Polycythemia Vera: Diagnostic Work-up

Harry P. Erba, MD, PhD: Let’s move on. Srdan, I’d like you to discuss how patients with PV [polycythemia vera] present and what the differential diagnosis of that presentation is.

Srdan Verstovsek, MD, PhD: Although polycythemia vera is the name, it implies that all the cells grow, which is true. Polycythemia means high blood cell count: red blood cells, white blood cells, and lipids. Not everybody has high white cells and high platelets, but everybody does have high red blood cell counts. The cardinal feature of polycythemia vera is a high red blood cell count.

That can be in a setting of blood clots at the time of the presentation in about 20% of the patients, and it’s often associated with the systemic symptoms: itching, night sweating, low-grade fever, fatigue, flushing in the face, not feeling well overall, memory loss, and blurred vision are symptoms related to impaired circulation in the body because there are too many cells in the blood vessels. These are the characteristics of the patients we see, but not every patient who has a high red blood cell count has polycythemia vera.

As you alluded in your impression, there are other conditions that may resemble these kinds of presentations. Particularly in the setting of younger people, we need to be cautious when we look at the erythrocytosis associated with the use of certain medications like testosterone. Erythrocytosis is associated with problems with lung function—people who had sleep apnea, for example. There are also problems related to certain cancers—kidney cancer, for example.

Not everybody who has high a red blood cell count has polycythemia vera. The first goal is to make sure we are talking about the bone marrow neoplasm and not reactivated erythrocytosis, because the approach is different. With the disease, we have not only the number of cells increasing but also their activity. They are sticky, and that is the problem: too many cells that are sticking together, and that increases the risk of thrombosis. Therefore, the approach there is to decrease the thrombotic risk in polycythemia vera patients.

To go back to the diagnostic process, once we roll out the secondary diseases that would increase blood cell counts, which are usually benign, you would look at lung functions, medications, and other possible causes. You would focus specifically on the criteria for PV that, in 2016, has been simplified and modified to quite a significant degree. We now have 3 major criteria to fulfill, or you can fill at least 2 of them, and I’ll give you a brief summary of those.

The cardinal picture is high red blood cell count. We are talking about decreased hematocrit or hemoglobin, as is routine when you do CBC [complete blood count]. That should be associated with the testing you can do in blood for the presence of JAK2 V617F mutation, which is present in about 95% of the patients, or in those who don’t have that 1, testing for JAK2 exon 12 mutation.

That will cover almost everybody: either of the 2 mutations, and there is still a possibility of having anecdotal cases of patients who do not have any of these, which may be a matter of the sensitivity of the test, or they have something else that can link mutation for which we cannot test.

You have high blood cell count with JAK2 mutation, and then the question of the bone marrow biopsy: Do you need to have it done? In the synopsis for the diagnostic criteria it says No. 1, high red blood cell count; No. 2, bone marrow biopsy; and No. 3, the JAK2 mutation. If you have all 3, you have PV, no question about it, but there is a minor criterion there which is suboptimal serum erythropoietin level, meaning low erythropoietin level.

It’s in case you cannot do genetic testing. The purpose of genetic testing is to fulfill diagnostic criteria, but sometimes you may not have it, or the testing is not available. You can use the high red blood cell count, the bone marrow, and the suboptimal erythropoietin as a combination for making diagnosis. This is the standard practice.

Many ask the question: Do we need to do a bone marrow biopsy in every single case? If you read the guidance on how the diagnosis process needs to be done, it clearly says in the small print—and that’s the problem, it’s very small—that you don’t need to do it every single time. If you have an above-normal red blood cell count, a JAK2 mutation, and a suboptimal erythropoietin level, there is no other disease than polycythemia vera that can cause this trifecta of findings.

In that case, with very high red blood cell count above normal, JAK2 mutation on blood protein, and a low erythropoietin level, that’s PV. I don’t do the bone marrow biopsies, and the small print in the guidance says not to do it.

I hope I simplified for you what needs to be done to get the diagnosis of PV.

Transcript Edited for Clarity