Figure 7. Human DVT arises in association with loss of the perivalvular endothelial transcription factor and antithrombotic phenotypes.

(A and B) Model of the relationship between muscular activity, perivalvular oscillatory flow, perivalvular endothelial cell gene expression, and venous thrombosis. In the active state, muscular activity stimulates oscillatory flow in the venous valve sinus, driving endothelial expression of the shear-regulated FOXC2 and PROX1 transcription factors. Shear-regulated transcription factor activity upregulates expression of the antithrombotic proteins THBD, EPCR, and TFPI while simultaneously downregulating expression of the prothrombotic proteins vWF, P-selectin, and ICAM1 to maintain a highly antithrombotic environment (A). Inactivity and lack of muscular contraction results in perivalvular endothelial loss of expression of the shear-regulated transcription factors, loss of THBD, EPCR, and TFPI expression, and gain of vWF, P-selectin, and ICAM1 expression, resulting in thrombin generation and formation of DVT (B). (C–E) Human DVT is associated with loss of endothelial expression of FOXC2 and PROX1 in the valve sinus. (C) After death due to pulmonary embolism, femoral vein samples containing the valve at the anastomosis of the superficial and deep femoral veins were harvested from a leg without DVT (top) and from the contralateral leg with DVT in situ (bottom). (D–F) Immunostaining for FOXC2 and PROX1 were performed on sections from the valves shown in C. Arrowheads indicate FOXC2⁺ and PROX1⁺ nuclei in E and F. (G–J) DVT is associated with endothelial gain of expression of the prothrombotic protein vWF and loss of the antithrombotic proteins THBD, EPCR, and TFPI in the valve sinus. The white dashed line indicates the endothelial layer. V^L, luminal face of the valve; V^S, sinus face of the valve; S, vessel wall in the valve sinus.