Increased risk of venous thromboembolism with a sirolimus-based immunosuppression regimen in lung transplantation

Ahya, Vivek N.; McShane, Pamela J.; Baz, Maher A.; Valentine, Vincent G.; Arcasoy, Selim M.; Love, Robert B.; Seethamraju, Harish; Garrity, Edward R.; Alex, Charles G.; Bag, Remzi; DeOliveira, Nilto; Vigneswaran, Wickii T.; Charbeneau, Jeffery; Krishnan, Jerry A.; Durazo‐Arvizu, Ramón; Norwick, Lourdes; Bhorade, Sangeeta

doi:10.1016/j.healun.2010.08.010

Cited by 55 publications

(66 citation statements)

References 33 publications

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“…Newer immunomodulatory drugs directed toward inhibition of Mammalian target of Rapamycin (mTOR), like sirolimus and everolimus, offer significant hope in prevention of allograft rejection (20). Previous studies have shown that therapy with Rapamycin attenuates fibrocyte trafficking from bone marrow and prevents fibrocyte and collagen deposition in lungs challenged with bleomycin via altering CXCR4 expression (5).…”

Section: Discussionmentioning

confidence: 99%

“…Despite this potential, there remain many therapeutic challenges to proper administration of these drugs. In lung transplant recipients receiving sirolimus, there was an increased risk of severe venous thromboembolism (20) and in separate trials, patients treated with sirolimus suffered from airway anastomosis dehiscence and generalized poor wound healing (24,25). As a result, many clinicians have decided to administer sirolimus post completion of bronchiolar wound healing (24) and as such, the use of sirolimus across all centers was 8% at 1 year and 18% at 5 years post transplantation (1).…”

Section: Discussionmentioning

confidence: 99%

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Inhibiting CXCL12 blocks fibrocyte migration and differentiation and attenuates bronchiolitis obliterans in a murine heterotopic tracheal transplant model

Harris

Zhao

LaPar

et al. 2013

The Journal of Thoracic and Cardiovascular Surgery

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Objectives Fibrocytes are integral in the development of fibroproliferative disease post lung transplantation. Undifferentiated fibrocytes (CD45+Col1+CXCR4+) preferentially traffic via the CXCR4/CXCL12 axis and differentiate into smooth muscle actin producing (CD45+CXCR4+αSMA+) cells. We postulated that an antibody directed against CXCL12 would attenuate fibrocyte migration and fibro-obliteration of heterotopic tracheal transplant allografts. Methods A total alloantigenic mismatch murine heterotopic tracheal transplant model of obliterative bronchiolitis was used. Animals were treated with either goat-anti-human CXCL12 F(ab′)2 or Goat IgG F(ab′)2. Buffy coat, bone marrow, and trachea allografts were collected and analyzed by flow cytometry. Tracheal luminal obliteration was assessed via hematoxylin/eosin and Direct Red 80 collagen stain. Results Compared to controls, anti-CXCL12 treated animals showed a significant decrease in tracheal allograft fibrocyte populations at 7 and 21 days post-transplantation. Bone marrow and buffy coat aspirates showed the same trend at 7 days. In anti-CXCL12 treated mice, there was a 35% decrease in luminal obliteration at 21 days (65.00 [interquartile range = 38]% vs. 100 [10]% obliterated; p=0.010) and decreased luminal collagen deposition at 21 and 28 days post transplantation (p=0.042 and 0.012, respectively). Conclusions Understanding the role of fibrocytes in airway fibrosis post lung transplantation may lead to a paradigm shift in treatment strategy. Anti-CXCL12 antibody afforded protection against infiltrating fibrocytes and reduced deterioration of tracheal allografts. Thus the CXCR4/CXCL12 axis is a novel target for the treatment of fibro-obliteration post lung transplantation and quantification of fibrocyte populations may provide clinicians with a biomarker of fibrosis allowing individualized drug therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibiting CXCL12 blocks fibrocyte migration and differentiation and attenuates bronchiolitis obliterans in a murine heterotopic tracheal transplant model

