and expanded plasma volume in a transitional stage towards classic myelofibrosis.
Today, we still need to go over the important lessons from the history of MPN. Back in 1908, Osler taught us that the RBC count is superior to the Hb concentration as an indicator of erythrocytosis.2,4,16,50,59,60 This should, there- fore, be used in the diagnosis of PV, and the lesson from the PV study group and from several authorities there- after is that the RCM is “the gold standard” for an accu- rate diagnosis of PV in patients with mPV and its precur- sor stage: JAK2V617F positive ET.2-8,16 In the paper by Silver et al. in this issue of Haematologica and in other papers, the importance of these lessons have been repeat- edly highlighted. These will hopefully stimulate research into MPN towards additional comparative and correlative studies on the value of RCM estimations, the RBC count, and BM morphology in the diagnosis of MPN. Such stud- ies are even more urgent taking into consideration a most recent review challenging and critically discussing the role of the hematocrit as a determinant risk factor for thrombosis in erythrocytosis.61 It is to be hoped that such studies may promote a consensus amongst MPN experts that the RCM is essential for a correct classification of JAK2V617F positive ET patients, mPV and PV patients.
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