Listen to this audio podcast with MPN experts Anthony M. Hunter, MD, and Douglas Tremblay, MD, as they discuss prevalence, risk, and types of thrombotic events associated with PV and ET.
In this episode, hear Anthony Hunter, MD and Douglas Tremblay, MD discuss the various presentations of thrombotic events in patients with PV or ET including how thrombotic events may lead to diagnosis:
Program faculty:
Anthony M. Hunter, MD
Associate Professor, Department of Hematology and Medical Oncology
Leader, Myeloproliferative Neoplasm Program
Medical Director, Rollins Immediate Care Center
Winship Cancer Institute of Emory University, Leukemia Group
Atlanta, Georgia
Douglas Tremblay, MD
Associate Professor of Medicine
Division of Hematology/Oncology
Tisch Cancer Institute
Icahn School of Medicine at Mount Sinai
New York, New York
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Dr. Douglas Tremblay (Mount Sinai School of Medicine): Hi, my name is Douglas Tremblay, and I am from Mount Sinai School of Medicine in New York City, where I am an associate professor with a focus on myeloid malignancies, including MPNs.
Dr. Anthony Hunter (Emory University): Hey, there. Anthony Hunter, associate professor here at Emory University in Atlanta, Georgia. Similarly, here I lead our MPN program and really focus specifically on treating MPNs in the clinic as well as my research focus here.
Dr. Tremblay: Great. Thanks so much. Dr. Hunter, can you describe what are thrombotic events and how do they relate to the diagnosis of PV and ET?
Dr. Hunter: Yeah, absolutely. Thrombotic events really are the number one complication or issue, so to speak, that was always historically been the concern here with MPN diseases. They really do come in a handful of different flavors. We certainly see a number of arterial events. This is going to include things like ischemic strokes, cardiovascular events like heart attacks, unstable angina, and things as well. Your typical arterial type events that we can see.
Obviously, those can be a little bit more challenging. They are not necessarily unique, of course, MPN diseases. We see these as a leading cause of death, certainly in Americans and in adults in general. They are quite common, but certainly a key event that we see in MPN diseases. Then beyond that, we also see venous events. A deep vein thrombosis, DVT is occurring in the lower extremities, pulmonary embolism or PE when those go to the lungs.
Again, relatively well-known events, but certainly both arterial and venous events are increased across MPN diseases. Which one is more common varies a little bit from study to study. Maybe a little bit more common for arterial. Again, that represents probably a little bit the age too that we see in MPN diseases. Certainly, older patients. That is a risk factor as well, and I always talk to my patients about all these other things that are factors for the average patient who does not have an MPN for heart attack and stroke. Things like high blood pressure, diabetes, cholesterol, really, still factors here for MPN patients and things to think about as well in these patients.
Now, beyond these more dramatic events, we do see some more vascular symptoms sometimes as well. Certainly, with TIAs, a version of arterial events and strokes, but also more just non-specific symptoms, more atypical chest pains, and things like that. Then of course, we have this relatively well-defined, although not super common clinical symptomatology of erythromelalgia. That is something that has been reported for a long time in MPN diseases is episodic, burning, tingling, redness, etc., often in the palms and the soles of the feet and can last anywhere from minutes to hours. This is not the only cause, but certainly, we see quite a bit in MPN patients as well.
When we think about these events, certainly the risk varies from disease to disease. MPNs are a family of disease, not one individual entity. We can certainly see variation, typically think of PV or polycythemia vera is probably the highest overall thrombosis risk followed by essential thrombocytosis or ET.
Certainly, these are some of the major events in clinical manifestations that we worry about in patients with these diseases. Myelofibrosis, of course, one of our other classical MPN diseases, we do not always think about thrombosis as much. We have a lot of other issues to think about with myelofibrosis, but that does not mean they do not clot. We certainly see thrombotic events in these patients, but certainly overall incidence for patients having clots is definitely lower in myelofibrosis than we see in PV and ET.
Although, certainly there are clinical features like thrombocytopenia and things that may contribute to that. Some of that, is just that myelofibrosis patients, the survival is less than half of that of PV and ET. They are just not always living as long and accumulate these events over time as well.
When I think about these thrombotic events, we talk about risk that tends to vary through the course of the disease as well. Hopefully, when we have patients on therapy, we are helping mitigate that risk. We do see in a lot of these studies, up to half of these events are really occurring as the presenting feature at diagnosis or in that preceding year, a couple of years up to the diagnosis standpoint when that disease is probably there but not diagnosed yet. We do see a lot of these events happening earlier preceding the diagnosis.
We talked about these arterial venous events, but it is also worth pointing out that we see some more unusual thrombotic events. I think heart attacks, strokes, DVT, there is something all of us as physicians see all the time. We see these more rare clots, things like cerebral vein thrombosis, for example, a little bit more unique areas of venous clots. That really should make us think about MPN diseases probably.
