Nattokinase-Promoted tPA Release From Human Cells: Indirect Fibrinolytic Mechanism

This in vitro study exposed human cell cultures (including HeLa cells) to preparations of heat-deactivated nattokinase — in which the enzyme’s direct proteolytic activity has been destroyed by heating — and measured tissue plasminogen activator (tPA) secretion from the cells. The goal was to identify whether nattokinase exerts fibrinolytic effects through indirect mechanisms independent of its enzymatic activity.

Heat-inactivated nattokinase preparations significantly stimulated tPA release — up to 24-fold in HeLa cells — without affecting cell viability. This suggests that non-enzymatic components of the nattokinase preparation (likely polysaccharide or peptide fragments) stimulate endogenous tPA secretion from cells, providing a potential indirect fibrinolytic mechanism.

The finding adds a second proposed mechanism — beyond direct fibrinolysis — by which nattokinase might theoretically promote coagulation system balance. tPA is the body’s principal endogenous fibrinolytic enzyme, and stimulating its release from cells could amplify plasmin generation and clot dissolution.

The fundamental limitations apply: in vitro cell culture does not predict in vivo pharmacology, and the preparation used (heat-deactivated nattokinase) differs from both the active enzyme and the orally ingested form after digestion. This mechanistic observation requires human pharmacokinetic and clinical validation before any clinical inference is warranted.

We rate the evidence limited. An in vitro study identifying that non-enzymatic nattokinase preparations can stimulate tPA release from human cells — adding a potential indirect fibrinolytic mechanism to the nattokinase pharmacology picture, but requiring in vivo validation.