Overview of Transplant-Associated Thrombotic Microangiopathy (TA-TMA)


Jeffrey Laurence, MD, provides an overview of transplant-associated thrombotic microangiopathy (TA-TMA), the associated risk factors, and the role of the complement pathway in TA-TMA development.

Samer Khaled, MD: Hello, and welcome to this OncLive® Peer Exchange® titled “Transplant-Associated Thrombotic Microangiopathy,” or TA-TMA. TA-TMA remains a difficult complication to address with a high mortality rate and a lack of standard diagnostic criteria and limited therapeutic options.

I am Dr Samer Khaled from City of Hope Comprehensive Cancer Center in Duarte, California. Actually, I am transitioning to a new position in the near future. I have the privilege to join my colleagues Dr Christine Duncan from Dana-Farber Cancer Institute in Boston, Massachusetts, Dr Parameswaran Hari from Medical College of Wisconsin in Milwaukee, and Dr Jeffrey Laurence from Weill Cornell Medicine in New York, New York.

Today we are going to discuss the contemporary management of transplant-associated TMA [thrombotic microangiopathy], including a novel approach that’s being considered by the FDA. I would like to start our first segment and talk about what TA-TMA. I would like to invite Dr Laurence to lead this segment.

Jeffrey Laurence, MD: Certainly. Thank you. TA-TMA is a thrombotic microangiopathy that occurs in a stem cell transplant setting. It can occur either with peripherally mobilized stem cells or with bone marrow–derived stem cells; the incidence seems to be the same. It is present in both adults and children where there is 1 difference: allogeneic transplants are generally the association in the adult setting, whereas both autologous and allogeneic transplants have set off a TA-TMA in the pediatric setting.

In terms of a brief overview of pathophysiology, we talk about 2 hits for the development of a TA-TMA. There are a lot of the risk factors for the development of this disease in these transplants; calcineurin inhibitors, mTOR inhibitors, radiation, certain infectious diseases, certain viruses such as adenovirus and cytomegalovirus, Aspergillus, potentially graft-vs-host disease, and extensive HLA. If you ask, “What do these risk factors have in common for setting off a TA-TMA?” They’re all involved with endothelial cell injury. That’s 1 hit, and you have endothelial cell injury.

However, we also feel that you possibly need other things to happen. The vast majority, if not exclusively, of the TA-TMAs involve complement activation and set off a TMA that is most reminiscent of another major complement-associated TMA: atypical HUS [hemolytic uremic syndrome].

This also indicates that TTP, thrombotic thrombocytopenic purpura, which involves the ADAMTS13 pathway, is typically not involved. If you measure ADAMTS13 levels, they’re virtually exclusively above the range that we associated with TTP; these are more complementary pathways.

The same things that injure endothelial cells—infections, radiation, and mTOR and calcineurin inhibitors—can also activate complement. That is very important in this disorder.

Let’s get back to complement. You have an endothelial cell injury; injured endothelium exposes certain molecules, known as DAMPs [damage-associated molecular patterns], which bind a molecule known as MBL, mannan-binding lectin. MBL then activates MASP2, which is an important enzyme in the cascade of a part of a complement system known as the lectin pathway. The reason why this is so critical is because when activated, the lectin pathway itself can also then turn on the alternative pathway of complement. It is always on at very low levels waiting for a foreign invader to happen, or for endothelial cell injury.

Now you have marked activation of the lectin pathway and the complement pathway and the alternative pathway of complement in this system. If you can’t shut it off and that’s progressive, that can lead to 1 of these TA-TMAs.

When you activate complement, break down C5 into C5a and C5b, which joins to C5, C6, C7, C8, and C9 to form a complex known as C5b-9, you have 2 things that are bad in terms of setting up a positive feedback loop to continue endothelial cell injury. C5a is also known as anaphylatoxin; it’s highly pro-inflammatory. C5b-9 is known as MAC, membrane attack complex. It injures endothelial further.

Also, by activating particularly the lectin pathway complement, we’ll come back to this theme throughout this discussion: MASP2, its premiere enzyme, can directly activate prothrombin to thrombin; you now have the complement pathway involved. You have this triple-header of inflammation, complement, and coagulation, with all 3 cascades activated in the presence of continued endothelial cell injury. If you can’t shut that off, you may progress to the disease we call TA-TMA.

Transcript Edited for Clarity

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