Characteristics and Genetic Defects of Systemic Lupus Erythematosus-Associated Thrombotic Microangiopathy

Background: Thrombotic microangiopathy (TMA) is a life-threatening complication of systemic lupus erythematosus (SLE). However, the etiology of a considerable number of patients is still unclear and the best treatment is unknown. Sporadic reports suggest that the activation of complement pathway may play a role in SLE-TMA. Methods: We prospectively enrolled 40 SLE-TMA patients in Peking Union Medical College Hospital, 14 patients with lupus nephritis (LN) and 38 patients with other types of TMA. The clinical data were collected. Peripheral blood concentrations of CFH, cCFB, soluble C5b-9, relative activity of complement pathway, ICAM1, VCAM1 and E-Selectin were measured by ELISA in SLE-TMA patients and control groups. Whole exome sequencing (WES) was performed to analyze the genetic variants in SLE-TMA patients. Results: SLE-TMA mediated by ADAMTS13 inhibitors had severe nervous system involvement, but less kidney involvement and good response to plasma exchange. Among SLE-TMA with unknown etiology, patients with TMA confined to kidney had lighter hematological manifestations and lower serum creatinine level than SLE-aHUS (p = 0.005). Compared with SLE-aHUS, the concentration of CFH in SLE-TMA limited to kidney was higher (p = 0.026). The level of E-selectin in patients with SLE-TMA limited to kidney was significantly lower than that in SLE-aHUS patients with MAHA (p = 0.016). There was no significant difference in genetic susceptibility among SLE-aHUS, SLE-TMA limited to kidney and SLE-TMA with other causes. In SLE-TMA patients, thrombophilia variants may play a more important role than complement variants. Treatment response of SLE-TMA patients with variants is worse than those without variants. In serological test, VCAM1 level in SLE-TMA patients with complement related genetic variants was significantly higher than that in SLE-TMA patients without variants (p = 0.001). Patients with compound complement variants are more likely to detect abnormal level of complement factors. Conclusions: SLE-TMA with unknown etiology can be divided into two subgroups with different severity according to the presence or absence of MAHA. The detection of complement factor and E-selectin may play a role in differentiating the two subgroups of SLE-TMA. The complement pathway is highly activated in patients with compound complement mutations, resulting in increased complement factors consumption.