Download PDF
CC BY-NC-ND 4.0 · Thromb Haemost 2019; 119(05): 807-820
DOI: 10.1055/s-0039-1679939
New Technologies, Diagnostic Tools and Drugs
Georg Thieme Verlag KG Stuttgart · New York

A Novel Diagnostic and Prognostic Score for Abdominal Aortic Aneurysms Based on D-Dimer and a Comprehensive Analysis of Myeloid Cell Parameters

Branislav Zagrapan
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Wolf Eilenberg
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Suriya Prausmueller
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Paimann Nawrozi
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Katharina Muench
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Sarah Hetzer
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Vanessa Elleder
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Renata Rajic
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Felix Juster
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Luca Martelanz
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Hubert Hayden
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Johannes Klopf
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Cansu Inan
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Peter Teubenbacher
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Markus P. Weigl
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Patrick Kirchweger
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Dietrich Beitzke
2   Division of Cardiovascular and Interventional Radiology, Department of Biomedical Imaging and Image Guided Therapy, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Bernd Jilma
3   Department of Clinical Pharmacology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Johann Wojta
4   Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Marc A. Bailey
5   Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
6   Leeds Vascular Institute, Leeds General Infirmary, Leeds, United Kingdom
,
D. Julian A. Scott
6   Leeds Vascular Institute, Leeds General Infirmary, Leeds, United Kingdom
5   Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
,
Ihor Huk
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Christoph Neumayer
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
,
Christine Brostjan 
1   Division of Vascular Surgery and Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
› Author Affiliations Funding This work was primarily supported by the Austrian Science Fund (SFB project F 5409-B21) as well as the Medical Scientific Fund of the Mayor of the City of Vienna (project 15012) and The Garfield Weston Foundation (for the Leeds Aneurysm Development Study). Marc Bailey is supported by the British Heart Foundation. The sponsors had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; nor in the decision to submit the article for publication.
Further Information

Publication History

27 October 2018

12 January 2019

Publication Date:
01 March 2019 (online)

Also available at
   Permissions and Reprints

Abstract

The pathogenesis of abdominal aortic aneurysm (AAA) involves a central component of chronic inflammation which is predominantly mediated by myeloid cells. We hypothesized that the local inflammatory activity may be reflected in systemic alterations of neutrophil and monocyte populations as well as in soluble factors of myeloid cell activation and recruitment. To establish their marker potential, neutrophil and monocyte sub-sets were measured by flow cytometry in peripheral blood samples of 41 AAA patients and 38 healthy controls matched for age, sex, body mass index and smoking habit. Comparably, circulating factors reflecting neutrophil and monocyte activation and recruitment were assayed in plasma. Significantly elevated levels of CD16+ monocytes, activated neutrophils and newly released neutrophils were recorded for AAA patients compared with controls. In line, the monocyte chemoattractant C-C chemokine ligand 2 and myeloperoxidase were significantly increased in patients' plasma. The diagnostic value was highest for myeloperoxidase, a mediator which is released by activated neutrophils as well as CD16+ monocytes. Multivariable regression models using myeloid activation markers and routine laboratory parameters identified myeloperoxidase and D-dimer as strong independent correlates of AAA. These two biomarkers were combined to yield a diagnostic score which was subsequently challenged for confounders and confirmed in a validation cohort matched for cardiovascular disease. Importantly, the score was also found suited to predict rapid disease progression. In conclusion, D-dimer and myeloperoxidase represent two sensitive biomarkers of AAA which reflect distinct hallmarks (thrombus formation and inflammation) of the pathomechanism and, when combined, may serve as diagnostic and prognostic AAA score warranting further evaluation.

Keywords

abdominal aortic aneurysm - D-dimer - diagnosis - myeloperoxidase - prognosis

Supplementary Material

 

