Download PDF
CC BY-NC-ND 4.0 · TH Open 2017; 01(01): e11-e23
DOI: 10.1055/s-0037-1603927
Original Article
Georg Thieme Verlag KG Stuttgart · New York

ADAMTS13 Deficiency Worsens Colitis and Exogenous ADAMTS13 Administration Decreases Colitis Severity in Mice

Naamah L. Zitomersky
1   Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, Massachusetts, United States
2   Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States
3   Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, United States
,
Melanie Demers
2   Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States
3   Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, United States
,
Kimberly Martinod
2   Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States
3   Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, United States
,
Maureen Gallant
3   Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, United States
,
Stephen M. Cifuni
3   Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, United States
,
Amlan Biswas
1   Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, Massachusetts, United States
2   Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States
,
Scott Snapper
1   Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, Massachusetts, United States
4   Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States
5   Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, United States
,
Denisa D. Wagner
2   Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States
3   Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, United States
6   Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, United States
› Author Affiliations
Further Information

Publication History

Publication Date:
28 June 2017 (online)

Also available at
   Permissions and Reprints

Abstract

Background Inflammatory bowel disease (IBD) affects 1.6 million people in the United States. IBD is associated with an increased risk of thrombosis, which rises with disease activity. The pathogenesis of IBD and its increased thrombotic risk is not completely understood. Ultra large von Willebrand factor (ULVWF) multimers are secreted from activated endothelium, leading to recruitment of platelets and leukocytes. A disintegrin and metalloproteinase with thrombospondin type I repeats motif 13 (ADAMTS13) cleaves highly adhesive ULVWF into smaller, less bioactive, multimers, releasing them into circulation. Mice deficient in ADAMTS13 (ADAMTS13−/−) have heightened inflammatory and thrombotic responses.

Objectives We hypothesized that upon colitis induction, ADAMTS13−/− mice would have more severe symptoms compared with wild-type (WT) mice, and rhADAMTS13 administration to mice with colitis would improve their condition.

Results Dextran sodium sulfate–induced colitis was worse in ADAMTS13−/− mice than WT. ADAMTS13−/− showed increased weight loss, worse anemia, and increased clinical and histologic colitis severity, compared with WT mice. ADAMTS13−/− mice had increased VWF release, with accumulation at inflamed colonic sites. Also, the majority of mice showed one or more submucosal colonic thrombi. ADAMTS13 deficiency worsened colitis and propagated intestinal inflammation, most likely through increased platelet–leukocyte recruitment by VWF. Treatment of WT mice with rhADAMTS13 decreased colitis severity without worsening anemia. Additionally, several immune-mediated chronic murine colitis models, and inflamed colon tissue specimens from IBD patients, showed increased VWF release at inflamed sites, suggesting a generalizability of our findings.

Conclusion Measuring VWF/ADAMTS13 levels could have clinical utility. When applicable, the administration of ADAMTS13, in addition to primary treatment, may improve outcomes for IBD patients.

Keywords

ADAMTS13 - colitis - Crohn's disease - thrombosis - VWF

Funding

This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health grants R01HL102101, R35HL135765 (to D.D.W.), and 5T32HL066987-13 (K.M.), and by Basic Research Grant H13–20955 from Baxter Bioscience (to D.D.W.).


Supplementary Material

 

