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Vessel-plugging clots (arrow) form in mice lacking the protease ADAMTS13.
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Blood clots are needed to patch vessel injuries. But clot size must be carefully controlled, as oversized clots (thrombi) can plug up blood vessels. The combined action of protease inhibitors, which inactivate clotting factors, and fibrin-cleaving enzymes, which dissolve the fibrin meshwork of the clot, keeps clot size in check. On page 767, Chauhan and colleagues find that another enzyme—the metalloprotease ADAMTS13—is also required to limit clot size.
ADAMTS13 chops up ultra-large multimers of von Willebrand factor (UL-VWF), the blood protein that tethers platelets to injured blood vessels. The importance of dicing up UL-VWF became clear when defects in ADAMTS13 were identified as the cause of the life-threatening disease thrombotic thrombocytopenic purpura (TTP). In patients with TTP, small clots—composed largely of platelets and VWF—form in vessels, eventually breaking free and clogging downstream vessels. What instigates clot formation in these patients is unknown, although infections are often associated with the onset of TTP symptoms.
A collaborating group recently created a mouse model of TTP by making mice that lack ADAMTS13. In these mice, newly released UL-VWF remained stuck to the vessel wall for longer than normal, snaring passing platelets and forming long strings that wave in the bloodstream. When injected with a vessel-damaging bacterial toxin, the ADAMTS13-deficient mice developed a TTP-like disease, with unstable VWF platelet–rich clots forming in their veins.
Now, Chauhan and colleagues show that ADAMTS13 not only inhibits the initial adhesion of platelets to the vessel wall, but also limits the growth of platelet-containing clots. In the deficient mice, spontaneous clots formed and injury-induced clots grew larger and faster than in normal mice. Treating the mice with recombinant ADAMTS13 dissolved injury-induced clots, suggesting that ADAMTS13's clot-busting power could potentially be harnessed for the treatment of thrombotic conditions such as heart attacks and strokes.
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