Abstract
Connective tissue disease (CTD) is sometimes complicated with thrombotic microangiopathy (TMA). Despite of the reports on several sporadic cases with acquired deficiency of ADAMTS13 activity (ADAMTS13:AC), it has been said that a majority of the patients with CTD-TMA have almost normal or slightly reduced levels of ADAMTS13:AC in their plasmas. But this has not been evaluated in a large population of such patients. As a nationwide referral center of TMA during the past 10 years, we were able to identify 783 patients with TMAs across Japan. Among these patients, 188 were categorized into CTD-TMA, of which 170 patients with a set of clinical and laboratory data were extensively analysed in this study. The patient’s categorization and their numbers were the followings; systemic lupus erythematosus (SLE, n=59), systemic sclerosis (SSc, n=40), polymyositis /dermatomyositis (PM/DM, n=9), antiphospholipid syndrome (APS, n=9), Sjögren’s syndrome (SS, n=8), rheumatoid arthritis (RA, n=9), mixed connective tissue disease (MCTD, n=7), overlap syndrome (OS, n=5), vasculitis syndrome (VS, n=8), and others (n=14). Plasma levels of ADAMTS13:AC and its inhibitors were determined by both a classic von Willebrand factor multimer (VWFM) assay and a commercially available ADAMTS13-act-ELISA kit (Kainos Inc., Tokyo), and a high correlation of the values between them was identified (r=0.72). To visualize the IgG-autoantibodies to ADAMTS13 in tested plasmas, western blot (WB) analysis using the purified human plasma derived (pd)-ADAMTS13 (Hiura et al, ISTH abs P-M-295, 2007) was also performed. Severe deficiency of ADAMTS13:AC (<3% of the control) was found in 34 patients with CTD-TMA (34/170, 20%), who had the neutralizing autoantibodies (inhibitors) against ADAMTS13 except for one. Supporing these results, the IgG-autoantibodies were detected in 22 of 34 patients (65%) by the WB method. When these data were analysed separately in a specific category of CTD, the frequency of severe deficiency of ADAMTS13:AC was the following order; SS (5/8, 63%), MCTD (4/7, 57%), APS (4/9,44%), SLE (15/59, 25%), RA (2/9, 22%), PM/DM (1/11, 9%), others (1/14, 7%), SSc (2/40, 5%), OS (0/5, 0%), and VS (0/8, 0%). Further, the plasma levels of ADAMTS13:AC and VWF:AG in the patients with CTD-TMA were 26.1±21.2% and 288±179%, respectively, and the ratio of VWF:AG/ADAMTS13:AC in these patients was extremely high (112±256), as compared to normal control (1.0±0.3). Our data indicate that firstly 20% (34/170) of the patients with CTD-TMA are induced by severe deficiency of ADAMTS13:AC due to its inhibitors. Secondly, the rest 80% are caused by other precipitating factors, which may include the non-neutralizing autoantibodies to ADAMTS13 that reduce plasma level of ADAMTS13:AC by accelerating clearance of the immune complex from circulation or inhibit the enzyme binding to vascular endothelial cell surface, requiring for an efficient cleavage of newly-released unusually large VWFMs. A significant effectiveness of plasma exchange therapy to both the groups of patients with CTD-TMA may reflect this hypotheisis. Thirdly, however, the vascular endothelial cell damages with or without the thickening of small vessel walls in these patients may cause the hemodynamic changes in microcirculation that accelerate platelet aggregation or thrombi formation leading to TMAs.