  • References

  • 1 Kappelman MD, Moore KR, Allen JK, Cook SF. Recent trends in the prevalence of Crohn's disease and ulcerative colitis in a commercially insured US population. Dig Dis Sci 2013; 58 (02) 519-525
    CrossrefPubMedSearch in Google Scholar
  • 2 Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007; 448 (7152): 427-434
    CrossrefPubMedSearch in Google Scholar
  • 3 Bernstein CN, Blanchard JF, Houston DS, Wajda A. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study. Thromb Haemost 2001; 85 (03) 430-434
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Zitomersky NL, Verhave M, Trenor III CC. Thrombosis and inflammatory bowel disease: a call for improved awareness and prevention. Inflamm Bowel Dis 2011; 17 (01) 458-470
    CrossrefPubMedSearch in Google Scholar
  • 5 Ha C, Magowan S, Accortt NA, Chen J, Stone CD. Risk of arterial thrombotic events in inflammatory bowel disease. Am J Gastroenterol 2009; 104 (06) 1445-1451
    CrossrefPubMedSearch in Google Scholar
  • 6 Ozturk K, Guler AK, Cakir M. , et al. Pulse wave velocity, intima media thickness, and flow-mediated dilatation in patients with normotensive normoglycemic inflammatory bowel disease. Inflamm Bowel Dis 2015; 21 (06) 1314-1320
    PubMedSearch in Google Scholar
  • 7 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 (01) 174-186
    CrossrefPubMedSearch in Google Scholar
  • 8 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
  • 9 Lentz SR. Thrombosis in the setting of obesity or inflammatory bowel disease. Blood 2016; 128 (20) 2388-2394
    CrossrefPubMedSearch in Google Scholar
  • 10 Esmon CT. The impact of the inflammatory response on coagulation. Thromb Res 2004; 114 (5-6): 321-327
    CrossrefPubMedSearch in Google Scholar
  • 11 Feys HB, Canciani MT, Peyvandi F, Deckmyn H, Vanhoorelbeke K, Mannucci PM. ADAMTS13 activity to antigen ratio in physiological and pathological conditions associated with an increased risk of thrombosis. Br J Haematol 2007; 138 (04) 534-540
    CrossrefPubMedSearch in Google Scholar
  • 12 Feagan BG, Rutgeerts P, Sands BE. , et al; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369 (08) 699-710
    CrossrefPubMedSearch in Google Scholar
  • 13 Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol 1990; 6: 217-246
    CrossrefPubMedSearch in Google Scholar
  • 14 Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 2007; 7 (09) 678-689
    CrossrefPubMedSearch in Google Scholar
  • 15 Pendu R, Terraube V, Christophe OD. , et al. P-selectin glycoprotein ligand 1 and beta2-integrins cooperate in the adhesion of leukocytes to von Willebrand factor. Blood 2006; 108 (12) 3746-3752
    CrossrefPubMedSearch in Google Scholar
  • 16 Sporn LA, Marder VJ, Wagner DD. von Willebrand factor released from Weibel-Palade bodies binds more avidly to extracellular matrix than that secreted constitutively. Blood 1987; 69 (05) 1531-1534
    PubMedSearch in Google Scholar
  • 17 Dong JF, Moake JL, Nolasco L. , et al. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood 2002; 100 (12) 4033-4039
    CrossrefPubMedSearch in Google Scholar
  • 18 Chauhan AK, Kisucka J, Brill A, Walsh MT, Scheiflinger F, Wagner DD. ADAMTS13: a new link between thrombosis and inflammation. J Exp Med 2008; 205 (09) 2065-2074
    CrossrefPubMedSearch in Google Scholar
  • 19 De Cock E, Hermans C, De Raeymaecker J. , et al. The novel ADAMTS13-p.D187H mutation impairs ADAMTS13 activity and secretion and contributes to thrombotic thrombocytopenic purpura in mice. J Thromb Haemost 2015; 13 (02) 283-292
