Longitudinal assessments of plasma ADAMTS13 biomarkers predict recurrence of immune thrombotic thrombocytopenic purpura

Abstract

Immune thrombotic thrombocytopenic purpura (iTTP) is primarily caused by immunoglobulin G (IgG)-type autoantibodies that bind and inhibit plasma ADAMTS13 activity and/or accelerate its clearance from circulation. Approximately 50% of patients with iTTP who achieve initial clinical response to therapy experience recurrence (ie, exacerbation and/or relapse); however, a reliable biomarker that predicts such an event is currently lacking. The present study determines the role of longitudinal assessments of plasma ADAMTS13 biomarkers in predicting iTTP exacerbation/recurrence. Eighty-three unique iTTP patients with 97 episodes from the University of Alabama at Birmingham Medical Center between April 2006 and June 2019 were enrolled. Plasma levels of ADAMTS13 activity, antigen, and anti-ADAMTS13 IgG on admission showed no significant value in predicting iTTP exacerbation or recurrence. However, persistently low plasma ADAMTS13 activity (<10 U/dL; hazard ratio [HR], 4.4; 95% confidence interval [CI], 1.6-12.5; P = .005) or high anti-ADAMTS13 IgG (HR, 3.1; 95% CI, 1.2-7.8; P = .016) 3 to 7 days after the initiation of therapeutic plasma exchange was associated with an increased risk for exacerbation or recurrence. Furthermore, low plasma ADAMTS13 activity (<10 IU/dL; HR, 4.8; 95% CI, 1.8-12.8; P = .002) and low ADAMTS13 antigen (<25th percentile; HR, 3.3; 95% CI, 1.3-8.2; P = .01) or high anti-ADAMTS13 IgG (>75th percentile; HR, 2.6; 95% CI, 1.0-6.5; P = .047) at clinical response or remission was also predictive of exacerbation or recurrence. Our results suggest the potential need for a more aggressive approach to achieve biochemical remission (ie, normalization of plasma ADAMTS13 activity, ADAMTS13 antigen, and anti-ADAMTS13 IgG) in patients with iTTP to prevent the disease recurrence.

Graphical abstract

Figure 1.

Selection of patients with iTTP for the study. A total of 164 patients with suspected TTP between April 2006 and June 2019 were referred for TPE. Of those, 67 patients had alternative diagnoses, 1 patient had hereditary TTP, 11 patients died during the acute episode, and 2 patients did not respond to treatment (1 later died, and 1 was lost to follow-up). These patients were excluded from the study. This left 83 unique patients (97 episodes) for analysis. Of these, 46 patients with iTTP had serial blood samples (≥3) and 48 patients had at least 2 samples collected during the treatment.

Figure 2.

Longitudinal changes of plasma ADAMTS13 activity, antigen, and anti-ADAMTS13 IgG in 46 patients with iTTP. Each solid line depicts the change of plasma ADAMTS13 activity (A), ADAMTS13 antigen (B), and anti-ADAMTS13 IgG (C) over time (eg, on admission, 3-7 days after the initiation of TPE, and at clinical response/remission), as indicated in each panel. Mann-Whitney test was performed to determine the statistical difference between any 2 groups. Here, P < .0001 indicates that the difference is statistically highly significant.

Figure 3.

Exacerbation-free survival rates in patients with iTTP based on ADAMTS13 activity, ADAMTS13 antigen, and anti-ADAMTS13 IgG. The exacerbation-free survival rates in patients with low (<25th percentile) and high (≥25th percentile) levels of plasma ADAMTS13 activity on admission (A) or in patients with low (<10 IU/dL) and high (≥10 U/dL) levels of plasma ADAMTS13 activity 3 to 7 days after initiation of TPE (B) and at clinical response/remission (C); the exacerbation-free survival rates in patients with low (<25th percentile) and high (≥25th percentile) levels of plasma ADAMTS13 antigen on admission (D), 3 to 7 days after initiation of therapies (E), and at clinical response/remission (F); the exacerbation-free survival rates in patients with high (≥75th percentile or ≥7468.4 U/mL) and low (<75th percentile or < 7468.4 U/mL) levels of plasma anti-ADAMTS13 IgG on admission (G), 3 to 7 days after initiation of therapies (H), and at clinical response/remission (I). P values less than .05 and .01 are considered to be statistically significant and highly significant, respectively.

Figure 4.

Cox proportional hazard regression analysis identifies the parameters associated with iTTP recurrence. HRs were determined in patients with low ADAMTS13 activity (<10 U/dL) 3 to 7 days after TPE (A), low ADAMTS13 activity (<10 U/dL) at clinical response/remission (B), low levels of ADAMTS13 antigen (the lowest quartile) at clinical response/remission (C), and high levels of anti-ADAMTS13 IgG (the highest quartile) 3 to 7 days after TPE (D) and at clinical response (E). Additional covariates were added to the analysis (as indicated in panels A-E). P values less than .05 and .01 are considered to be statistically significant and highly significant, respectively. WBC, white blood cells.