Presenting ADAMTS13 antibody and antigen levels predict prognosis in immune-mediated thrombotic thrombocytopenic purpura

Abstract

Key Points• High anti-ADAMTS13 antibody and low ADAMTS13 antigen levels adversely affect outcome in immunemediated TTP with greater mortality seen.• A raised troponin at presentation confers a sixfold increase and reduced GCS a nine-fold increase in mortality in acute TTP.Immune-mediated thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder caused by antibodies against ADAMTS13. From the United Kingdom TTP registry, we undertook a prospective study investigating the impact of the presenting anti-ADAMTS13 IgG antibody and ADAMTS13 antigen on mortality. A total of 312 episodes involving 292 patients over 87 months were included; 68% were female, median age 46 (range, 11-88 years), and median presenting ADAMTS13 of <5% (range, <5%-18%). The mortality rate was 10.3% (n 5 32); 68% of patients had a raised troponin at presentation conferring a sixfold increase in mortality compared with those with normal troponin levels (12.1% vs 2.0%, P 5 .04). Twenty-four percent had a reduced Glasgow Coma Score (GCS) at presentation with a ninefold increase in mortality (20% vs 2.2% for normal GCS at presentation, P < .0001). Mortality increased with higher anti-ADAMTS13 antibody levels and lower ADAMTS13 antigen levels. Those with antibody levels in the upper quartile (antibody >77%) had a mortality of 16.9% compared with 5.0% for the lowest quartile (antibody <20%) (P 5 .004). Those with an antigen level in the lowest quartile (antigen <1.5%) had a mortality of 18% compared with 3.8% for the highest quartile (antigen >11%) (P 5 .005). The synergistic effect of anti-ADAMTS13 IgG antibody in the upper quartile and ADAMTS13 antigen in the lowest quartile had the highest mortality of 27.3%. We conclude that both anti-ADAMTS13 IgG antibody and ADAMTS13 antigen levels correlate with outcome in TTP with increased cardiac and neurological involvement and increased mortality. (Blood. 2017;130(4):466-471)

Anti‐ADAMTS13 autoantibodies in immune‐mediated thrombotic thrombocytopenic purpura do not hamper ELISA‐based quantification of ADAMTS13 antigen

“…Reproducibility, expressed as %CV when testing four quality control samples on six replicates over 3 days by two technicians, was <18% for each quality control (Table ). In addition, the reference range of ADAMTS13 antigen levels in our large (n = 423) healthy donor cohort was 53%‐174%, which is in line with reference ranges previously measured in smaller healthy donor cohorts …”

“…First, ADAMTS13 antigen levels were determined in a large cohort of 423 healthy donor and 112 acute iTTP patient plasma samples. As previously reported, ADAMTS13 antigen levels were significantly ( P < .0001) reduced in acute iTTP patients (15 ± 18%) compared to healthy donors (101 ± 18%; Figure ). The detection limit (DL) and quantification limit (QL) were 3% and 4%, respectively.…”

“…This ADAMTS13 antigen ELISA was validated in‐house, but the validation was not published at that time . Different clinical laboratories used our ADAMTS13 antigen ELISA in the meantime and validated the assay in their laboratories . In the current paper we report the in‐house validation of this ADAMTS13 antigen ELISA to document the reliability of our assay.…”

“…Routine ADAMTS13 antigen determination could therefore facilitate improvement of the initial treatment. Furthermore, ADAMTS13 antigen assessment revealed antibody‐mediated ADAMTS13 clearance as the major pathogenic mechanism in this disease, as ADAMTS13 antigen levels are reduced in the majority of iTTP patients …”

“…Currently, biological investigation of iTTP is based on determination of ADAMTS13 activity (<10%) and on the presence of anti‐ADAMTS13 autoantibodies . ADAMTS13 antigen levels, however, appear to be more variable (moderately to severely reduced) and are not routinely measured, but presenting ADAMTS13 antigen levels were shown to be associated with disease prognosis in three independent studies . Routine ADAMTS13 antigen determination could therefore facilitate improvement of the initial treatment.…”