05). Of note, in the plasma of six patients, ADAMTS13 activity MLN0128 clinical trial was <1%; two of these patients had APAP-induced ALF, and four had ALF from other etiologies. As shown in Fig. 2B, ADAMTS13 antigen levels were reduced in patients with ALI/ALF (466 ng/mL [204-1,335 ng/mL] versus 655 ng/mL [359-956 ng/mL] in healthy individuals (P < 0.01), but the decrease in antigen levels was not as severe as the decrease in activity levels. This is demonstrated in Fig. 2C by a significantly depressed ADAMTS13 activity/antigen ratio in patients with ALI/ALF (0.06 [0-0.19] versus healthy controls (0.14 [0.11-0.22]) (P < 0.01), indicating that the specific activity of

ADAMTS13 was reduced by >50% in patients with ALI/ALF. Despite the observation that the activity of ADAMTS13 was decreased and even below 1% in some patients, the proportion of high-molecular weight VWF multimers was reduced in patients with ALI/ALF (13.5% [4.6-24.9] versus 20.3% [11-24.6] in the plasma of healthy individuals) (P < 0.01). We studied the ability of VWF in a given plasma sample to support adhesion and aggregation of platelets isolated

from healthy individuals under conditions of high shear in a reconstituted blood model. Representative images from platelets adhered in the presence of plasma from healthy volunteers or plasma from patients with ALF are shown in Fig. 3A,B. On these images, a higher surface coverage BGB324 chemical structure was observed when platelets were sheared in the presence of ALI/ALF plasma. Also, the morphological appearance of the platelet thrombi indicated larger

aggregates when compared with thrombi generated in plasma of healthy controls. Indeed, as shown in Fig. 3C, the surface Cediranib (AZD2171) covered with platelet thrombi was significantly larger when using patient versus control plasma (11% [4.7-23] versus 9.5% [4.9-14], respectively) (P < 0.01). Concomitantly, platelet aggregation was increased when using plasma of patients with ALI/ALF compared with controls, with an average aggregate size of 29 μm2 (18-77 μm2) versus 23 μm2 (18-35 μm2), respectively (P < 0.01). We explored possible relationships between VWF:Ag levels, ADAMTS13 activity, and the outcome of patients with ALI/ALF. In Fig. 4A, it is shown that patients who received a liver transplant or those who died had a substantially lower ADAMTS13 activity of 17% [0%-69%] on admission when compared with transplant-free survivors (40% [0%-106%]) (P < 0.01). Similarly, as shown in Fig. 4B, patients with encephalopathy grade 4 on admission had profoundly lower ADAMTS13 activity (11% [0%-40%]) compared with patients without encephalopathy on admission (55% [0%-106%]) (P < 0.01). No differences in VWF:Ag levels between patients who spontaneously survived and those who did not were detected, nor were VWF:Ag levels different between the different grades of encephalopathy (Fig. 4C,D).