Pre-treatment of donor with 1-deamino-8-d-arginine vasopressin could alleviate early failure of porcine xenograft in a cobra venom factor treated canine recipient.
OBJECTIVE
Unlike cardiac or renal xenotransplants, the depletion of complement using cobra venom factor (CVF) does not improve pulmonary xenograft survival. Several cases suggest that the swine von Willebrand factor (vWF) may play a major role in presenting a different pathogenesis of pulmonary xenograft dysfunction from other organs. To evaluate the role of vWF and the complement system in mediating hyperacute vascular injury of pulmonary xenografts and elucidate pathogenesis of the injury, we performed swine-to-canine orthotropic single lung xenotransplantation after pre-treatment of 1-deamino-8-d-arginine vasopressin (DDAVP) and CVF.


METHODS
We set up three groups for lung xenotransplantation: group I served as the control group; group II, recipients pre-treated with CVF; group III, donors pre-treated with DDAVP (9 mg/kg, 3 days)/recipients pre-treated with CVF (60 u/kg). Hemodynamic data, coagulation and complement system parameters, and grafted lung pathologies were examined serially for 3h after transplantation.


RESULTS
DDAVP infusion reduced the vWF content in swine lung tissue in vivo (7.7+/-2.4 AU/mg vs 16.0+/-5.6 AU/mg, P < 0.0001). Infusion of CVF 24 h prior to transplantation effectively depleted the recipient's serum C3 and complement hemolytic activity below the detectable range. Regardless of the use of CVF, both groups I and II transplanted with unmodified grafts showed an immediate drop in leukocytes and platelet counts after transplantation. However, in group III, in recipients transplanted with DDAVP pre-treated swine lung, the platelet count did not decrease after transplantation (P = 0.0295). The decrease of plasma antithrombin and fibrinogen tended to be attenuated in group III. Light microscopic examination revealed extensive vascular thromboses in both capillary and larger vessels, as well as early pulmonary parenchymal damage in groups I and II, but were rarely observed in group III.


CONCLUSIONS
Complement inhibition alone was not enough to alleviate intravascular thrombosis, the main pathology in pulmonary xenotransplantation. Pre-infusion of DDAVP to the donor animal was effective in preventing platelet sequestration and attenuated intravascular thrombosis. It is suggested that the strategies targeting vWF would be promising for successful pulmonary xenotransplantation.
Kang
Hee Jung
HJ
Department of Laboratory Medicine, Hallym University College of Medicine, Anyang, South Korea.
Lee
Gene
G
Kim
Ji Yeon
JY
Lee
Seung Hee
SH
Wi
Hyun Cho
HC
Hwang
Pil Gyu
PG
Chung
Doo Hyun
DH
Kim
Young Tae
YT
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D003176:Complement C3 / Q000187:drug effects / Q000378:metabolism; D015941:Complement Hemolytic Activity Assay; D003169:Complement Inactivator Proteins / Q000494:pharmacology; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology*; D004546:Elapid Venoms / Q000494:pharmacology*; D006084:Graft Rejection / Q000276:immunology; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology; D016040:Lung Transplantation / Q000276:immunology / Q000379:methods*; D010976:Platelet Count; D011652:Pulmonary Circulation / Q000187:drug effects; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology / Q000379:methods*; D014655:Vascular Resistance / Q000187:drug effects; D014841:von Willebrand Factor / Q000187:drug effects* / Q000378:metabolism
D003176:Complement C3; D003169:Complement Inactivator Proteins; D004546:Elapid Venoms; C016310:cobra venom factor; D014841:von Willebrand Factor; D003894:Deamino Arginine Vasopressin