Coagulation and Thrombotic Disorders Associated With Pig Organ and Hematopoietic Cell Transplantation in Nonhuman Primates

Bühler, Léo H.; Basker, M.; Alwayn, Ian P. J.; Goepfert, Christian; Kitamura, Hiroshi; Kawai, Tatsuo; Gojo, Satoshi; Kozłowski, Tomasz; Ierino, Francesco L.; Awwad, Michel; Sachs, David H.; Sackstein, Robert; Robson, Simon C.; Cooper, D. K. C.

doi:10.1097/00007890-200011150-00010

Cited by 171 publications

(139 citation statements)

References 28 publications

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“…Despite the development of strategies to deplete xenoreactive antibodies, inhibit complement activation, and suppress the cellular immune response, thrombotic complications in primate recipients of porcine solid organ xenografts are still frequently observed (18). Similarly, porcine cellular grafts (islets of Langerhans) have been shown to trigger the coagulation and complement cascades in primates, although damage was reduced by treatment with heparin and soluble complement receptor 1 (19).…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Recombinant Human Antithrombin III in Pig-to-Primate Renal Xenotransplantation

Cowan

Aminian

Barlow

et al. 2002

American Journal of Transplantation

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Delayed rejection of pig kidney xenografts by primates is associated with vascular injury that may be accompanied by a form of consumptive coagulopathy in recipients. Using a life-supporting pig-to-baboon renal xenotransplantation model, we have tested the hypothesis that treatment with recombinant human antithrombin III would prevent or at least delay the onset of rejection and coagulopathy. Non-immunosuppressed baboons were transplanted with transgenic pig kidneys expressing the human complement regulators CD55 and CD59. Recipients were treated with an intravenous infusion of antithrombin III eight hourly (250 units per kg body weight), with or without low molecular weight heparin. Antithrombin-treated recipients had preservation of normal renal function for 4-5 days, which was twice as long as untreated animals, and developed neither thrombocytopenia nor significant coagulopathy during this period. Thus, recombinant antithrombin III may be a useful therapeutic agent to ameliorate both early graft damage and the development of systemic coagulation disorders in pig-to-human xenotransplantation.

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Section: Discussionmentioning

confidence: 99%

Protective Effects of Recombinant Human Antithrombin III in Pig-to-Primate Renal Xenotransplantation

Cowan

Aminian

Barlow

et al. 2002

American Journal of Transplantation

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“…Thrombosis in vascularized xenografts is most probably exacerbated by molecular incompatibilities between porcine anticoagulant enzymes and primate coagulation factors (13,14) and is frequently severe enough to lead to coagulopathy in recipients (15,16). This has been observed not only with porcine solid organ transplants but also with porcine cellular transplants, where profound alterations in hemostasis and coagulation parameters are observed (17). Oxidative inactivation of CD39 (18) during ischemia/reperfusion of the transplanted organ may further contribute to the prothrombotic state.…”

Section: Introductionmentioning

confidence: 99%

Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation

Dwyer¹,

Robson²,

Nandurkar³

et al. 2004

J. Clin. Invest.

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Extracellular nucleotides play an important role in thrombosis and inflammation, triggering a range of effects such as platelet activation and recruitment, endothelial cell activation, and vasoconstriction. CD39, the major vascular nucleoside triphosphate diphosphohydrolase (NTPDase), converts ATP and ADP to AMP, which is further degraded to the antithrombotic and anti-inflammatory mediator adenosine. Deletion of CD39 renders mice exquisitely sensitive to vascular injury, and CD39-null cardiac xenografts show reduced survival. Conversely, upregulation of CD39 by somatic gene transfer or administration of soluble NTPDases has major benefits in models of transplantation and inflammation. In this study we examined the consequences of transgenic expression of human CD39 (hCD39) in mice. Importantly, these mice displayed no overt spontaneous bleeding tendency under normal circumstances. The hCD39 transgenic mice did, however, exhibit impaired platelet aggregation, prolonged bleeding times, and resistance to systemic thromboembolism. Donor hearts transgenic for hCD39 were substantially protected from thrombosis and survived longer in a mouse cardiac transplant model of vascular rejection. These thromboregulatory manifestations in hCD39 transgenic mice suggest important therapeutic potential in clinical vascular disease and in the control of serious thrombotic events that compromise the survival of porcine xenografts in primates. 1440The Nonstandard abbreviations used: endothelial cell (EC); galactose α1,3-galactose (αGal); nucleoside triphosphate diphosphohydrolase (NTPDase).

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“…Delayed xenograft rejection (DXR) 3 is an intermediate form of graft rejection characterized by overwhelming monocyte and NK cell infiltration, Ab deposition along the endothelium, endothelial cell activation, thrombosis, and eventually graft loss (1,2). Many components of the innate and acquired immune systems, including xenoreactive Abs, complement, coagulation factors, monocytes, and NK cells, can act independently or in concert to effect xenograft damage, but the mechanisms that initiate DXR are poorly understood (3)(4)(5)(6)(7)(8). Since DXR represents the most important immunological hurdle preventing routine use of xenografts for the treatment of end-organ failure, additional studies are necessary to elucidate the mechanisms underlying DXR.…”

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confidence: 99%

Monocyte Adhesion to Xenogeneic Endothelium during Laminar Flow Is Dependent on α-Gal-Mediated Monocyte Activation

Peterson

Jin

Hyduk

et al. 2005

The Journal of Immunology

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Monocytes are the predominant inflammatory cell recruited to xenografts and participate in delayed xenograft rejection. In contrast to allogeneic leukocytes that require up-regulation of endothelial adhesion molecules to adhere and emigrate into effector tissues, we demonstrate that human monocytes adhere rapidly to unstimulated xenogeneic endothelial cells. The major xenoantigen galactoseα(1,3)galactoseβ(1,4)GlcNAc-R (α-gal) is abundantly expressed on xenogeneic endothelium. We have identified a putative receptor for α-gal on human monocytes that is a member of the C-type family of lectin receptors. Monocyte arrest under physiological flow conditions is regulated by α-gal, because cleavage or blockade results in a dramatic reduction in monocyte adhesion. Recruitment of human monocytes to unactivated xenogeneic endothelial cells requires both α4 and β2 integrins on the monocyte; binding of α-gal to monocytes results in rapid activation of β2, but not α4, integrins. Thus, activation of monocyte β2 integrins by α-gal expressed on xenogeneic endothelium provides a mechanism that may explain the dramatic accumulation of monocytes in vivo.

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Coagulation and Thrombotic Disorders Associated With Pig Organ and Hematopoietic Cell Transplantation in Nonhuman Primates

Cited by 171 publications

References 28 publications

Protective Effects of Recombinant Human Antithrombin III in Pig-to-Primate Renal Xenotransplantation

Protective Effects of Recombinant Human Antithrombin III in Pig-to-Primate Renal Xenotransplantation

Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation

Monocyte Adhesion to Xenogeneic Endothelium during Laminar Flow Is Dependent on α-Gal-Mediated Monocyte Activation

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