That is particularly probably true for splanchnic vein thrombosis. These mesenteric splanchnic vein thromboses that we can see. Dr. Tremblay, that is something that you had a great presentation at ASH this past year on the large cohort. Can you describe splanchnic vein thrombosis a little bit for us?
Dr. Tremblay: Great. Thanks so much, Dr. Hunter. Splanchnic vein thrombosis is really defined by blood clotting within the splanchnic bed, which includes the portal vein, the superior mesenteric vein, the splenic vein or the hepatic vein. A hepatic vein thrombosis is the syndrome called Budd-Chiari syndrome. It is one of the more, I would say, classic presentations of thrombosis and myeloproliferative neoplasms.
We know that patients who have an unprovoked portal vein or hepatic vein thrombosis, up to 40% of those patients will have JAK2 mutation identified. Really, anytime I see someone who has a splanchnic vein thrombosis that is unexplained, particularly, or maybe has a more dramatic presentation, 100% of the time, a JAK2 should be checked. That is the predominant mutation found in these patients is JAK2. Now the tricky part is that many times, because of the splanchnic vein thrombosis there is portal hypertension, which increases plasma volume. There can also be chronic bleeding. That classic PV and ET blood counts with erythrocytosis or thrombocytosis or leukocytosis, is often not seen.
There are other unique parts about MPN and splanchnic vein thrombosis as it relates to blood clotting in general, in that blood clotting is generally thought to be more common in older patients rather than younger patients, and often has a male predominance. In MPNs splanchnic vein thrombosis and our studies, about 60% of patients are female, and the average age is well below 60 and the median age is somewhere around 50.
If you have someone who has a splanchnic vein thrombosis, it really behooves you to check a JAK2. Many times a bone marrow biopsy is warranted to be performed even if the CBC looks normal, because you can be a masked PV where it looks like polycythemia vera under the microscope, but there is no high red blood cell count, no high hematocrit. It is really a unique manifestation of MPNs that I think all hematologists should really have their antennas up for whenever you see this. Especially in younger patients and female patients, this should really be a reflexive part. There is some unique management decisions that go along with that, too.
Whenever this presentation comes up, Dr. Hunter, when should a clinician suspect a myeloproliferative neoplasm in someone with a new blood clot or new thrombosis?
Dr. Hunter: Yeah, that is a good question. I think, certainly, recognition is key here. I think we see, as MPN physicians, a lot of folks who probably had an undiagnosed MPN for years potentially, before they were really fully diagnosed potentially. I think, obviously, as you just alluded to presentation is certainly a key one. I think it is a little bit harder when a 70-year-old patient comes in with a stroke to really be thinking right away about MPNs, but when you see these more rare clots, unexplained Budd-Chiari, these splanchnic vein thrombosis and the absence of liver disease that we know is a risk factor for it. As you mentioned, everyone really deserves a workup at that point for an MPN and a JAK2 mutation.
I will add maybe especially in the cohort of young women, certainly with dural, venous, or cerebral vein thrombosis is one where I lump into that as well, and will often think about that. I think certainly these atypical clots are a key one. I think the other is just really important to look at the CBC and look what the blood counts look like. MPNs obviously, by their nature, obviously with some caveats, as you point out in some of these splanchnic patients, but certainly, we are going to expect to see abnormalities in the CBC. They may not always be that dramatic, and they can be affected by other things. When you are seeing someone with a new clot and has an abnormal CBC, obviously, erythrocytosis in particular for our PV patients, thrombocytosis across these MPN subtypes, even leukocytosis. Leukocytosis we see in these diseases. We see in myelofibrosis and MPN-U and things like that as well. Recognizing even subtle blood count abnormalities is important.
I think that is tricky because you do not always want to jump to a new diagnosis on top of a blood clot. What I have often done too is look back. What I often see is these patients who are at that point have abnormal blood counts is that even if it was very mild, they maybe had some slightly abnormal blood counts before. If you say six months ago at their primary care visit, they also had platelet count of 520. Like maybe there is something to this. It is not just a reactive thing going on in the setting of their clot. I think that is certainly key.
As you mentioned, JAK2 the particularly common one that we think about with things like splanchnic vein thrombosis. I think obviously, well recognized now in the past decade, is this entity of what we call clonal hematopoiesis or CHIP. We know JAK2 is one of these more common mutations that we see where we have got some percentage, especially of the older population that are out there, healthy, normal blood counts, but walking around with JAK2 mutations.
