TY - JOUR
T1 - Localized endothelial-based control of platelet aggregation and coagulation under flow
T2 - A proof-of-principle vessel-on-a-chip study
AU - Brouns, Sanne L. N.
AU - Provenzale, Isabella
AU - van Geffen, Johanna P.
AU - van der Meijden, Paola E. J.
AU - Heemskerk, Johan W. M.
N1 - Funding Information:
Support was obtained from the Cardiovascular Centre (HVC), Maastricht University Medical Centre, the Interreg program Euregio Meuse-Rhin (Polyvalve), and from the H2020-MSCA-ITN-2017 Marie Sk?odowska-Curie Innovative Training Network, TAPAS 766118.
Publisher Copyright:
© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis
PY - 2020/4
Y1 - 2020/4
N2 - Background In the intact vessel wall, endothelial cells form a barrier between the blood and the remaining vascular structures, serving to maintain blood fluidity and preventing platelet activation and fibrin clot formation. The spatiotemporal space of this inhibition is largely unknown.Objective To assess the local inhibitory roles of a discontinuous endothelium, we developed a vessel-on-a-chip model, consisting of a microfluidic chamber coated with the thrombogenic collagen and tissue factor (TF), and covered with patches of human endothelial cells. By flow perfusion of human blood and plasma, the heterogeneous formation of platelet aggregates and fibrin clots was monitored by multicolor fluorescence microscopy.Results On collagen/TF coatings, a coverage of 40% to 60% of human umbilical vein endothelial cells resulted in a strong overall delay in platelet deposition and fibrin fiber formation under flow. Fibrin formation colocalized with the deposited platelets, and was restricted to regions in between endothelial cells, thus pointing to immediate local suppression of the clotting process. Fibrin kinetics were enhanced by treatment of the cells with heparinase III, partially disrupting the glycocalyx, and to a lesser degree by antagonism of the endothelial thrombomodulin. Co-coating of purified thrombomodulin and collagen had a similar coagulation-suppressing effect as endothelial thrombomodulin.Conclusions In this vessel-on-a-chip system with patches of endothelial cells on thrombogenic surfaces, the coagulant activity under flow is regulated by: (a) the residual exposure of trigger (collagen/TF), (b) the endothelial glycocalyx, and (c) to a lesser degree the endothelial thrombomodulin.
AB - Background In the intact vessel wall, endothelial cells form a barrier between the blood and the remaining vascular structures, serving to maintain blood fluidity and preventing platelet activation and fibrin clot formation. The spatiotemporal space of this inhibition is largely unknown.Objective To assess the local inhibitory roles of a discontinuous endothelium, we developed a vessel-on-a-chip model, consisting of a microfluidic chamber coated with the thrombogenic collagen and tissue factor (TF), and covered with patches of human endothelial cells. By flow perfusion of human blood and plasma, the heterogeneous formation of platelet aggregates and fibrin clots was monitored by multicolor fluorescence microscopy.Results On collagen/TF coatings, a coverage of 40% to 60% of human umbilical vein endothelial cells resulted in a strong overall delay in platelet deposition and fibrin fiber formation under flow. Fibrin formation colocalized with the deposited platelets, and was restricted to regions in between endothelial cells, thus pointing to immediate local suppression of the clotting process. Fibrin kinetics were enhanced by treatment of the cells with heparinase III, partially disrupting the glycocalyx, and to a lesser degree by antagonism of the endothelial thrombomodulin. Co-coating of purified thrombomodulin and collagen had a similar coagulation-suppressing effect as endothelial thrombomodulin.Conclusions In this vessel-on-a-chip system with patches of endothelial cells on thrombogenic surfaces, the coagulant activity under flow is regulated by: (a) the residual exposure of trigger (collagen/TF), (b) the endothelial glycocalyx, and (c) to a lesser degree the endothelial thrombomodulin.
KW - blood platelets
KW - endothelial cells
KW - fibrin
KW - hemostasis
KW - microfluidics
KW - VON-WILLEBRAND-FACTOR
KW - THROMBUS FORMATION
KW - CELL ACTIVATION
KW - GLYCOCALYX
KW - INHIBITOR
KW - PATHWAY
KW - SYSTEM
KW - ROLES
U2 - 10.1111/jth.14719
DO - 10.1111/jth.14719
M3 - Article
C2 - 31863548
SN - 1538-7933
VL - 18
SP - 931
EP - 941
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
IS - 4
ER -