Alpha-2-plasmin inhibitor deficiency was first described in 1978 by Koie et al. (PMID: 82839), and is characterized by delayed bleeding after trauma, surgery and dental procedures. Bleeding in areas of high fibrinolytic activity is also common, such as menorrhagia and epistaxis. In 1987, the first variant was identified in patients by Holmes et al. (PMID: 2958938) establishing the relationship between SERPINF2 and autosomal recessive alpha-2-plasmin inhibitor deficiency. Patients with biallelic alpha-2-plasmin inhibitor deficiency may have severe bleeding manifestations, whereas heterozygotes may have milder bleeding tendencies or remain asymptomatic. At least 10 unique variants (including missense, nonsense, splicing and frameshift variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 9 publications (PMIDs: 31441040, 2958938, 17961166, 2496145, 2572590, 31577375, 29656168, 10959705, 12152655). Variants in this gene segregated with disease in 6 additional family members. Alpha-2-plasmin inhibitor acts as a primary and fast-acting inhibitor of plasmin; its major physiological role is to stabilize hemostatic plugs by inhibiting plasmin-mediated fibrinolysis that follows fibrin formation. The bleeding associated with a deficiency in alpha-2-plasmin inhibitor is because of the premature dissolution of hemostatic plugs before tissue and vessel repair. This gene-disease relationship is supported by its biochemical function in fibrinolysis (PMID: 134998), the functional alteration observed in patient cells which can be rescued with exogenous protein (PMID: 156196), and a knockout mouse model which recapitulates the alteration in fibrinolysis (PMID: 10090937). In summary, SERPINF2 is definitively associated with autosomal recessive alpha-2-plasmin inhibitor deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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