Even though they have normal blood counts, just that mutation being there does increase their thrombosis. We see across the board that clonal hematopoiesis does increase, particularly cardiovascular risk, and JAK2 of all those genes, probably the highest among all of those, as well as increasing some venous events. So, so certainly something to think about as well that is probably under-recognized but widespread entity, especially over 70 or 80 years old. We are talking about 10%, 15% of folks walking around in the population have these type of mutations.
As we have talked about diagnosing and recognizing MPNs and things in these cases, but can you share for us, Dr. Tremblay, maybe some cases from your clinic that someone presented with a thrombosis found to have an MPN, maybe some good representative examples for us.
Dr. Tremblay: That is great. I went ahead and reviewed some cases I saw in the last week. One was a middle-aged man around 45 years old who did not have many cardiovascular risk factors, but suffered a myocardial infarction and had to have a stent placed. Then, during that hospitalization had a thrombosis, a PE at the same time. During the hospitalization, the white blood cell count was around 500 to 600, and the inpatient team at the local hospital did not really make much of this because it was in the setting of these acute events.
After the discharge from the hospital, the patient has been treated with antiplatelet agents and anticoagulation. The platelet count was still in the 500-600. They referred to a hematologist who identified a JAK2 mutation and a bone marrow biopsy was performed that showed essential thrombocythemia. This was a case of someone too where actually, I looked back at some of those old records, and his platelet count had hovered around high 400s, low 500s for a number of years. Just like you mentioned before, Tony, was having some history of abnormal blood counts in the past.
The other one is a really classic one that I see in my clinic, which is a young female, a nurse who had abdominal pain and then swelling in her abdomen and went to the hospital and was diagnosed with a hepatic vein thrombosis on CT scan. This was someone who had normal blood counts. The hemoglobin was actually slightly low, slight anemia. Because of that known association, when they were in the hospital here, we checked the JAK2. They had a JAK2 mutation that was very low frequency of about 30%, and we did a bone marrow biopsy which diagnosed a myeloproliferative neoplasm unclassifiable. Meaning it looked like an MPN but did not meet the count criteria for any of the other ones. These were two thrombosis presentations of MPNs.
Dr. Hunter, do you have additional cases you would like to bring up?
Dr. Hunter: I saw a patient this week, a woman in her 60s who basically was incidentally found out the hemoglobin actually of 24.9 medical was 75%. Very, very high hemoglobin and in retrospect had symptoms, this facial plethora, this classic finding of PV, pruritus, and things like that for years. It really went undiagnosed for quite some time. Even looking back four or five years prior to her diagnosis, she had a hemoglobin in the eighteens. She had met the criteria probably for PV for a long time now. Thankfully, she was fine. She got some phlebotomy, she got some treatment and felt better, and has never had a thrombotic event in a few years of diagnosis right now.
I have a case that jumps and sticks out to me a lot that I saw last year that I always often think about. When I teach my fellows and residents and med students about MPN here, use this as an example. If we had an older gentleman who really his presenting feature was a catastrophic left MCA stroke. He came in aphasic, complete right-sided paralysis, basically hemiplegia. On that presentation, hemoglobin was 17-18, platelets were in the 600s. So, pretty quickly, obviously the hematologists at that point diagnosed him with PV. This is another one, when we looked back, he’d actually had hemoglobin and hematocrit that had met the threshold for PV diagnosis for eight years at that point. Not once, we are talking about repeated values of various primary care, urgent care, whatever incidental reasons, that no one necessarily acted on.
I see this all the time in my clinic, and I think that was a challenging one because this is one where it would have been lovely if we could have caught it early and done things to mitigate that risk. This is a gentleman, catastrophic stroke that he never recovered and ultimately died in the next year. I think it represents A, the potential severity that these events can have. That is someone dying from complications of a disease like PV where we sometimes hear about these earlier PV, ET diseases that, in the oncology clinic, maybe are not the biggest concern, the most aggressive disease, but they can be when they present like that.
I think it really focuses on that need to recognize these a little bit more uncommon diseases, certainly in hematology clinics. A lot of these folks do not initially present to heme. They are seeing primary care doctors or seen in the hospital and things like that, too. I think it highlights that prevention is sometimes key here. Obviously, we are talking about diagnosis and treatment for thrombosis, but prevention is a big part of that in my opinion, too. Once we can establish a diagnosis like this, but that really requires us to make that diagnosis first and then act on that to try to mitigate that risk. That is certainly a key thing to think about when we think about MPNs and thrombosis.
Certainly the bigger focus here, of course, is more on, actually diagnosis of thrombosis and treatment. Dr. Tremblay, can you talk a little bit about once you have diagnosed the patient with a thrombotic event, and how do you manage this and maybe differences in venous versus arterial events for us?
