Criteria for Diagnosing TA-TMA

Samer Khaled, MD: Christine, what criteria are you using? The BMT-CTN [Blood and Marrow Transplant Clinical Trials Network] criteria or the Sonata Jodele criteria for diagnosing TMA [thrombotic microangiopathy] at your center?

Christine Duncan, MD: We use the Jodele criteria at our center Dana-Farber Cancer Institute. We’re looking if you can meet 4 of 7 criteria. As Dr Hari mentioned, most of those are hematology based. But you are looking for proteinuria in there, which is important, and the lack of coagulopathy, as Dr Laurence has mentioned.

I will say quite honestly: We think about those criteria, but we don’t necessarily always say you have to meet all those points. If you have someone who has hypertension and proteinuria, we’re not going to wait and check everything else off to make sure they absolutely fulfill the criteria. Criteria are really important for studies. Criteria are really important if you don’t have a high level of suspicion. But we also try to use clinical expertise while using the criteria while thinking about the components of the criteria, rather than trying to use them as sort of a checkbox.

There is relatively uniform acceptance of the Jodele criteria used in pediatrics. We have a smaller number of transplanters, a smaller number of patients being transplanted, and most of us are using the same criteria. That may lead toward a higher awareness of the disease because those criteria were developed so strongly in pediatrics. It may also mean that we are picking up on patients. We’re all picking up on similar types of patients because we’re using those same criteria.

That’s 1 of the differences in pediatrics. That difference between auto transplant and allo [allogenic stem cell transplant] is unique, and we’ll talk about that when we get to risk factors. Why do we see TMA with pediatric patients, probably the highest in some of our auto patients compared with our allos.

One of the things also comes down to awareness. We looked at our patient population. We had an investigator here at Dana-Farber and Boston Children’s Hospital who looked retrospectively at our patients to find out who was actually diagnosed in real time by the providers and who actually met criteria. Looking at shell criteria, you’re looking at Jodele criteria. We found actual incidence of diagnosis in real time by providers of roughly 8% and 25% to 30% of patients who actually met criteria.

Part of the issue is the criteria are as good as we can get until we have really clear, rapid actual screening tests that we can use. They are a sensitive criteria; if you have TMA you’re probably going to screen positive. They may not be the most specific criteria, so if we’re following only criteria, we may be diagnosing people with TMA who meet criteria but perhaps have a different contribution to their disease or to their symptoms.

There are real differences. Most pediatricians or most pediatric studies that I see are roughly around the 20% to 25% criteria rather than the 30% that we’ve seen in certain papers. We all respect, the work that’s come out of Sonata Jodele and Cincinnati, we’re still trying to learn. One of the challenges is we look at large databases and registries trying to learn about incidence, and it’s just really hard. When you look at CIBMTR [Center for International Blood and Marrow Transplant Research]–type data, it’s not the perfect tool because people are all screening differently and people are reporting differently. What we do need are large prospective studies and screening studies to get at the incidence a little better, in both the pediatric and adult populations.

Parameswaran Hari, MD: I totally agree. It’s 1 of these eye-of-the-beholder-type situations. The other thing is, how stringent: What are you looking for in your population? In our ward a few years ago, we instituted that patients should have an LDH [lactate dehydrogenase] checked twice a week during their transplant at in patients.

We pick up a little more, and I find that’s not common across centers. How many times you are adding on antihypertensives to the patient but not failing to check a protein in the urine, a spot protein creatinine ratio, or something like that.

If you are tuned to picking it up, you will diagnose a little more.

Christine Duncan, MD: You’re right.

Jeffrey Laurence, MD: You both have stressed important points that we’re going to get to again. If we can get an earlier diagnosis we therefore can get an earlier treatment and we hopefully will have better outcomes than some of the historical outcomes so that in the adult population we’re all just looking at serum creatinines, but in many of the pediatric series, they’re taking into account a degree of proteinuria and the development of new hypertension, and the serum creatinines can be completely normal.

Another thing, getting back into the discussion of pathophysiology, which may be different between pediatrics and adults, is that at least in the Jodele series she thought she had a genetic fingerprint for the development of a TA-TMA [transplant-associated TMA]. Upward of 30% to 40% of her pediatric patients who developed the TMA had some recognized mutation in a complement coagulation or complement-regulatory factor gene. Whereas in our studies at Weill Cornell Medicine, we never found that. In many other series in adults, it’s incredibly rare to find those kinds of genetic mutations. There may be something special about that population with higher underlying inability to control complement that makes the incidence much greater.

Samer Khaled, MD: I agree with all of you. In 1 of the retrospective analysis at City of Hope, we analyzed about 170, and the incidence was around 17%. It could also be, as Christine alluded to, that it depends on what you are using and who is treating the patients. We tend to have tacrolimus and sirolimus as the backbone graft-vs-host disease for prophylaxis. This combination is known to have a little higher TMA incidence.

That will probably be the range; it’s 10% to 20%. I’m aware that there are national efforts to have a multi-institutional retrospective study to characterize the TA-TMA and the incidence will be 1 of those important characteristics.

Samer Khaled, MD: Is there anything in the patient presentation that makes you investigate further the case for TA-TMA in pediatric populations?

Christine Duncan, MD: In looking for it, it can be done in different ways. For us in pediatrics, particularly when you don’t have a lot of patients who come in with preexisting hypertension, we expect to see a certain degree of hypertension due to your calcineurin inhibitors, your steroid, etc. Hypertension is a big flag for us.

The other thing that’s pretty simple that’s made a big difference is just routine LDH screening once or twice a week. You don’t even have to think about it much if that is part of your routine on an inpatient, and if you see that with your lab values, that helps to trigger.

The same with urine, although we’re still trying to improve at looking at the urine as often. The urine is there, but you have to take the time to look at that urine. It may even be something as simple as where LDH resides and where you look at your labs. You see that if that number is high. Whether or not it turns out to be TA-TMA, if you have a significantly elevated LDH, you’re going to think about it and try to figure out why that is. Hopefully it will take you down that road to thinking about TA-TMA.

Samer Khaled, MD: Thank you, Christine. Jeff, are you using or do you send the ADAMTS13 frequently?

Jeffrey Laurence, MD: We send ADAMTS13s on everyone just for form. It’s a cheap test, and it can tell you right away. And it informs the head of our plasmapheresis unit that we’re not going to plasma exchange you for your TA-TMA and your transplant. We can talk about what response means to plasma exchange in the transplant setting later. We do it just to rule it out so that someone doesn’t force us to say we don’t know that it’s not TTP, so please exchange them.

Samer Khaled, MD: Is it the same thing, Dr Hari?

Parameswaran Hari, MD: Yes, it’s the same thing. We do it basically to say that this is not TTP. Unless it’s severely low, like 5% or something like that, we say no plasma exchange.

Transcript Edited for Clarity