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.

Plasma levels of S100A8/A9, histone/DNA complexes, and cell‐free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura

“…Ninety‐four patients with 108 acute episodes of iTTP admitted to the University of Alabama at Birmingham Medical Center from April 2006 to June 2019 were enrolled into the study. This cohort of patients was of course previously reported for other biomarker analyses 14,30 . Control samples were collected from healthy donors who were age‐, gender‐, and ethnic background‐matched, but did not have a history of hematological diseases, malignancy, and acute inflammatory disorders.…”

“…Additional follow‐ups were conducted through outpatient visits, telephone interviews, and interviews at locally organized annual TTP Fairs. Diagnostic criteria for iTTP were the same as previously described 14,30,31 . These include severe thrombocytopenia, microangiopathic hemolytic anemia with or without end‐organ damage; and plasma ADAMTS13 activity <10 IU/dL with a detectable ADAMTS13 inhibitor or anti‐ADAMTS13 IgG.…”

Cerebral Infarction in Immune Thrombotic Thrombocytopenic Purpura Is Associated with Old Age, Hypertension, Smoking, and Anti-ADAMTS13 Ig, But Not with Mortality

“…Consistent with those previously reported, the high levels of anti-ADAMTS13 IgG correlate with disease progression and potential relapse in patients with acute iTTP. 38,45 However, the strong association between anti-ADAMTS13 IgG levels (but not inhibitor titer) and stroke had not previously observed. To our surprise, there was no association between plasma levels of histone/DNA complexes, citH3, and cfDNA and imaging confirmed stroke, despite a marked elevation of these markers in patients with acute iTTP compared with the healthy controls or in patients during remission.…”

“…Anti-ADAMTS13 IgG was determined using a commercial ELISA kit (DiaPharma, West Chester, Ohio) according to the manufacturer's protocol. 38 Plasma histone-DNA complexes (Millipore Sigma), cell-free DNA (cfDNA) (Thermo Fisher Scientific, Waltham, Massachusetts), 4 and citrullinated histone H3 (Cayman chemicals, Ann Arbor, Michigan) were determined using commercially available reagents, according to the manufacturers' protocols.…”

<p>Assessment and Monitoring of Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura (iTTP): Strategies to Improve Outcomes</p>

“…<13 days) showed a significantly lower risk of relapse. In addition, Sui et al 55 recommended that plasma ADAMTS13 activity, ADAMTS13 antigen, and anti-ADAMTS13 IgG levels be tested 3 to 7 days after the initiation of TPE and at clinical response/remission. They demonstrated the critical role of longitudinal assessments of plasma ADAMTS13 biomarkers including ADAMTS13 activity, ADAMTS13 antigen, and anti-ADAMTS13 IgG in predicting iTTP exacerbation and/or recurrence.…”