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Semin Thromb Hemost 2015; 41(06): 582-589
DOI: 10.1055/s-0035-1556590
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Hypercoagulability and Platelet Abnormalities in Inflammatory Bowel Disease

Elena Senchenkova
1   Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana
,
Hilary Seifert
1   Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana
,
D. Neil Granger
1   Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana
› Author Affiliations
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Publication History

Publication Date:
13 August 2015 (online)

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Abstract

Patients with inflammatory bowel disease (IBD) exhibit a threefold higher risk for development of systemic thrombosis than the general population. Although the underlying causes of the increased risk for thrombus development remain poorly understood, there is a large body of evidence suggesting that abnormalities in coagulation, fibrinolysis, and platelet function may contribute to this response. Changes in hemostatic biomarkers are consistent with subclinical activation of coagulation system, including tissue factor activation, impaired protein C pathway, enhanced thrombin generation, and diminished fibrinolytic capacity. There is also evidence for an increased production and reactivity of platelets, with an enhanced formation of platelet–platelet and platelet–leukocyte aggregates. The altered coagulation and platelet function, and the predisposition to thrombus formation have also been demonstrated in animal models of IBD. The animal studies have revealed a major role for inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, as mediators of the platelet abnormalities and enhanced thrombus development in experimental IBD. These findings in animal models raise hope for the development of novel therapeutic strategies to reduce thrombosis-related mortality in IBD patients.

Keywords

colitis - thrombocytosis - coagulation - fibrinolysis - platelet–leukocyte aggregation - interleukin-6
 

