ADAMTS13 controls thrombus formation in microvasculature by proteolysis of ultralarge von Willebrand Factor in plasma. Severe ADAMTS13 dysfunction or deficiency due to genetic or immunological causes can result in the life-threatening microangiopathic disorder Thrombotic Thrombocytopenic Purpura (TTP). Although it may also be involved in limiting thrombus growth in larger vessels, the role of ADAMTS13 in other thrombotic disorders has not yet been clearly established. In this study we determined the levels of ADAMTS13 antigen, activity, autoantibody, and ADAMTS13/fXI complex in plasma from patients with venous thromboembolism (VTE) and from normal donors. ADAMTS13 antigen was measured using IMUBIND® ADAMTS13 Antigen ELISA, ADAMTS13 activity using the ACTIFLUOR™ ADAMTS13 Activity (FRET-based assay), ADAMTS13 autoantibody titers using IMUBIND® ADAMTS13 Autoantibody ELISA, and complex using IMUBIND® ADAMTS13/fXI Complex ELISA. The various ADAMTS13 related markers were all found to be abnormal in patients with VTE (deep vein thrombosis and pulmonary embolism) as compared with normal donors. For normal donors, the mean ADAMTS13 activity is 740 ± 110 ng/ml, whereas in patients with VTE ADAMTS13 activity is significantly lower (524 ± 200 ng/ml, P<0.001). ADAMTS13 antigen levels, however, do not differ significantly for patients with VTE compared with normal donors. Receiver-operating characteristic analysis of activity/antigen ratios shows high sensitivity and specificity for patients with VTE. Although the biochemistry and in vivo biology of the ADAMTS13/fXI complex is not completely understood, the ADAMTS13/fXI complex is 3.8-fold higher in patients with VTE relative to normal donors (P<0.05). Using an upper autoantibody cutoff level of 14.8 AU/ml, a higher percentage of patients with VTE have elevated levels of autoantibodies (26/94 or ∼28%) compared with normal donors (1/47 or ∼2%). D-dimer plasma level is a strong negative predictor for VTE. A substantial number of patients without VTE exhibit D-dimer levels above the normal cutoff, which thus excludes this assay for the positive diagnosis of VTE. We correlated D-dimer levels with the various ADAMTS13 parameters. Elevated D-dimer in patients correlates with abnormal levels of activity, autoantibody, and complex. Donors with high D-dimer levels that do not exhibit symptoms of VTE do not have abnormal activity or complex levels, but do have elevated autoantibody levels. These data suggest that ADAMTS13 activity, autoantibody, and ADAMTS13/fXI complex are potential biomarkers for VTE and furthermore, suggest that ADAMTS13 may play a role in the initiation or progression of VTE.
Disclosure:Employment: Four of the authors are in the employment of the company whose kits are used in this abstract.