Harris

Zhao

LaPar

et al. 2013

The Journal of Thoracic and Cardiovascular Surgery

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“…There have been reports of an increased incidence of airway anastomosis dehiscence in patients treated with sirolimus immediately after lung transplantation [23, 24]. Other adverse effects of mTOR inhibitors include lipid abnormalities, venous thromboembolism, stomatitis, diarrhea, and less commonly interstitial pneumonitis [25–27]. …”

Section: Commentmentioning

confidence: 99%

Rapamycin Blocks Fibrocyte Migration and Attenuates Bronchiolitis Obliterans in a Murine Model

Gillen

Zhao

Harris

et al. 2013

The Annals of Thoracic Surgery

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Background Fibrocytes are integral in the development of fibroproliferative disease. The CXCL12/CXCR4 chemokine axis has been shown to play a central role in fibrocyte migration and the development of bronchiolitis obliterans post lung transplantation. Inhibition of the mTOR (mammalian target of rapamycin) pathway with rapamycin has been shown to decrease expression of both CXCR4 and its receptor agonist, CXCL12. Thus, we hypothesize that rapamycin treatment would decrease fibrocyte trafficking into tracheal allografts and prevent bronchiolitis obliterans. Methods A total alloantigenic mismatch, murine heterotopic tracheal transplant model of bronchiolitis obliterans was used. Animals were either treated with rapamycin or dimethyl sulfoxide (DMSO) for 14 days post tracheal transplant. Fibrocyte levels were assessed via flow cytometry, and allograft neutrophil, CD3+ T-cell, macrophage, and smooth muscle actin levels were assessed via immunohistochemistry. Tracheal luminal obliteration was assessed on hematoxylin and eosin stains. Results Compared to DMSO controls, rapamycin-treated mice showed a significant decrease in fibrocyte levels in tracheal allografts. Fibrocytes levels in recipient’s blood showed a similar pattern, although not statistically significant. Furthermore, animals treated with rapamycin showed a significant decrease in tracheal allograft luminal obliteration compared to controls. Based on immunohistochemistry analyses, populations of α-SMA positive cells, neutrophils, CD3+ T-cells, and macrophages were all decreased in rapamycin-treated allograft versus DMSO controls. Conclusions Rapamycin effectively reduces recruitment of fibrocytes into tracheal allografts and mitigates development of tracheal luminal fibrosis. Further studies are needed to determine the cellular and molecular mechanisms that mediate the protective effect of rapamycin against bronchiolitis obliterans.

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“…[3][4][5][6][7][8][9][10][11][12][13][14] In 2 large population-based cohorts from United Kingdom 15 and Canada, 16 the estimated incidence rates of VTE among individuals from the general population were, respectively, 1.33 and 1.22 cases per 1,000 persons-years, decreasing to 1.07 cases per 1,000 persons-years when cancer-related VTE episodes were excluded. 15 With variable follow-up duration among studies, the reported cumulative incidence of VTE varied between 4.5% and 9.1% in kidney transplant recipients, 3-6 between 8.6% and 29% in lung transplant recipients, 7-10 and between 0.4% and 4.6 % in liver transplant recipients.…”

mentioning

confidence: 99%

Venous thromboembolism in heart transplant recipients: Incidence, recurrence and predisposing factors

Álvarez‐Álvarez¹,

Barge‐Caballero²,

Chávez-Leal³

et al. 2015

The Journal of Heart and Lung Transplantation

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Increased risk of venous thromboembolism with a sirolimus-based immunosuppression regimen in lung transplantation

Cited by 55 publications

References 33 publications

Inhibiting CXCL12 blocks fibrocyte migration and differentiation and attenuates bronchiolitis obliterans in a murine heterotopic tracheal transplant model

Inhibiting CXCL12 blocks fibrocyte migration and differentiation and attenuates bronchiolitis obliterans in a murine heterotopic tracheal transplant model

Rapamycin Blocks Fibrocyte Migration and Attenuates Bronchiolitis Obliterans in a Murine Model

Venous thromboembolism in heart transplant recipients: Incidence, recurrence and predisposing factors

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