Prognostic utility of ADAMTS13 activity for the atypical hemolytic uremic syndrome (aHUS) and comparison of complement serology between aHUS and thrombotic thrombocytopenic purpura

Jisu Oh; Doyeun Oh; Seon Ju Lee; Jeong Oh Kim; Nam Keun Kim; So Young Chong; Ji Young Huh; Ross I. Baker; the Korean TTP Registry Investigators

doi:10.5045/br.2019.54.3.218

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Original Article

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Blood Res 2019; 54(3):

Published online September 30, 2019

https://doi.org/10.5045/br.2019.54.3.218

Prognostic utility of ADAMTS13 activity for the atypical hemolytic uremic syndrome (aHUS) and comparison of complement serology between aHUS and thrombotic thrombocytopenic purpura

Jisu Oh¹, Doyeun Oh¹, Seon Ju Lee², Jeong Oh Kim², Nam Keun Kim², So Young Chong¹, Ji Young Huh³, Ross I. Baker⁴, on behalf of the Korean TTP Registry Investigators

Author Info. +

¹Department of Internal Medicine, CHA Bundang Medical Center, CHA University, ²Institute for Clinical Research, School of Medicine CHA University, ³Department Laboratory Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea, ⁴Western Australian Centre for Thrombosis and Haemostasis, Murdoch University, Perth, Australia

Correspondence to : Doyeun Oh, M.D., Ph.D.
Department of Internal Medicine, CHA Bundang Medical Center, CHA University, 59 Yatapro, Bundang-gu, Seongnam-si, Gyeonggi 13496, Korea
E-mail: doh@cha.ac.kr

Received: June 10, 2019; Revised: August 9, 2019; Accepted: August 12, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

Background

Atypical hemolytic uremic syndrome (aHUS) involves dysregulation of the complement system, but whether this also occurs in thrombotic thrombocytopenic purpura (TTP) remains unclear. Although these conditions are difficult to differentiate clinically, TTP can be distinguished by low (<10%) ADAMTS13 activity. The aim was to identify the differences in complement activation products between TTP and aHUS and investigate ADAMTS13 activity as a prognostic factor in aHUS.

Methods

We analyzed patients with thrombotic microangiopathy diagnosed as TTP (N=48) or aHUS (N=50), selected from a Korean registry (N=551). Complement activation products in the plasma samples collected from the patients prior to treatment and in 40 healthy controls were measured by ELISA.

Results

The levels of generalized (C3a), alternate (factor Bb), and terminal (C5a and C5b-9) markers were significantly higher (all P<0.01) in the patients than in the healthy controls. Only the factor Bb levels significantly differed (P=0.008) between the two disease groups. In aHUS patients, high normal ADAMTS13 activity (≥77%) was associated with improved treatment response (OR, 6.769; 95% CI, 1.605?28.542; P=0.005), remission (OR, 6.000; 95% CI, 1.693?21.262; P=0.004), exacerbation (OR, 0.242; 95% CI, 0.064?0.916; P=0.031), and disease-associated mortality rates (OR, 0.155; 95% CI, 0.029?0.813; P=0.017).

Conclusion

These data suggest that complement biomarkers, except factor Bb, are similarly activated in TTP and aHUS patients, and ADAMTS13 activity can predict the treatment response and outcome in aHUS patients.

Keywords Thrombotic thrombocytopenic purpura, Atypical hemolytic uremic syndrome, Complement, High ADAMTS13 activity, Treatment outcomes

Article

Original Article

Blood Res 2019; 54(3): 218-228

Published online September 30, 2019 https://doi.org/10.5045/br.2019.54.3.218

Prognostic utility of ADAMTS13 activity for the atypical hemolytic uremic syndrome (aHUS) and comparison of complement serology between aHUS and thrombotic thrombocytopenic purpura

Jisu Oh¹, Doyeun Oh¹, Seon Ju Lee², Jeong Oh Kim², Nam Keun Kim², So Young Chong¹, Ji Young Huh³, Ross I. Baker⁴, on behalf of the Korean TTP Registry Investigators

Correspondence to:Doyeun Oh, M.D., Ph.D.
Department of Internal Medicine, CHA Bundang Medical Center, CHA University, 59 Yatapro, Bundang-gu, Seongnam-si, Gyeonggi 13496, Korea
E-mail: doh@cha.ac.kr

Received: June 10, 2019; Revised: August 9, 2019; Accepted: August 12, 2019

Abstract

Background

Methods

Results

Conclusion

Keywords: Thrombotic thrombocytopenic purpura, Atypical hemolytic uremic syndrome, Complement, High ADAMTS13 activity, Treatment outcomes

Abstract

Fig 1.

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Figure 1.

CONSORT diagram of the patients included in analysis.

Abbreviations: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aHUS, atypical hemolytic uremic syndrome; PEX, plasma exchange; STEC-HUS, Shiga-like toxin-producing E. coli hemolytic uremic syndrome; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura.

Blood Research 2019; 54: 218-228https://doi.org/10.5045/br.2019.54.3.218

Fig 2.

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Figure 2.

Summary box plots for the levels of complement activation products in healthy controls (N=40) and in patients with TTP (N=48), aHUS (N=41), or GC-aHUS (N=9) measured with ELISA. (A) C3a [ng/mL: control, 139.8 (31–473.8); TTP, 195.9 (62–404.4); aHUS, 221.3 (80.7–791.8); GC-aHUS, 266.4 (115.7–483.8); P=0.005]. (B) Factor Bb [ng/mL: control, 499 (110–2,072); TTP, 760 (1–16,557); aHUS, 1,200 (270–11,797); GC-aHUS, 1,380 (52–2490); P<0.001]. (C) C5a [ng/mL: control, 11.4 (2.7–69.1); TTP, 20.1 (2.7–68.6); aHUS, 19.9 (5.4–66.1); GC-aHUS, 22.7 (8.7 –37.4); P=0.001]. (D) C5b-9 [ng/mL: control, 155 (58–459); TTP, 292 (85–939); aHUS, 317 (82–1,415); GC-aHUS, 340 (183–515); P<0.001]. All the data represent the medians (ranges). The P-values were calculated using the Kruskal-Wallis test.

Abbreviations: aHUS, atypical hemolytic uremic syndrome; GC-aHUS, genetically confirmed aHUS; NS, not significant; TTP, thrombotic thrombocytopenic purpura.

Blood Research 2019; 54: 218-228https://doi.org/10.5045/br.2019.54.3.218

Characteristics of the patients with TTP and aHUS.

Bolded text signifies the values that were statistically significant at the P<0.05 level..

Abbreviations: ADAMTS13, a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13; aHUS, atypical hemolytic uremic syndrome; GC-aHUS, genetically confirmed aHUS; Hgb, hemoglobin; IQR, interquartile range; LDH, lactate dehydrogenase; PLT, platelet; TTP, thrombotic thrombocytopenic purpura; WBC, white blood cell..

Correlations between the hematological outcomes and ADAMTS13 activity in patients with aHUS.

High ADAMTS13 activity ≥77%. Bolded text signifies the values that were statistically significant at the P<0.05 level. “Yes” or “no” indicates whether hematologic outcomes were present or absent..

Abbreviations: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; CI, confidence interval; OR, odds ratio..

Multivariate association between laboratory features and hematological outcomes.

Bolded text signifies the values that were statistically significant at the P<0.05 level..

Abbreviations: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aHUS, atypical hemolytic uremic syndrome; CI, confidence interval; LDH, lactate dehydrogenase; OR, odds ratio; TTP, thrombotic thrombocytopenic purpura..