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Thromb Haemost 2016; 116(03): 486-495
DOI: 10.1160/TH16-02-0167
Cellular Haemostasis and Platelets
Schattauer GmbH

Oxidative stress and thromboxane-dependent platelet activation in inflammatory bowel disease: effects of anti-TNF-α treatment

Antonio Di Sabatino
2   First Department of Internal Medicine and Biotechnology Laboratories
,
Francesca Santilli
1   Internal Medicine and Center of Excellence on Aging, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy
,
Marco Guerci
2   First Department of Internal Medicine and Biotechnology Laboratories
,
Paola Simeone
1   Internal Medicine and Center of Excellence on Aging, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy
,
Sandro Ardizzone
4   Division of Gastroenterology, “L. Sacco” University Hospital, Milan, Italy
,
Alessandro Massari
4   Division of Gastroenterology, “L. Sacco” University Hospital, Milan, Italy
,
Paolo Giuffrida
2   First Department of Internal Medicine and Biotechnology Laboratories
,
Romina Tripaldi
1   Internal Medicine and Center of Excellence on Aging, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy
,
Alessandro Malara
3   Department of Molecular Medicine, University of Pavia, IRCCS San Matteo Foundation, Pavia, Italy
,
Rossella Liani
1   Internal Medicine and Center of Excellence on Aging, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy
,
Evelyn Gurini
3   Department of Molecular Medicine, University of Pavia, IRCCS San Matteo Foundation, Pavia, Italy
,
Nicola Aronico
2   First Department of Internal Medicine and Biotechnology Laboratories
,
Alessandra Balduini
3   Department of Molecular Medicine, University of Pavia, IRCCS San Matteo Foundation, Pavia, Italy
,
Gino Roberto Corazza
2   First Department of Internal Medicine and Biotechnology Laboratories
,
Giovanni Davì
1   Internal Medicine and Center of Excellence on Aging, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy
› Author Affiliations Financial support: This paper was partially supported by Cariplo Foundation (2013.0717) to AB, CARIPLO Biomedicine 2011 (No. 2011–0473) to GD, and by the Italian Ministry of University and Research (PRIN No. 2010JS3PMZ to FS).
Further Information

Publication History

Received: 26 February 2016

Accepted after minor revision: 13 May 2016

Publication Date:
29 November 2017 (online)

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Summary

Patients with inflammatory bowel disease (IBD) are at higher risk of venous thromboembolism and coronary artery disease despite having a lower burden of traditional risk factors. Platelets from IBD patients release more soluble CD40 ligand (CD40L), and this has been implicated in IBD platelet hyper-activation. We here measured the urinary F2-isoprostane 8-iso-prostaglandin (PG)2α (8-iso-PGF2α), urinary 11–dehydro–thromboxane (TX) B2 (11-dehydro–TXB2) and plasma CD40L in IBD patients, and explored the in vitro action of anti-tumour necrosis factor (TNF)–α antibody infliximab on IBD differentiating megakaryocytes. Urinary and blood samples were collected from 124 IBD patients and 37 healthy subjects. Thirteen IBD patients were also evaluated before and after 6–week infliximab treatment. The in vitro effect of infliximab on patient-derived megakaryocytes was evaluated by immunoflorescence microscopy and by flow cytometry. IBD patients had significantly (p<0.0001) higher urinary 8–iso–PGF2α and 11–dehydro–TXB2 as well as plasma CD40L levels than controls, with active IBD patients displaying higher urinary and plasma values when compared to inactive patients in remission. A 6-week treatment with infliximab was associated with a significant reduction of the urinary excretion of 8–iso–PGF2α and 11–dehydro–TXB2 (p=0.008) and plasma CD40L (p=0.001). Infliximab induced significantly rescued pro-platelet formation by megakaryocytes derived from IBD patients but not from healthy controls. Our findings provide evidence for enhanced in vivo TX–dependent platelet activation and lipid peroxidation in IBD patients. Anti-TNF–α therapy with infliximab down-regulates in vivo isoprostane generation and TX biosynthesis in responder IBD patients. Further studies are needed to clarify the implication of infliximab induced-proplatelet formation from IBD megakaryocytes.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

CD40 ligand - Crohn’s disease - infliximab - lipid peroxidation - platelet activation - ulcerative colitis

 

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