  • References

  • 1 Moll FL, Powell JT, Fraedrich G. , et al; European Society for Vascular Surgery. Management of abdominal aortic aneurysms clinical practice guidelines of the European society for vascular surgery. Eur J Vasc Endovasc Surg 2011; 41 (Suppl. 01) S1-S58
    CrossrefPubMedSearch in Google Scholar
  • 2 Takagi H, Manabe H, Kawai N, Goto S, Umemoto T. Plasma fibrinogen and D-dimer concentrations are associated with the presence of abdominal aortic aneurysm: a systematic review and meta-analysis. Eur J Vasc Endovasc Surg 2009; 38 (03) 273-277
    CrossrefPubMedSearch in Google Scholar
  • 3 Sidloff DA, Stather PW, Choke E, Bown MJ, Sayers RD. A systematic review and meta-analysis of the association between markers of hemostasis and abdominal aortic aneurysm presence and size. J Vasc Surg 2014; 59 (02) 528-535
    CrossrefPubMedSearch in Google Scholar
  • 4 De Haro J, Acin F, Bleda S, Varela C, Medina FJ, Esparza L. Prediction of asymptomatic abdominal aortic aneurysm expansion by means of rate of variation of C-reactive protein plasma levels. J Vasc Surg 2012; 56 (01) 45-52
    CrossrefPubMedSearch in Google Scholar
  • 5 Lee AJ, Fowkes FG, Lowe GD, Rumley A. Haemostatic factors, atherosclerosis and risk of abdominal aortic aneurysm. Blood Coagul Fibrinolysis 1996; 7 (07) 695-701
    CrossrefPubMedSearch in Google Scholar
  • 6 Vele E, Kurtcehajic A, Zerem E, Maskovic J, Alibegovic E, Hujdurovic A. Plasma D-dimer as a predictor of the progression of abdominal aortic aneurysm. J Thromb Haemost 2016; 14 (11) 2298-2303
    CrossrefPubMedSearch in Google Scholar
  • 7 Golledge J, Muller R, Clancy P, McCann M, Norman PE. Evaluation of the diagnostic and prognostic value of plasma D-dimer for abdominal aortic aneurysm. Eur Heart J 2011; 32 (03) 354-364
    CrossrefPubMedSearch in Google Scholar
  • 8 Vega de Ceniga M, Esteban M, Barba A, Estallo L, Blanco-Colio LM, Martin-Ventura JL. Assessment of biomarkers and predictive model for short-term prospective abdominal aortic aneurysm growth-a pilot study. Ann Vasc Surg 2014; 28 (07) 1642-1648
    CrossrefPubMedSearch in Google Scholar
  • 9 Hellenthal FAMVI, Geenen ILA, Teijink JAW, Heeneman S, Schurink GW. Histological features of human abdominal aortic aneurysm are not related to clinical characteristics. Cardiovasc Pathol 2009; 18 (05) 286-293
    CrossrefPubMedSearch in Google Scholar
  • 10 Houard X, Touat Z, Ollivier V. , et al. Mediators of neutrophil recruitment in human abdominal aortic aneurysms. Cardiovasc Res 2009; 82 (03) 532-541
    CrossrefPubMedSearch in Google Scholar
  • 11 Qin Y, Cao X, Yang Y, Shi GP. Cysteine protease cathepsins and matrix metalloproteinases in the development of abdominal aortic aneurysms. Future Cardiol 2013; 9 (01) 89-103
    CrossrefPubMedSearch in Google Scholar
  • 12 Ramos-Mozo P, Madrigal-Matute J, Vega de Ceniga M. , et al. Increased plasma levels of NGAL, a marker of neutrophil activation, in patients with abdominal aortic aneurysm. Atherosclerosis 2012; 220 (02) 552-556
    CrossrefPubMedSearch in Google Scholar
  • 13 Juvonen J, Surcel HM, Satta J. , et al. Elevated circulating levels of inflammatory cytokines in patients with abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 1997; 17 (11) 2843-2847
    CrossrefPubMedSearch in Google Scholar
  • 14 Ziegler-Heitbrock L, Ancuta P, Crowe S. , et al. Nomenclature of monocytes and dendritic cells in blood. Blood 2010; 116 (16) e74-e80
    CrossrefPubMedSearch in Google Scholar
  • 15 Patel AA, Zhang Y, Fullerton JN. , et al. The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J Exp Med 2017; 214 (07) 1913-1923
    CrossrefPubMedSearch in Google Scholar
