Genetic Landscape of Thrombotic Microangiopathies with Focus on Plasminogen Mutation Variants

Background: Complement-mediated thrombotic microangiopathy (CM-TMA) or atypical hemolytic uremic syndrome (aHUS) is a subtype of thrombotic microangiopathy (TMA) characterized by a triad of thrombocytopenia, hemolytic anemia, and kidney injury, presumably caused by dysregulation of the complement system. Around 50-60% of all the patients carry a genetic mutation that predisposes them to CM-TMA and influences primarily their risk of recurrence if therapy is stopped. While most of these mutations are in the complement pathway, other genes beyond the complement system have also been recognized. Plasminogen (PLG) gene encodes for plasminogen and plays a role in the coagulation pathway. Bu et al screened 36 patients with clinical diagnosis of aHUS and found 4 patients with variants in the PLG gene ( Bu et al. J Am Soc Nephrol 2014). However, phenotypic correlation with PLG gene mutations and comparisons to other CM-TMAs have not been reported.

Aims: 1) To summarize the genetic variants identified in individuals with CM-TMA from a single center cohort and compare the clinical characteristics of individuals with complement mutation versus coagulation pathway mutation 2) Describe the unique phenotypic features of patients with PLG mutations.

Methods: This was a single center retrospective study of patients referred or presenting to the Ohio State University for evaluation for an initial clinical diagnosis of CM-TMA that had TMA gene panel testing performed from 2011 until February 2023. Patients were excluded if the diagnosis of CM-TMA was inconclusive or information regarding their initial presentation or treatment were not available. For individuals who met the criteria, data were collected regarding demographics, clinical features at their first presentation, management, renal outcomes, genetic test findings and disease recurrence.

Results: We initially identified 121 individuals who met the study criteria. Final analysis included 105 individuals. Median age at diagnosis was 42 years. Two-thirds of the cohort was female. About half of the patients had no identifiable mutation (n=59, 58.6%). Of those with an identifiable mutation (n=46), 66% (n=30) had a complement mutation and 21% (n=9) had a coagulation pathway mutation. When comparing the presentation at diagnosis, individuals with a coagulation pathway mutation had a comparable degree acute kidney injury (AKI) as reflected by elevated creatinine at presentation, but less thrombocytopenia and hemolysis compared to patients with complement pathway mutations (Table 1).

Within the coagulation pathway gene variants cohort, there were initially 6 individuals with PLG mutation and 4 with THBD mutation. We excluded one individual with PLG mutation from this cohort since he also had MCP mutation, and his clinical course was well explained by the presence of MCP mutation. The 5 patients with PLG mutation were females (Table 2). Compared to THBD and complement gene variants, patients with PLG mutation had less AKI, thrombocytopenia, and hemolysis at presentation. These individuals demonstrated quicker recovery of renal function within a few weeks to a month, even in the absence of complement blockade therapy, and most were independent of hemodialysis by 3 months after diagnosis. 2 of the 5 (40%) had recurrent TMA and one of had recurrent TMA episodes despite being on long-term complement blockade therapy which was started after a future relapse. These recurrent events resolved completely with supportive therapy that included plasmapheresis. Three patients are on long-term anticoagulation therapy. None have had any aHUS recurrences while on anticoagulation. None of the patients with PLG mutations developed postpartum presentations despite multiple pregnancies in this limited cohort.

Conclusions: Our cohort of CM-TMA subjects shows that patients with PLG mutation associated TMAs have a distinct clinical presentation and possible a lack of response to complement blockade therapy compared with complement gene variants in this cohort. Larger multicenter studies are needed to further validate our findings. Given the role of plasminogen in the coagulation pathway, studies are indicated to explore the role of anticoagulation to prevent recurrence in this subset of patients. Additionally, functional studies of these disease specific PLG variants are vital to identify the pathogenic mechanisms for what might be a distinct form of TMA from CM-TMA.