Content area
Full Text
Hemostasis requires conversion of fibrinogen to fibrin fibers that generate a characteristic network, interact with blood cells, and initiate tissue repair. The fibrin network is porous and highly permeable, but the spatial arrangement of the external clot face is unknown. Here we show that fibrin transitioned to the blood-air interface through Langmuir film formation, producing a protective film confining clots in human and mouse models. We demonstrated that only fibrin is required for formation of the film, and that it occurred in vitro and in vivo. The fibrin film connected to the underlying clot network through tethering fibers. It was digested by plasmin, and formation of the film was prevented with surfactants. Functionally, the film retained blood cells and protected against penetration by bacterial pathogens in a murine model of dermal infection. Our data show a remarkable aspect of blood clotting in which fibrin forms a protective film covering the external surface of the clot, defending the organism against microbial invasion.
Introduction
Hemostasis is a pivotal mechanism to prevent life-threatening blood loss from sites of injury, and involves close interplay between coagulation and platelets. The resulting blood clot contains activated platelets, red blood cells, and fibrin polymer, which holds the clot together. Fibrin is formed by limited proteolysis of fibrinogen by thrombin. Thrombin cleaves small peptidic sequences from the N-termini of the Aa- and Bß-polypeptides, exposing interaction sites for binding pockets in the C-terminal domains ofthe ß- and у-chains, respectively (1). Fibrin thus polymerizes into protofibrils, which aggregate laterally into fibers. The fibers branch and produce a 3D network with remarkable elastic properties (2). The structure of the fibrin network is determined by fiber diameter, protofibril packing, and pore size, the latter of which is sufficient for the incorporation of cells. Dense networks with thin fibers and increased rigidity are associated with increased risk of thrombosis, while loose clot networks with thick fibers and reduced rigidity are associated with bleeding (1, 3, 4).
A major conundrum after decades of fibrin polymer research is that fibrin fibers in blood clots appear endless, with little evidence of fiber ends (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.H72/ JCI98734DS1). Thus, the mechanisms and structures that determine the external boundary of an extravascular (hemostatic) blood...