Background/Aims: Pneumonia is a significant risk factor for the development of venous thrombosis (VT). Cell-adhesion molecules (CAMs) are linked to the pathogenesis of both pneumonia and VT. We hypothesized that remote infection would confer a prothrombogenic milieu via systemic elevation of CAMs. Methods: Lung injury was induced in wild-type (C57BL/6) mice by lung contusion or intratracheal inoculation with Klebsiella pneumoniae or saline controls. K. pneumoniae-treated mice and controls additionally underwent inferior vena cava (IVC) ligation to generate VT. Results: Lung-contusion mice demonstrated no increase in E-selectin or P-selectin whereas mice infected with K. pneumoniae demonstrated increased circulating P-selectin, ICAM-1, VCAM-1 and thrombin-antithrombin (TAT) complexes. Mice with pneumonia formed VT 3 times larger than controls, demonstrated significantly more upregulation of vein-wall and systemic CAMs, and formed erythrocyte-rich thrombi. Conclusion: Elevated CAM expression was identified in mice with pneumonia, but not lung contusion, indicating that the type of inflammatory stimulus and the presence of infection drive the vein-wall response. Elevation of CAMs was associated with amplified VT and may represent an alternate mechanism by which to target the prevention of VT.

Towfighi A, Saver JL: Stroke declines from third to fourth leading cause of death in the United States: historical perspective and challenges ahead. Stroke 2011;42:2351-2355.
Shojania KG DB, McDonald KM, Wachter RM, Markowitz AJ: Making health care safer: a critical analysis of patient safety practices. Evid Rep Technol Assess 2001;1-668.
Schmidt M, Horvath-Puho E, Thomsen RW, Smeeth L, Sorensen HT: Acute infections and venous thromboembolism. J Intern Med 2012;271:608-618.
Gangireddy C, Rectenwald JR, Upchurch GR, Wakefield TW, Khuri S, Henderson WG, Henke PK: Risk factors and clinical impact of postoperative symptomatic venous thromboembolism. J Vasc Surg 2007;45:335-341; discussion 341-342.
Wakefield TW, Myers DD, Henke PK: Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol 2008;28:387-391.
Zarbock A, Ley K, McEver RP, Hidalgo A: Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow. Blood 2011;118:6743-6751.
Myers D Jr, Farris D, Hawley A, Wrobleski S, Chapman A, Stoolman L, Knibbs R, Strieter R, Wakefield T: Selectins influence thrombosis in a mouse model of experimental deep venous thrombosis. J Surg Res 2002;108:212-221.
Darbousset R, Thomas GM, Mezouar S, Frere C, Bonier R, Mackman N, Renne T, Dignat-George F, Dubois C, Panicot-Dubois L: Tissue factor-positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood 2012;120:2133-2143.
Basit A, Reutershan J, Morris MA, Solga M, Rose CE Jr, Ley K: ICAM-1 and lFA-1 play critical roles in LPS-induced neutrophil recruitment into the alveolar space. Am J Physiol Lung Cell Mol Physiol 2006;291:L200-L207.
Qin L, Quinlan WM, Doyle NA, Graham L, Sligh JE, Takei F, Beaudet AL, Doerschuk CM: The roles of CD11/CD18 and ICAM-1 in acute Pseudomonas aeruginosa-induced pneumonia in mice. J Immunol 1996;157:5016-5021.
Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, Brinkmann V, Lorenz M, Bidzhekov K, Khandagale AB, Konrad I, Kennerknecht E, Reges K, Holdenrieder S, Braun S, Reinhardt C, Spannagl M, Preissner KT, Engelmann B: Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010;16:887-896.
Yipp BG, Petri B, Salina D, Jenne CN, Scott BN, Zbytnuik LD, Pittman K, Asaduzzaman M, Wu K, Meijndert HC, Malawista SE, de Boisfleury Chevance A, Zhang K, Conly J, Kubes P: Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med 2012;18:1386-1393.
Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A: Neutrophil extracellular traps kill bacteria. Science 2004;303:1532-1535.
Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A: Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 2010;191:677-691.
von Bruhl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, Khandoga A, Tirniceriu A, Coletti R, Kollnberger M, Byrne RA, Laitinen I, Walch A, Brill A, Pfeiler S, Manukyan D, Braun S, Lange P, Riegger J, Ware J, Eckart A, Haidari S, Rudelius M, Schulz C, Echtler K, Brinkmann V, Schwaiger M, Preissner KT, Wagner DD, Mackman N, Engelmann B, Massberg S: Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012;209:819-835.
