Disseminated intravascular coagulation in association with the delayed rejection of pig-to-baboon renal xenografts

Background. Intravascular fibrin deposition and platelet sequestration occu r with porcine xenograft rejection by baboons. Disseminated intravascular c oagulopathy may arise either as a direct consequence of the failure to full y deplete xenoreactive natural antibodies and block complement, or because of putative cross-species molecular incompatibilities in this discordant sp ecies combination. Methods. Three baboons were conditioned with retrovirally transduced autolo gous bone marrow to induce tolerance to swine antigens, Xenoreactive natura l antibodies and complement were depleted by plasmapheresis and the use of Gal alpha 1-3Gal column adsorptions; baboons were then splenectomized and u nderwent renal xenografting from inbred, miniature pigs, Soluble complement receptor type-1 with protocol immunosuppression (mycophenolate mofetil, 15 -deoxyspergualin, steroids, and cyclosporine) was administered. Results. A bleeding diathesis was clinically evident from days 5 to 12 afte r transplantation in two baboons, Low levels of circulating C3a, C3d, and i C3b were measured despite the absence of functional circulating complement components. Profound thrombocytopenia with abnormalities in keeping with di sseminated intravascular coagulopathy were observed. Prolongation of prothr ombin and partial thromboplastin times was accompanied by evidence for tiss ue factor-mediated coagulation pathways, high levels of thrombin generation (prothrombin fragment F1+2 production and thrombin-antithrombin complex fo rmation), fibrinogen depletion, and production of high levels of the fibrin degradation product D-dimer, Importantly, these disturbances resolved rapi dly after the excision of the rejected xenografts in two surviving animals. Histopathological examination of the rejected xenografts confirmed vascula r injury, fibrin deposition, platelet deposition, and localized complement activation, Conclusions. Systemic coagulation disturbances are associated with delayed xenograft rejection.