Early Increase in Complement Terminal Pathway Activation Marker sC5b-9 Is Predictive for the Development of Thrombotic Microangiopathy after Stem Cell Transplantation

Abstract

Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is a multifactorial complication, and its prediction is largely unresolved. Our aim was to analyze changes of complement profile after HSCT to identify potential markers of TA-TMA development. Thirty-three consecutive pediatric patients (9.6 ± 4.4 years old) who underwent allogeneic HSCT due to malignant (n = 17) or nonmalignant (n = 16) indications were included in this study. Graft-versus-host disease (GVHD) was diagnosed using Glucksberg criteria, viral reactivation was monitored, 5 different TA-TMA diagnostic criteria were applied, and all important clinical and laboratory parameters of TA-TMA activity were registered. Complement pathway activities, components and terminal pathway activation marker (sC5b-9) levels were systematically measured before transplantation and on days 28, 56, and 100 after HSCT. During the first 100 days after HSCT, 1 of 33 patients died (day 50, multiple organ failure), whereas 10 subjects met the criteria for TA-TMA, typically on day 61 (range, 16 to 98 days). TA-TMA was preceded by acute GVHD in 3 of 10 patients, by viral reactivation in 2 of 10, or by both in 4 of 10 cases. Baseline sC5b-9 levels did not differ in patients without (200 [interquartile range, 144 to 266] ng/mL), or with (208 [interquartile range, 166 to 271] ng/mL) subsequent TA-TMA; however, on day 28 significant differences were observed (201 [interquartile range, 185 to 290] ng/mL versus 411 [interquartile range, 337 to 471] ng/mL; P = .004). Importantly, all 10 patients with TMA showed increase in sC5b-9 level from baseline level to day 28, whereas in patients without TMA the same tendency was observed for only 9 of 23 patients (P = .031). No additional complement parameters were closely associated with the development of TA-TMA. Development of TA-TMA occurred in 30% of our patients, typically after GVHD and/or viral reactivation. However, early raise of sC5b-9 activation marker was predictive for later development of TA-TMA, and should therefore be considered as an alarming sign necessitating a careful monitoring of all TA-TMA activity markers. Further studies enrolling a higher number of patients are necessary to determine if terminal pathway activation is an independent predictor of TA-TMA.

Circulating Heme Oxygenase-1 and Complement Activation in Transplant-Associated Thrombotic Microangiopathy

“…Our previous investigations had demonstrated that plasma levels of C5b-9 and C3b were significantly increased in patients with TA-TMA [6]. An early rise in the C5b-9 level indicates poor prognosis of TA-TMA [25]. In these patients, complement factor autoantibodies and gene variations or mutations were found to be associated with TA-TMA [1,8], which is similar to the complement-mediated aHUS.…”

Validation of Early Increase in Complement Activation Marker sC5b-9 as a Predictive Biomarker for the Development of Thrombotic Microangiopathy After Stem Cell Transplantation

“…In our previous study we utilized the advantages of our institutional protocol and conducted an explorative, consecutive, comprehensive analysis of complement biomarkers to search for TA-TMA associated, predictive biomarkers. Early increase of terminal pathway activation marker was identified as a sensitive marker of later development of TA-TMA (13). To decrease the risk of a false positive conclusion that may be related to the small size of our previous observational study, we found it of utmost importance to validate our initial observations in an independent cohort, before making any firm conclusions based on the initial data.…”

“…The sample and data collection as well as the methods used for the detection and analysis of complement parameters were described with full details in our previously published paper (13).…”

Bone marrow transplant-associated thrombotic microangiopathy without peripheral blood schistocytes: a case report and review of the literature

“…Care must be taken to rule-out conditions that can present with similar clinical and laboratory findings, such as veno-occlusive disease, infection, and GVHD. One recent reports suggests that a serial increase in serum levels of the terminal complement activation complex C5b-9 is a very sensitive predictor of subsequent TA-TMA [ 13 ]. While TA-TMA has been most closely linked to allogeneic SCT, it has also been described following autologous SCT as well [ 14 ], though this is far less common.…”