P399Vessel wall- and blood-borne- tissue factor contribute to arterial thrombus growth in a shear rate and lesion type dependent fashion

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Abstract

Background

Vascular wall tissue factor (TF) accounts for most of the thrombogenic potential of atherosclerosis plaques; however, blood-borne TF may also contribute to thrombus formation and propagation.

Objectives

To evaluate under controlled flow conditions the contribution of arterial and blood-borne TF to arterial thrombus formation triggered by healthy eroded (HE)(healthy sub-endothelium) and healthy disrupted (HD)(media) vessels devoid of TF, and TF-rich human atherosclerotic arteries (AT).

Methods

Thrombogenicity of HE-TF-, HD-TF-, and AT-TF + was evaluated at baseline (control) and after inhibition of the TF pathway (FFR-rFVIIa in vivo administered in the porcine model) in the Badimon perfusion chamber and by immunohistochemistry. In addition, platelets, peripheral blood mononuclear cells (PBMC), and microparticles from the perfused blood exposed to HD-TF- were isolated and tested for TF-protein content. TF pro-coagulant (TF-PCA) activity was also assessed in platelet-poor-plasma and whole blood.

Results

Both platelet and fibrin deposition on AT-TF + and HD-TF- were significantly inhibited by systemic FFR-rFVIIa, in a time- and shear-dependent manner (p < 0.01). Platelet deposition on HE-TF- was low and independent of TF. Contrariwise, local treatment with FFR-rFVIIa on vessels devoid of TF exerted no antithrombotic effects. While in AT-TF + TF protein was found in the tissue and in the deposited thrombus, in the HD-TF--perfused substrates TF was detected only in the thrombus. Moreover, TF protein was found in microparticles, PBMC, and platelets, especially microparticles (p < 0.0001 vs platelets; p < 0.05 vs PBMC; p=ns vs thrombus). FFR-rFVIIa reduced whole blood TF procoagulant activity (p < 0.01) whereas exhibited no effect on platelet-poor-plasma. Prothrombin time was prolonged with treatment (p=0.0001) and correlated positively with FFR-rFVIIa plasma levels (r2=0.82; p=0.0001).

Conclusions

AT-TF + plays a major role on thrombus formation; however, our results additionally show that HD-TF- also trigger TF-rich thrombus. Therefore, blood-borne-TF contributes in a shear rate and lesion type dependent manner to thrombosis.

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