Prognostic Biomarkers for Thrombotic Microangiopathy after Acute Graft-versus-Host Disease: A Nested Case-Control Study

Abstract

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a complication of allogeneic hematopoietic cell transplantation (HCT) that often occurs following the development of acute graft-versus-host disease (aGVHD). In this study, we aimed to identify early TMA biomarkers among patients with aGVHD. We performed a nested-case-control study from a prospective cohort of allogeneic HCT recipients, matching on the timing and severity of antecedent aGVHD. We identified 13 TMA cases and 25 non-TMA controls from 208 patients in the cohort. Using multivariable conditional logistic regression, the odds ratio for TMA compared with non-TMA was 2.65 (95% confidence interval [CI], 1.00 to 7.04) for every 100 ng/mL increase in terminal complement complex sC5b9 and 2.62 (95% CI, 1.56 to 4.38) for every 1000 pg/mL increase in angiopoietin-2 (ANG2) at the onset of aGVHD. ADAMTS13 and von Willebrand factor (VWF) antigens were not appreciably associated with TMA. Using a Cox regression model incorporating sC5b9 >300 ng/mL and ANG2 >3000 pg/mL at the onset of aGVHD, the adjusted hazard ratio for mortality was 5.33 (95% CI, 1.57 to 18.03) for the high-risk group (both elevated) and 4.40 (95% CI, 1.60 to 12.07) for the intermediate-risk group (one elevated) compared with the low-risk group (neither elevated). In conclusion, we found that elevated sC5b9 and ANG2 levels at the onset of aGVHD were associated with the development of TMA and possibly mortality after accounting for the timing and severity of aGVHD. The results suggest important roles of complement activation and endothelial dysfunction in the pathogenesis of TMA. Measurement of these biomarkers at the onset of aGVHD may inform prognostic enrichment for preventive trials and improve clinical care.

Keywords: Bone Marrow Transplantation; Complement Membrane Attack ComplexAngiopoietin-2; TA-TMA; TMA; Thrombotic Microangiopathies.

Figure 1.

Incidence density sampling for the nested case-control study. This diagram shows the schema of case and control selection. At the onset of every TA-TMA case, 2 non-TMA controls were chosen randomly after matching on the timing and severity of previous aGVHD. Among 208 adult allogeneic HCT recipients enrolled in the prospective cohort, 13 TA-TMA cases were identified, and 25 matched non-TMA aGVHD controls were sampled.

Figure 2.

Comparison of biomarkers at time points before the onset of TMA. The mean values and 95% CIs of biomarkers are shown for 13 TA-TMA cases (dark bar) versus 25 non-TMA controls (light bar) at each discrete time point (pretransplantation and onset of aGVHD). Significance differences (*P < .05) were detected for sC5b9 and ANG2 at the onset of aGVHD.

Figure 3.

Longitudinal assessment of biomarkers over time pre- and post-HCT. The mean values and 95% CIs of biomarkers are shown longitudinally for 13 TA-TMA cases (solid line) and 25 non-TMA matched controls (dash line). There was a significant difference between cases and controls for sC5b9 and ANG2 from 2 to 4 weeks.