Genetic and hemostatic characterization of PAI-1 deficiency and isolated hyperfibrinolysis: data from the RBiN study.

BACKGROUND: Plasminogen activator inhibitor 1 (PAI-1) is a key regulator of fibrinolysis, and its deficiency causes bleeding symptoms. PAI-1 deficiency is rare, and pathogenic SERPINE1 variants are only sporadically reported. OBJECTIVES: To assess SERPINE1 variant occurrence and plasmin generation in patients with PAI-1 deficiency compared to patients with isolated hyperfibrinolysis or rare coagulation factor deficiencies (RCFDs). METHODS: This substudy of the nationwide, cross-sectional RBiN cohort included patients with PAI-1 deficiency, isolated hyperfibrinolysis, and RCFDs. SERPINE1 variants were assessed by targeted exome sequencing and promoter polymorphisms by polymerase chain reaction and Sanger sequencing. Plasmin generation was measured using the Nijmegen Hemostasis Assay. RESULTS: Fourteen patients with PAI-1 deficiency, 15 with isolated hyperfibrinolysis, and 214 with RCFDs were included. SERPINE1 variants were identified in one patient with PAI-1 deficiency, one with isolated hyperfibrinolysis, and 30 with RCFDs. Variants p.Ala15Thr (rs6092) and p.Val17Ile (rs6090) were most frequently observed and did not significantly affect PAI-1 antigen levels (median 7.8 and 9.0 vs 7.3 ng/mL without variant) or bleeding scores (8 and 12.5 vs 10). The SERPINE1 promoter polymorphisms c.-675 4G/5G (rs1799889) and c.-844A>G (rs2227631) were not associated with PAI-1 antigen levels or bleeding severity. Patients with PAI-1 deficiency or isolated hyperfibrinolysis showed significantly shorter fibrin lysis times (median 74% and 66%) and higher plasmin peak heights (145% and 170%) than healthy controls (100%). CONCLUSION: PAI-1 deficiency and isolated hyperfibrinolysis showed enhanced plasmin generation, but were not linked to SERPINE1 variants or promoter polymorphisms. Further studies should explore noncoding, regulatory, and epigenetic mechanisms underlying PAI-1 deficiency.