Brill A, Fuchs TA, Savchenko A, Thomas GM, Martinod K, De Meyer SF, Bhandari AA, Wagner DD: Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 2012;10:136-144.
Martinod K, Demers M, Fuchs TA, Wong SL, Brill A, Gallant M, Hu J, Wang Y, Wagner DD: Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci USA 2013;110:8674-8679.
Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM, Pollock DA, Fridkin SK; National Healthcare Safety Network Team; Participating National Healthcare Safety Network Facilities: NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. Infect Control Hosp Epidemiol 2008;29:996-1011.
Suresh MV, Yu B, Lakshminrusimha S, Machado-Aranda D, Talarico N, Zeng L, Davidson BA, Pennathur S, Raghavendran K: The protective role of MNTBAP in oxidant-mediated injury and inflammation in a rat model of lung contusion. Surgery 2013;154:980-990.
Dolgachev VA, Yu B, Reinke JM, Raghavendran K, Hemmila MR: Host susceptibility to Gram-negative pneumonia after lung contusion. J Trauma Acute Care Surg 2012;72:614-622; discussion 622-623.
Hemmila MR, Fan MH, Kim J, Sun JM, Steinstraesser L, Gong KQ, Arbabi S, Minter RM, Remick DG, Su GL, Wang SC: Improved survival in mice given systemic gene therapy in a Gram-negative pneumonia model. J Trauma 2005;58:1110-1118; discussion 1118.
Ipaktchi K, Mattar A, Niederbichler AD, Kim J, Hoesel LM, Hemmila MR, Su GL, Remick DG, Wang SC, Arbabi S: Attenuating burn wound inflammation improves pulmonary function and survival in a burn-pneumonia model. Crit Care Med 2007;35:2139-2144.
Diaz JA, Obi AT, Myers DD Jr, Wrobleski SK, Henke PK, Mackman N, Wakefield TW: Critical review of mouse models of venous thrombosis. Arterioscler Thromb Vasc Biol 2012;32:556-562.
Obi AT, Diaz JA, Ballard-Lipka NL, Roelofs KJ, Farris DM, Lawrence DA, Wakefield TW, Henke PK: Plasminogen activator-1 overexpression decreases experimental postthrombotic vein wall fibrosis by a non-vitronectin-dependent mechanism. J Thromb Haemost 2014;12:1353-1363.
Aleman MM, Byrnes JR, Wang JG, Tran R, Lam WA, Di Paola J, Mackman N, Degen JL, Flick MJ, Wolberg AS: Factor XIII activity mediates red blood cell retention in venous thrombi. J Clin Invest 2014;124:3590-3600.
Anderson ME, Yakovleva T, Hu Y, Siahaan TJ: Inhibition of ICAM-1/LFA-1-mediated heterotypic T-cell adhesion to epithelial cells: design of ICAM-1 cyclic peptides. Bioorg Med Chem Lett 2004;14:1399-1402.
Magnani JL: The discovery, biology, and drug development of sialyl Lea and sialyl Lex. Arch Biochem Biophys 2004;426:122-131.
Suresh MV, Yu B, Machado-Aranda D, Bender MD, Ochoa-Frongia L, Helinski JD, Davidson BA, Knight PR, Hogaboam CM, Moore BB, Raghavendran K: Role of macrophage chemoattractant protein-1 in acute inflammation after lung contusion. Am J Respir Cell Mol Biol 2012;46:797-806.
Quarmby J, Smith A, Collins M, Cederholm-Williams S, Burnand K: A model of in vivo human venous thrombosis that confirms changes in the release of specific soluble cell adhesion molecules in experimental venous thrombogenesis. J Vasc Surg 1999;30:139-147.
Smith A, Quarmby JW, Collins M, Lockhart SM, Burnand KG: Changes in the levels of soluble adhesion molecules and coagulation factors in patients with deep vein thrombosis. Thromb Haemost 1999;82:1593-1599.
Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD: Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 2010;107:15880-15885.
Bartlett JG, Mundy LM: Community-acquired pneumonia. N Engl J Med 1995;333:1618-1624.
Obi AT, Pannucci CJ, Nackashi A, Abdullah N, Alvarez R, Bahl V, Wakefield TW, Henke PK: Validation of the Caprini venous thromboembolism risk assessment model in critically ill surgical patients. JAMA Surg 2015;150:941-948.
