Coagulation cascade activation triggers early failure of pig hearts expressing human complement regulatory genes.
BACKGROUND
Hyperacute rejection (HAR) and early graft failure (EGF) have been described in a minority of pig-to-baboon heart transplants using organs transgenic for human complement regulatory proteins (hCRP). Here we investigate the role of coagulation cascade activation in the pathogenesis of HAR and EGF in a consecutive series where a high incidence of these outcomes was observed.


METHODS
Twenty-eight naïve wild-caught Papio anubis baboons received heterotopic heart transplants from pigs transgenic for hDAF (n = 23) or hMCP (n = 5). Immunosuppression consisted of cyclosporine A, cyclophosphamide and MMF (n = 18) or anti-CD154 mAb (IDEC-131) and ATG (n = 10). Eleven received anti-Gal carbohydrates (GAS914, n = 8, or NEX1285, n = 3), of which four also underwent extracorporeal immunoadsorption (EIA), and 12 also received pharmacologic complement inhibitors (C1 INH, n = 9, or APT070, n = 3).


RESULTS
Excluding one technical failure, 14 of 27 transplants (11 hDAF, 3 hMCP) exhibited either HAR (n = 10) or EGF (n = 4). Surprisingly, neither complement inhibition (with C1 INH or APT070) nor anti-Gal antibody depletion with GAS914, NEX1285, or additional EIA consistently prevented HAR or EGF despite low or undetectable complement deposition. Strikingly, most grafts with HAR/EGF exhibited prominent fibrinogen and platelet deposition associated with systemic coagulation cascade activation, consistent with non-physiologic intravascular coagulation, in many instances despite little evidence for antibody-mediated complement activation.


CONCLUSIONS
We conclude that dysregulated coagulation correlates closely with and probably causes primary failure of pig hearts transgenic for hCRP. These data support efforts to define effective strategies to prevent dysregulated coagulation in pig organ xenografts.
Wu
Guosheng
G
Baltimore VAMC, University of Maryland, Baltimore, MD, USA.
Pfeiffer
Steffen
S
Schröder
Carsten
C
Zhang
Tianshu
T
Nguyen
Bao N
BN
Kelishadi
Sean
S
Atkinson
James B
JB
Schuurman
Henk-Jan
HJ
White
David J G
DJ
Azimzadeh
Agnes M
AM
Pierson
Richard N
RN
D000208:Acute Disease; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001706:Biopsy; D001777:Blood Coagulation; D050718:Complement C1 Inhibitor Protein / Q000378:metabolism; D015926:Complement C3a / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology*; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism*; D013552:Swine; D013997:Time Factors; D017186:Titrimetry; D014183:Transplantation, Heterologous / Q000276:immunology*
D000906:Antibodies; D050718:Complement C1 Inhibitor Protein; D003169:Complement Inactivator Proteins; D015926:Complement C3a