PB0589 Human Transthyretin (hTTR) Amyloid Fibrils Induce Plasma Clotting by Activating the Intrinsic Pathway of Blood Coagulation: Implications in the Pathogenesis of hTTR Intracardiac Thrombosis

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determined that 5C12 binds to a 5 amino acid external loop I383APCW on FXIIa that is near the active-site H393.The C386W387 sequence is highly conserved in the FXII family of proteins: tPA, uPA, and HGFA.Competition inhibition assays using peptides IAPAW and IAPCA reveal that the cysteine and tryptophan in α-FXIIa are critical for 5C12 binding.Last, 5C12 is unable to immunoblot a FXII C386-C456 mutant.Conclusion(s): We postulate that 5C12 binding to FXIIa causes a change in the orientation of the active site histidine, incapacitating the catalytic triad.Use of anti-FXIIa Mabs may reduce or eliminate the need for heparin with medical devices.Presently, there is no agent like this approved for this therapeutic indication.[

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