Time Frame for Development of TA-TMA


The expert panel considers the time frame of transplant-associated thrombotic microangiopathy, the subtle signs to pay attention to, and testing for proteinuria.

Samer Khaled, MD: Let’s talk about the time frame for the development of the TA-TMA [transplant-associated thrombotic microangiopathy] and when we expect to see the TA-TMA. Christine, do you want to start?

Christine Duncan, MD: Sure. This is probably 1 of those areas where between adult and pediatric transplantation we have consensus and it’s not so different. I was just going to say in that last conversation, we see TMA [thrombotic microangiopathy] in autos all the time. That is more related to a disease process in the patient with neuroblastoma who has been very heavily pretreated before coming in. But we certainly see it in allogeneic patients and those with GVHD [graft-vs-host disease] as well.

In my experience, while you can find reports of TMA past day 100, you can see people report that most significant TA-TMA is happening in that first 20 to 100 days after the transplant. That’s where we see the TA-TMA that we feel most compelled to treat because of the severity. That may be because of the convergence of multiple things happening in those patients at the same time.

For at least us in pediatrics, what is similar to what we see in the adult population is that during that real acute and subacute period of transplant is where you’re experiencing that highest risk. Would you agree, Dr Hari?

Parameswaran Hari, MD: Yes, absolutely. Even when I’ve seen it after 100 days, it’s always in the context of GVHD. When I see it before GVHD, it’s almost always within that first 100 days, especially in the hospitalization period immediately after the transplant.

It goes back to the pathophysiology that Dr Laurence explained. If you have an endothelium injury and then a T cell needs the endothelium and you already have immediate complement damage, then that usually happens in the type of the postconditioning injury when you have a turnover and allo-reactive T cells coming in; that probably speaks to that. The other common side is that the patient is most closely monitored in that period. That’s the time when we are seeing hypertension, LDH [lactate dehydrogenase], histiocytosis—everything happened.

Jeffrey Laurence, MD: I agree, with 1 caveat of that last point: It depends on how closely you’re monitoring the patients. In the first 100 that I described, our earliest case was 30 days, and our median was about 90 days after the transplant. But we had a couple of people out at 200, 250 days. When you look through their charts, you realize a couple of months before they were officially diagnosed with their TA-TMA, they had unexplained hemolytic anemia. Because there was no organ failure, no issue other than a couple of schistocytes were just not worked up to the extent we would now with more recognition. So yes, I agree.

Christine Duncan, MD: Dr Laurence, is that patient population in that series? In that series, did you see different presentations of the patients, whether they were more proximal to the transplant or more distant in that post-100 days period of time?

Jeffrey Laurence, MD: Yes, but that depends on how closely they were followed. The ones that were more proximal that period had really high LDHs that no one could figure out, had pulmonary infiltrates that were unexpected that didn’t appear to be infectious, and had serum creatinines because that’s what people were measuring. The later ones also had dramatic things happening. When you went back to the chart, you realize that the subtler things that we should be paying more attention to should be a part of the basis: new proteinuria, new hypertension. We could have diagnosed a number of them earlier.

Samer Khaled, MD: I want to ask the panel: Do you do proteinuria or urine tests frequently in your transplant patients? Dr Hari?

Parameswaran Hari, MD: Honestly, no. I try to diagnose TMA early as much as possible. One thing I do is monitor the LDH fairly closely. Because the schistocytosis being is a little subjective and the smears are not uniformly seen or inspected by the same level of expertise each time, I really don’t pay that much attention. If I see it, obviously it is to be taken into consideration. But if you didn’t see schistocytes but a patient has hypertension or the patient’s creatinine is the same, we see a lot of muscle wasting, so the creatinine can actually be falsely normal during this time.

In the setting of hypertension, I always do a protein check to pick it up and discount the creatinine and the schistocytosis a little compared with the established guidelines.

Samer Khaled, MD: Jeff, do you do proteinuria at Weill Cornell Medicine?

Jeffrey Laurence, MD: No. As Dr Hari said, it’s not something we follow regularly. If we see something else that makes us suspicious, then all of a sudden you have a urine analysis. When I was going back to our patients to try to find urine samples and whether protein was measured, it was very infrequent. It’s a message that maybe we should be checking it more frequently.

I agree with the comment about schistocytes. Not only is it subjective, but you can have evidence of TMA in tissue if you’ve all been doing a renal biopsy, and that doesn’t appear in the peripheral blood. If you’ve got good reticuloendothelial cell and good splenic function, you’re just sopping up those fragmented red blood cells, and they don’t appear in the periphery. We also see that in cases of regular atypical HUS [hemolytic uremic syndrome] where the patient may have sky-high creatinines, yet we don’t see the schistocytes for some period of time.

With schistocytes, if you see it, that’s wonderful. If you see a change, that’s wonderful. But it shouldn’t be something that would be the sine qua non of saying something is a TA-TMA vs isn’t.

Samer Khaled, MD: Unfortunately, we don’t check for proteinuria routinely, and the schistocytes reported. It used to be reported more consistently, but now it’s done more randomly. You have to actually ask for the peripheral smear and check it yourself.

Christine, in pediatrics you probably are much better than in the adult population, and you check for proteinuria more often. How is the schistocytes? Is it reported routinely in your center?

Christine Duncan, MD: It’s yes and no about the urine. We’re really good in the hospital. When someone is hospitalized, it’s very common for us to have a urinalysis done once per shift, or at least once per day. That certainly depends on the different hospitals. We’ll look, and so you’ll pick that up all at the time. Like Dr Hari, we look at LDH twice a week. You’re trying to put together all these pieces of the puzzle to figure out what’s sensitive, and if you see 1 then you look for the other.

One of the things that can happen is it can be really easy to try to explain away 1 finding. Someone with hypertension is going up because they’re on steroids, because they’re on GVHD, because of their calcineurin inhibitor. When you put all these pieces together, you see a clearer picture.

We had the same schistocyte issues everyone else does. You have to go and look at the smear. Some techs are great at reporting them, others are not. When we see it, that is more of a red flag than anything. Not necessarily because it’s a more sensitive finding, but because once you rise to that level and see it routinely, that means something about the screening.

Outpatient is a little trickier to get our urine. This is where adult patient populations may have a little advantage, trying to get your patients to provide a sample on demand. An adult patient may be a little easier than trying to do that, say in a 4- or 5-year-old. If we have concerns, we know there are tricks to try to get that as well. In hospitals, our urine screening is great. Outpatient, we could do better.

Transcript Edited for Clarity

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