Microcoagulation processes after xenotransplantation

Current Opinion in Organ Transplantation

Volumn 10, Issue 3, 2005, Pages 240-245

  Chen, Daxin ^a   Dorling, Anthony ^a  

^a HAMMERSMITH HOSPITAL   (United Kingdom)

Author keywords

Endothelium; Monocytes; Platelets; Thrombosis tissue factor

Indexed keywords

ANTICOAGULANT AGENT; BLOOD CLOTTING FACTOR; BLOOD CLOTTING FACTOR 10A; THROMBOPLASTIN;

BLOOD CLOTTING; BLOOD CLOTTING DISORDER; DISSEMINATED INTRAVASCULAR CLOTTING; GRAFT REJECTION; GRAFT SURVIVAL; HUMORAL IMMUNITY; NONHUMAN; REVIEW; SWINE; SYSTEMIC INFLAMMATORY RESPONSE SYNDROME; THROMBOSIS; XENOGRAFT; XENOTRANSPLANTATION;

EID: 25144505756     PISSN: 10872418     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.mot.0000174044.75567.d0     Document Type: Review

References (38)

1. Dorling A, Lechler RI. Disordered thromboregulation after xenografting. Curr Opin Organ Transplant 2001; 6:36-41.
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8. McGregor CG, Teotia SS, Byrne GW, et al. Cardiac xenotransplantation: progress toward the clinic. Transplantation 2004; 78:1569-1575. This paper describes the longest median survival of hearts from transgenic pigs expressing a human regulator of complement activity (CD46 here) at 79 days. Despite evidence of AHXR in most of the organs, only one animal showed evidence of transient thrombocytopenia after transplantation.
9. Kuwaki K, Tseng YL, Dor FJ, et al. Heart transplantation in baboons using alpha1,3-galactosyltransferase gene-knockout pigs as donors: initial experience. Nat Med 2005; 11:29-31. Both this and the following paper, published back-to-back, report the survival of organs from Gal-KO pigs in baboons. The hearts showed evidence of AHXR or TM, whereas the kidneys were free of these complications. There were significant differences in the immunosuppressive regimes employed, and donor thymic tissue was co-transplanted with the kidneys, in an attempt to induce donor-specific tolerance. There was little evidence of an induced humoral response against the kidneys, whereas many of the hearts showed evidence of IgG and complement deposition.
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20. Gollackner B, Goh SK, Qawi I, et al. Acute vascular rejection of xenografts: roles of natural and elicited xenoreactive antibodies in activation of vascular endothelial cells and induction of procoagulant activity. Transplantation 2004; 77:1735-1741. This study shows an association between expression of TF on the luminal aspect of vessels within transplanted porcine hearts and antibody deposition. Both were associated with the development of consumptive coagulopathy and AHXR. Accompanying in vitro studies investigated the ability of XNA, elicited antibodies against α(1-3)gal, or elicited antibodies directed against other xenoantigens to induce TF on porcine EC. TF induced by the XNA or elicited antibodies specific for α(1-3)gal was complement-dependent, whereas that induced by antibodies against non- α(1-3)gal epitopes did not require complement activation.
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22. Chen D, Weber M, McVey JH, et al. Complete inhibition of acute humoral rejection using regulated expression of membrane-tethered anticoagulants on xenograft endothelium. Am J Transplant 2004; 4:1958-1963. A study from our group in a mouse heart-to-rat model of AHXR. Expression of membrane-tethered anticoagulants on the endothelium of the transplanted hearts completely inhibited the intravascular thrombosis seen in AHXR. The hearts appeared to suffer no adverse consequences from the rat humoral response, and had similar levels of IgG, IgM, and complement deposited on graft EC as was seen in non-transgenic controls.
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25. Schulte Am Esch J 2nd, Robson SC, Knoefel WT, et al. O-linked glycosylation and functional incompatibility of porcine von Willebrand factor for human platelet GPIb receptors. Xenotransplantation 2005; 12:30-37. Using transfected human or porcine vWF A1 domains in COS cells, this study establishes that the spontaneous activation of primate platelets through glycoprotein 1b is due to O-linked glycosylation of the porcine, but not human domain.
26. Meyer C, Wolf P, Romain N, et al. Use of von Willebrand diseased kidney as donor in a pig-to-primate model of xenotransplantation. Transplantation 1999; 67:38-45.
