Multicenter Prospective Pilot Study Identifying Thrombomodulin as a Potential Biomarker for Neurocognitive Outcomes in Immune Thrombotic Thrombocytopenic Purpura

Abstract

Background/Objectives: Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, chronically relapsing disorder that causes life-threatening thrombotic microangiopathy. Many survivors in clinical remission show evidence of ongoing silent cerebral infarction and neurocognitive deficits. Prospective longitudinal studies of this population are needed to acquire a complete understanding of the mechanism behind this ongoing neurologic injury. We aimed to assess the feasibility of a multicenter prospective study of neuropsychological and cognitive function in iTTP survivors in remission and examine novel biomarkers. Methods: We aimed to enroll 50 iTTP patients across three USTMA consortium sites between 2019 and 2022 in a 24-month longitudinal study. Clinical, cognitive, and biomarker assessments, including ADAMTS13 activity, were performed. Results: Despite the COVID-19 pandemic, we enrolled 38 subjects, and 31 (81.6%) completed closeout evaluations at 24 months. Upon the participants' enrollment in the study, we confirmed previous findings, including high rates of moderate to severe neurocognitive and psychiatric sequelae (anxiety, 47%; depression, 45%; and headaches, 55%). Changes in cognitive function were measurable and included decreased immediate memory and visuospatial abilities. Over this two-year study, we did not see a significant change in neurocognitive findings. There was no association between cognitive function and ADAMTS13 activity; however, we found that the level of soluble thrombomodulin (CD141) was significantly correlated with cognitive impairment. Conclusions: We conclude that a more extensive study is feasible, and at least 5-10 years may be required to detect trends in neurocognitive function. Soluble thrombomodulin is a promising biomarker for cognitive impairment in survivors of iTTP, and it is worthy of additional study.

Keywords: neurocognitive function; thrombotic microangiopathy; thrombotic thrombocytopenic purpura.

Figure A1

All ADAMTS13 measurements made during this study are shown; the red shaded area indicates ADAMTS13 activities < 20%. The table shows the participant-level details of these data points.

Figure A2

(a) RBANS total scale percentile vs. syndecan. (b) RBANS total scale percentile vs. SVAP. (c) RBANS total scale percentile vs. selectin. (d) RBANS total scale percentile vs. ADAMTS13 activity. The line is a fitted local regression, with Spearman correlation and p-value shown above each figure.

Figure 1

RBANS Total score percentile vs. thrombomodulin (CD141). All visits during which we measured both the RBANS and CD141 are shown. The line is a fitted local regression with Spearman correlation and p-value listed.