Platelet-endothelial interactions have been shown to be main mediators of leukocyte-independent endothelial damage. Besides altering platelet-endothelial interactions, both antithrombin and factor XIII reduce microvascular permeability in leukocyte-dependent experimental models. Thus, it was our aim to investigate the effects of antithrombin and factor XIII on microvascular permeability during leukocyte-independent endotoxemia.In male Wistar rats, venular wall shear rate, macromolecular efflux, and leukocyte-endothelial interaction were determined in mesenteric postcapillary venules using intravital microscopy at baseline, 60, and 120 min after the start of the experiment. Fucoidin and a continuous infusion of lipopolysaccharides were used to generate leukocyte-independent endotoxemia. The experiment was divided into two parts 1) an antithrombin study and 2) a factor XIII study.No differences between groups in leukocyte rolling and venular wall shear rate could be observed in both parts of the experiment. Pretreatment with antithrombin reduced microvascular permeability significantly compared with control subjects (120 min: Fuco [untreated]: 0.14 +/- 0.03; Fuco/ETX [control]: 0.37 +/- 0.06; Fuco + ATIII/ETX: 0.15 +/- 0.02; P < 0.05). Factor XIII reduced microvascular permeability significantly after 60 min (Fuco [untreated]: 0.10 +/- 0.03; Fuco/ETX [control]: 0.36 +/- 0.07; Fuco + FXIII/ETX: 0.13 +/- 0.04; P < 0.05). This effect diminished after 120 min (Fuco [untreated]: 0.12 +/- 0.03; Fuco/ETX [control]: 0.5 +/- 0.08; Fuco + FXIII/ETX: 0.29 +/- 0.05; P < 0.05).Antithrombin and factor XIII reduce leukocyte-independent microvascular permeability. Yet, factor XIII also shows a nonprotective effect on a long-term basis. These data emphasize the central role of platelets in leukocyte-independent endotoxemia.