Dr. Tremblay: Thanks so much, Dr. Hunter. Someone with the venous thrombosis just like any other venous thrombosis, anticoagulation is the mainstay of therapy. We have options here, including low molecular weight heparin, as well as warfarin, and direct oral anticoagulants. There is increasing data, although these types of thromboses with MPN related were not necessarily included in a lot of the registration trials, there is now, I would say, a chorus of data from the real world suggesting that direct oral anticoagulants are safe and effective in MPN patients. Anticoagulation should really be instituted in patients with venous thrombosis.
Now, how long is always a question and, from most practices, including mine, is that because the initiating event of a blood clot was started because of the MPN and because MPNs are generally incurable without a bone marrow transplant, anticoagulation should really be given indefinitely. Sometimes after six months or a year, I will reduce the dose but, because that JAK2 mutation or calreticulin mutation or MPL mutation is still present, I do not think it is a good idea to stop anticoagulation after someone has started it for a venous thrombosis.
Now, antiplatelet therapy for arterial thrombosis is often managed by the cardiologists or neurologists who are managing that, which is a whole topic in itself. I spend a lot of time too, talking about the importance of cardiovascular risk modifications, including things like blood pressure control or anti-cholesterol medications, active exercise and dieting to try to reduce any additional risk factors for cardiovascular events.
Once someone has a blood clot in MPN, no matter what risk stratification system you are looking at, they are automatically high risk. When they are high risk, they really need to be treated with cytoreductive therapy. There are several options, and it depends on the disease and the availability, the patient profile, the side effect profile, and the choice for standard active therapy, it could be its own podcast itself and would include choices that include hydroxyurea, ropeginterferon alfa-2B, ruxolitinib, anagrelide. We are not going to speak too much about this, but that to say that cytoreductive therapy after someone has a blood clot really needs to be instituted to prevent the risk of another potentially even more catastrophic thrombosis from occurring.
We have covered a lot today. Dr. Hunter, as we wrap up, do you have any key takeaways to leave the listeners with?
Dr. Hunter: I will add to cytoreductive therapy for these high-risk patients who have not had a clot yet. Again, getting to the prevention side of things here too, of hopefully we can try to avoid these big clinical events in the first place.
I think key things obviously, we have talked about is you just got to think about MPN. We certainly want to think about these and these unexplained, especially unique clots. These splanchnic veins that you have done a lot of work in and have talked about for us here, cerebral vein thrombotic events, and really just thinking about the diagnosis. You got to think about it to make the diagnosis right and to be able to manage these diseases. I think that is certainly key.
Obviously, that next first step usually is, in particular JAK2, but we will say MPN driver mutation as a whole. Certainly, JAK2 is the driver for PV. It is really a disease of the JAK2 mutation. But we do see these other mutations. CALR and MPL and ET. So, it is important to think about more broad testing. We even see triple negative ET patients, and really requires a bone marrow biopsy to make that diagnosis in particular.
You really want to be thinking about the diagnosis, starting some of that testing to look into it, and thinking about that, especially when we find these patients who do have even subtle, but sometimes preceding lab abnormalities and things as well. It really should be a red flag that something has been going on and leading to that event.
I think again, as you pointed out, obviously, the anticoagulation is certainly key. Data is a little all over the place there and sometimes limited since a lot of our patients have not been included in bigger trials. As you mentioned, good real-world data, but cytoreductive therapy is key. I think we know that it is going to work separately of anticoagulation therapy, both in high-risk patients to prevent initial events, and patients who have had a diagnosed event. We know it is going to decrease recurrence risk. It is really key to treat and think about the appropriate patient for cytoreductive therapy. Risk stratification is probably overly simplistic in PV and ET, but we know that clotting event is a huge one no matter what MPN you have. That alone is really any patient needs to be on cytoreductive therapy after that.
I think, really big challenge is just the recognition, suspecting the diagnosis. I think obviously, Dr. Tremblay and I are both biased in the sense that all we do is see MPNs. It is easy for us to think about these events to make that diagnosis, to do the work up, but if you do not do that every day, then it is not always. That is true for heme-onc doctors who are treating everything in clinic, which is certainly a challenge with the number of diseases and data that we have in oncology now. Even more so, I think, for primary care doctors, for hospitalists, emergency room doctors, which, in reality, that is really the first line for a lot of these patients. They got to be able to get referred to me in the first place for me to work them up. We need non-specialists who are really the frontline of medicine for us and frontline for these patients, and MPNs can be hard to recognize. These are rare diseases in the grand scheme of things.
I will send it back to you. Dr. Tremblay, for any last thoughts and things that you have for us.
Dr. Tremblay: Thank you so much. It is always great to talk to you, and I really appreciate this discussion on thrombosis, which is the leading cause of mortality and a huge cause of morbidity, which we have really discussed today. I think it is an important topic. I really appreciate the conversation today. I hope the listeners were able to learn a lot from what we spoke about. Thanks so much.