Risk of Thrombosis With TPO-RAs in Immune Thrombocytopenia


Comprehensive discussion on nuancing the risk of thrombosis with thrombopoietin receptor agonists in immune thrombocytopenia.


Morey Blinder, MD:Before we leave this topic, I would like to talk about thrombosis as an adverse event. I recall a number of years ago, I was at an ASH [American Society of Hematology] meeting where I saw 2 hematologists almost come to fisticuffs about how important thrombosis was with respect to TPO [thrombopoietin] receptor agonists. So, maybe I could ask just what are your thoughts, particularly with the oral agents and the risk of thrombosis? What do you tell patients, and do you change therapy if you're more concerned about thrombosis? Probably say a phospholipid antibody might make a difference or something like that. If you could just comment on the data. Danny, what are your thoughts on how you think about thrombosis with respect to the data for the oral thrombopoietin receptor agonists?

Daniel Landau, MD: Absolutely. It's definitely something that I mention to my patients. I don't know that it's an event that I've personally come across an issue with. The only issue that I can think of was in a postsplenectomized patient. In a patient who still has their spleen, I've really never come across a major thrombotic event. But I'll tell you where I use this slightly to my advantage. Whereas we consider an acceptable platelet count to be north of 50, typically, by the studies, many of my patients want to see their platelets in the 400 range just out of comfort. So, this is an area where I can say no, we don't want to overshoot. 200 is the highest we want to go. Thrombotic risk. So, I try to use that data to my advantage to make patients comfortable. Since my patients see their labs before I see their labs, I don't want to have a panicked phone callthat the platelets were only 55 or 60. So I try to use it to my advantage when I can.

Morey Blinder, MD:I think that makes sense. And are there any other settings where you would worry particularly about thrombosis other than maybe post-splenectomy that would maybe shy you away from one approach versus another?

Daniel Landau, MD: I'd imagine maybe a patient who's had extensive thrombotic events in the past, maybe with or without a known hypercoagulable stage. It will at least make me think for a moment. But generally speaking, I feel comfortable with the use of the TPOs despite that risk.

Morey Blinder, MD:That seems fair. I think the risk is small, but always striking. In the randomized studies, there didn't seem to be an increased risk, but it did persist to have some low level of thrombosis throughout the long-term use of the bone receptor agonists. Yes?

Howard Liebman, MD: If I may comment.

Morey Blinder, MD:Sure.

Howard Liebman, MD: First of all, there are several large registry studies done, the United Kingdom and the Danish registries, that show even before we had TPO [receptor] agonists, the risk of thrombosis was higher in patients [with idiopathic thrombocytopenic purpura] compared with HMS controls and population base studies, mostly venous thrombosis. It runs about maybe 1.5- to 2-fold higher. More recent data from a combined Danish and French registry combination puts it even higher than that. Now, whether that's from TPO receptor agonists or more aggressive treatment, I don't know whether better data sets. So inflammatory diseases and autoimmune diseases. Inflammatory disease was in a study about fatigue in ITP, and Jim Bussel [, MD, Weill Medical College, Cornell University] and I reported that in a blinded study, you could link up the fatigue analysis report with the levels of interleukin [IL]-6 in a blinded study. He sent me the samples, we ran them in my lab, we get sent back the IL-6 and he correlated with fact fatigue analysis and SP36 analysis. So yes, there's inflammation, and IL-6 is a very prothrombotic cytokine. It raises factor VIII, and suppressed protein S. So, let's just say an ITP patient's going to have an increased risk. If they're post-splenectomy they may have a higher risk, at least in population studies.

So the interesting thing is that the venous risk doesn't seem to be activated. [A study from Norway was published] with platelets that showed that patients on some of the TPO receptor agonists didn't seem to increase their D-dimers. If that's proof, I don't know. So, if you use it and you get a platelet count that's in the reasonable range, where in the randomized studies it comes out that if you have older patients and the platelet counts are higher, you saw a shift towards arterial events. That's probably if you have bad blood vessels from diabetes and heart disease from too much McDonald's and a little bit of smoking, yes, that's a group I want to keep them at 50,000. In terms of the venous events, they occur at low or high from the clinical trials, a few venous events. So, I think you just can't predict the venous events, but I think it's still safe to say. I tell patients 50,000 to 100,000, you don't need a normal platelet count. Unless you're going for brain surgery, we'll get it higher, but if you're just walking around day-to-day, not do double…you're going to do great on 50,000 to 75,000 to 100,000, but you don't need 200,000 platelets. And I think most patients when you talk about it, spend enough time explaining the risks individually, that their risks as you look at them, will settle for the platelet count that you think's the best for them.

Morey Blinder, MD:I think the way I've said it to patients briefly, Howard, is we don't need a perfect platelet count. We need a safe platelet count and depending on the patient that varies a little bit. But we're not shooting for the moon here and I think that does help with respect to thrombosis.

Transcript edited for clarity.

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