Extended coagulation profiles of healthy baboons and of baboons rejecting GT-KO pig heart grafts.
BACKGROUND
Derangements of coagulation, e.g. thrombotic microangiopathy (TM) and disseminated intravascular coagulation (DIC), limit the success of pig-to-baboon organ transplantation. Studies have investigated the coagulation profile in baboons post-xenotransplantation (XTx), but an extended coagulation profile of healthy baboons pre-XTx has not been reported.


METHODS
Blood was drawn from nine healthy male baboons (approximate age 5 yr, mean weight 15 kg) that had not undergone any prior surgical or therapeutic procedures. An extended coagulation profile, consisting of markers of thrombin activation, fibrinolysis, endothelial activation, the protein C pathway, and overall reactive state, was investigated by a reference coagulation laboratory, using tests for human plasma. The mean value +/- SD was calculated for 18 parameters (analytes); values outside of the mean +/- 2 SD were excluded. Three baboons subsequently underwent transplantation with hearts from GT-KO pigs, and received either no therapy (B24603), CVF (B25003), or CVF + leflunomide (B24903), and their extended coagulation parameters were followed.


RESULTS
For 14 of the 18 analytes, the human reference range reflected the coagulation status of healthy baboons. Exceptions included thrombin/antithrombin complex and fibrinopeptide A, which were elevated compared with the human reference range, while plasminogen activity was lower. The human assay failed to detect baboon plasminogen activator inhibitor-1. Immediately after GT-KO pig heart transplantation, the untreated B24603 demonstrated a coagulation profile consistent with its postoperative clinical status; DIC was not apparent, and the heart was electively excised within 2.5 h. In B25003 and B24903, that rejected their grafts on days 8 and 12, respectively, the coagulation profile showed evidence of DIC, particularly in B24903, which was clinically coagulopathic by this time.


CONCLUSIONS
(i) The human reference range of extended coagulation parameters forms a basis for studies in baboons, with a few exceptions. (ii) Antibody-mediated rejection of GT-KO pig hearts in baboons can be associated with laboratory and clinical evidence of DIC.
Ezzelarab
Mohamed
M
Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Cortese-Hassett
Andrea
A
Cooper
David K C
DK
Yazer
Mark H
MH
D000818:Animals; D030801:Animals, Genetically Modified; D001777:Blood Coagulation; D005700:Galactosyltransferases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D006084:Graft Rejection / Q000473:pathology; D006262:Health; D016027:Heart Transplantation / Q000473:pathology; D006801:Humans; D008297:Male; D010215:Papio; D013552:Swine; D014183:Transplantation, Heterologous
D005700:Galactosyltransferases