Vitronectin promotes immunothrombotic dysregulation in the venular microvasculature

Microvascular immunothrombotic dysregulation is a critical process in the pathogenesis of severe systemic inflammatory diseases. The mechanisms controlling immunothrombosis in inflamed microvessels, however, remain poorly understood. Here, we report that under systemic inflammatory conditions the matricellular glycoproteinvitronectin (VN) establishes an intravascular scaffold, supporting interactions of aggregating platelets with immune cells and the venular endothelium. Blockade of the VN receptor glycoprotein (GP)IIb/IIIa interfered with this multicellular interplay and effectively prevented microvascular clot formation. In line with these experimental data, particularly VN was found to be enriched in the pulmonary microvasculature of patients with non-infectious (pancreatitis-associated) or infectious (coronavirus disease 2019 (COVID-19)-associated) severe systemic inflammatory responses. Targeting the VN-GPIIb/IIIa axis hence appears as a promising, already feasible strategy to counteract microvascular immunothrombotic dysregulation in systemic inflammatory pathologies.

Automated summary

Microvascular immunothrombotic dysregulation plays a critical role in severe systemic inflammatory diseases, but the underlying mechanisms are poorly understood. This study shows that the matricellular glycoprotein vitronectin (VN) forms an intravascular scaffold under systemic inflammatory conditions, promoting interactions between platelets, immune cells, and the venular endothelium. Blocking the VN receptor glycoprotein (GP)IIb/IIIa prevents microvascular clot formation. The presence of VN is enriched in the pulmonary microvasculature of patients with severe systemic inflammatory responses. Targeting the VN-GPIIb/IIIa axis may be a promising strategy to counteract microvascular immunothrombotic dysregulation.