High Affinity Autoantibodies to ADAMTS13 in the Antiphospholipid Syndrome.

Autoantibodies to ADAMTS13 are well known to play an important role in the development of microthrombosis and organ ischaemia in thrombotic thrombocytopenic purpura (TTP). Antiphospholipid syndrome (APS) is an autoimmune disorder associated with thrombosis and pregnancy failure, but in severe cases of APS, microvascular thrombosis can occur similar to that seen in TTP - suggesting possible mutual pathogenic factors. The role of ADAMTS13 in APS patients is unknown and we hypothesize that ADAMTS13 may play a role in the development of thrombosis in the APS population. We evaluated ADAMTS13 in 68 patients: 52 with APS (as defined by the revised Sapporo Criteria), and 16 with anti-phospholipid antibodies (aPL) only. Of the 68 patients, 38 (56%) had IgG antibody to ADAMTS13 (median 13.2 ug/ml, range 9.8 – 28.3 ug/ml, NR< 9.6 ug/ml) by ELISA (Imubind ELISA, American Diagnostica Inc). 25/68 patients (37%) demonstrated low ADAMTS13 activity by our in-house collagen binding assay (median 33.2%, range 0–64%, NR 66–126%), with 12 of the 25 patients demonstrating detectable antibody to ADAMTS13. Low activity was not associated with elevated VWF:Ag levels suggesting that high VWF turnover did not account for the low ADAMTS Activity. In addition, ADAMTS13 Antigen levels (Imubind ELISA, American Diagnostica Inc) were elevated in 45/68 (66%) (median 850 ng/ml, range 890–1379 ng/ml, NR350-730ng/ml) indicating discordance with the observed low ADAMTS13 activity levels. The increased ADAMTS13 antigen may reflect a compensatory response to the presence of autoantibodies to ADAMTS13 in APS. The abnormal ADAMTS13 findings were not associated with the presence of anticardiolipin antibody, anti-β²glycoprotein1 or lupus anticoagulant. Similarly, no association was seen in analysis of clinical subgroups (arterial or venous thrombosis, recurrent miscarriage). We subsequently purified IgG from plasma of 3 of the APS patients with detectable anti-ADAMTS13 autoantibody and observed strong binding to ADAMTS13 via ELISA. Furthermore using the purified IgG, increasing NaCl concentrations did not prevent antibody binding to ADAMTS suggesting that these antibodies are high affinity. These findings suggest that ADAMTS13 autoantibodies may have a role in other autoimmune thrombotic conditions aside from TTP. In APS, the prevalence of these high affinity antibodies may well be a pathogenic feature integral to shifting the haemostatic balance in favour of thrombosis.