  • References

  • 1 Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009; 361 (21) 2066-2078
    CrossrefPubMedSearch in Google Scholar
  • 2 Esmon CT. The impact of the inflammatory response on coagulation. Thromb Res 2004; 114 (5-6) 321-327
    CrossrefPubMedSearch in Google Scholar
  • 3 Yoshida H, Granger DN. Inflammatory bowel disease: a paradigm for the link between coagulation and inflammation. Inflamm Bowel Dis 2009; 15 (8) 1245-1255
    CrossrefPubMedSearch in Google Scholar
  • 4 Irving PM, Pasi KJ, Rampton DS. Thrombosis and inflammatory bowel disease. Clin Gastroenterol Hepatol 2005; 3 (7) 617-628
    CrossrefPubMedSearch in Google Scholar
  • 5 Levi M, van der Poll T. Two-way interactions between inflammation and coagulation. Trends Cardiovasc Med 2005; 15 (7) 254-259
    CrossrefPubMedSearch in Google Scholar
  • 6 Twig G, Zandman-Goddard G, Szyper-Kravitz M, Shoenfeld Y. Systemic thromboembolism in inflammatory bowel disease: mechanisms and clinical applications. Ann N Y Acad Sci 2005; 1051: 166-173
    CrossrefPubMedSearch in Google Scholar
  • 7 Alkim H, Ayaz S, Alkim C, Ulker A, Sahin B. Continuous active state of coagulation system in patients with nonthrombotic inflammatory bowel disease. Clin Appl Thromb Hemost 2011; 17 (6) 600-604
    CrossrefPubMedSearch in Google Scholar
  • 8 Deutschmann A, Schlagenhauf A, Leschnik B, Hoffmann KM, Hauer A, Muntean W. Increased procoagulant function of microparticles in pediatric inflammatory bowel disease: role in increased thrombin generation. J Pediatr Gastroenterol Nutr 2013; 56 (4) 401-407
    CrossrefPubMedSearch in Google Scholar
  • 9 Scaldaferri F, Sans M, Vetrano S , et al. Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. J Clin Invest 2007; 117 (7) 1951-1960
    CrossrefPubMedSearch in Google Scholar
  • 10 Danese S, Papa A, Saibeni S, Repici A, Malesci A, Vecchi M. Inflammation and coagulation in inflammatory bowel disease: The clot thickens. Am J Gastroenterol 2007; 102 (1) 174-186
    CrossrefPubMedSearch in Google Scholar
  • 11 Danese S, Papa A. PAI-1 and TAFI in inflammatory bowel disease: the yin and yang of the fibrinolytic system. Eur J Gastroenterol Hepatol 2008; 20 (9) 826-828
    CrossrefPubMedSearch in Google Scholar
  • 12 Juhlin L, Krause U, Shelley WB. Endotoxin-induced microclots in ulcerative colitis and Crohn's disease. Scand J Gastroenterol 1980; 15 (3) 311-314
    CrossrefPubMedSearch in Google Scholar
  • 13 Jackson LM, O'Gorman PJ, O'Connell J, Cronin CC, Cotter KP, Shanahan F. Thrombosis in inflammatory bowel disease: clinical setting, procoagulant profile and Factor V Leiden. Q J Med 1997; 90: 183-188
    CrossrefPubMedSearch in Google Scholar
  • 14 Anthoni C, Russell J, Wood KC , et al. Tissue factor: a mediator of inflammatory cell recruitment, tissue injury, and thrombus formation in experimental colitis. J Exp Med 2007; 204 (7) 1595-1601
    CrossrefPubMedSearch in Google Scholar
  • 15 Stouthard JM, Levi M, Hack CE , et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 1996; 76 (5) 738-742
    PubMedSearch in Google Scholar
  • 16 Kvietys PR, Granger DN. Role of reactive oxygen and nitrogen species in the vascular responses to inflammation. Free Radic Biol Med 2012; 52 (3) 556-592
    CrossrefPubMedSearch in Google Scholar
  • 17 Görlach A. Redox regulation of the coagulation cascade. Antioxid Redox Signal 2005; 7 (9-10) 1398-1404
    CrossrefPubMedSearch in Google Scholar
  • 18 Collins CE, Cahill MR, Newland AC, Rampton DS. Platelets circulate in an activated state in inflammatory bowel disease. Gastroenterology 1994; 106 (4) 840-845
    CrossrefPubMedSearch in Google Scholar
  • 19 Collins CE, Rampton DS. Platelet dysfunction: a new dimension in inflammatory bowel disease. Gut 1995; 36 (1) 5-8
    CrossrefPubMedSearch in Google Scholar
  • 20 Danese S, de la Motte C, Sturm A , et al. Platelets trigger a CD40-dependent inflammatory response in the microvasculature of inflammatory bowel disease patients. Gastroenterology 2003; 124 (5) 1249-1264
    CrossrefPubMedSearch in Google Scholar
  • 21 Öztürk ZA, Dag MS, Kuyumcu ME , et al. Could platelet indices be new biomarkers for inflammatory bowel diseases?. Eur Rev Med Pharmacol Sci 2013; 17 (3) 334-341
    PubMedSearch in Google Scholar
  • 22 Harries AD, Fitzsimons E, Fifield R, Dew MJ, Rhoades J. Platelet count: a simple measure of activity in Crohn's disease. Br Med J (Clin Res Ed) 1983; 286 (6376) 1476
    PubMedSearch in Google Scholar
  • 23 Heits F, Stahl M, Ludwig D, Stange EF, Jelkmann W. Elevated serum thrombopoietin and interleukin-6 concentrations in thrombocytosis associated with inflammatory bowel disease. J Interferon Cytokine Res 1999; 19 (7) 757-760
    CrossrefPubMedSearch in Google Scholar
