Disseminated intravascular coagulation in association with the delayed rejection of pig-to-baboon renal xenografts.
BACKGROUND
Intravascular fibrin deposition and platelet sequestration occur with porcine xenograft rejection by baboons. Disseminated intravascular coagulopathy may arise either as a direct consequence of the failure to fully deplete xenoreactive natural antibodies and block complement, or because of putative cross-species molecular incompatibilities in this discordant species combination.


METHODS
Three baboons were conditioned with retrovirally transduced autologous bone marrow to induce tolerance to swine antigens. Xenoreactive natural antibodies and complement were depleted by plasmapheresis and the use of Gal alpha1-3Gal column adsorptions; baboons were then splenectomized and underwent 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 after transplantation in two baboons. Low levels of circulating C3a, C3d, and iC3b were measured despite the absence of functional circulating complement components. Profound thrombocytopenia with abnormalities in keeping with disseminated intravascular coagulopathy were observed. Prolongation of prothrombin and partial thromboplastin times was accompanied by evidence for tissue factor-mediated coagulation pathways, high levels of thrombin generation (prothrombin fragment F(1+2) production and thrombin-antithrombin complex formation), fibrinogen depletion, and production of high levels of the fibrin degradation product D-dimer. Importantly, these disturbances resolved rapidly after the excision of the rejected xenografts in two surviving animals. Histopathological examination of the rejected xenografts confirmed vascular injury, fibrin deposition, platelet deposition, and localized complement activation.


CONCLUSIONS
Systemic coagulation disturbances are associated with delayed xenograft rejection.
Ierino
F L
FL
Transplantation Biology Research Center, Massachusetts General Hospital, Boston 12129, USA.
Kozlowski
T
T
Siegel
J B
JB
Shimizu
A
A
Colvin
R B
RB
Banerjee
P T
PT
Cooper
D K
DK
Cosimi
A B
AB
Bach
F H
FH
Sachs
D H
DH
Robson
S C
SC
D000818:Animals; D003167:Complement Activation; D003165:Complement System Proteins / Q000032:analysis; D004211:Disseminated Intravascular Coagulation / Q000150:complications*; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005342:Fibrinolysis / Q000502:physiology; D006084:Graft Rejection / Q000150:complications; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology*; D008854:Microscopy, Electron; D010215:Papio; D013552:Swine; D019172:Transplantation Conditioning; D014183:Transplantation, Heterologous
D005338:Fibrin Fibrinogen Degradation Products; D005340:Fibrinogen; D003165:Complement System Proteins