Background From 20 to 50% of patients who survive an acute episode of the acquired form of thrombotic thrombocytopenic purpura relapse but clinical and laboratory markers of recurrence are not well established. Design and Methods In 109 patients enrolled in an international registry we evaluated, in the frame of a retrospective cohort study, the predictive role of the metalloprotease ADAMTS13 as measured in plasma during remission. Anti-ADAMTS13 antibodies and von Willebrand factor were also evaluated in a smaller number of the same patients. Results Median values of ADAMTS13 activity and antigen were significantly lower in patients with recurrent thrombotic thrombocytopenic purpura than in those with no recurrence (activity: 12% vs. 41%; p=0.007; antigen: 36% vs. 58%; p=0.003). A severe deficiency of ADAMTS13 activity (10% or less) was associated with a higher likelihood of recurrence (odds ratio 2.9; 95% confidence interval 1.3 to 6.8; p=0.01). Anti-ADAMTS13 antibodies were also more prevalent in patients with recurrent thrombotic thrombocytopenic purpura (odds ratio 3.1; 95% confidence interval 1.4 to 7.3; p=0.006). The presence during remission of both severe ADAMTS13 deficiency and anti-ADAMTS13 antibodies increased the likelihood of recurrence 3.6 times (95% confidence interval 1.4 to 9.0; p=0.006). The presence of ultralarge von Willebrand factor multimers and of associated diseases or conditions did not increase recurrence. Conclusions Survivors of an acute episode of acquired thrombotic thrombocytopenic purpura with severely reduced levels of ADAMTS13 and/or with anti-ADAMTS13 antibodies during remission have an approximately three-fold greater likelihood of developing another episode of thrombotic thrombocytopenic purpura than patients with higher protease activity and no antibody.

The function of thrombospondin-1 (TSP-1) in hemostasis was investigated in wild-type (WT) and Tsp1^-/- mice, via dynamic platelet interaction studies with A23187-stimulated mesenteric endothelium and with photochemically injured cecum subendothelium. Injected calcein-labeled WT platelets tethered or firmly adhered to almost all A23187-stimulated blood vessels of WT mice, but Tsp1^-/- platelets tethered to 45% and adhered to 25.8% of stimulated Tsp1^-/- vessels only. Stimulation generated temporary endothelium-associated ultralarge von Willebrand factor (VWF) multimers, triggering platelet string formation in 48% of WT versus 20% of Tsp1^-/- vessels. Injection of human TSP-1 or thrombotic thrombocytopenic purpura (TTP) patient-derived neutralizing anti-ADAMTS13 antibodies corrected the defective platelet recruitment in Tsp1^-/- mice, while having a moderate effect in WT mice. Photochemical injury of intestinal blood vessels induced thrombotic occlusions with longer occlusion times in Tsp1^-/- venules (1027 ± 377 seconds) and arterioles (858 ± 289 seconds) than in WT vessels (559 ± 241 seconds, P < .001; 443 ± 413 seconds, P < .003) due to defective thrombus adherence, resulting in embolization of complete thrombi, a defect restored by both human TSP-1 and anti-ADAMTS13 antibodies. We conclude that in a shear field, soluble or local platelet-released TSP-1 can protect unfolded endothelium-bound and subendothelial VWF from degradation by plasma ADAMTS13, thus securing platelet tethering and thrombus adherence to inflamed and injured endothelium, respectively.

Significance: The blood protein von Willebrand factor (VWF) is required for platelets to stop bleeding at sites of injury, and the metalloprotease ADAMTS13 limits platelet adhesion by cleaving VWF only when flowing blood stretches it, especially within a growing thrombus. This feedback inhibition is essential because ADAMTS13 deficiency causes fatal microvascular thrombosis. How ADAMTS13 recognizes VWF so specifically is not understood. We now find that ADAMTS13 is folded roughly in half so that its distal domains inhibit the metalloprotease domain. VWF relieves this autoinhibition and promotes its own destruction by allosterically activating ADAMTS13. Thus, VWF is both a substrate and a cofactor in this critical regulatory process.

The inability to regulate the inflammatory response initiated upon infection leads to severe sepsis, characterized by widespread microvascular injury and thrombosis, organ ischemia, and dysfunction. A disintegrin-like and metalloprotease with thrombospondin type 1 repeats (ADAMTS)-13 regulates primary hemostasis by proteolyzing von Willebrand factor (VWF). Decreased ADAMTS-13 has been reported in disseminated intravascular coagulation due to severe sepsis. The present study investigates whether the sepsis-related dysregulation of endothelial activation leads to specific changes of ADAMTS-13. Case-control study. Adult intensive care unit in a university hospital. Three groups were studied: a case group of 30 patients with severe sepsis, a control group of 29 patients with comparable organ failure unrelated to sepsis, and 30 age- and gender-matched healthy subjects. None. Significantly lower ADAMTS-13 activity was observed in patients with severe sepsis (43.2%; interquartile range, 32.7, 67.0) than in patients with organ failure unrelated to sepsis (67.8%; 57.4, 87.9; p < .05) and healthy subjects (105.6%; 87.2, 125.6; p < .001). Accordingly, ADAMTS-13 antigen was more decreased in patients with severe sepsis than in patients with organ failure unrelated to sepsis and healthy subjects. VWF antigen was higher in patients with severe sepsis than in patients with organ failure unrelated to sepsis and healthy subjects. We found strong negative correlations in severe sepsis but not in organ failure unrelated to sepsis, between ADAMTS-13 activity and 1) VWF antigen; 2) thrombomodulin; 3) interleukin-6; 4) Acute Physiology and Chronic Health Evaluation II score; 5) shock; 6) acute renal injury. Moreover, patients above the median of ADAMTS-13 activity presented a higher survival compared with those below the median in the patients with severe sepsis but not in the patients with organ failure unrelated to sepsis. In contrast, there was no significant association between VWF antigen and survival in either the severe sepsis group or the group with organ failure unrelated to sepsis. We observed low ADAMTS-13 activity and antigen in severe sepsis and in other conditions associated with organ dysfunction. ADAMTS-13 levels were significantly associated with differences in morbidity, mortality, and variables of inflammation and endothelial dysregulation only in severe sepsis patients. This suggests that ADAMTS-13 deficiency may have a pathophysiological relevance specific to severe sepsis.