Plasminogen mutation-associated thrombotic microangiopathy and role of anticoagulation: a single institution case...

Knowledge gaps exist regarding the role of coagulation pathway mutations such as those in the plasminogen (PLG) gene in the pathogenesis of thrombotic microangiopathy (TMA) and treatment outcomes.

This study aims to describe the unique phenotypic features of patients with PLG mutations and perform structural mapping of the variants to enhance variant interpretation.

This was a single-center retrospective study of patients with TMA in whom genetic testing was performed between 2011 and 2023. Data were collected regarding demographics, clinical features at their first presentation, renal outcomes, genetic mutations, and recurrence for those who were found to have a PLG mutation. Structural mapping of the PLG variants was performed using X-ray structural data.

Over the 12-year study period, we identified 6 individuals in our TMA cohort with PLG mutations. Median age at the time of first TMA event was 45.5 years (range: 5-57 years). Nearly all were female (n = 5, 83%). Half of the cohort (n = 3, 50%) had recurrent TMA, with 1 having recurrent episodes while on long-term complement blockade therapy. Three patients are now on long-term anticoagulation with no further TMA recurrences observed. Structural mapping of the variants revealed that the mutations could be categorized into 3 groups. Among these, group 2 variants (residues K38 in the PAN-apple domain and residue R523 in kringle-5) had a more severe phenotype with severe thrombocytopenia at presentation and a recurrent TMA course.

Patients with PLG mutation-associated TMAs appear to have a poor response to complement blockade therapy, suggesting that pathways in addition to or independent of complement dysregulation may be involved in some patients. Future studies are warranted to explore the role of anticoagulation in preventing recurrence in patients with PLG mutations.