ADAMTS13: a new link between thrombosis and inflammation

Abstract

von Willebrand factor (VWF) levels are elevated and a disintegrin-like and metalloprotease with thrombospondin type I repeats–13 (ADAMTS13) activity is decreased in both acute and chronic inflammation. We hypothesized that by cleaving hyperactive ultralarge VWF (ULVWF) multimers, ADAMTS13 down-regulates both thrombosis and inflammation. Using intravital microscopy, we show that ADAMTS13 deficiency results in increased leukocyte rolling on unstimulated veins and increased leukocyte adhesion in inflamed veins. Both processes were dependent on the presence of VWF. Depletion of platelets in Adamts13−/− mice reduced leukocyte rolling, suggesting that platelet interaction with ULVWF contributes to this process. Increased levels of endothelial P-selectin and plasma VWF in Adamts13−/− compared with wild-type (WT) mice indicated an elevated release of Weibel-Palade bodies. ULVWF multimers released upon stimulation with histamine, a secretagogue of Weibel-Palade bodies, slowed down leukocyte rolling in Adamts13−/− but not in WT mice. Furthermore, in inflammatory models, ADAMTS13 deficiency resulted in enhanced extravasation of neutrophils, and this process was also dependent on VWF. Our findings reveal an important role for ADAMTS13 in preventing excessive spontaneous Weibel-Palade body secretion, and in the regulation of leukocyte adhesion and extravasation during inflammation.

ADAMTS-12 Metalloprotease Is Necessary for Normal Inflammatory Response

“…Hence, predicting the phenotype of animal models deficient in a certain protease is very difficult and often offers unexpected findings. To date, several mouse models lacking ADAMTSs have been generated with a heterogeneous spectrum of phenotypes including those found in Adamts4-and Adamts5-deficient mice, which are protected from osteoarthritis (26), and in Adamts13-deficient mice, which show increased inflammation due to enhanced extravasation of neutrophils (27).…”

von Willebrand factor–cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke

“…More recently, VWF was also shown to contribute to leukocyte adhesion and inflammatory cell recruitment. 6,7 VWF is stored in an ultra-large form (UL-VWF; Ͼ 20 million kDa) in platelet ␣-granules and Weibel-Palade bodies of endothelial cells from which it is released during injury or inflammation. 8,9 If not immediately consumed for platelet adhesion, the UL-VWF is cleaved by ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13) to smaller less-adhesive multimers that circulate in plasma.…”

Preserved Expression of mRNA Coding von Willebrand Factor-Cleaving Protease ADAMTS13 by Selenite and Activated Protein C

“…The mechanisms involved warrant further investigation. Furthermore, a direct interaction between ADAMTS13 activity and inflammation is provided by the evidence that ADAMTS13 deficiency results in increased leukocyte rolling and adhesion, as well as enhanced extravasation of neutrophils, where both processes are dependent on the presence of ulVWF and platelets (65). In accordance with these observations, our findings suggest that ADAMTS13 deficiency during systemic inflammation and infection accelerate inflammatory responses by slowing down leukocytes and facilitating their extravasation, which functions intrinsically as a protective mechanism, but becomes destructive due to an overwhelming systemic response which might be limited by APC.…”