Contact system sends defensins to the rescue

Abstract

In this issue of Blood, Abu-Fanne et al identify a link between activation of the contact system of coagulation involving factor XIIa (FXIIa) and kallikrein, promoting neutrophils to release the antimicrobial peptide α-defensin-1, which enhances fibrin polymerization kinetics, alters fibrin morphology, and inhibits fibrinolysis. These reactions may serve as an extension or consequence of innate immunity and are shown to affect in vivo murine thrombosis.

Neutrophil α-defensin-1 as a central mediator of thrombus formation. Abu-Fanne et al demonstrated that the contact activation factors kallikrein and FXIIa induce azurophil granule release from neutrophils, increasing plasma concentrations of the microbicidal peptide α-defensin-1 (α-def-1); this process was inhibited by aprotinin, corn trypsin inhibitor (CTI), or colchicine. Their study shows that α-defensin-1 promotes fibrin formation by thrombin, modifies fibrin morphology, and through its incorporation into the clot, inhibits tissue-type plasminogen activator (tPA)-mediated fibrinolysis. Consequently, α-defensin-1 increases thrombosis in vivo. In mice transgenic for human α-defensin-1, heparin showed greatly reduced antithrombotic potency, but when colchicine was used to inhibit α-defensin-1 release, heparin’s normal antithrombotic potency was restored. FDP, fibrin degradation products; PK, prekallikrein.