Alpha-2 antiplasmin deficiency: a rare fibrinolytic disorder identified after decades of diagnostic delay

Alpha-2 antiplasmin (α2AP) deficiency is a rare fibrinolytic disorder characterized by unregulated plasmin activity and premature clot breakdown. Mechanistically, α2AP restrains fibrinolysis by (i) forming a covalent serpin complex with plasmin, (ii) blocking plasminogen binding to fibrin, and (iii) undergoing factor XIIIa-mediated cross-linking into fibrin to harden clots against local lysis. We describe a woman with decades of delayed postoperative bleeding, transfusion dependence, and a presumed diagnosis of von Willebrand disease, ultimately found to have congenital α2AP deficiency. Her evaluation showed normal coagulation studies, platelet function, and von Willebrand factor assays, with persistently low α2AP activity and a homozygous SERPINF2 variant confirming the diagnosis. Standard hemostatic panels may fail to detect α2AP deficiency, and testing with functional activity assays or genetic analysis is required. This case highlights diagnostic pitfalls and underscores the importance of considering fibrinolytic disorders in patients with unexplained or delayed bleeding.