ADAMTS-13 Deficiency in Children with Septic Shock.
Authors: Nguyen Trung , Liu Anne , Liu Li , Choi Hiuwan , Bergeron Angela , Mapua Patricia , Nolasco Leticia , Moake Joel F. , Dong Jing-Fei 
Published: October 2019

Abstract
Von Willebrand factor (VWF) is synthesized and released from endothelial cells and megakaryocytes/platelets in a form that is ultra-large (UL) in size and hyper-reactive in functions, capable of spontaneously activating and aggregating platelets. Upon its release, ULVWF is cleaved by the metalloprotease ADAMTS-13 at a single peptide bond of Tyr842 and Met843 in the A2 domain of VWF, converting this hyper-reactive ULVWF to smaller and less active form. If it is left uncleaved, ULVWF could activate and aggregate platelets, leading to systemic thrombosis, as often found in patients with thrombotic thrombocytopenic purpura. However, defects in ULVWF proteolysis may also occur in other conditions where ADAMTS-13 activity may be suppressed and ULVWF release from endothelial cells is systemic and persistent. To test this hypothesis, we have measured changes in ADAMTS-13 activity and ULVWF proteolysis in pediatric patients with severe sepsis with one or more organ failure, an extremely severe form of systemic inflammation that is likely to trigger the release of a large amount of ULVWF. Ten patients (and 6 matching controls) were recruited and followed for a period of 7 to 28 days in a pediatric intensive care unit. We found that the mean ADAMTS-13 activity in patients on admission as determined by a flow assay was 60.1±30.4%, significantly lower than 97.7±1.5% found control subjects. Among these patients, 70% presented severe to moderate thrombocytopenia (22,000–150,000/ml) on admission. Three patients (30%) had ADAMTS-13 activity less than 30%, below the threshold level of deficiency predetermined for this assay. Two of these three patients also presented severe thrombocytopenia (platelet counts of 22,000 and 66,000/ml, respectively). During the follow-up period, changes in ADAMTS-13 activity correlated approximately with changes in platelet counts. Patients with little or no improvement in ADAMTS-13 activity often showed persistent thrombocytopenia, whereas improvement in the enzyme activity associated with increase in platelet counts. We have also measured plasma levels of four inflammatory cytokines and found that IL-6 and TNF-α were 98.7±10.8 and 516.2±66.0 pM in patients with severe ADAMTS-13 deficiency (< 30% in activity), significantly higher than those with the enzyme activity greater than 30% (49.2±21.3 and 46.3±19.1 pM for IL-6 and TNF-a, respectively, p < 0.001). In comparison, plasma levels of IL-1β and IL-8 were elevated, but showed no difference between the two groups. The reduction in plasma IL-6 and TNF-α levels in some patients correlated with increase in ADAMTS-13 activity and platelet counts. These results suggest that severe sepsis may result in a transient deficiency in ULVWF proteolysis, likely due to deficiency in ADAMTS-13 activity (consumptive or direct inhibition). The suppression of ULVWF proteolysis may contribute to thrombocytopenia often seen in these patients. The deficiency in ULVWF proteolysis may therefore play a bridge role between inflammation and thrombosis.