Reduced Fibrin Deposition and Intravascular Thrombosis in hDAF Transgenic Pig Hearts Perfused With Tirofiban

Brandl, Ulrike; Jöckle, H; Erhardt, Matthias; Michel, Sebastian; Burdorf, Lars; Brenner, Paolo; Bittmann, Iris; Rössle, Matthias; Mordstein, Volker; Hammer, C.; Thein, E.; Reichart, B.; Schmoeckel, Michael

doi:10.1097/01.tp.0000295742.45413.dc

Cited by 9 publications

(6 citation statements)

References 52 publications

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“…Although activated protein C, 59 desmopressin 60 and tirofiban 61 have shown promise in inhibiting thrombosis in ex vivo pig organ perfusion models, the results from pig‐to‐non‐human primate studies using agents including aspirin, clopidogrel, heparin, warfarin and antithrombin have been mixed 33 , 62 , 63 , 64 , 65 . This failure to consistently prolong xenograft survival may reflect progressive injury and loss of xenograft EC by non‐thrombotic mechanisms, such as cell‐mediated cytotoxicity, removing the surface required by many of these agents to exert their full effect.…”

Section: Coagulation and Thrombosis In Xenotransplantationmentioning

confidence: 99%

Complement activation and coagulation in xenotransplantation

Cowan

d’Apice

2009

Immunol Cell Biol

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Xenotransplantation using porcine donors holds tremendous promise for alleviating the chronic shortage of human organ donors. However, transplantation from pigs into higher primates triggers a vigorous immune response involving complement activation and thrombosis. Hyperacute rejection can be prevented by using donors in which GalT, the gene responsible for the predominant target of anti-pig natural antibodies, has been deleted. Unfortunately, the adaptive response to GalT knockout (KO) organs has been difficult to immunosuppress. The focus has shifted to identifying additional genetic modifications that will extend xenograft survival beyond the several months currently achievable. Which gene(s) should be added to the GalT KO background is open to debate. Overexpression of a complement regulatory factor(s) seems a logical first choice, supported by recent in vitro data but not yet validated in preclinical models. The next obvious candidate would be an anticoagulant protein(s) to deal with the dysregulated coagulation that is almost invariably associated with xenograft rejection. Several potentially useful molecules have been identified, although this study is yet to be translated to the pig. Our understanding of the mechanisms of GalT KO xenograft rejection continues to grow, providing a rational basis for tailoring further genetic modification of the donor and immunosuppression of the recipient.

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Section: Coagulation and Thrombosis In Xenotransplantationmentioning

confidence: 99%

Complement activation and coagulation in xenotransplantation

Cowan

d’Apice

2009

Immunol Cell Biol

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“…Eptifibatide effectively prevented platelet aggregation in an in vitro primate study and prolonged xenograft survival in a rat‐to‐guinea pig cardiac model . Tirofiban improved heart performance and reduced myocardial damage and intravascular thrombosis in pig cardiac xenotransplantation models .…”

Section: Therapeutic Options To Inhibit Platelet Activation And/or Agmentioning

confidence: 97%

“…Eptifibatide effectively prevented platelet aggregation in an in vitro primate study [100,101,103,190] and prolonged xenograft survival in a rat-to-guinea pig cardiac model [227]. Tirofiban improved heart performance and reduced myocardial damage and intravascular thrombosis in pig cardiac xenotransplantation models [228]. Thromboxane A2 is produced by activated platelets and has pro-thrombotic properties, increasing platelet aggregation.…”

Section: Othersmentioning

confidence: 99%

The role of platelets in coagulation dysfunction in xenotransplantation, and therapeutic options

Iwase

Ezzelarab

Ekser

et al. 2014

Xenotransplantation

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Xenotransplantation could resolve the increasing discrepancy between the availability of deceased human donor organs and the demand for transplantation. Most advances in this field have resulted from the introduction of genetically engineered pigs, e.g., α1,3-galactosyltransferase gene-knockout (GTKO) pigs transgenic for one or more human complement-regulatory proteins (e.g., CD55, CD46, CD59). Failure of these grafts has not been associated with the classical features of acute humoral xenograft rejection, but with the development of thrombotic microangiopathy in the graft and/or consumptive coagulopathy in the recipient. Although the precise mechanisms of coagulation dysregulation remain unclear, molecular incompatibilities between primate coagulation factors and pig natural anticoagulants exacerbate the thrombotic state within the xenograft vasculature. Platelets play a crucial role in thrombosis and contribute to the coagulation disorder in xenotransplantation. They are therefore important targets if this barrier is to be overcome. Further genetic manipulation of the organ-source pigs, such as pigs that express one or more coagulation-regulatory genes (e.g., thrombomodulin, endothelial protein C receptor, tissue factor pathway inhibitor, CD39), is anticipated to inhibit platelet activation and the generation of thrombus. In addition, adjunctive pharmacologic anti-platelet therapy may be required. The genetic manipulations that are currently being tested are reviewed, as are the potential pharmacologic agents that may prove beneficial.

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“…In a working-heart model with non-transgenic and human complement regulator (hDAF) pig hearts, Brandl et al [47] confirmed a certain impact for tirofiban by showing that this GPIIb/IIIa inhibitor leads to an improvement in heart performance and reduction in myocardial damage and intravascular thrombosis. Depletion of fibrinogen was equally diminished by tirofiban and hDAF, but the combination of tirofiban and GPIIb/IIIa showed additional benefits with respect to AT consumption and intravascular fibrin deposition [47].…”

Section: Glycoprotein Iib/iiia Inhibitorsmentioning

confidence: 98%

Which anti‐platelet therapies might be beneficial in xenotransplantation?

Schmelzle

Cowan

Robson

2011

Xenotransplantation

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Xenotransplantation could provide an unlimited and elective supply of grafts, once mechanisms of graft loss and vascular injury are better understood. The development of α-1,3-galactosyltransferase gene-knockout (GalT-KO) swine with the removal of a dominant xeno-antigen has been an important advance; however, delayed xenograft and acute vascular reaction in GalT-KO animals persist. These occur, at least in part, because of humoral reactions that result in vascular injury. Intrinsic molecular incompatibilities in the regulation of blood clotting and extracellular nucleotide homeostasis between discordant species may also predispose to thrombophilia within the vasculature of xenografts. Although limited benefits have been achieved with currently available pharmacological anti-thrombotics and anti-coagulants, the highly complex mechanisms of platelet activation and thrombosis in xenograft rejection also require potent immunosuppressive interventions. We will focus on recent thromboregulatory approaches while elucidating appropriate anti-platelet mechanisms. We will discuss potential benefits of additional anti-thrombotic interventions that are possible in transgenic swine and review recent developments in pharmacological anti-platelet therapy.

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Reduced Fibrin Deposition and Intravascular Thrombosis in hDAF Transgenic Pig Hearts Perfused With Tirofiban

Abstract: Improvement of heart performance and reduction of myocardial damage and intravascular thrombosis confirm a role of the GPIIb/IIIa inhibitor tirofiban for the prevention of hDAF pig heart rejection and xenograft function.

Cited by 9 publications

References 52 publications

Complement activation and coagulation in xenotransplantation

Complement activation and coagulation in xenotransplantation

The role of platelets in coagulation dysfunction in xenotransplantation, and therapeutic options

Which anti‐platelet therapies might be beneficial in xenotransplantation?

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