Reeling in complement in transplant‐associated thrombotic microangiopathy: You're going to need a bigger boat

Abstract

Over the last decade there have been numerous advances in both the diagnosis and treatment of transplant-associated thrombotic microangiopathy (TA-TMA). These are largely the result of an improved understanding of complement activation in TA-TMA and the ability to prevent end organ injury and death with timely initiation of complementblocking therapies. In this article, we review our current understanding of the pathophysiology of TA-TMA, particularly as it pertains to complement activation, endothelial injury, and clinical management. We then review novel complement-blocking therapies that are currently under investigation for use in TA-TMA, as well as discuss special considerations for complement-blocking therapy in hematopoietic stem cell transplant recipients. Through these reviews we aim to answer or at least provide an educated discussion on the most commonly posed TA-TMA management questions and dilemmas.

Thrombotic microangiopathy – the importance of a multidisciplinary approach

“…Various TA-TMA diagnostic criteria have been published [16], but use of the modified Jodele criteria is recommended – see Table 2 (a & b) [17 ▪ ]. In TA-TMA, a three-hit model is postulated: activation of endothelium to a procoagulant state (first hit) followed by activation of antigen presenting cells, lymphocytes, and downstream immunologic and inflammatory activation (second hit); and finally, activation of complement with ensuing endothelial activation and damage [16,17 ▪ ,18,19 ▪▪ ].…”

“…Various TA-TMA diagnostic criteria have been published [16], but use of the modified Jodele criteria is recommended – see Table 2 (a & b) [17 ▪ ]. In TA-TMA, a three-hit model is postulated: activation of endothelium to a procoagulant state (first hit) followed by activation of antigen presenting cells, lymphocytes, and downstream immunologic and inflammatory activation (second hit); and finally, activation of complement with ensuing endothelial activation and damage [16,17 ▪ ,18,19 ▪▪ ]. Excessive terminal complement activation can be measured using soluble C5b-9 levels (also known as ‘soluble MAC’) [17 ▪ ].…”

“…In TA-TMA, recognized first-hit risk factors include pre-HSCT or conditioning regimen attributes (i.e., busulfan-based myeloablative versus reduced-intensity/nonmyeloablative conditioning), genetic predisposition, donor-recipient ABO incompatibility, or HLA mismatch [17 ▪ ,20]. Additional risk factors that may be present immediately posttransplantation include use of concurrent calcineurin and mammalian target of rapamycin (mTOR) inhibitors for graft versus host disease (GVHD) prophylaxis, development of severe GVHD, or incidental infections [20].…”

“…In addition, they also found that higher body mass, higher complement activation state at diagnosis (i.e., elevated sC5b-9), and gastrointestinal bleeding leads to increased eculizumab clearance [26]. This increased clearance results in reduced suppression of complement activation, thus prompting the need for pharmacodynamic-guided precision dosing (i.e., targeting of eculizumab drug levels >100 μg/ml and targeting trough CH50 <10% and normalization of sC5b-9 to <244 ng/ml) to ensure adequate suppression of complement activation [25,26,27 ▪▪ ].…”

Complement inhibition in medicine: Hematology and beyond; complement inhibition in hematology: PNH and beyond

“…The complicated (and still not clear) physiopathology of those disorders is largely addressed, as well as the treatment approach. Transplant‐associated thrombotic microangiopathy (TA‐TMA) is also a challenging situation for clinicians, which is reviewed by Jodele and Salbuski in «Reeling in Complement in Transplant‐Associated Thrombotic Microangiopathy: You're Going to Need a Bigger Boat» 5 . The current understanding of the pathophysiology of TA‐TMA is presented and discussed, particularly as it pertains to complement activation, endothelial injury, and clinical management.…”