Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients

Essentials Neutrophil extracellular traps (NETs) might play a role in cancer‐related coagulopathy. We determined NET biomarkers and followed cancer patients for venous thromboembolism (VTE). We found a constant association with VTE for citrullinated histone H3. Biomarkers of NET formation could reflect a novel pathomechanism of cancer‐related VTE.

[1]  G. Zlabinger,et al.  Soluble Vascular Endothelial Growth Factor (sVEGF) and the Risk of Venous Thromboembolism in Patients with Cancer: Results from the Vienna Cancer and Thrombosis Study (CATS) , 2015, Clinical Cancer Research.

[2]  C. Allis,et al.  Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation , 2009, The Journal of cell biology.

[3]  R. Pawlinski,et al.  In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps. , 2017, Blood.

[4]  E. Horváth-Puhó,et al.  Prostate cancer, comorbidity, and the risk of venous thromboembolism: A cohort study of 44,035 Danish prostate cancer patients, 1995‐2011 , 2015, Cancer.

[5]  D. Lötsch,et al.  Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism. , 2017, Blood.

[6]  K. Preissner,et al.  Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. , 2015, Circulation research.

[7]  Klaus Pantel,et al.  Cell-free nucleic acids as biomarkers in cancer patients , 2011, Nature Reviews Cancer.

[8]  K. Iczkowski,et al.  Cell-free DNA in human blood plasma: length measurements in patients with pancreatic cancer and healthy controls. , 1998, Pancreas.

[9]  D. Wagner,et al.  NETosis promotes cancer-associated arterial microthrombosis presenting as ischemic stroke with troponin elevation. , 2016, Thrombosis research.

[10]  C. Zielinski,et al.  Association Between Decreased Serum Albumin With Risk of Venous Thromboembolism and Mortality in Cancer Patients. , 2016, The oncologist.

[11]  A. Zychlinsky,et al.  Neutrophil Extracellular Traps Kill Bacteria , 2004, Science.

[12]  N. Vorobjeva,et al.  Neutrophil Extracellular Traps: Mechanisms of formation and role in health and disease , 2014, Biochemistry (Moscow).

[13]  A. Falanga,et al.  The mechanisms of cancer-associated thrombosis. , 2015, Thrombosis research.

[14]  J. Inal,et al.  A novel role for peptidylarginine deiminases in microvesicle release reveals therapeutic potential of PAD inhibition in sensitizing prostate cancer cells to chemotherapy , 2015, Journal of extracellular vesicles.

[15]  A. Khorana,et al.  Guidance for the prevention and treatment of cancer-associated venous thromboembolism , 2016, Journal of Thrombosis and Thrombolysis.

[16]  Paul C. Lambert,et al.  Flexible parametric alternatives to the Cox model , 2009 .

[17]  Z. Werb,et al.  Netting neutrophils in autoimmune small-vessel vasculitis , 2009, Nature Medicine.

[18]  Paul C. Lambert.  STCRPREP: Stata module to prepare data for competing risks analysis using time-dependent weights , 2016 .

[19]  R. Gray.  A Class of $K$-Sample Tests for Comparing the Cumulative Incidence of a Competing Risk , 1988 .

[20]  B. Amulic,et al.  Neutrophil extracellular traps , 2011, Current Biology.

[21]  A. Zychlinsky,et al.  Automatic quantification of in vitro NET formation , 2013, Front. Immun..

[22]  Gary H Lyman,et al.  Development and validation of a predictive model for chemotherapy-associated thrombosis. , 2008, Blood.

[23]  V. Heinemann,et al.  Clinical Relevance of Circulating Nucleosomes in Cancer , 2008, Annals of the New York Academy of Sciences.

[24]  D. Wagner,et al.  Thrombosis: tangled up in NETs. , 2014, Blood.

[25]  C. Winterford,et al.  Apoptosis. Its significance in cancer and cancer Therapy , 1994, Cancer.

[26]  C. Steinman,et al.  Endogenous circulating DNA in systemic lupus erythematosus. Occurrence as multimeric complexes bound to histone. , 1990, The Journal of clinical investigation.

[27]  D. Wagner,et al.  Neutrophil extracellular traps promote deep vein thrombosis in mice , 2012, Journal of thrombosis and haemostasis : JTH.

[28]  S. Negrotto,et al.  Functional responses and molecular mechanisms involved in histone-mediated platelet activation , 2013, Thrombosis and Haemostasis.

[29]  S. Middeldorp,et al.  Circulating Nucleosomes and Neutrophil Activation as Risk Factors for Deep Vein Thrombosis , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[30]  D. Scadden,et al.  Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis , 2012, Proceedings of the National Academy of Sciences.

[31]  A. Kaider,et al.  Estimating risk of venous thromboembolism in patients with cancer in the presence of competing mortality , 2015, Journal of thrombosis and haemostasis : JTH.

[32]  I. Pabinger,et al.  Venous thromboembolism in cancer patients – Risk scores and recent randomised controlled trials , 2012, Thrombosis and Haemostasis.

[33]  K. Preissner,et al.  Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases , 2010, Nature Medicine.

[34]  A. Walch,et al.  Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo , 2012, The Journal of experimental medicine.

[35]  David M. Wilson,et al.  Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation , 2015, Nature chemical biology.

[36]  J. Hartwig,et al.  Extracellular DNA traps promote thrombosis , 2010, Proceedings of the National Academy of Sciences.

[37]  D. Wagner,et al.  PHAGOCYTES , GRANULOCYTES , AND MYELOPOIESIS PAD 4-de fi ciency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock , 2015 .

[38]  M Schemper,et al.  A note on quantifying follow-up in studies of failure time. , 1996, Controlled clinical trials.

[39]  S. Massberg,et al.  Demystifying the prothrombotic role of NETs. , 2017, Blood.

[40]  A. Cohen,et al.  Cancer-associated venous thromboembolism: Burden, mechanisms, and management , 2016, Thrombosis and Haemostasis.

[41]  V. Coviello,et al.  Cumulative Incidence Estimation in the Presence of Competing Risks , 2004 .

[42]  C. Marosi,et al.  Prediction of venous thromboembolism in cancer patients. , 2010, Blood.

[43]  Michael R. Lindberg,et al.  PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps , 2010, The Journal of experimental medicine.

[44]  D. Pinsky,et al.  In Vivo Role of Neutrophil Extracellular Traps in Antiphospholipid Antibody–Mediated Venous Thrombosis , 2017, Arthritis & rheumatology.

[45]  A. Khorana,et al.  Leukocytosis, thrombosis and early mortality in cancer patients initiating chemotherapy. , 2010, Thrombosis research.

[46]  I. Pabinger,et al.  Biomarkers for prediction of venous thromboembolism in cancer. , 2013, Blood.

[47]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[48]  D. Wagner,et al.  Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice , 2013, Proceedings of the National Academy of Sciences.

[49]  B. Lämmle,et al.  Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies. , 2012, Blood.