Activation of protein C and thrombin activable fibrinolysis inhibitor on cultured human endothelial cells

Wu, Chengliang; Kim, Paul Y.; Swystun, Laura L.; Liaw, Patricia C.; Weitz, Jeffrey I.

doi:10.1111/jth.13222

Cited by 21 publications

(19 citation statements)

References 36 publications

(49 reference statements)

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“…Thrombomodulin is a transmembrane glycoprotein, which is present at the luminal side of the endothelial cell vessel wall barrier. When binding thrombin, thrombomodulin converts protein C into APC in a protein S‐dependent manner, thus resulting in inactivation of the coagulation factors Va and VIIIa, and thereby preventing the formation of fibrin. In our microfluidics approach, this anticoagulant effect of thrombomodulin on HUVEC was found to be restricted to conditions of low TF, in a similar way as we have reported before for the anticoagulant effect of plasmatic TFPI .…”

Section: Discussionmentioning

confidence: 99%

Localized endothelial‐based control of platelet aggregation and coagulation under flow: A proof‐of‐principle vessel‐on‐a‐chip study

Brouns

Provenzale

Geffen

et al. 2020

Journal of Thrombosis and Haemostasis

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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.

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Section: Discussionmentioning

confidence: 99%

Localized endothelial‐based control of platelet aggregation and coagulation under flow: A proof‐of‐principle vessel‐on‐a‐chip study

Brouns

Provenzale

Geffen

et al. 2020

Journal of Thrombosis and Haemostasis

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“… 44 , 45 Third crosstalk is at the level of fibrinolysis where aPC has been suggested to neutralize fibrinolysis inhibitors TAFI and PAI-1 resulting in the activation of the fibrinolysis. 46 Decreased levels of aPC might in turn limit the fibrinolytic response. The haemostatic system is a complex and dynamic process and continuously subject to changes based on inflammation related factors, especially in critically ill.…”

Section: Coagulation and Inflammationmentioning

confidence: 99%

A Pathophysiological Perspective on the SARS‐CoV‐2 Coagulopathy

et al. 2020

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Recent evidence is focusing on the presence of a hypercoagulable state with development of both venous and arterial thromboembolic complications in patients infected with SARS-CoV-2. The ongoing activation of coagulation related to the severity of the illness is further characterized by thrombotic microangiopathy and endotheliitis. These microangiopathic changes cannot be classified as classical disseminated intravascular coagulation (DIC). In this short review we describe the interaction between coagulation and inflammation with focus on the possible mechanisms that might be involved in SARS-CoV-2 infection associated coagulopathy in the critically ill.

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“…In addition, the endothelial surface contains membrane-bound ecto-nucleotidases (CD39/CD73), which function to degrade platelet-activating ATP and ADP [17]. Anticoagulant properties of the endothelium are provided by the thrombin-inactivating thrombomodulin and by tissue factor pathway inhibitor (TFPI) [7,18]. In recent years, it has become clear that under conditions of vascular inflammation an unbalanced crosstalk is present between the ‘inflamed’ endothelium allowing limited activation of platelets and the coagulation system [19].…”

Section: Vessel Wall-blood Component Interactions In Haemostasis Amentioning

confidence: 99%

Whole Blood Based Multiparameter Assessment of Thrombus Formation in Standard Microfluidic Devices to Proxy In Vivo Haemostasis and Thrombosis

et al. 2019

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Microfluidic assays are versatile tests which, using only small amounts of blood, enable high throughput analyses of platelet function in several minutes. In combination with fluorescence microscopy, these flow tests allow real-time visualisation of platelet activation with the possibility of examining combinatorial effects of wall shear rate, coagulation and modulation by endothelial cells. In particular, the ability to use blood and blood cells from healthy subjects or patients makes this technology promising, both for research and (pre)clinical diagnostic purposes. In the present review, we describe how microfluidic devices are used to assess the roles of platelets in thrombosis and haemostasis. We place emphasis on technical aspects and on experimental designs that make the concept of “blood-vessel-component-on-a-chip” an attractive, rapidly developing technology for the study of the complex biological processes of blood coagulability in the presence of flow.

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Activation of protein C and thrombin activable fibrinolysis inhibitor on cultured human endothelial cells

Cited by 21 publications

References 36 publications

Localized endothelial‐based control of platelet aggregation and coagulation under flow: A proof‐of‐principle vessel‐on‐a‐chip study

Localized endothelial‐based control of platelet aggregation and coagulation under flow: A proof‐of‐principle vessel‐on‐a‐chip study

A Pathophysiological Perspective on the SARS‐CoV‐2 Coagulopathy

Whole Blood Based Multiparameter Assessment of Thrombus Formation in Standard Microfluidic Devices to Proxy In Vivo Haemostasis and Thrombosis

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