Preliminary analysis of the role of magnesium in transplant-associated thrombotic microangiopathy via complement activation pathways

Abstract Objective: This study aimed to retrospectively analyze the clinical features, potential risk factors, and prognosis of patients diagnosed with transplant-associated thrombotic microangiopathy (TA-TMA).Additionally, it explored the role of magnesium in the pathogenesis and prognosis of TA-TMA, particularly their impact on complement activation, to provide new insights into the prevention and treatment of TA-TMA. Methods: A retrospective analysis was conducted on the clinical data of 619 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at Fujian Medical University Union Hospital, from August 2022 to August 2024.Among them, 14 patients diagnosed with transplant-associated thrombotic microangiopathy (TA-TMA) were included in the observation group (TA-TMA group). Meanwhile, a control group (non-TA-TMA group) was established by randomly selecting patients from the entire transplant cohort at a 1:3 ratio, ensuring a transplantation time difference within ±6 months. A TA-TMA mouse model was established by intraperitoneal injection of dimethyloxalyl glycine to induce TMA after transplantation. The experimental group received high-magnesium intervention, and complement activation marker sC5b-9 levels, platelet counts, lactate dehydrogenase (LDH) levels, and survival times were compared between the experimental and control groups to evaluate the effect of high-magnesium treatment on survival and prognosis. Results: 1.The median age of the 14 TA-TMA patients was 30 years (IQR: 23-43 years), with a median diagnosis time of 94 days (range: 54-676 days). Compared to the non-TA-TMA group, the TA-TMA group exhibited significantly more severe anemia, thrombocytopenia, and elevated LDH levels, with statistically significant differences (P<0.05). Univariate and multivariate analyses identified cardiac dysfunction as an independent risk factor for TA-TMA (P<0.05). Analysis of serum magnesium levels in TA-TMA patients with different prognoses showed that the magnesium level in the survival group was significantly lower than that in the deceased group (P=0.017). However, after adjusting for confounding factors such as the use of calcineurin inhibitorsand renal dysfunction, the difference in magnesium levels between the two groups was not statistically significant (P=0.057). 2.Animal experiments showed that high-magnesium treatment had statistical significance in prolonging the survival time of TA-TMA mice (p=0.0286). Additionally, serum sC5b-9 levels in the high-magnesium treatment group were lower than those in the control group, but no significant difference was observed. Conclusion: TA-TMA significantly impacts the prognosis of allo-HSCT patients. Magnesium may reduce microvascular injury by inhibiting complement activation and protecting endothelial function, thereby playing an essential role in the occurrence and progression of TA-TMA. Magnesium supplementation may potentially improve the clinical outcomes of TA-TMA patients. However, further large-scale clinical studies and mechanistic investigations are required to confirm its potential clinical value. Keywords:Transplant-associated thrombotic microangiopathy, Allogeneic hematopoietic stem cell transplantation, Magnesium, Complement activation, Endothelial injury