Coagulation cascade activation triggers early failure of pig hearts expressing human complement regulatory genes

Guosheng Wu, Steffen Pfeiffer, Carsten Schroeder, Tianshu Zhang, Bao N. Nguyen, Sean Kelishadi, James B. Atkinson, Henk Jan Schuurman, David J.G. White, Agnes M. Azimzadeh, Richard N. Pierson

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)34-47
Number of pages14
JournalXenotransplantation
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

Fingerprint

Regulator Genes
Swine
Heart Failure
Transplants
Graft Rejection
Papio
Complement Inactivating Agents
Complement System Proteins
Papio anubis
Complement C1
Complement Activation
Heterografts
Cyclophosphamide
Immunosuppression
Fibrinogen
Cyclosporine
Anti-Idiotypic Antibodies
Blood Platelets
Carbohydrates
Antibodies

Keywords

  • Coagulation
  • Decay accelerating factor (CD55)
  • Heart
  • Hyperacute rejection
  • Membrane cofactor protein
  • Pig
  • Xenoantibody
  • Xenotransplantation

ASJC Scopus subject areas

  • Immunology
  • Transplantation

Cite this

Wu, G., Pfeiffer, S., Schroeder, C., Zhang, T., Nguyen, B. N., Kelishadi, S., ... Pierson, R. N. (2007). Coagulation cascade activation triggers early failure of pig hearts expressing human complement regulatory genes. Xenotransplantation, 14(1), 34-47. https://doi.org/10.1111/j.1399-3089.2006.00362.x

Coagulation cascade activation triggers early failure of pig hearts expressing human complement regulatory genes. / Wu, Guosheng; Pfeiffer, Steffen; Schroeder, Carsten; Zhang, Tianshu; Nguyen, Bao N.; Kelishadi, Sean; Atkinson, James B.; Schuurman, Henk Jan; White, David J.G.; Azimzadeh, Agnes M.; Pierson, Richard N.

In: Xenotransplantation, Vol. 14, No. 1, 01.01.2007, p. 34-47.

Research output: Contribution to journalArticle

Wu, G, Pfeiffer, S, Schroeder, C, Zhang, T, Nguyen, BN, Kelishadi, S, Atkinson, JB, Schuurman, HJ, White, DJG, Azimzadeh, AM & Pierson, RN 2007, 'Coagulation cascade activation triggers early failure of pig hearts expressing human complement regulatory genes', Xenotransplantation, vol. 14, no. 1, pp. 34-47. https://doi.org/10.1111/j.1399-3089.2006.00362.x
Wu, Guosheng ; Pfeiffer, Steffen ; Schroeder, Carsten ; Zhang, Tianshu ; Nguyen, Bao N. ; Kelishadi, Sean ; Atkinson, James B. ; Schuurman, Henk Jan ; White, David J.G. ; Azimzadeh, Agnes M. ; Pierson, Richard N. / Coagulation cascade activation triggers early failure of pig hearts expressing human complement regulatory genes. In: Xenotransplantation. 2007 ; Vol. 14, No. 1. pp. 34-47.
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AU - Nguyen, Bao N.

AU - Kelishadi, Sean

AU - Atkinson, James B.

AU - Schuurman, Henk Jan

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