In healthy individuals factor IXa (FIXa), in a complex with factor VIIIa on the surfaces of activated platelets, catalyzes the formation of activated factor X with high efficiency. A substitution of leucine for arginine at residue 384 in FIX (FIX R384L, also know as FIX Padua) is a gain-of-function mutation that resulted in elevated FIX clotting activity in a patient with venous thrombosis (Simioni P et al. 2009). The level of the FIX R384L protein in the patient plasma was normal, but the clotting activity from the proband was approximately eight times the normal level. In vitro, recombinant FIX R384L had a specific activity that was 5 to 10 times as high as that in the recombinant wild-type FIX (Simioni P et al. 2009). In addition, FIXa R384L showed a resistance to inhibition by protein S (PROS1), a plasma protein that directly binds and inhibits FIXa to modulate a clotting rate in vitro and in vivo (Plautz WE et al. 2018a,b). The ability of the FIX Padua variant to increase the clotting activity prompted researchers to try to produce chimeric FIX Padua concentrates for potential use in the treatment of patients with hemophilia B (Lozier JN 2012; Monahan PE et al. 2015; Spronck EA et al. 2019). Epidemiological studies in groups of patients with venous thrombosis failed to discover other cases with this FIX abnormality, indicating that the defect is rare (Koenderman JS et al. 2011; de Moraes Mazetto B et al. 2010). The Reactome event describes elevation of FIX activity due to gain-of-function mutation FIX R384L.
serine-type endopeptidase activity of FVIIIa:FIXa R384L [plasma membrane]
Gain of function of FVIIIa:FIXa R384L [plasma membrane]