Clinical factors and biomarkers predict outcome in patients with immune-mediated thrombotic thrombocytopenic purpura

Abstract

Immune-mediated thrombotic thrombocytopenic purpura is characterized by severe thrombocytopenia and microangiopathic hemolytic anemia. It is primarily caused by immunoglobin G type autoantibodies against ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor. However, reliable markers predictive of patient outcomes are yet to be identified. Seventy-three unique patients with a confirmed diagnosis of immune-mediated thrombotic thrombocytopenic purpura between April 2006 and December 2017 were enrolled from the Univeristy of Alabama at Birmingham Medical Center. Clinical information, laboratory values, and a panel of special biomarkers were collected and/or determined. The results demonstrated that the biomarkers associated with endothelial injury (e.g., von Willebrand factor antigen and collagen-binding activity), acute inflammation (e.g., human neutrophil peptides 1-3 and histone/deoxyribonucleic acid complexes), and activation of the complement alternative pathway (e.g., factors Bb and iC3b) were all significantly increased in patients with acute immune-mediated thrombotic thrombocytopenic purpura compared to those in the healthy controls. Moreover, failure to normalize platelet counts within 7 days or failure to markedly reduce serum lactate dehydrogenase by day 5, low total serum protein or albumin, and high serum troponin levels were also predictive of mortality, as were the prolonged activated partial thromboplastin time, high fibrinogen, and elevated serum lactate dehydrogenase, Bb, and sC5b-9 on admission. These results may help to stratify patients for more intensive management. The findings may also provide a framework for future multicenter studies to identify valuable prognostic markers for immune-mediated thrombotic thrombocytopenic purpura.

Figure 1.

The Alabama TTP Cohort. A. A map of the state of Alabama denotes the geographic distribution of the 73 unique patients with iTTP that were included in the study. Five patients residing in Oregon, Ohio, New York, Georgia, and Mississippi are not shown on the map. The location of the UAB Medical Center is marked with a blue star. B. Algorithm demonstrates the number of admissions, patients being excluded, and the final cohort of patients in the study.

Figure 2.

Plasma ADAMTS13 activity and autoantibodies in 73 unique patients with iTTP. Plasma levels of ADAMTS13 activity (A) and functional inhibitor titers (B) in patients with iTTP compared with those in the healthy controls. Additionally, plasma anti-ADAMTS13 IgG levels in iTTP patients with negative (<0.4 U/mL) and positive (>=0.4 U/mL) inhibitors are shown (C). Each individual dot represents a single patient with the median ± 95% confidence intervals (solid red lines). Mann-Whitney was used to determine the statistical significance between two groups. Here *, **, ***, and **** indicate the P values of <0.05, <0.001, 0.0005, and <0.0001, respectively; n.s. stands for no statistical difference between two groups.

Figure 3.

Plasma levels of VWF antigen and collagen-binding activitity in patients with iTTP. Plasma VWF antigen (VWF-Ag) (A), collagen-binding activity (VWF-CBA) (B), and the ratio of VWF-CBA to VWF-Ag (C) were determined in patients with iTTP (initial vs. exacerbated or relapsed) and the healthy controls. Each dot represents a single patient and solid lines are the median ± 95% confidence intervals. Kruskal-Willis analysis was used to determine the statistical significance among three different groups. Here *, **, ***, and **** indicate the P values of <0.05, <0.001, 0.0005, and <0.0001, respectively; n.s. stands for no statistical difference.

Figure 4.

Plasma levels of HNP1-3 and histone/DNA complexes in patients with iTTP. Plasma levels of HNP1-3 (A) and histone/DNA complexes (B) in patients with acute iTTP (initial vs. exacerbated or relapsed) and healthy controls are shown as the dot plots for individual patients with the median ± 95% confidence intervals (solid red lines). Kruskal-Willis analysis was used to determine the statistical significance. Here **** indicates P value <0.0001 when compared the values in the healthy controls.

Figure 5.

Plasma levels of complement activation markers in patients with iTTP. Plasma levels of complement activation markers including C4d (A), Bb (B), iC3b (C), and sC5b-9 (D) in patients with acute iTTP (initial vs. exacterbated or relapsed) and the healthy controls. Each dot represents the value of each individual subject. The red solid lines are the medians ± 95% confidence interval. Kruskal-Willis analysis was used to determine the statistical significance. Here *, **, and **** indicate the P values of <0.01, and <0.0001, respectively; n.s. stands for no statistical difference.