From a study of patients with immune thrombotic thrombocytopenic purpura (iTTP), potential associations with genes related to complement dysfunction were identified. These results were presented at the 2022 Association for the Advancement of Blood and Biotherapies (AABB) Virtual Annual Meeting by Wenjing Cao, MD, PhD, of the University of Kansas Medical Center in Kansas City, Kansas, and colleagues.

Autoantibodies against ADAMTS13 play a key role in the development of iTTP. A common occurrence with iTTP is the development of some level of renal injury. Some patients who have had refractory iTTP have responded to complement-targeted therapy. Dr Cao and colleagues conducted this study to identify genotype-phenotype correlations in iTTP and to examine genetic variation related to complement dysfunction in iTTP and renal injury.

The researchers obtained DNA samples from 40 adults with confirmed iTTP and performed whole exome sequencing and genetic clustering analysis using these samples. The team selected 19 genes for analysis that are linked to hemostasis and complement dysfunction, and they analyzed nonsynonymous variants of these. They computed the combined annotation dependent depletion (CADD) score for each variant, to estimate how deleterious each variant may be. They also evaluated associations between variants and kidney function, based on creatinine level.

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Clustering analysis revealed 2 patient groups, and these groups showed a significant difference in creatinine levels (P =.03753). The 2 patient groups also showed significant differences in lactate dehydrogenase levels (P =.04665). However, they did not show significant differences for other factors that were examined in an analysis of genotype-phenotype correlations.

Across the evaluated genes, the researchers found 65 nonsynonymous variants in 12 genes that appeared to be associated with complement dysfunction or atypical hemolytic uremic syndrome in the study population. All patients showed some level of genetic variation in examined genes, with CFI, CFH, and C5 genes being the most commonly altered.

Overall, there were 6 missense or nonsense variations among examined genes that were associated with CADD scores above 30. Of these variations, 3 occurred in C5, 2 occurred in CFHR5, and1 occurred in DGKE. C5 and CFHR5 are both complement-related genes, while DGKE is not.

More than half (55%) of the patients in this study showed abnormal creatinine levels. Among patients of this study, 7 had creatinine levels above 2 mg/dL on admission, and 5 of these patients showed variations in 3 evaluated genes. These were CFHR5, DGKE, and THBD, and patients with variation in these genes appeared to more often show persistently elevated creatinine levels. Patients with C5 variations, however, did not show persistently elevated creatinine.

Dr Cao and colleagues concluded that there might be a benefit to receiving anti-complement therapy early on in some patients with iTTP who have complement dysfunction and renal impairment. However, they also noted that patients who appear to have kidney injury stemming from a complement-independent process, such as potentially involving DGKE, may not respond to such treatment.


Cao W, Staley EM, Basu M, Zheng L. Genetic variants associated with complement dysfunction in patients with immune-mediated thrombotic thrombocytopenic purpura. Presented at 2022 AABB Virtual Annual Meeting; November 6-7, 2022; Abstract OA2-SN14.