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. 2021 Feb;19(2):370-379.
doi: 10.1111/jth.15176. Epub 2021 Jan 3.

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

Jingrui Sui  1 , Ruinan Lu  1   2 , Konstantine Halkidis  1   3 , Nicole K Kocher  1 , Wenjing Cao  1   2 , Marisa B Marques  1 , X Long Zheng  1   2
Affiliations

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

Jingrui Sui et al. J Thromb Haemost. 2021 Feb.

Abstract

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening blood disorder, primarily resulting from autoantibodies against ADAMTS13. Infection or inflammation often precedes acute iTTP. However, the association of inflammation and inflammatory mediators with disease severity and outcome of acute iTTP is not fully assessed.

Objectives: Here, we determined plasma levels of S100A8/A9, histone/DNA complexes, citrullinated histone H3 (CitH3), and cell-free DNA (cfDNA) in a cohort of 108 acute episodes from 94 unique iTTP patients and healthy controls, and assessed the association of each of these biomarkers with the disease severity and mortality.

Results: All acute iTTP patients had significantly increased plasma levels of S100A8/A9 (median 84.8, interquartile range [IQR] 31.2-157.4 µg/mL), histone/DNA complexes (median 55.7, IQR 35.8-130.8 U/mL), CitH3 (median 3.8, IQR 2.2-6.4 ng/mL), and cfDNA (median 937.7, IQR 781.3-1420.0 ng/mL) on the admission blood samples when compared with healthy controls. An increased plasma level of S100A8/A9, histone/DNA complex and cfDNA was associated with organ damage, coagulopathy, and mortality in iTTP. After being adjusted for age and history of hypertension, Cox proportional hazard regression analysis demonstrated that a hazard ratio (95% confidence interval) for an elevated plasma level of S100A8/A9, histone/DNA complexes, and cfDNA was 11.5 (1.4-90.9) (P = .021), 10.3 (2.7-38.5) (P = .001), and 12.8 (3.9-42.0) (P = .014), respectively.

Conclusion: These results indicate that inflammation or plasma inflammatory mediators such as S100A8/A9 or NETosis markers such as histone/DNA complexes and cfDNA may play a role in pathogenesis of iTTP, which may help stratify patients with a high risk of death during acute iTTP episodes.

Keywords: NETosis; and mortality; inflammation; neutrophil activation; thrombosis.

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Conflict of interest statement

CONFLICT OF INTEREST

Dr. Zheng is a speaker or consultant for Alexion, Sanofi, and Takeda.

Dr. Zheng is also a cofounder of Clotsolution, Inc, Kansas City, Kansas. All other authors have declared no relevant conflict.

Figures

FIGURE 1
FIGURE 1
Plasma S100A8/A9, histone/DNA complexes, CitH3, and cfDNA in patients with acute iTTP and healthy controls. Plasma levels of (A) S100A8/A9, (B) histone/DNA complexes, (C) CitH3, and (D) cfDNA in patients with acute iTTP on admission and in healthy controls. All data points are presented as individual values (dots), median, and interquartile range (IQR) (horizontal bars). Mann-Whitney U test was performed to determine the statistical significance. ****P value <.0001
FIGURE 2
FIGURE 2
Plasma S100A8/A9, histone/DNA complexes, CitH3, and cfDNA in iTTP patients during acute episodes and at clinical response/remission. Plasma levels of (A) S100A8/A9, (B) histone/DNA complexes, (C) CitH3, and (D) cfDNA in iTTP patients on admission and at clinical response/remission. Wilcoxon test was performed to determine the statistical significance between the two time-points. *, ***, **** indicate P value <.05, .001, and <.0001, respectively
FIGURE 3
FIGURE 3
Plasma S100A8/A9, histone-DNA complexes, CitH3, and cfDNA in iTTP patients with or without myocardial ischemia. Plasma levels of (A) S100A8/A9, (B) histone/DNA complexes, (C) cfDNA, and (D) CitH3 in iTTP patients with and without myocardial involvement. Eighty patient episodes showed elevated troponin levels, but 26 patients had normal troponin. However, one patient with normal troponin did not have sufficient plasma for assessing plasma CitH3. All data points are expressed as individual values (dots), median, and interquartile range (IQR) (horizontal bars). Mann-Whitney U test determined the statistical significance. ns, **, and *** indicate P value >.05, <.01, and <.005, respectively
FIGURE 4
FIGURE 4
Kaplan-Meier survival analysis of iTTP patients with high and low plasma levels of S100A8/A9, histone-DNA complexes, CitH3, and cfDNA. Survival probability (%) predicted in patients with high (red line) and low (blue line) levels of S100A8/A9, histone/DNA complexes, CitH3, and cfDNA in iTTP patients as indicated in each figure. Log-rank test was performed to obtain the statistical significance. P values <.05 and <.01 are considered to be statistically significant and highly significant, respectively
FIGURE 5
FIGURE 5
Cox proportional hazard regression analysis for identification of laboratory markers associated with iTTP exacerbation. The cut off of the left was determined by receiver operating characteristic curve and Forest plot in the middle demonstrates the relative risk of exacerbation (defined by the disease recurs within 30 d of stopping TPE). Hb, hemoglobin. Covariates are age and history of hypertension. HR, hazard ratio; 95% CI, 95% confidence interval. P values <.05 and .01 are considered to be statistically significant and highly significant, respectively
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