Systemic
inflammation can lead to coagulopathy and
disseminated intravascular coagulation (
DIC). In prior studies, the recombinant A2 domain of human
von Willebrand factor (VWF; A2
protein) attenuated
DIC and decreased mortality in
lipopolysaccharide (LPS)-treated mice. Here, we performed studies to dissect the mechanism by which the A2
protein moderates
DIC. We used confocal microscopy to analyze the
fibrin clot structure in plasma from healthy humans and endotoxemic mice, turbidity assays to examine
fibrin polymerization, and a murine model for LPS-induced
DIC and introduced a loss-of-function mutation into the A2
protein for
fibrin. The mutation of the residue E1567 located in the α2 helix of the folded A2 domain of VWF inhibited binding activity for
fibrin, possibly mapping a novel region containing a putative binding site for
fibrin. The A2
protein increased the initial rate of change of
fibrin polymerization, intercalated into the
fibrin network, and modified the resultant clot structure in vitro. Furthermore, ex vivo experiments using plasma from mice with
endotoxemia treated with the A2
protein revealed an increased rate of
fibrin formation and an altered clot structure as compared with plasma from nontreated sick animals. Moreover, and in contrast to the A2 mutant, the A2
protein improved survival and reduced
fibrin deposition and microvascular
thrombosis in mice with
endotoxemia-induced
DIC. Importantly, in vivo and in vitro studies indicated that the A2
protein did not affect experimental
thrombosis. Thus, we provide evidence for a novel treatment to attenuate systemic
inflammation-induced coagulopathy/
DIC via targeting
fibrin formation, without an increased risk for
bleeding.