Measurement and prevalence of circulating ADAMTS13‐specific immune complexes in autoimmune thrombotic thrombocytopenic purpura

Abstract

prevalence of circulating ADAMTS13-specific immune complexes in autoimmune thrombotic thrombocytopenic purpura. J Thromb Haemost 2014; 12: 329-36.Summary. Background: The formation of ADAMTS13-specific circulating immune complexes (CICs) may be a pathophysiologic mechanism in autoimmune thrombotic thrombocytopenic purpura (TTP), but has not been systematically investigated. Objectives: (a) To develop an assay for ADAMTS13-specific CICs; (b) to evaluate their prevalence in autoimmune TTP; and (c) to assess their association with ADAMTS13-related measurements and clinical features in autoimmune TTP patients. Patients/ Methods: We developed and validated an ELISA method for ADAMTS13-specific CICs. ADAMTS13-specific CICs were searched for in 55 patients with autoimmune TTP from the Milan TTP Registry (URL:http://www.ttpdatabase.org/) and 28 controls. The associations between ADAMTS13-specific CIC levels and ADAMTS13 activity, antigen, anti-ADAMTS13 IgGs and acute TTP clinical features were assessed by multivariate linear regression. Results: Intra-and inter-assay coefficients of variation of the new test were 5.3 and 9.6%. In 36 patients with severe ADAMTS13 deficiency and anti-AD-AMTS13 autoantibodies, the prevalence of ADAMTS13-specific CICs was 47% (n = 17; 95% confidence interval [CI], 32-63%). ADAMTS13-specific CICs were detected also in seven of 19 (37%; 95% CI, 19-59%) patients with reduced ADAMTS13 activity, but apparently negative anti-ADAMTS13 autoantibodies. ADAMTS13-specific CICs were not associated with ADAMTS13 activity, antigen or anti-ADAMTS13 IgGs. In patients with acute TTP, increasing levels of ADAMTS13-specific CICs were associated with a higher number of plasma-exchange procedures required to attain remission (per 0.1 increase in normalized OD values, beta, 2.9; 95% CI, À0.7 to 6.5).Conclusions: Approximately one to two-thirds of patients with autoimmune TTP display ADAMTS13-specific CICs. A thorough investigation of the prognostic relevance of ADAMTS13-specific CIC levels in autoimmune TTP is warranted.

Pediatric thrombotic thrombocytopenic purpura

“…The anti-ADAMTS13 antibodies are mainly directed against the spacer domain of the protease (95% of autoantibodies) ( Figure 1). 22 However, in some acquired TTP cases with ADAMTS13 deficiency, antibodies may be undetectable which could be related to the lack of sensitivity of available methods, 23 to anti-ADAMTS13 antibodies of IgM or IgA type, 24 to an altered synthesis or secretion of ADAMTS13, 25 to consumption or further enzymatic degradation of the protease. [26][27][28] The differential diagnosis between TTP and other cytopenias in children can be challenging and 31% of initial misdiagnosis (HUS, atypical HUS, autoimmune cytopenia, hematological malignancy) have been reported.…”

Laboratory Assays for ADAMTS13

“…The same study found an association between increasing levels of ADAMTS13-specifi c CICs and the number of plasma exchanges needed to achieve remission [ 57 ]. An ELISA method has recently been developed and validated by an Italian group to detect ADAMTS13-specifi c CICs, with mean intra-and inter-assay CVs of 5.3 and 9.6 %, respectively [ 57 ]. This type of ELISA is not yet commercially available, and the potential usefulness of measuring ADAMTS13-associated CICs in clinical practice warrants further studies.…”

“…A recent study demonstrated CICs in one-to two-thirds of patients with TTP, and the levels of ADAMTS13-specifi c CICs were independent from other ADAMTS13 measurements. The same study found an association between increasing levels of ADAMTS13-specifi c CICs and the number of plasma exchanges needed to achieve remission [ 57 ]. An ELISA method has recently been developed and validated by an Italian group to detect ADAMTS13-specifi c CICs, with mean intra-and inter-assay CVs of 5.3 and 9.6 %, respectively [ 57 ].…”

Pathophysiology of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

“…The observed long‐term morbidities in this patient group (arterial hypertension, major depression, neurocognitive deficits, and, particularly, the unexplained reduced life‐expectancy) hint at a much higher chronicity of iTTP than had been anticipated. The presence of circulating ADAMTS‐13 immune complexes even years after an acute iTTP episode also suggests a chronic ongoing disease, and challenges the concept of remission in iTTP.…”