Abstract
In advanced inflammatory disease, microvascular thrombosis leads to the interruption of blood supply and provokes ischemic tissue injury. Recently, intravascularly adherent leukocytes have been reported to shape the blood flow in their immediate vascular environment. Whether these rheological effects are relevant for microvascular thrombogenesis remains elusive. Employing multi-channel in vivo microscopy, analyses in microfluidic devices, and computational modeling, we identified a previously unanticipated role of leukocytes for microvascular clot formation in inflamed tissue. For this purpose, neutrophils adhere at distinct sites in the microvasculature where these immune cells effectively promote thrombosis by shaping the rheological environment for platelet aggregation. In contrast to larger (lower-shear) vessels, this process in high-shear microvessels does not require fibrin generation or extracellular trap formation, but involves GPIbα-vWF and CD40-CD40L-dependent platelet interactions. Conversely, interference with these cellular interactions substantially compromises microvascular clotting. Thus, leukocytes shape the rheological environment in the inflamed venular microvasculature for platelet aggregation thereby effectively promoting the formation of blood clots. Targeting this specific crosstalk between the immune system and the hemostatic system might be instrumental for the prevention and treatment of microvascular thromboembolic pathologies, which are inaccessible to invasive revascularization strategies.
Highlights
In advanced inflammatory disease, microvascular thrombosis leads to the interruption of blood supply and provokes ischemic tissue injury
To investigate the mechanisms underlying microvascular thrombosis in inflamed tissue, we performed in vivo microscopy analyses in the mouse cremaster muscle
Microvascular thrombosis is a hallmark of advanced inflammatory disease which leads to the interruption of blood supply and provokes ischemic tissue injury[1,3,4]
Summary
Microvascular thrombosis leads to the interruption of blood supply and provokes ischemic tissue injury. In addition to platelets and the coagulation system, leukocytes have recently been reported to collaborate for clot formation in larger vessels (as assessed in models of arterial injury and deep vein thrombosis) and hepatic sinusoids (during the clearance of circulating pathogens) in a process termed ‘immunothrombosis’: Under exposure to relatively low shear stress, neutrophils support thrombus growth by the release of extracellular traps (NETs; network of extracellular fibers containing DNA and other molecules10) which, in turn, activate components of the coagulation system and facilitate platelet aggregation[11,12,13,14] Whether these elementary immune cell-driven events are relevant for the formation of thrombi in the microvasculature of inflamed tissue, is still unclear. We hypothesize that these distinct rheological effects arising from leukocytes recruited to the inner vessel wall of inflamed tissue propagate microvascular thrombus formation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
