Valves of the deep venous system: an overlooked risk factor

Abstract

Deep venous valves are frequent sites of deep venous thrombosis initiation. However, the possible contribution of the valvular sinus endothelium has received little attention in studies of thrombosis risk. We hypothesized that the endothelium of valve sinus differs from that of vein lumen with up-regulation of anticoagulant and down-regulation of procoagulant activities in response to the local environment. In pursuit of this hypothesis, we quantified endothelial protein C receptor (EPCR), thrombomodulin (TM), and von Willebrand factor (VWF) by immunofluorescence in great saphenous veins harvested at cardiac bypass surgery. We found significantly increased expression of EPCR and TM in the valvular sinus endothelium as opposed to the vein lumenal endothelium, and the opposite pattern with VWF (paired t test for TM and EPCR, each P < .001; for VWF, P = .01). These data support our hypothesis and suggest that variation in valvular sinus thromboresistance may be an important factor in venous thrombogenesis.

Figure 1

Diagrammatic representation of the differences of the means measured on the valvular versus the nonvalvular vein endothelium. (A) Diagram showing the locations of the endothelial confocal measurements made on the vein lumenal surface and in the valve sinus. (B-D) Graphic representations of the differences in mean intensity between the vein lumenal endothelium (combined areas A-C) and the valvular sinus endothelium (combined areas D-F) for EPCR, TM, and VWF, respectively. Paired t tests were used to test the differences in the means for each vein (see supplemental data and supplemental Table 1 with supporting data for this figure).

Figure 2

Split and merged confocal images of a representative venous valve and vein wall. (A) 4′,6-diamidino-2-phenylindole hydrochloride (blue) binds to DNA; (B) VWF (white); (C) EPCR (red); (D) TM (green); (E) merged image (the overlap of red and green fluorophores is perceived as yellow); (F) higher magnification of the merged image of the valve sinus and (G) higher magnification of the merged image of the vein lumenal wall just distal to the valve images in A-D. (F-G) Images were inserted to include an extended area of both the valvular sinus endothelium and the nonvalvular endothelium distal to the valve (see supplemental data). White arrow in panel E indicates vein luminal endothelium; and white asterisk, valve sinus. Scale bars indicate 100 μm (A-E) and 50 μm (F-G).