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Figure.
Platelet Counts by Circulating Histone Level Among Patients With Thrombocytopenia Who Are Critically Ill
Platelet Counts by Circulating Histone Level Among Patients With Thrombocytopenia Who Are Critically Ill

P values are calculated by Mann-Whitney U test. Horizontal bars represent median levels. The percentage of decrease in platelet counts is calculated in reference to platelet count on admission. Thrombocytopenic patients with high admission histones (≥30 ug/mL) have significantly lower platelet counts and higher percentage of decrease in platelet counts at 24 hours (P = .02 and P = .04, respectively) and 48 hours (P = .003 and P = .005, respectively) after intensive care unit admission.

Table.  
Characteristics of Patients in the Intensive Care Unit
Characteristics of Patients in the Intensive Care Unit
1.
Fuchs  TA, Bhandari  AA, Wagner  DD.  Histones induce rapid and profound thrombocytopenia in mice. Blood. 2011;118(13):3708-3714.
PubMedArticle
2.
Abrams  ST, Zhang  N, Dart  C,  et al.  Human CRP defends against the toxicity of circulating histones. J Immunol. 2013;191(5):2495-2502.
PubMedArticle
3.
Alhamdi  Y, Abrams  ST, Cheng  Z,  et al.  Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit Care Med. 2015;43(10):2094-2103.
PubMedArticle
4.
Abrams  ST, Zhang  N, Manson  J,  et al.  Circulating histones are mediators of trauma-associated lung injury. Am J Respir Crit Care Med. 2013;187(2):160-169.
PubMedArticle
5.
De Labriolle  A, Bonello  L, Lemesle  G,  et al.  Decline in platelet count in patients treated by percutaneous coronary intervention: definition, incidence, prognostic importance, and predictive factors. Eur Heart J. 2010;31(9):1079-1087.
PubMedArticle
6.
Xu  J, Zhang  X, Pelayo  R,  et al.  Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15(11):1318-1321.
PubMedArticle
Research Letter
February 23, 2016

Histone-Associated Thrombocytopenia in Patients Who Are Critically Ill

Author Affiliations
  • 1Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
  • 2Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
JAMA. 2016;315(8):817-819. doi:10.1001/jama.2016.0136

Thrombocytopenia is observed in approximately 30% to 40% of patients in the intensive care unit (ICU) and associated with poor outcomes. Histones induce profound thrombocytopenia in mice1,2 and are associated with organ injury when released following extensive cell damage in patients who are critically ill.3,4 We explored the association between circulating histones and thrombocytopenia in patients in the ICU.

Methods

A case-control study was performed including patients admitted to the ICU at Royal Liverpool University Hospital between June 2013 and January 2014 with approval from the North West Centre of the Research Ethics Committees in the United Kingdom. Written informed consent was obtained.

Thrombocytopenia was defined as a platelet count less than 150 × 103/µL, a 25% or greater decrease in platelet count, or both5 within the first 96 hours of ICU admission (study duration). Patients with known prior cause(s) of thrombocytopenia were excluded. The control group was patients in the ICU without thrombocytopenia during the same study duration, matched to patients with thrombocytopenia for age, sex, APACHE II scores, and admission diagnoses. Plasma histones were measured, as described previously,3,4 and daily levels were compared between thrombocytopenic patients and nonthrombocytopenic controls. Because histones at approximately 30 µg/mL bind platelets and cause platelet aggregation, resulting in profound thrombocytopenia in mice,1,2 this level was used to stratify thrombocytopenic patients (high admission histones ≥30 µg/mL; low, <30 µg/mL). Platelet counts and percentage decrease in platelet counts at 24 hours and 48 hours after admission were compared between these 2 thrombocytopenic groups. In addition, daily histone levels were compared between patients with mild (platelets, 100-149 × 103/µL), moderate (platelets, 50-99 × 103/µL), and severe (platelets, <50 × 103/µL) thrombocytopenia.

The Mann-Whitney U test was used for comparisons. The Receiver Operating Characteristic (ROC) curve assessed the performance of admission histone levels in predicting moderate to severe thrombocytopenia during the study. The χ2 test was used for categorical groups (sex, presence or absence of a certain diagnosis, and presence or absence of circulating histones). Statistical tests were performed on SPSS software (IBM), version 22. A 2-sided P value less than .05 was considered significant.