  • 24 Yan SL, Russell J, Harris NR, Senchenkova EY, Yildirim A, Granger DN. Platelet abnormalities during colonic inflammation. Inflamm Bowel Dis 2013; 19 (6) 1245-1253
    CrossrefPubMedSearch in Google Scholar
  • 25 Yan SL, Russell J, Granger DN. Platelet activation and platelet-leukocyte aggregation elicited in experimental colitis are mediated by interleukin-6. Inflamm Bowel Dis 2014; 20 (2) 353-362
    CrossrefPubMedSearch in Google Scholar
  • 26 Senchenkova EY, Komoto S, Russell J , et al. Interleukin-6 mediates the platelet abnormalities and thrombogenesis associated with experimental colitis. Am J Pathol 2013; 183 (1) 173-181
    CrossrefPubMedSearch in Google Scholar
  • 27 Collins CE, Rampton DS, Rogers J, Williams NS. Platelet aggregation and neutrophil sequestration in the mesenteric circulation in inflammatory bowel disease. Eur J Gastroenterol Hepatol 1997; 9 (12) 1213-1217
    PubMedSearch in Google Scholar
  • 28 Danese S, Katz JA, Saibeni S , et al. Activated platelets are the source of elevated levels of soluble CD40 ligand in the circulation of inflammatory bowel disease patients. Gut 2003; 52 (10) 1435-1441
    CrossrefPubMedSearch in Google Scholar
  • 29 André P, Prasad KS, Denis CV , et al. CD40L stabilizes arterial thrombi by a beta3 integrin—dependent mechanism. Nat Med 2002; 8 (3) 247-252
    CrossrefPubMedSearch in Google Scholar
  • 30 Stokes KY, Granger DN. Platelets: a critical link between inflammation and microvascular dysfunction. J Physiol 2012; 590 (Pt 5): 1023-1034
    CrossrefPubMedSearch in Google Scholar
  • 31 Webberley MJ, Hart MT, Melikian V. Thromboembolism in inflammatory bowel disease: role of platelets. Gut 1993; 34 (2) 247-251
    CrossrefPubMedSearch in Google Scholar
  • 32 Andoh A, Yoshida T, Yagi Y , et al. Increased aggregation response of platelets in patients with inflammatory bowel disease. J Gastroenterol 2006; 41 (1) 47-54
    CrossrefPubMedSearch in Google Scholar
  • 33 Yoshida H, Russell J, Senchenkova EY, Almeida Paula LD, Granger DN. Interleukin-1beta mediates the extra-intestinal thrombosis associated with experimental colitis. Am J Pathol 2010; 177 (6) 2774-2781
    CrossrefPubMedSearch in Google Scholar
  • 34 Irving PM, Macey MG, Shah U, Webb L, Langmead L, Rampton DS. Formation of platelet-leukocyte aggregates in inflammatory bowel disease. Inflamm Bowel Dis 2004; 10 (4) 361-372
    CrossrefPubMedSearch in Google Scholar
  • 35 Irving PM, Macey MG, Feakins RM , et al. Platelet-leucocyte aggregates form in the mesenteric vasculature in patients with ulcerative colitis. Eur J Gastroenterol Hepatol 2008; 20 (4) 283-289
    CrossrefPubMedSearch in Google Scholar
  • 36 Vowinkel T, Anthoni C, Wood KC , et al. CD40-CD40 ligand mediates the recruitment of leukocytes and platelets in the inflamed murine colon. Gastroenterology 2007; 132 (3) 955-965
    CrossrefPubMedSearch in Google Scholar
  • 37 Vowinkel T, Wood KC, Stokes KY , et al. Mechanisms of platelet and leukocyte recruitment in experimental colitis. Am J Physiol Gastrointest Liver Physiol 2007; 293 (5) G1054-G1060
    CrossrefPubMedSearch in Google Scholar
  • 38 Cognat E, Crassard I, Denier C, Vahedi K, Bousser MG. Cerebral venous thrombosis in inflammatory bowel diseases: eight cases and literature review. Int J Stroke 2011; 6 (6) 487-492
    CrossrefPubMedSearch in Google Scholar
  • 39 Miehsler W, Reinisch W, Valic E , et al. Is inflammatory bowel disease an independent and disease specific risk factor for thromboembolism?. Gut 2004; 53 (4) 542-548
    CrossrefPubMedSearch in Google Scholar
  • 40 Grisham MB. Do different animal models of IBD serve different purposes?. Inflamm Bowel Dis 2008; 14 (Suppl. 02) S132-S133
    PubMedSearch in Google Scholar
  • 41 Yoshida H, Russell J, Granger DN. Thrombin mediates the extraintestinal thrombosis associated with experimental colitis. Am J Physiol Gastrointest Liver Physiol 2008; 295 (5) G904-G908
    CrossrefPubMedSearch in Google Scholar
  • 42 Yoshida H, Russell J, Stokes KY, Yilmaz CE, Esmon CT, Granger DN. Role of the protein C pathway in the extraintestinal thrombosis associated with murine colitis. Gastroenterology 2008; 135 (3) 882-888
    CrossrefPubMedSearch in Google Scholar
  • 43 Yoshida H, Yilmaz CE, Granger DN. Role of tumor necrosis factor-α in the extraintestinal thrombosis associated with colonic inflammation. Inflamm Bowel Dis 2011; 17 (11) 2217-2223
    CrossrefPubMedSearch in Google Scholar
  • 44 Mudter J, Neurath MF. Il-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance. Inflamm Bowel Dis 2007; 13 (8) 1016-1023
    CrossrefPubMedSearch in Google Scholar
  • 45 Gavins FN, Li G, Russell J, Perretti M, Granger DN. Microvascular thrombosis and CD40/CD40L signaling. J Thromb Haemost 2011; 9 (3) 574-581
    CrossrefPubMedSearch in Google Scholar