Diagnostic Workup for PV: Risk Stratification

Srdan Verstovsek, MD:Diagnosis of polycythemia vera is a tricky business sometimes. This actually led to a modification of our diagnostic process, recently, in April of this year, when a publication from an international group, that leads the efforts to properly diagnose patients with hematological malignancies, published new guidelines. So, at the moment, these guidelines are really emphasized as necessary for diagnosis to be made. And that would include several factors, but there are three major factors. The first is elevation in the red blood cell count, the second is performance of the bone marrow biopsy that would show too many cells in the bone marrow, and one-third is identification of the molecular marker, like JAK2 V617F mutation present in about 95% of the patients, or JAK2 exon 12 mutation that is present in about 2% or 3% of the patients. These are three major criteria for diagnosis of polycythemia vera. The fourth minor criterion is decrease in erythropoietin. This is a growth factor for red blood cells that is typically very low, low normal, or below normal in patients with polycythemia vera because it’s not necessary red blood cells grow without control. But, it recognizes the uncontrolled growth of red blood cells and shuts down the production of erythropoietin growth factor for red blood cells, so it’s very low. That’s a minor fourth criterion for diagnosis.

Now, let’s emphasize one part of this, which is important. The threshold on the red blood cell count, which is measured by hemoglobin or hematocrit, has been decreased in the new guidelines for making a diagnosis. Because, over time, specifically over the last 5 or 6 years, we recognize that many patients may not even have that high a red blood cell count that typically polycythemia vera patients may have. Some patients have somewhat lower numbers in the red blood cells because they develop iron deficiency, which is a common finding in polycythemia vera. Iron is utilized by red blood cells, and many patients are discovered to have a somewhat lower red blood cell count with iron deficiency without detectable or very low erythropoietin, and still have PV. So, one needs to be very cautious, and understand the diagnostic process and all the required parts.

Once we have a clear diagnosis of polycythemia vera, then the next question is, what is the prognosis of that patient, and not in terms of the survival? The survival is close to normal. But, in terms of the risk of thrombosis—and, traditionally, for many decades—we have been using two factors to assess the risk of thrombosis: age over 60 or a history of a blood clot. So, if you have any of these, then you are within the polycythemia vera patient group, considered to have a high risk for thrombosis. If you are younger than 60 or you did not have history of a blood clot so far, that would be a patient with a low risk for thrombosis.

One would say that a patient who has a low-risk polycythemia vera, phlebotomy and aspirin are good enough. If the patient has a high risk for polycythemia vera, thrombosis, then you need to do something better than a phlebotomy and aspirin. This is where we introduce cytoreductive therapy. That means therapy that will decrease the blood cell count to certain levels; the goal of the therapy is to further minimize the risk of thrombosis. And, traditionally, we have been using hydroxyurea and also interferon at some points in time.

Now, the issue is, is it good enough to have just these two factors to assess the risk of thrombosis in polycythemia vera at this time and age? We know about other cardiovascular risk factors that may contribute to the risk of thrombosis in patients, and we always emphasize that these need to be improved. There is some evidence over the last 5 years in a number of new papers that perhaps increased white cell count above normal is contributing to a risk of thrombosis. Certainly, progressive leukocytosis needs to be considered as a risk factor for thrombosis. We are not really ready yet to accept a high white blood cell count on its own, particularly not knowing what the cut-off for high white blood cell count would be in that risk assessment as a standard practice point for assessment of the risk. But, I think in the near future, we will certainly delve into white cell count as a risk factor for sure.

Case 1:A Patient with Disease Progression on Hydroxyurea