The coagulation barrier in xenotransplantation: incompatibilities and strategies to overcome them.
OBJECTIVE
Dysregulated coagulation is now recognized as a major contributor to graft loss in xenotransplantation. This review summarizes recent data on putative mechanisms of pathogenic coagulation in xenotransplantation and discusses progress on strategies to overcome them.


RESULTS
Evidence continues to grow that the primary cause of failure of pig cardiac and renal xenografts is probably antibody-mediated injury to the endothelium, leading to development of microvascular thrombosis. Several factors that may exacerbate the problem will remain, even in the absence of a humoral response. These include molecular incompatibilities that affect the control of coagulation - in particular the failure of pig thrombomodulin to activate the primate protein C pathway - and platelet reactivity. Expression of anticoagulant and antiplatelet molecules within the graft is a potential solution that has been successfully tested in rodent models and will soon be applied to the pig-to-primate model. This strategy, in parallel with physical methods such as encasing islets in a protective layer, also holds promise for reducing the thrombogenicity of pig islet xenografts.


CONCLUSIONS
Thrombosis is a barrier to long-term survival and function of porcine xenografts, which may eventually be overcome by various combinations of genetic and physical manipulation.
Cowan
Peter J
PJ
Immunology Research Centre, St. Vincent's Health, and Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia. peter.cowan@svhm.org.au
d'Apice
Anthony J F
AJ
D000818:Animals; D001777:Blood Coagulation; D005818:Genetic Engineering; D006084:Graft Rejection / Q000517:prevention & control; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects*; D016377:Organ Transplantation / Q000009:adverse effects*; D015539:Platelet Activation; D013927:Thrombosis / Q000209:etiology; D014183:Transplantation, Heterologous / Q000009:adverse effects*