    CrossrefPubMedSearch in Google Scholar
  • 20 Banno F, Chauhan AK, Kokame K. , et al. The distal carboxyl-terminal domains of ADAMTS13 are required for regulation of in vivo thrombus formation. Blood 2009; 113 (21) 5323-5329
    CrossrefPubMedSearch in Google Scholar
  • 21 Stevens TR, James JP, Simmonds NJ. , et al. Circulating von Willebrand factor in inflammatory bowel disease. Gut 1992; 33 (04) 502-506
    CrossrefPubMedSearch in Google Scholar
  • 22 Zezos P, Papaioannou G, Nikolaidis N, Vasiliadis T, Giouleme O, Evgenidis N. Elevated plasma von Willebrand factor levels in patients with active ulcerative colitis reflect endothelial perturbation due to systemic inflammation. World J Gastroenterol 2005; 11 (48) 7639-7645
    CrossrefPubMedSearch in Google Scholar
  • 23 Ahmed S, Siddiqui AK, Chandrasekaran V. Correlation of thrombotic thrombocytopenic purpura disease activity with von Willebrand factor-cleaving protease level in ulcerative colitis. Am J Med 2004; 116 (11) 786-787
    CrossrefPubMedSearch in Google Scholar
  • 24 Mori M, Salter JW, Vowinkel T, Krieglstein CF, Stokes KY, Granger DN. Molecular determinants of the prothrombogenic phenotype assumed by inflamed colonic venules. Am J Physiol Gastrointest Liver Physiol 2005; 288 (05) G920-G926
    CrossrefPubMedSearch in Google Scholar
  • 25 Chauhan AK, Walsh MT, Zhu G, Ginsburg D, Wagner DD, Motto DG. The combined roles of ADAMTS13 and VWF in murine models of TTP, endotoxemia, and thrombosis. Blood 2008; 111 (07) 3452-3457
    CrossrefPubMedSearch in Google Scholar
  • 26 Shouval DS, Biswas A, Goettel JA. , et al. Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity 2014; 40 (05) 706-719
    CrossrefPubMedSearch in Google Scholar
  • 27 Nguyen DD, Maillard MH, Cotta-de-Almeida V. , et al. Lymphocyte-dependent and Th2 cytokine-associated colitis in mice deficient in Wiskott-Aldrich syndrome protein. Gastroenterology 2007; 133 (04) 1188-1197
    CrossrefPubMedSearch in Google Scholar
  • 28 Wirtz S, Neurath MF. Mouse models of inflammatory bowel disease. Adv Drug Deliv Rev 2007; 59 (11) 1073-1083
    CrossrefPubMedSearch in Google Scholar
  • 29 Savchenko AS, Borissoff JI, Martinod K. , et al. VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. Blood 2014; 123 (01) 141-148
    CrossrefPubMedSearch in Google Scholar
  • 30 Brill A, Fuchs TA, Chauhan AK. , et al. von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models. Blood 2011; 117 (04) 1400-1407
    CrossrefPubMedSearch in Google Scholar
  • 31 Mizoguchi E. Chitinase 3-like-1 exacerbates intestinal inflammation by enhancing bacterial adhesion and invasion in colonic epithelial cells. Gastroenterology 2006; 130 (02) 398-411
    CrossrefPubMedSearch in Google Scholar
  • 32 Yan SL, Russell J, Harris NR, Senchenkova EY, Yildirim A, Granger DN. Platelet abnormalities during colonic inflammation. Inflamm Bowel Dis 2013; 19 (06) 1245-1253
    CrossrefPubMedSearch in Google Scholar
  • 33 Alex P, Zachos NC, Nguyen T. , et al. Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBS-induced colitis. Inflamm Bowel Dis 2009; 15 (03) 341-352
    CrossrefPubMedSearch in Google Scholar
  • 34 Spencer SD, Di Marco F, Hooley J. , et al. The orphan receptor CRF2-4 is an essential subunit of the interleukin 10 receptor. J Exp Med 1998; 187 (04) 571-578
    CrossrefPubMedSearch in Google Scholar
  • 35 Petri B, Broermann A, Li H. , et al. von Willebrand factor promotes leukocyte extravasation. Blood 2010; 116 (22) 4712-4719