  • 16 Wong KL, Tai JJ, Wong WC. , et al. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood 2011; 118 (05) e16-e31
    CrossrefPubMedSearch in Google Scholar
  • 17 Zawada AM, Rogacev KS, Rotter B. , et al. SuperSAGE evidence for CD14++CD16+ monocytes as a third monocyte subset. Blood 2011; 118 (12) e50-e61
    CrossrefPubMedSearch in Google Scholar
  • 18 Chimen M, Yates CM, McGettrick HM. , et al. Monocyte subsets coregulate inflammatory responses by integrated signaling through TNF and IL-6 at the endothelial cell interface. J Immunol 2017; 198 (07) 2834-2843
    CrossrefPubMedSearch in Google Scholar
  • 19 Auffray C, Fogg D, Garfa M. , et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 2007; 317 (5838): 666-670
    CrossrefPubMedSearch in Google Scholar
  • 20 Cros J, Cagnard N, Woollard K. , et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 2010; 33 (03) 375-386
    CrossrefPubMedSearch in Google Scholar
  • 21 Shantsila E, Lip GY. The role of monocytes in thrombotic disorders. Insights from tissue factor, monocyte-platelet aggregates and novel mechanisms. Thromb Haemost 2009; 102 (05) 916-924
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Rogacev KS, Cremers B, Zawada AM. , et al. CD14++CD16+ monocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective coronary angiography. J Am Coll Cardiol 2012; 60 (16) 1512-1520
    CrossrefPubMedSearch in Google Scholar
  • 23 Ghigliotti G, Barisione C, Garibaldi S. , et al. CD16(+) monocyte subsets are increased in large abdominal aortic aneurysms and are differentially related with circulating and cell-associated biochemical and inflammatory biomarkers. Dis Markers 2013; 34 (02) 131-142
    CrossrefPubMedSearch in Google Scholar
  • 24 Rubio-Navarro A, Amaro Villalobos JM, Lindholt JS. , et al. Hemoglobin induces monocyte recruitment and CD163-macrophage polarization in abdominal aortic aneurysm. Int J Cardiol 2015; 201: 66-78
    CrossrefPubMedSearch in Google Scholar
  • 25 Pillay J, Ramakers BP, Kamp VM. , et al. Functional heterogeneity and differential priming of circulating neutrophils in human experimental endotoxemia. J Leukoc Biol 2010; 88 (01) 211-220
    CrossrefPubMedSearch in Google Scholar
  • 26 Kamp VM, Pillay J, Lammers JWJ, Pickkers P, Ulfman LH, Koenderman L. Human suppressive neutrophils CD16bright/CD62Ldim exhibit decreased adhesion. J Leukoc Biol 2012; 92 (05) 1011-1020
    CrossrefPubMedSearch in Google Scholar
  • 27 Al-Barjas HS, Ariëns R, Grant P, Scott JA. Raised plasma fibrinogen concentration in patients with abdominal aortic aneurysm. Angiology 2006; 57 (05) 607-614
    CrossrefPubMedSearch in Google Scholar
  • 28 Bailey MA, Griffin KJ, Sohrabi S. , et al. Plasma thrombin-antithrombin complex, prothrombin fragments 1 and 2, and D-dimer levels are elevated after endovascular but not open repair of infrarenal abdominal aortic aneurysm. J Vasc Surg 2013; 57 (06) 1512-1518
    CrossrefPubMedSearch in Google Scholar
  • 29 Parry DJ, Al-Barjas HS, Chappell L, Rashid ST, Ariëns RA, Scott DJ. Markers of inflammation in men with small abdominal aortic aneurysm. J Vasc Surg 2010; 52 (01) 145-151
    CrossrefPubMedSearch in Google Scholar
  • 30 Scott DJ, Prasad P, Philippou H. , et al. Clot architecture is altered in abdominal aortic aneurysms and correlates with aneurysm size. Arterioscler Thromb Vasc Biol 2011; 31 (12) 3004-3010
    CrossrefPubMedSearch in Google Scholar
  • 31 Sohrabi S, Wheatcroft S, Barth JH. , et al. Cardiovascular risk in patients with small and medium abdominal aortic aneurysms, and no history of cardiovascular disease. Br J Surg 2014; 101 (10) 1238-1243
    CrossrefPubMedSearch in Google Scholar
