Recipient tissue factor expression is associated with consumptive coagulopathy in pig-to-primate kidney xenotransplantation.
Consumptive coagulopathy (CC) remains a challenge in pig-to-primate organ xenotransplantation (Tx). This study investigated the role of tissue factor (TF) expression on circulating platelets and peripheral blood mononuclear cells (PBMCs). Baboons (n = 9) received a kidney graft from pigs that were either wild-type (n = 2), alpha1,3-galactosyltransferase gene-knockout (GT-KO; n = 1) or GT-KO and transgenic for the complement-regulatory protein, CD46 (GT-KO/CD46, n = 6). In the baboon where the graft developed hyperacute rejection (n = 1), the platelets and PBMCs expressed TF within 4 h of Tx. In the remaining baboons, TF was detected on platelets on post-Tx day 1. Subsequently, platelet-leukocyte aggregation developed with formation of thrombin. In the six baboons with CC, TF was not detected on baboon PBMCs until CC was beginning to develop. Graft histopathology showed fibrin deposition and platelet aggregation (n = 6), but with only minor or no features indicating a humoral immune response (n = 3), and no macrophage, B or T cell infiltration (n = 6). Activation of platelets to express TF was associated with the initiation of CC, whereas TF expression on PBMCs was concomitant with the onset of CC, often in the relative absence of features of acute humoral xenograft rejection. Prevention of recipient platelet activation may be crucial for successful pig-to-primate kidney Tx.
Lin
C C
CC
Thomas E. Starzl Transplantation Institute, University of Pittsburgh, PA, USA.
Ezzelarab
M
M
Shapiro
R
R
Ekser
B
B
Long
C
C
Hara
H
H
Echeverri
G
G
Torres
C
C
Watanabe
H
H
Ayares
D
D
Dorling
A
A
Cooper
D K C
DK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D023201:CD40 Ligand / Q000276:immunology; D004211:Disseminated Intravascular Coagulation / Q000473:pathology*; D015738:Famotidine / Q000627:therapeutic use; D005700:Galactosyltransferases / Q000235:genetics; D055786:Gene Knockout Techniques; D006084:Graft Rejection / Q000473:pathology; D006635:Histamine H2 Antagonists / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000009:adverse effects*; D010215:Papio / Q000276:immunology; D015539:Platelet Activation; D010974:Platelet Aggregation; D013552:Swine; D013917:Thrombin / Q000096:biosynthesis; D013925:Thromboplastin / Q000235:genetics*; D014183:Transplantation, Heterologous / Q000009:adverse effects*
D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D006635:Histamine H2 Antagonists; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D015738:Famotidine; D013925:Thromboplastin; D005700:Galactosyltransferases; D013917:Thrombin