Pediatric Patients Have Elevated Thrombomodulin Levels Prior to Onset of Transplant Associated Thrombotic Microangiopathy and Are Associated with Increased Treatment Related Mortality

Abstract

Background The incidence of transplant-associated thrombotic microangiopathy (TMA) is 20-40%, likely triggered by endothelial injury, which may be due to conditioning regimen, neutrophil extracellular traps, drugs or infections. Several previous studies have associated thrombomodulin (THBD) single-nucleotide polymorphism (SNP) variants with TMA and TRM, but use of protein levels to identify endothelial injury and predict future risk of TMA has not been reported. Objectives Primary objective was to determine whether THBD levels 14 days post hematopoietic stem cell transplant (HSCT) predict increased risk of TMA. We hypothesized that elevated serum THBD levels are associated with higher incidence of TMA and TRM as a consequence of endothelial injury. Methods Serum and DNA of 106 pediatric patients, transplanted between 2014 and 2017 were collected prior to conditioning and at day 14. THBD levels were measured using human thrombomodulin/BDCA-3 quantikine elisa kits (R and D, Minneapolis). We compared HSCT outcomes to THBD levels above and below the median. TaqMan SNP genotyping assays determined THBD genotype. Results Results of our study are summarized in figure 1. We observed increased THBD levels at day 14 in children who later developed TMA at a median of 26 days (range 0-667 days) after HSCT (p=0.05, figure 2), compared with children who never developed TMA. Moreover, mortality (at a median of 248 days, range 60-1258 days) was increased in children with THBD levels above the median at day 14 (p=0.02 figure 3). Interestingly there was no statistical difference between THBD level in children with or without graft versus host disease (GVHD), although the point estimate was higher in children with GVHD. THBD levels prior to conditioning were not predictive of TMA or TRM (P=0.95 and 0.41). THBD levels were not increased in those with a high risk genotype compared with those with a low risk genotype at baseline or day +14 (p=0.86 and 0.16, Table 1). Of the 23 deaths, 3 succumbed to infection, 7 to endothelial injury (TMA or GVHD), and 13 to relapse. Conclusion Our data show elevation of THBD as early as day +14 was associated with increased TMA and TRM at later time points. Our data indicate the importance of events happening within 14 days after HSCT in “setting up” later events and offer a window of time for potential interventions to reduce later complications. We are currently studying the kinetics of THBD during transplant recovery and mechanisms of associations of THBD levels with later outcomes.