Challenges of Accurate Diagnosis of TA-TMA After Hematopoietic Stem Cell Transplant

EP: 1.Overview of Transplant-Associated Thrombotic Microangiopathy (TA-TMA)

EP: 2.Incidence of TA-TMA

EP: 3.Criteria for Diagnosing TA-TMA

EP: 4.Time Frame for Development of TA-TMA

EP: 5.Uncontrolled Versus Self-Limited TA-TMA

EP: 6.Risk Factors Associated With TA-TMA

EP: 7.Relationship Between TA-TMA Development and GVHD

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EP: 8.Challenges of Accurate Diagnosis of TA-TMA After Hematopoietic Stem Cell Transplant

EP: 9.Interventions Used for TA-TMA

EP: 10.Practical Experience in TA-TMA Interventions

EP: 11.TA-TMA Treatment: Alternative Medications

EP: 12.Role of Leptin in the MASP-2 Pathway

EP: 13.Narsoplimab: The Phase 2 Trial

EP: 14.Narsoplimab Trial Results

Samer Khaled, MD: That is a good segue to our next segment about the challenges of a prompt and accurate diagnosis of TA-TMA [transplant-associated thrombotic microangiopathy]. One of the challenges is to identify TA-TMA early in the course of the disease. It is key to identify it early, which again is challenging because different criteria have been used by different centers. We found that in our center, when you suspect a TA-TMA early and you act by withdrawal or modifying the dose of calcineurin inhibitor or sirolimus, you can reverse the course of the disease. While when it’s identified late in the disease, after the renal insufficiency, primary hypertension and all that, you enter an irreversible mold.

We used to have that joke, what graft-versus-host disease [GVHD prophylaxis] do you use, and when you say tacrolimus and sirolimus, then they say you must be an expert in TMA. When we have a patient on that combination, we are alert to look for these signs. In my experience and my colleagues’ experience at City of Hope [Duarte, California], once the LDH [lactate dehydrogenase] has increased above 1000 [IU/L] and you start to have refractory thrombocytopenia, it does trigger you to think, “Are we dealing with TA-TMA here or not?” And you start looking into the schistocytes and then other signs of TA-TMA.

In certain situations, it is very difficult because you have a lot of things going on at the same time. You can have infection; you can have graft-versus-host disease; in some situations you have relapsed disease as well. It can be quite difficult. Other conditions might occur that we don’t see that frequently, like TTP [thrombotic thrombocytopenic purpura], for which we send for ADAMTS13 [testing]. If it is more than 10%, then it’s assuring you that you are not dealing with TTP, and it is atypical a chance for TA-TMA. You then start treating according to that.

Maybe others can comment; I can start with Hari about how you suspect the TA-TMA in your center. What is the earliest presentation that makes you think about TA-TMA?

Parameswaran Hari, MD: No. 1 is you don’t see what you don’t look for, that’s the thing that I would tell all my colleagues at our center and who are watching; you have to keep that in the back of your mind. This is a diagnosis that is often missed. When you have a patient who is doing poorly for unexplained reasons, this is something that you have to keep in mind.

Then there are the classic features. When we have the classic features, it’s easier to make a diagnosis. The classic features clinically I would say are things like uncontrolled hypertension. I’ve heard it mentioned by many people that when you are adding on a second or a third agent to control hypertension, you need to think of what is causing this resistance, especially in a person who is not hypertensive coming in. We always use one agent for their calcineurin and then you use one more agent; when you have the third agent coming in, you’ve got to really worry about what’s causing it.

Our diagnostic criteria, starting with Vincent Ho, [MD,]’s criteria that were created at the behest of the BMT CTN [Blood and Marrow Transplant Clinical Trials Network] toxicity committee in 2010, all rely quite a bit on the hematological parameters. They all need some evidence of hemolysis, some evidence of red cell fragmentation as the cause of hemolysis, and ruling out of other things, such as normal coagulation assays and a negative Coombs test or something that tells us that this is not autoimmune hemolytic anemia, etc.