27. Lau CL, Cantu E 3rd, Gonzalez-Stawinski GV, et al. The role of antibodies and von Willebrand factor in discordant pulmonary xenotransplantation. Am J Transplant 2003; 3:1065-1075.
28. Dorling A. Are anti-endothelial cell antibodies a pre-requisite for the acute vascular rejection of xenografts? Xenotransplantation 2003; 10: 16-23.
29. Galbusera M, Buelli S, Gastoldi S, et al. Activation of porcine endothelium in response to xenogeneic serum causes thrombosis independently of platelet activation. Xenotransplantation 2005; 12:110-120. An interesting study showing that porcine EC, incubated with human serum and complement, could mediate the spontaneous binding of human platelets under laminar flow conditions, without the need to pre-activate the platelets. Generation of reactive oxygen species, expression of P-selectin and vitronectin receptor and porcine vWF were shown to be involved.
30. Sheikh S, Parhar R, Kwaasi A, et al. Alpha-gal-independent dual recognition and activation of xenogeneic endothelial cells and human naive natural killer cells. Transplantation 2000; 70:917-928.
31. Dwyer KM, Robson SC, Nandurkar HH, et al. Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation. J Clin Invest 2004; 113:1440-1446. The first description of transgenic mice expressing human CD39 under an MHC class I promoter, driving expression in all the major tissues, including on EC and platelets. The mice are healthy and have normal platelet counts and haematological parameters but do show prolonged bleeding times (at 370C) and abnormal responses on platelet stimulation. They are protected from the intravascular thrombosis that occurs after injection of collagen and, importantly in this context, organs were resistant to humoral rejection after transplantation into Gal-KO mice after injection of anti-gal antibody.
32. Riesbeck K, Dorling A, Kemball-Cook G, et al. Human tissue factor pathway inhibitor fused to CD4 binds both FXa and TF/FVIIa at the cell surface. Thromb Haemost 1997; 78:1488-1494.
33. Riesbeck K, Chen D, Kemball-Cook G, et al. Expression of hirudin fusion proteins in mammalian cells: a strategy for prevention of intravascular thrombosis. Circulation 1998; 98:2744-2752.
34. Chen D, Giannopoulos K, Shiels PG, et al. Inhibition of intravascular thrombosis in murine endotoxemia by targeted expression of hirudin and tissue factor pathway inhibitor analogs to activated endothelium. Blood 2004; 104:1344-1349. A paper from our group, highlighting the efficiency with which anticoagulant expression on EC can inhibit intravascular thrombosis in the context of systemic inflammation after injection of lipopolysaccharide, despite the fact that clotting involves circulating monocytes and platelets. This establishes a basis for targeting the expression of anticoagulants to graft EC after transplantation.
35. Knosalla C, Giovino MA, Harper D, et al. Relative effects of GAL+ and GALlow/- porcine hematopoietic cells on primate platelet aggregation and endothelial cell activation: implications for the induction of mixed hematopoietic chimerism in the pig-to-primate model. Xenotransplantation 2004; 11: 72-77. An in vitro study showing reduced platelet and EC activation after incubation with porcine haematopoietic cells from Gal-KO donors. The authors suggest this may make induction of mixed haematopoietic chimerism easier to achieve.
36. Bennet W, Sundberg B, Lundgren T, et al. Damage to porcine islets of Langerhans after exposure to human blood in vitro, or after intraportal transplantation to cynomologus monkeys: protective effects of sCR1 and heparin. Transplantation 2000; 69:711-719.
37. Moberg L, Johansson H, Lukinius A, et al. Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet 2002; 360:2039-2045.
38. Goto M, Johansson H, Maeda A, et al. Low molecular weight dextran sulfate prevents the instant blood-mediated inflammatory reaction induced by adult porcine islets. Transplantation 2004; 77:741-747. Using their in vitro loop system with human blood and an in vivo diabetic mouse model, this group document the efficacy of dextran sulphate at inhibiting the clotting that occurs around porcine islets after exposure to whole blood. Islet graft survival was prolonged from 3 to nearly 9 days in mice that were otherwise unmanipulated.