Ruben Mesa, MD, and Srdan Verstovsek, MD, PhD, discuss the disease burden of polycythemia vera and the range of complications, symptoms, and quality of life, as well as current diagnostic criteria.
Ruben Mesa, MD: The burden that a patient with polycythemia vera experiences is heterogeneous, but can be problematic. Our group has been very engaged in trying to quantify that burden. It includes many aspects. It includes the risk of thrombosis or bleeding, as well as many symptoms that can be related to difficulties with blood flow–related to the high red blood cell count. And this can be everything from TIAs (transient ischaemic attacks) to sensory changes, erythromelalgia, headaches, and even more subtle things such as difficulties with concentration, insomnia, or challenges with intimacy–so, a whole spectrum of things we really associate with inadequate blood flow. It can have a strong impact of fatigue, and that can be very multi-factorial; that may be treatment related. That may be related to iron deficiency from phlebotomies. But some of it is inherent to the disease itself, probably related to abnormal cytokines that are elevated in the disease. They might have symptoms from an enlargement of the spleen, and that might cause fullness, discomfort, or pain.
Polycythemia vera can cause a range of complications. Indeed, just this week I had seen 2 individuals who had thrombotic events to the abdominal veins—what we call Budd-Chiari syndrome. And that, like blood clots in any of the vascular distributions, not only can cause symptoms but can also cause long-term risk in complications for the patient, in terms of their hepatic health. There are patients who have had venous sinus thrombosis in the skull, and that can lead to difficulties with headaches. Individuals could have had pulmonary embolism, pulmonary hypertension, deep vein thrombosis, and chronic edema. There’s a range of impact that they can have had from thrombosis or bleeding, in addition to the spectrum of the other disease-associated symptoms we can encounter.
Srdan Verstovsek, MD, PhD: Polycythemia vera is the blood condition that makes cells grow without control. The main problem is elevation in the red blood cells, but many patients can also have high white blood cell and platelet counts. Some may have enlargement in the spleen. It’s not very common, but it’s possible. Too many blood cells in the circulation causes many problems, particularly circulation in the small vessels—so problems with the circulation in extremities—memory problems, visionary problems, hypersensitivity of the skin, and blood clotting. Many patients with polycythemia vera actually present, already, with a blood clot at the time of diagnosis. So, these are the factors, the symptoms, of circulation impairment leading to circulatory problems, blood clots—which can perhaps be trivial in a finger, but can also occur in the belly, heart, or brain—and abnormalities in blood cell count without any symptoms. Any of these would lead one to suspect to polycythemia vera.
Ruben Mesa, MD: The most recent diagnostic criteria for polycythemia vera are the World Health Organization 2016 criteria. The main change in those criteria over the past, is a lower threshold for erythrocytosis, realizing that—as a continuous variable—any number we pick as a threshold will impact sensitivity and specificity, depending upon how up or down we go on that value. But individuals need unexplained erythrocytosis and the presence of a mutation, and if this is the case, they likely have polycythemia vera. In addition, new diagnostic criteria do mandate a bone marrow aspirin biopsy. That criterion has been somewhat controversial. I do think that it is very helpful as a baseline. One may be somewhat confident of the diagnosis, even without bone marrow histology; however, I do think that it does have value, particularly in younger patients, as we like to get a baseline assessment of their cytogenetics and degree of fibrosis, as well as make certain there’s not an increase in blast cells at baseline.
There continues to be discussion around these diagnostic criteria, particularly given the issue of how much erythrocytosis is necessary for diagnosing the disease. This is for a variety of reasons. One, it is sometimes found by a red cell mass that erythrocytosis is present, and it is not obvious just with measurement of the hematocrit that these 2 things can be somewhat unrelated.
Second, the impact of iron deficiency has a variable impact on the degree of erythrocytosis—that can mask erythrocytosis in terms of developing the disease phenotype. Now, the JAK2 V617F is a very important part of that diagnostic process. We recognize, in 2017, that the vast majority of patients with polycythemia vera will have JAK2 V617F present. There is a much smaller number, 3% to 5%, that will have the JAK2 exon 12 mutation. Many commercial laboratories now will evaluate both, in sequence, in that diagnostic process. They’ll check the V617 at first, but if your diagnostic goal is to exclude polycythemia vera, they will typically reflex to then check the JAK2 exon 12. They are mutually exclusive, so there is really no great value in checking both simultaneously—it’s better to do it as a reflex test.
Srdan Verstovsek, MD, PhD: Elevation in the blood cell count, particularly red blood cell count, can exist without any disease in the bone marrow. Bone marrow is the organ that is sensitive to insults to a body. In the case of platelets, the platelets can be high because of iron deficiency. Red blood cells can be high because of lung problems, for example. If one has sleep apnea or is a heavy smoker, the lungs are unable to process enough oxygen for the body to function normally, and therefore the bone marrow will produce too many red blood cells that can be secondary to a relatively benign condition. It’s not malignancy. There are other conditions. Some are hereditary abnormalities in the sensing of the oxygen or producing of the cells in the bone marrow, and some are tumors of the solid organs—like kidney problems—that can cause elevation in red blood cell count. All of these factors need to be taken into consideration when we suspect polycythemia vera.
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