Typical Presentation of Polycythemia Vera


Dr Bose shares his initial impressions of a PV patient case before discussing typical patient presentation and criteria for PV diagnosis.

Prithviraj Bose: So my impressions on the patient we just talked about is that this is somebody over 60 with a clear diagnosis of PV. You had the classic bone marrow findings, you had the JAK2 mutation, actually a high allele burden as well. And this is an older patient. So by definition, actually a high-risk patient, and we'll get to that later. But the patient was initially started on phlebotomy and aspirin without a cytoreductive therapy. However, it quickly became apparent that this was a progressive case of PV with the frequent requirement for phlebotomy, pruritus, and some other symptoms. And then eventually also the spleen enlarging about one year into the disease course. So the patient, as you saw, was put on hydroxyurea fairly quickly, but the dose had to be increased from 1000 to 1500 to 2000, telling you that this is really a proliferative patient, a proliferative disease, I should say. And not to mention that the disease is progressive based on what I said earlier in terms of symptoms, splenomegaly, and also the continued requirement for phlebotomy. The patient also had some leukocytosis to start with. So overall, my impression is that this is a PV and it has a few red flags. It's a patient that is very proliferative, started with a bit of a leukocytosis, had progressive symptoms as well as a splenomegaly that showed up within a year. So certainly a patient with several, you know, higher risk features. Now regarding how one makes a diagnosis of PV, what are the criteria, how patients typically present, I'll go back to the formal criteria, of course, the WHO criteria were updated in 2016. And it's really important to understand why they updated them and what the changes were. So what they did is that, first of all, the criteria basically are three major criteria, one minor criteria. And the three major criteria are hemoglobin, hematocrit above certain cutoffs for men and women, for men 16.5, for women 16, for the hemoglobin, sorry. And then the second criterion, we're still within the major criteria. The second criterion was actually the bone marrow biopsy. So the bone marrow biopsy doing one was substantially elevated in importance. And the bone marrow should show you this panmyelosis, pleomorphic MEGs, as we saw in our case, hypercellular, of course. And then the third major criterion is the JAK2 mutation. So 95% will have JAK2, V617F, 4% will have JAK2 exon 12. And that leaves a very small proportion that may not have a JAK2 mutation. The minor criterion is a subnormal or a low erythropoietin level. Now, of course, as our colleagues know, erythropoietin can also be normal in PV. So you don't always have every criterion, of course. And so the WHO requires the first three major, or I should say all three major criteria, or the first two major and the minor criteria. And the reason for that is, again, those very rare cases where there's not a JAK2 mutation, there, if you meet the hemoglobin hematocrit criterion and the bone marrow criterion and the low EPO level, you're good as far as the diagnosis. So what is important to appreciate is why they made these changes. And that's because there is an entity called masked PV that is often missed or was being missed by the earlier set of criteria, the WHO 2008, which had higher cutoffs or thresholds of hemoglobin and hematocrit for the diagnosis. So if you followed those, you could miss some of these masked PV cases where because of iron deficiency, the hemoglobin hematocrit is not that high, but it's still PV. And these patients have a worse outcome, perhaps because they are treated less intensely. So they reduce the cutoffs purposely to enable or facilitate diagnosis of masked PV, but in doing so, and in trying to counter that, so that you don't get a whole bunch of false positives, they made sure that the bone marrow became an important criterion, specifically the second major criterion. Now, this is actually often criticized. And people ask, what's the need to do a bone marrow if it's an obvious case? So they actually made an allowance for that and noted that if the patient is meeting the prior criteria, the ones with the higher hemoglobin hematocrit cutoffs, and the EPO is low, the JAK2 is mutated, then you're good. You can dispense with the bone marrow if that's what the patient wants. However, because some patients can have initial fibrosis in the bone marrow, if you don't do it, you miss out on that information, because that portends a higher risk of progression to myelofibrosis. So that's something to be said for getting a bone marrow. And I like to add that because a lot of ET is JAK2 mutated, about 50 to 60%, there are those patients who may in fact have JAK2 mutant ET, and their hemoglobin is not that high, but meets these newer, lower cutoffs. So if you don't do a bone marrow, there is a possibility that some of this ET and PV could be so-called conflated. I mean, that they could appear indistinguishable without a bone marrow. As far as how these patients present, well, oftentimes it's actually just a pickup on routine labs. In PV, you have high hemoglobin platelets and white cells. It's a polycythemia. So oftentimes they're just picked up like that. And of course, otherwise, they could present with a clot. It's not too infrequent when somebody presents with a clot and further work up, picks up the JAK2 mutation, and then leads on to the diagnosis. So that happens. And then of course, some of the classic symptoms, from hyperviscosity, these headaches, blurry vision, migraines, a ruddy complexion, all of those things, less commonly spleen-related symptoms. All of these can be different flavors of presentation of PV.

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