  • 32 Tjur T. Coefficients of determination in logistic regression models—a new proposal: the coefficient of discrimination. Am Stat 2009; 63: 366-372
    CrossrefPubMedSearch in Google Scholar
  • 33 Vardulaki KA, Walker NM, Day NE, Duffy SW, Ashton HA, Scott RA. Quantifying the risks of hypertension, age, sex and smoking in patients with abdominal aortic aneurysm. Br J Surg 2000; 87 (02) 195-200
    CrossrefPubMedSearch in Google Scholar
  • 34 Piechota-Polanczyk A, Jozkowicz A, Nowak W. , et al. The abdominal aortic aneurysm and intraluminal thrombus: current concepts of development and treatment. Front Cardiovasc Med 2015; 2: 19
    PubMedSearch in Google Scholar
  • 35 Dale MA, Ruhlman MK, Baxter BT. Inflammatory cell phenotypes in AAAs: their role and potential as targets for therapy. Arterioscler Thromb Vasc Biol 2015; 35 (08) 1746-1755
    CrossrefPubMedSearch in Google Scholar
  • 36 Ancuta P, Wang J, Gabuzda D. CD16+ monocytes produce IL-6, CCL2, and matrix metalloproteinase-9 upon interaction with CX3CL1-expressing endothelial cells. J Leukoc Biol 2006; 80 (05) 1156-1164
    CrossrefPubMedSearch in Google Scholar
  • 37 Middleton RK, Lloyd GM, Bown MJ, Cooper NJ, London NJ, Sayers RD. The pro-inflammatory and chemotactic cytokine microenvironment of the abdominal aortic aneurysm wall: a protein array study. J Vasc Surg 2007; 45 (03) 574-580
    CrossrefPubMedSearch in Google Scholar
  • 38 Jones GT, Phillips LV, Williams MJ, van Rij AM, Kabir TD. Two C-C family chemokines, eotaxin and RANTES, are novel independent plasma biomarkers for abdominal aortic aneurysm. J Am Heart Assoc 2016; 5 (05) 5
    CrossrefPubMedSearch in Google Scholar
  • 39 Mayr FB, Spiel AO, Leitner JM. , et al. Influence of the Duffy antigen on pharmacokinetics and pharmacodynamics of recombinant monocyte chemoattractant protein (MCP-1, CCL-2) in vivo. Int J Immunopathol Pharmacol 2009; 22 (03) 615-625
    CrossrefPubMedSearch in Google Scholar
  • 40 Feng AL, Zhu JK, Sun JT. , et al. CD16+ monocytes in breast cancer patients: expanded by monocyte chemoattractant protein-1 and may be useful for early diagnosis. Clin Exp Immunol 2011; 164 (01) 57-65
    CrossrefPubMedSearch in Google Scholar
  • 41 Yamanouchi D, Morgan S, Kato K, Lengfeld J, Zhang F, Liu B. Effects of caspase inhibitor on angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2010; 30 (04) 702-707
    CrossrefPubMedSearch in Google Scholar
  • 42 Wang Q, Ren J, Morgan S, Liu Z, Dou C, Liu B. Monocyte chemoattractant protein-1 (MCP-1) regulates macrophage cytotoxicity in abdominal aortic aneurysm. PLoS One 2014; 9 (03) e92053
    CrossrefPubMedSearch in Google Scholar
  • 43 Pradhan-Palikhe P, Vikatmaa P, Lajunen T. , et al. Elevated MMP-8 and decreased myeloperoxidase concentrations associate significantly with the risk for peripheral atherosclerosis disease and abdominal aortic aneurysm. Scand J Immunol 2010; 72 (02) 150-157
    PubMedSearch in Google Scholar
  • 44 Odobasic D, Kitching AR, Holdsworth SR. Neutrophil-mediated regulation of innate and adaptive immunity: the role of myeloperoxidase. J Immunol Res 2016; 2016: 2349817
    PubMedSearch in Google Scholar
  • 45 Wildgruber M, Aschenbrenner T, Wendorff H. , et al. The “Intermediate” CD14++CD16+ monocyte subset increases in severe peripheral artery disease in humans. Sci Rep 2016; 6: 39483
    CrossrefPubMedSearch in Google Scholar
  • 46 Choi M, Rolle S, Wellner M. , et al. Inhibition of NF-kappaB by a TAT-NEMO-binding domain peptide accelerates constitutive apoptosis and abrogates LPS-delayed neutrophil apoptosis. Blood 2003; 102 (06) 2259-2267
    CrossrefPubMedSearch in Google Scholar