Anticoagulant therapy-associated
bleeding and pathological
thrombosis pose serious risks to hospitalized patients. Both complications could be mitigated by developing new
therapeutics that safely neutralize
anticoagulant activity and inhibit activators of the intrinsic blood clotting pathway, such as
polyphosphate (
polyP) and extracellular
nucleic acids. The latter strategy could reduce the use of
anticoagulants, potentially decreasing
bleeding events. However, previously described cationic inhibitors of
polyP and extracellular
nucleic acids exhibit both nonspecific binding and adverse effects on blood clotting that limit their use. Indeed, the polycation used to counteract
heparin-associated
bleeding in surgical settings,
protamine, exhibits adverse effects. To address these clinical shortcomings, we developed a synthetic polycation, Universal
Heparin Reversal Agent (UHRA), which is nontoxic and can neutralize the
anticoagulant activity of heparins and the prothrombotic activity of
polyP. Sharply contrasting
protamine, we show that UHRA does not interact with
fibrinogen, affect
fibrin polymerization during clot formation, or abrogate plasma clotting. Using scanning electron microscopy, confocal microscopy, and clot lysis assays, we confirm that UHRA does not incorporate into clots, and that clots are stable with normal
fibrin morphology. Conversely,
protamine binds to the
fibrin clot, which could explain how
protamine instigates clot lysis and increases
bleeding after surgery. Finally, studies in mice reveal that UHRA reverses
heparin anticoagulant activity without the
lung injury seen with
protamine. The data presented here illustrate that UHRA could be safely used as an
antidote during adverse therapeutic modulation of hemostasis.