Systemic inflammation in xenograft recipients (SIXR): A new paradigm in pig-to-primate xenotransplantation?

• Systemic inflammation in xenograft recipients (Sixr) precedes activation of coagulation.
• Increased inflammation may promote activation of coagulation in xenograft recipients.
• Innate immune cells upregulate tissue factor expression after xeno-Tx.
• Immunosuppression does not consistently reduce pro-inflammatory cytokines after xeno-Tx.
• Prevention of Sixr may be essential to reduce dysregulation of coagulation after xeno-Tx.

Inflammation is a complex response that involves interactions between multiple proteins in the human body. The interaction between inflammation and coagulation is well-recognized, but its role in the dysregulation of coagulation in xenograft recipients is not well-understood. Additionally, inflammation is known to prevent the development of T cell tolerance after transplantation.Recent evidence indicates that systemic inflammation precedes and may be promoting activation of coagulation after pig-to-primate xenotransplantation. Activated recipient innate immune cells expressing tissue factor are increased after xenotransplantation, irrespective of immunosuppressive therapy. With immunosuppression, C-reactive protein (C-RP), fibrinogen, and interleukin-6 levels are significantly increased in pig artery patch recipients. In pig organ recipients, increased C-RP levels are observed prior to the development of features of consumptive coagulopathy. Systemic inflammation in xenograft recipients (Sixr) may be a key factor in the development of dysregulation of coagulation, as well as in resistance to immunosuppressive therapy.While genetic modification of the donor pigs provides protection against humoral responses and the development of thrombotic microangiopathy, therapeutic prevention of Sixr may be essential in order to prevent systemic dysregulation of coagulation in xenograft recipients without the use of intensive immunosuppression.