Effects of long-term administration of high-dose recombinant human antithrombin in immunosuppressed primate recipients of porcine xenografts.
BACKGROUND
Fibrin deposition is central to the acute humoral rejection process occurring in the presence of consumptive coagulopathy when pig organs are transplanted into primates.


METHODS
To assess whether strategies aimed at preventing fibrin formation may extend xenograft survival, we administered high daily doses of recombinant human antithrombin (rhAT) (500 U/kg twice daily) to obtain both anticoagulant and anti-inflammatory effects in immunosuppressed primate recipients of porcine kidneys.


RESULTS
Some degree of consumptive coagulopathy developed in both rhAT-treated (n=3) and untreated (n=3) primates. No major differences in the coagulation parameters analyzed were observed between the 2 groups. Similarly, no difference in survival was seen between rhAT-treated (20.6+/-4 days; range: 15-23 days) and untreated animals (17.3+/-11.6 days; range: 7-30 days), although the rhAT-treated primates had a higher bleeding tendency. Despite the high daily dose of rhAT, considerable fibrin deposition was observed in the graft as early as 2 weeks after transplantation.


CONCLUSIONS
These results suggest that a high daily dose of rhAT fails to influence survival or prevent fibrin formation and deposition in the graft in our pig-to-primate model. However, the potential role of rhAT administered in combination with heparins or other clotting inhibitor concentrates in this model remains to be determined.
Cozzi
Emanuele
E
Direzione Sanitaria, Padua General Hospital, Padua, Italy. Emanuele.cozzi@umpd.it
Simioni
Paolo
P
Boldrin
Massimo
M
Seveso
Michela
M
Calabrese
Fiorella
F
Baldan
Nicola
N
Busetto
Roberto
R
Tormene
Daniela
D
Gavasso
Sabrina
S
Castagnaro
Massimo
M
Echelard
Yann
Y
Rice
Tim
T
Plebani
Mario
M
Carraro
Paolo
P
Bosio
Erika
E
Valente
Marialuisa
M
Pagnan
Antonio
A
Thiene
Gaetano
G
Ancona
Ermanno
E
D000818:Animals; D030801:Animals, Genetically Modified; D000991:Antithrombins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005337:Fibrin / Q000037:antagonists & inhibitors; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D016030:Kidney Transplantation / Q000379:methods* / Q000473:pathology; D008252:Macaca fascicularis; D010314:Partial Thromboplastin Time; D011486:Protein C / Q000032:analysis; D017293:Protein S / Q000032:analysis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000473:pathology
D000991:Antithrombins; D011486:Protein C; D017293:Protein S; D011994:Recombinant Proteins; D005337:Fibrin