Pannucci CJ, Obi A, Alvarez R, Abdullah N, Nackashi A, Hu HM, Bahl V, Henke PK: Inadequate venous thromboembolism risk stratification predicts venous thromboembolic events in surgical intensive care unit patients. J Am Coll Surg 2014;218:898-904.
de Stoppelaar SF, van 't Veer C, Claushuis TA, Albersen BJ, Roelofs JJ, van der Poll T: Thrombocytopenia impairs host defense in Gram-negative pneumonia-derived sepsis in mice. Blood 2014;124:3781-3790.
Antonopoulos CN, Sfyroeras GS, Kakisis JD, Moulakakis KG, Liapis CD: The role of soluble P selectin in the diagnosis of venous thromboembolism. Thromb Res 2014;133:17-24.
Cushman M, Callas PW, Allison MA, Criqui MH: Inflammation and peripheral venous disease. The San Diego Population Study. Thromb Haemost 2014;112:566-572.
Shbaklo H, Holcroft CA, Kahn SR: Levels of inflammatory markers and the development of the post-thrombotic syndrome. Thromb Haemost 2009;101:505-512.
Zonneveld R, Martinelli R, Shapiro NI, Kuijpers TW, Plotz FB, Carman CV: Soluble adhesion molecules as markers for sepsis and the potential pathophysiological discrepancy in neonates, children and adults. Crit Care 2014;18:204.
Jin L, Batra S, Douda DN, Palaniyar N, Jeyaseelan S: CXCL1 contributes to host defense in polymicrobial sepsis via modulating T cell and neutrophil functions. J Immunol 2014;193:3549-3558.
Roller J, Wang Y, Rahman M, Schramm R, Laschke MW, Menger MD, Jeppsson B, Thorlacius H: Direct in vivo observations of P-selectin glycoprotein ligand-1-mediated leukocyte-endothelial cell interactions in the pulmonary microvasculature in abdominal sepsis in mice. Inflamm Res 2013;62:275-282.
Zhang L, Jin S, Wang C, Jiang R, Wan J: Histone deacetylase inhibitors attenuate acute lung injury during cecal ligation and puncture-induced polymicrobial sepsis. World J Surg 2010;34:1676-1683.
Wong KF, Wo J, Ho D, Poon RT, Casasnovas JM, Luk JM: Prophylactic uses of integrin CD18-betaA peptide in a murine polymicrobial peritonitis model. World J Gastroenterol 2010;16:2648-2656.
Pearson JD: Normal endothelial cell function. Lupus 2000;9:183-188.
Ware LB, Camerer E, Welty-Wolf K, Schultz MJ, Matthay MA: Bench to bedside: targeting coagulation and fibrinolysis in acute lung injury. Am J Physiol Lung Cell Mol Physiol 2006;291:L307-L311.
Myers DD Jr, Rectenwald JE, Bedard PW, Kaila N, Shaw GD, Schaub RG, Farris DM, Hawley AE, Wrobleski SK, Henke PK, Wakefield TW: Decreased venous thrombosis with an oral inhibitor of P selectin. J Vasc Surg 2005;42:329-336.
Sullivan VV, Hawley AE, Farris DM, Knipp BS, Varga AJ, Wrobleski SK, Thanapron P, Eagleton MJ, Myers DD, Fowlkes JB, Wakefield TW: Decrease in fibrin content of venous thrombi in selectin-deficient mice. J Surg Res 2003;109:1-7.
Schouten M, Wiersinga WJ, Levi M, van der Poll T: Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 2008;83:536-545.
Aird WC: The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 2003;101:3765-3777.
Woodfin A, Voisin MB, Beyrau M, Colom B, Caille D, Diapouli FM, Nash GB, Chavakis T, Albelda SM, Rainger GE, Meda P, Imhof BA, Nourshargh S: The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo. Nat Immunol 2011;12:761-769.
Myers DD Jr, Henke PK, Bedard PW, Wrobleski SK, Kaila N, Shaw G, Meier TR, Hawley AE, Schaub RG, Wakefield TW: Treatment with an oral small molecule inhibitor of P selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis. J Vasc Surg 2006;44:625-632.
El Sayed H, Kerensky R, Stecher M, Mohanty P, Davies M: A randomized phase II study of xilonix, a targeted therapy against interleukin 1alpha, for the prevention of superficial femoral artery restenosis after percutaneous revascularization. J Vasc Surg 2016;63:133- 141.e1.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.