Editors' ChoiceVascular Disease

Breaking Up the Clot

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Science Translational Medicine  11 Apr 2012:
Vol. 4, Issue 129, pp. 129ec61
DOI: 10.1126/scitranslmed.3004090

Taking a plane is generally a safe travel option. Yet in part because passengers are relatively immobile, traveling on a long-distance flight triples the risk of thrombotic clotting in the veins, which can be deadly if part of the clot breaks off and travels to the lung. More than 150 years ago, the German physician Rudolf Virchow described factors associated with deep vein thrombosis (DVT), including interrupted blood flow, but the events that translate depressed venous blood flow into thrombogenesis remained unknown. Von Brühl and colleagues now characterize events in a new mouse model that mimics human DVT, in that blood flow is restricted but the endothelial layer that lines the vessel is not injured, similar to what occurs during long-distance flights.

To reduce blood flow velocity, the researchers placed a permanent narrowing ligature on the outside of the inferior vena cava, a large vein, and found that this procedure caused DVT. Limited blood flow induced a proinflammatory endothelial phenotype that resulted, within 1 hour, in the recruitment of innate immune cells (predominantly neutrophils and monocytes) to the vessel wall. Such accumulation required endothelial P-selectin, an adhesive protein; mice that lacked P-selectin were protected against DVT. Additional experiments showed that tissue factor [(TF), the main initiator of blood coagulation] released by leukocytes was required for deposition of fibrin—a step in clot formation—but not for immune cell recruitment. Furthermore, a reduction in venous blood flow caused neutrophils to release extracellular traps—networks of fibers called NETs—that act as a prothrombotic surface by binding TF and coagulation factor XII.

The authors also observed that within 2 hours after ligature placement, platelets adhered to the endothelium, forming aggregates with adherent leukocytes. These platelets were found to support further leukocyte recruitment and release of NETs by neutrophils. Platelet–leukocyte interactions required the platelet receptor (glycoprotein Ibα) for the adhesive protein von Willebrand factor.

This study elucidates the crosstalk between platelets and inflammatory cells in the pathogenesis of DVT, findings that might lead to new therapeutic schemes to prevent and treat DVT. It is not yet clear, however, whether these results are relevant to DVT caused by factors other than reduced blood flow.

M. L. von Brühl et al., Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J. Exp. Med. 26 March 2012 (10.1084/jem.20112322). [Abstract]

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