Abstract

Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial damage syndrome that is increasingly identified as a complication of both autologous and allogeneic hematopoietic cell transplantation (HCT) in children and adults. The pathophysiology of TA-TMA is complex, resulting from a cycle of activation of endothelial cells to produce a procoagulant state, along with activation of antigen-presenting cells and lymphocytes, as well as activation of the complement cascade and microthrombi formation. If not promptly diagnosed and treated, TA-TMA can lead to significant morbidity (eg, permanent renal injury) or mortality. However, as the recognition of the early stages of TA-TMA may be difficult, we propose a TA-TMA “triad” of hypertension, thrombocytopenia (or platelet transfusion refractoriness), and elevated lactate dehydrogenase. While not diagnostic on its own, this triad should prompt further evaluation for TA-TMA. Risk factors for the development of TA-TMA are increasingly understood, including those that are inherent (eg, race or genetics), transplant-approach related (eg, second HCT or use of HLA-mismatched donors), and related to post-transplant events (eg, receipt of calcineurin inhibitors, development of graft-versus-host disease, or certain infections). These are summarized in the “3-hit hypothesis,” in which patients with either an underlying predisposition to complement activation or preexisting endothelial injury (hit 1) undergo a toxic conditioning regimen causing endothelial injury (hit 2), and then additional insults are triggered by medications, alloreactivity, infections, and/or antibodies (hit 3). Understanding this cycle of injury permits the development of a specific TA-TMA treatment algorithm designed to treat both the triggers and the drivers of the endothelial injury.

Correspondence: Christopher C. Dvorak, University of California San Francisco Children’s Hospital, 550 16th St, 4th Floor, Box 0434, San Francisco, CA 94143; e-mail: dvorakc@peds.ucsf.edu.

Author notes

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Contribution: C.C.D. conceived of and wrote the Blood Advances Talk.

Conflict-of-interest disclosure: C.C.D. declares no competing financial interests.

Supplemental data