Then the Ho criteria are a little bit stringent in that you need to have some sort of renal injury or neurological dysfunction with that. Other people have tried to loosen those criteria to get in the earlier, worse TMAs, so that you can actually intervene early or you can do whatever you could do clinically to reduce the burden on the tissues. Those criteria, such as the Ho criteria or the probable TMA criteria, leave out the tissue injury part; that increases your sensitivity so you pull in more cases. However, you may then have a bunch of cases who are early TMA who may have just DIC [disseminated intravascular coagulation] or something that explains the schistocytosis, perhaps not really TMA that would have led to a consequence.

At this point the nebulousness of the diagnosis and the fact that many things can lead to the same picture; thrombocytopenia, increasing transfusion requirements, and unexplained renal proteinuria can all happen from other things. We have to consider those things, too. But unless you think about TA-TMA, you cannot intervene. This is a condition that can lead to severe mortality and morbidity if left unchecked for a while, and intervening early might help. We don’t have very strong evidence, but I think clinically we can say that early identification does play an important part. If we have drugs that work on it, as may happen in the next few months, then we can do something about it. Previously all we could do was change the calcineurin, stop the calcineurin, switch to steroids, and things like that.

The diagnostic criteria need to be tightened up, but that can only happen after we get a little more of a prospective series across multiple centers.

Samer Khaled, MD: All right, thank you.

Jeffrey Laurence, MD: I would agree, you absolutely must tighten the criteria. To diagnosis hemolysis and insist on having a low haptoglobin doesn’t make a lot of sense; haptoglobin is acute phase reactive. Your haptoglobin may be 200 [mg/dL], it’s normal, but it really should be 2000 [mg/dL]; that’s not going to work. This whole thing about requiring a negative direct Coombs [test] makes sense, however, if you have a multiply transfused patient, particularly if they’re second transplant, you may have a direct Coombs positive because of all those transfusions. I do not like that.

I do like requiring a normal PT [prothrombin time] and a PTT [partial thromboplastin time], because I don’t know how to diagnose an HUS [hemolytic uremic syndrome] like TMA or a TA-TMA in the presence of DIC. Take care of the DIC, then call me back. In terms of organ involvement, all the points that were mentioned about being more sensitive in terms of picking up renal involvement are great, however I would emphasize also the issue of hypoxia. Dr Hari, you may have mentioned that with lung involvement. We’ve seen several cases now. The very first case I saw that I reported as a case report was a young man who had unexplained pulmonary infiltrates and kept going through bronchial lavages and antibiotic treatment. Once we successfully treated his TA-TMA, they all disappeared. That was presumably his microthrombi in the lungs, which occurs frequently with atypical HUS like complement-mediated TMA; it’s virtually never seen with TTP.

You can also see GI [gastrointestinal] involvement; you may see some GI bleeding. You figure well of course, they have graft-versus-host disease in the gut. But maybe if you biopsied it you might find out that they really had TMA in the gut; that’s a symptom that we overlook.

Christine Duncan, MD: That speaks to an important point as well, and that’s the education of our colleagues. Our multidisciplinary teams are taking care of our patients. We spent a lot of time working with our ICU [intensive care unit] to try to talk and educate about TMA; we treat a lot of TMA, so they are thinking about that, too. They’re maintaining a high level of suspicion. You could argue, by the time someone is in the ICU for whatever reason or whatever multiorgan system dysfunction they’re having, maybe it’s too late and we’ve missed a therapeutic window. However, they’re thinking about it, and so they’re thinking to check the urine and look at other diagnostics. Educating the ICU has been helpful for us as far as identification. With no disrespect to our ICU, I’m not sure it’s been helpful for us as far as outcome.

The other piece to think about is the pathologist. We always sort of joke here that I could take a gut biopsy for a patient with an autologous transplant to our pathologist and you’ll get a diagnosis of graft-versus-host disease. This is not fair to the pathologist, certainly, but I think we also need to keep reminding them to look beyond GVHD. You may have GvHD in that gut, but do you also have TMA? We need to make sure we’re always looking for more than one thing, since they do reside together so frequently.

Transcript edited for clarity.