    CrossrefPubMedSearch in Google Scholar
  • 36 Motto DG, Chauhan AK, Zhu G. , et al. Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice. J Clin Invest 2005; 115 (10) 2752-2761
    CrossrefPubMedSearch in Google Scholar
  • 37 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 (01) 173-181
    CrossrefPubMedSearch in Google Scholar
  • 38 Dhillon AP, Anthony A, Sim R. , et al. Mucosal capillary thrombi in rectal biopsies. Histopathology 1992; 21 (02) 127-133
    CrossrefPubMedSearch in Google Scholar
  • 39 Violi NV, Schoepfer AM, Fournier N, Guiu B, Bize P, Denys A. ; Swiss Inflammatory Bowel Disease Cohort Study Group. Prevalence and clinical importance of mesenteric venous thrombosis in the Swiss Inflammatory Bowel Disease Cohort. AJR Am J Roentgenol 2014; 203 (01) 62-69
    CrossrefPubMedSearch in Google Scholar
  • 40 Papay P, Miehsler W, Tilg H. , et al. Clinical presentation of venous thromboembolism in inflammatory bowel disease. J Crohn's Colitis 2013; 7 (09) 723-729
    PubMedSearch in Google Scholar
  • 41 Pinsky DJ, Naka Y, Liao H. , et al. Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies. A mechanism for rapid neutrophil recruitment after cardiac preservation. J Clin Invest 1996; 97 (02) 493-500
    CrossrefPubMedSearch in Google Scholar
  • 42 Suidan GL, Brill A, De Meyer SF. , et al. Endothelial Von Willebrand factor promotes blood-brain barrier flexibility and provides protection from hypoxia and seizures in mice. Arterioscler Thromb Vasc Biol 2013; 33 (09) 2112-2120
    CrossrefPubMedSearch in Google Scholar
  • 43 Middleton J, Americh L, Gayon R. , et al. A comparative study of endothelial cell markers expressed in chronically inflamed human tissues: MECA-79, Duffy antigen receptor for chemokines, von Willebrand factor, CD31, CD34, CD105 and CD146. J Pathol 2005; 206 (03) 260-268
    CrossrefPubMedSearch in Google Scholar
  • 44 Matsumoto T, Kitano A, Nakamura S. , et al. Possible role of vascular endothelial cells in immune responses in colonic mucosa examined immunocytochemically in subjects with and without ulcerative colitis. Clin Exp Immunol 1989; 78 (03) 424-430
    PubMedSearch in Google Scholar
  • 45 Thompson NP, Wakefield AJ, Pounder RE. Inherited disorders of coagulation appear to protect against inflammatory bowel disease. Gastroenterology 1995; 108 (04) 1011-1015
    CrossrefPubMedSearch in Google Scholar
  • 46 Powell N, Lo JW, Biancheri P. , et al. Interleukin 6 increases production of cytokines by colonic innate lymphoid cells in mice and patients with chronic intestinal inflammation. Gastroenterology 2015; 149 (02) 456-467
    CrossrefPubMedSearch in Google Scholar
  • 47 Burstein SA. Cytokines, platelet production and hemostasis. Platelets 1997; 8 (2-3): 93-104
    CrossrefPubMedSearch in Google Scholar
  • 48 Khan MM, Motto DG, Lentz SR, Chauhan AK. ADAMTS13 reduces VWF-mediated acute inflammation following focal cerebral ischemia in mice. J Thromb Haemost 2012; 10 (08) 1665-1671
    CrossrefPubMedSearch in Google Scholar
  • 49 De Meyer SF, Savchenko AS, Haas MS. , et al. Protective anti-inflammatory effect of ADAMTS13 on myocardial ischemia/reperfusion injury in mice. Blood 2012; 120 (26) 5217-5223
    CrossrefPubMedSearch in Google Scholar
  • 50 Gandhi C, Motto DG, Jensen M, Lentz SR, Chauhan AK. ADAMTS13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice. Blood 2012; 120 (26) 5224-5230
    CrossrefPubMedSearch in Google Scholar