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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2225.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Differential Role of von Willebrand Factor and P-Selectin on Microvascular Thrombosis in Endotoxemia

Kavita N. Patel; Said H. Soubra; Ricardo V. Bellera; Jing-Fei Dong; Colleen A. McMullen; Alan R. Burns; Rolando E. Rumbaut

From the Medical Care Line (S.H.S., R.E.R.), Michael E. DeBakey VA Medical Center, Houston, Tex; the Departments of Pediatrics (K.N.P., R.V.B., A.R.B., R.E.R.) and Medicine (S.H.S., J.-F.D., A.R.B., R.E.R.), Baylor College of Medicine, Houston, Tex; and the Department of Physiology (C.A.M.), University of Kentucky, Lexington.

Correspondence to Rolando E. Rumbaut, MD, PhD, Baylor College of Medicine, Children’s Nutrition Research Center, 1100 Bates, Room 6014, Houston, TX 77030. E-mail rrumbaut{at}bcm.tmc.edu

Objective— Endotoxin (lipopolysaccharide [LPS]) enhances microvascular thrombosis in mouse cremaster venules. Because von Willebrand factor (vWF) and P-selectin are suggested to mediate LPS-induced platelet–microvessel interactions, we determined whether vWF and P-selectin contribute to microvascular thrombosis in endotoxemia.

Methods and Results— A light/dye-induced thrombosis model was used in cremaster microvessels of saline or LPS-injected mice (wild-type, P-selectin–deficient, vWF-deficient, or littermate controls). In each strain except vWF-deficient mice, LPS enhanced thrombosis in venules, resulting in 30% to 55% reduction in times to thrombotic occlusion. LPS had no effect on thrombosis in vWF-deficient mice, although these mice had similar systemic responses to LPS (tachycardia, thrombocytopenia, and plasma coagulation markers). vWF-deficient mice demonstrated prolonged times to thrombotic occlusion relative to littermates. LPS increased plasma vWF in each strain studied. While immunofluorescence in wild-type mice failed to detect LPS-induced differences in microvascular vWF expression, it revealed markedly higher vWF expression in venules relative to arterioles.

Conclusions— vWF mediates light/dye-induced microvascular thrombosis and endotoxin-induced enhancement of thrombosis in mouse cremaster venules; P-selectin is not required for enhanced thrombosis in response to endotoxin. Enhanced vWF expression in venules relative to arterioles has potential implications for the differences in thrombotic responses among these microvessels.

Alhtough endotoxin is known to promote microvascular thrombosis, the mechanisms involved remain incompletely understood. Using an in vivo photochemical injury model of thrombosis in mouse cremaster microvessels, this study demonstrates that vWF, but not P-selectin, mediates microvascular thrombosis and its enhancement by endotoxin.

Key Words: endotoxin • platelets • venules • intravital microscopy • sepsis