Video
Interventions Used for TA-TMA
Jeffrey Laurence, MD, reviews the available interventions used to mitigate or treat transplant-associated thrombotic microangiopathy.
Samer Khaled, MD: After a patient has received a diagnosis of TA-TMA [transplant-associated thrombotic microangiopathy], what different interventions do we use to mitigate or treat the TA-TMA? Jeff, may you start?
Jeffrey Laurence, MD: First, the easiest ones that we’ve all discussed: stop the calcineurin inhibitor and the mTOR [mechanistic target of rapamycin] inhibitors. We recommend substituting higher doses of steroids and CellCept [mycophenolic acid]. Then look for an infection and then treat as if there is one. Look for GvHD [graft-versus-host disease] or an exacerbation of GvHD and attempt to treat it. If the patient is hypertensive, consider it a sign but use appropriate antihypertensive therapy.
We do not do plasma exchange anymore. In a review that I wrote a few years ago, I noticed that in 3 large transplant studies the aggregate hematologic response to plasma exchange in a TA-TMA was 55%; that included a decrease or normalization of the LDH [lactate dehydrogenase], increase in haptoglobin, and increase in platelet count. That 55% response rate to plasma exchange had [no] impact on mortality in this group; it was around 20%; despite all the plasma you wanted to give these patients, the patients died with normal numbers. The plasma exchange does nothing for the underlying condition, and we don’t know for certain why there is that hematologic response to plasma exchange in the TA-TMAs, with analogy to what happens in atypical HUS [hemolytic uremic syndrome].
In atypical HUS, before you’ve made the distinction between TTP [thrombotic thrombocytopenic purpura] and HUS, every patient gets plasma exchange. This is a good therapy to do for TTP; it’s one of the hallmarks of an effective therapy. It’s a very reasonable process to do for atypical HUS because there’s a complement factor H and complement factor I in fresh frozen plasma: the 2 most commonly mutated proteins in atypical HUS that you’re temporizing. You really are affecting something; you’re not doing anything for the underlying condition; however, until you figure out whether it’s TTP or HUS, do plasma exchange.
That’s not true in the transplant setting; you need to go on to more effective therapies. Again, if you don’t respond to a simple intervention to treat the underlying condition (the infection, graft-versus-host disease), stop the calcineurin and the mTOR inhibitors, then we start thinking about other experimental therapies. In the old days, people tried heparin to combat thrombotic disorders; that’s not a good idea. There are actually a few case reports of responses to heparin in the literature; the best anyone can figure out why someone might get a response to heparin in complement-mediated disease is heparin is like a poor man’s anticomplement therapy. Heparin can inhibit complement activation to some extent, so that could be a possible explanation.
Otherwise, in terms of a role for anticoagulation in these patients, we really don’t see it. Then we’re left with considering what the pathophysiology of this disease is; I know we’ll talk about this later, but it’s a complement-mediated disease in many cases, so people have tried anticomplement therapies. Eculizumab is [approved by the] FDA for the treatment of atypical HUS. We and others have certainly used and published on eculizumab and this disease. That affects the complement system. As we also mentioned, in terms of talking about pathophysiology, the coagulation system is also involved in this disorder.
That brings us back to the [question] of could you attempt to both intervene in the activation of thrombin and the activation of the elected pathway of complement; that’s why narsoplimab, an anti-MASP2 antibody, is being used experimentally....
Finally, there are case reports of the use of defibrotide in this disorder. Defibrotide is FDA approved for veno-occlusive disease [VOD]. Veno-occlusive disease has been associated with complement activation. Defibrotide may also have some antiplatelet activity. Platelets are activated in this disorder, so some people experimentally have looked for a role for that.
Samer Khaled, MD: Right, that’s what we also try to use in this population. After we discontinue or manipulate the dose of tacrolimus and sirolimus, we try to pay more attention to the comorbidity or any other concurrent condition, such as infections. We need to treat infections and graft-versus-host disease.
Transcript edited for clarity.