Results

Fifty-six thrombocytopenic patients and 56 nonthrombocytopenic controls were studied. Circulating histones were detectable in 51 thrombocytopenic patients (91%) compared with 31 controls (55%) (P < .001). Daily histone levels were significantly higher in thrombocytopenic patients compared with controls throughout the study (Table).

Thrombocytopenic patients with high admission histones (n = 32) had significantly lower platelet counts at 24 hours and 48 hours after admission compared with thrombocytopenic patients with low admission histones (n = 24) (Figure, panel A). Thrombocytopenic patients with high admission histones had significantly greater percentage decreases in platelet counts at 24 hours and 48 hours after admission compared with thrombocytopenic patients with low admission histones (Figure, panel B).

Histone levels on admission and 24 hours after admission were significantly higher in patients developing severe or moderate thrombocytopenia compared with mild thrombocytopenia (Table). Admission histone levels were associated with development of moderate to severe thrombocytopenia with an area under the ROC curve of 0.893 (95% CI, 0.843-0.944, P < .001). At 30 µg/mL histone concentration, the sensitivity was 76% and specificity was 91% (predictive values: positive, 79.4%; negative, 89.2%; likelihood ratios: positive, 8.5; negative, 0.2).

Discussion

In this study, histones circulated in the majority of thrombocytopenic patients and were 2.5- to 5.5-fold higher than in nonthrombocytopenic controls. There was a significant association between high admission histones and subsequent decline in platelet counts among thrombocytopenic patients. High admission histone levels were associated with moderate to severe thrombocytopenia and development of clinically important thrombocytopenia with high area under the ROC curve.

The limitations of this study include a relatively small number of patients from a single center and the difficulty in establishing a causal relationship between circulating histones and thrombocytopenia without interventional studies.

Circulating histones are potential markers of disease severity,3,4,6 and the association with thrombocytopenia may reflect this. Nevertheless, the novel associations reported in this study extend previous reports demonstrating profound thrombocytopenia following histone infusion into mice1,2 and suggest that, if confirmed, circulating histones may be valuable in predicting or monitoring thrombocytopenia in patients who are critically ill.

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Article Information
Section Editor: Jody W. Zylke, MD, Deputy Editor.

Corresponding Author: Cheng-Hock Toh, MD, Institute of Infection and Global Health, University of Liverpool, Ronald Ross Building, 8 West Derby St, Liverpool L69 7BE, United Kingdom (Toh@liverpool.ac.uk).

Author Contributions: Drs Alhamdi and Toh had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Alhamdi, Wang, Toh.

Acquisition, analysis, or interpretation of data: Alhamdi, Abrams, Lane, Wang, Toh.

Drafting of the manuscript: Alhamdi, Toh.

Critical revision of the manuscript for important intellectual content: Alhamdi, Abrams, Lane, Wang, Toh.

Statistical analysis: Alhamdi, Abrams, Lane.

Obtained funding: Wang, Toh.

Administrative, technical, or material support: Wang.

Study supervision: Wang, Toh.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This work was funded by the National Institute of Health Research, British Heart Foundation, and the Royal Liverpool & Broadgreen University Hospitals NHS Trust.

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Fuchs  TA, Bhandari  AA, Wagner  DD.  Histones induce rapid and profound thrombocytopenia in mice. Blood. 2011;118(13):3708-3714.
PubMedArticle
2.
Abrams  ST, Zhang  N, Dart  C,  et al.  Human CRP defends against the toxicity of circulating histones. J Immunol. 2013;191(5):2495-2502.
PubMedArticle
3.
Alhamdi  Y, Abrams  ST, Cheng  Z,  et al.  Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit Care Med. 2015;43(10):2094-2103.
PubMedArticle
4.
Abrams  ST, Zhang  N, Manson  J,  et al.  Circulating histones are mediators of trauma-associated lung injury. Am J Respir Crit Care Med. 2013;187(2):160-169.
PubMedArticle
5.
De Labriolle  A, Bonello  L, Lemesle  G,  et al.  Decline in platelet count in patients treated by percutaneous coronary intervention: definition, incidence, prognostic importance, and predictive factors. Eur Heart J. 2010;31(9):1079-1087.
PubMedArticle
6.
Xu  J, Zhang  X, Pelayo  R,  et al.  Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15(11):1318-1321.
PubMedArticle
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