Activation of human prothrombin by porcine aortic endothelial cells???a potential barrier to pig to human xenotransplantation

Jurd, KM; Gibbs, Roslyn V.; Hunt, B. J.

doi:10.1097/00001721-199604000-00008

Cited by 44 publications

(24 citation statements)

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“…After adjustment for assay conditions, baseline thrombin generation by quiescent PAECs in our study was similar to that reported by Siegel et al (20). This suggests that low-level constitutive expression of pfgl2 may contribute to the documented ability of PAECs to directly activate human prothrombin in vitro (20,21). We also speculate that fgl2 may contribute to the previously described tissue factor-independent coagulation activity of porcine endothelial cells, complete neutralization of which required the addition of hirudin, a thrombin inhibitor (41).…”

Section: Discussionsupporting

confidence: 89%

“…Studies suggest that dysregulated thrombin generation may play an important role in mediating xenograft AVR, in that inhibition of thrombin in vivo has been associated with prolonged xenograft survival (18). In vitro studies have demonstrated not only that human thrombin is able to activate porcine ECs (19), but that porcine ECs directly generate thrombin from human prothrombin in the absence of other coagulation factors (20,21). The mechanism by which the latter occurs has not been identified.…”

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confidence: 99%

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Endothelial Induction of fgl2 Contributes to Thrombosis during Acute Vascular Xenograft Rejection

Ghanekar

Mendicino

Líu

et al. 2004

The Journal of Immunology

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Thrombosis is a prominent feature of acute vascular rejection (AVR), the current barrier to survival of pig-to-primate xenografts. Fibrinogen-like protein 2 (fgl2/fibroleukin) is an inducible prothrombinase that plays an important role in the pathogenesis of fibrin deposition during viral hepatitis and cytokine-induced fetal loss. We hypothesized that induction of fgl2 on the vascular endothelium of xenografts contributes to thrombosis associated with AVR. We first examined fgl2 as a source of procoagulant activity in the pig-to-primate combination. The porcine fgl2 (pfgl2) was cloned and its chromosomal locus was identified. Recombinant pfgl2 protein expressed in vitro was detected on the cell surface and generated thrombin from human prothrombin. Studies of pig-to-baboon kidney xenografts undergoing AVR in vivo revealed induction of pfgl2 expression on graft vascular endothelial cells (ECs). Cultured porcine ECs activated by human TNF-α in vitro demonstrated induction of pfgl2 expression and enhanced activation of human prothrombin. The availability of gene-targeted fgl2-deficient mice allowed the contribution of fgl2 to the pathogenesis of AVR to be directly examined in vivo. Hearts heterotopically transplanted from fgl2+/+ and fgl2+/− mice into Lewis rats developed AVR with intravascular thrombosis associated with induction of fgl2 in graft vascular ECs. In contrast, xenografts from fgl2−/− mice were devoid of thrombosis. These observations collectively suggest that induction of fgl2 on the vascular endothelium plays a role in the pathogenesis of AVR-associated thrombosis. Manipulation of fgl2, in combination with other interventions, may yield novel strategies by which to overcome AVR and extend xenograft survival.

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Section: Discussionsupporting

confidence: 89%

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confidence: 99%

Endothelial Induction of fgl2 Contributes to Thrombosis during Acute Vascular Xenograft Rejection

Ghanekar

Mendicino

Líu

et al. 2004

The Journal of Immunology

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“…Robson, Dorling, and colleagues have pioneered work showing that various key components of the coagulation cascade are dysregulated (inappropriately activated, or not efficiently down-regulated) across species [53][54][55][56] and that the platelet can be activated even without the presence of complement activation in the context of xenoperfusion [57]. Just as porcine complement regulatory proteins either do not work or are less efficient to prevent complement activation by human blood, there are molecular incompatibilities between activated human coagulation factors and the natural anticoagulants expressed on porcine ECs.…”

Section: Thrombogenic Events In Antibody-mediated Rejection (Fig 3)mentioning

confidence: 99%

Beyond Antibody-Mediated Rejection: Hyperacute Lung Rejection as a Paradigm for Dysregulated Inflammation

Nguyen¹,

Zwets²,

Schroeder³

et al. 2005

CDTCHD

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The use of animal organs for transplantation in humans is seen as a potential solution to the short supply of human donor organs available for clinical transplantation. However, to develop this therapeutic option as clinical reality will require surmounting formidable obstacles. The primary immunologic barrier to pig-to-human xenotransplantation is hyperacute rejection (HAR), a phenomenon previously characterized as resulting from antibody binding and complement activation. This article will first review recent progress in the development of specific strategies to overcome hyperacute lung rejection (HALR), through production of genetically engineered pig organs, modification of the host innate immunity and control of antibody and complement. Additional therapeutic targets identified in HALR are reviewed, with particular emphasis on recent studies describing a critical role for the coagulation cascade in HAR.

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“…The remaining decrease of circulating platelets during perfusion with tirofiban is presumably due to the adhesion of platelets to the endothelium, since tirofiban inhibits aggregation but not adhesion of platelets. Furthermore, other mechanisms promoting platelet aggregation, such as the enhanced interactions between the porcine endothelial von Willebrand factor and the human platelet receptor GPIb or between porcine endothelial cells and human prothrombin, are likely to be responsible for this lack of effect (7,32,46). However, it is also possible that platelet activation during hyperacute rejection is so vigorous despite the complete inhibition of the GPIIb/IIIa receptors by tirofiban that platelet aggregation cannot be blocked completely (15).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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Activation of human prothrombin by porcine aortic endothelial cells???a potential barrier to pig to human xenotransplantation

Cited by 44 publications

References 0 publications

Endothelial Induction of fgl2 Contributes to Thrombosis during Acute Vascular Xenograft Rejection

Endothelial Induction of fgl2 Contributes to Thrombosis during Acute Vascular Xenograft Rejection

Beyond Antibody-Mediated Rejection: Hyperacute Lung Rejection as a Paradigm for Dysregulated Inflammation

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

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