The adhesive glycoprotein von Willebrand factor (VWF) supports platelet interactions and stabilizes coagulation factor VIII (FVIII). Under high shear stress conditions such as those occurring in arterioles and in large stenotic arteries, plasma VWF changes from a globular into a filamentous configuration, becoming susceptible to the cleaving action of a plasma metalloprotease (Zheng et al., J Biol Chem. 2001;276:41059-41063). The deficiency or dysfunction of this enzyme, which is the thirteenth member of the ADAMTS class of metalloproteases (ADAMTS-13), is often associated with the appearance in plasma of uncleaved ultralarge VWF multimers, normally present only in vascular endothelial cells and platelets. These abnormally reactive multimers support the formation of intravascular platelet aggregates. The clinical epitome of the association between ultralarge VWF multimers, inherited or antibody-induced ADAMTS-13 deficiency, and intravascular platelet aggregation is thrombotic thrombocytopenic purpura (TTP). Beside TTP other conditions are associated with ADAMTS-13 deficiency, such as rare cases of the hemolytic uremic syndrome and such chronic conditions as liver cirrhosis, metastatic cancer, inflammatory states, the postoperative state, and others.
In this issue Reiter and colleagues (page 946) report that plasma ADAMTS-13 decreased to approximately half-normal levels in 10 healthy individuals and 3 patients with type 1 von Willebrand disease (VWD) after infusion of the vasopressin analogue desmopressin (DDAVP). This compound has been used since 1977 to treat patients with mild hemophilia A and type 1 VWD because it transiently raises 2-3 times over baseline the plasma levels of FVIII and VWF (Mannucci P. M., Blood. 1997;90:2515-2521). What is the mechanism of the short-lasting ADAMTS-13 drop, that in DDAVP-treated individuals occurs concomitantly with the increase of VWF and the fresh appearance in plasma of ultralarge VWF multimers? Reiter et al put their findings in the frame of my previous observation (Mannucci et al, Blood. 2001;98:2730-2735) that the long-lasting decrease of ADAMTS-13 seen in patients with the forementioned chronic conditions was concomitantly associated with an increase of VWF. They purport that their DDAVP model of short-lasting changes of ADAMTS-13 and VWF into opposite directions provides further evidence for a regulatory negative feedback mechanism between enzyme and substrate. Whether the decrease of ADAMTS-13 activity is due to exhaustion or consumption of the enzyme activity due to an excess of the VWF substrate or to other mechanisms remains an open issue. The DDAVP-induced drop of ADAMTS-13 to half-normal levels is unlikely to create a condition similar to that of TTP and to engender a risk of thrombosis, because protease levels of 5% to 10% of normal are usually sufficient to prevent clinical manifestations of thrombotic microangiopathies.
