Activation of human prothrombin by porcine aortic endothelial cells--a potential barrier to pig to human xenotransplantation.
A potential solution to the shortage of human organs for transplantation lies in the use of animal organs with the pig as the most likely donor. Perfusion of porcine organs with human blood, however, results in hyperacute rejection (xenograft reaction) which occurs within minutes to hours and is characterised by intravascular thrombosis. The pathogenesis of this xenograft reaction is attributed to xenoreactive natural antibodies (XNA) binding to epitopes on porcine endothelium activating complement with subsequent haemostatic activation. We have investigated whether there is direct activation of human coagulation by porcine endothelium in the absence of XNA and complement. Previous experiments demonstrated possible pathological activation of the common pathway, thus human prothrombin and factor X were added separately to porcine endothelium and monitored for activation. Human prothrombin was activated by porcine but not human endothelium. There was no activation of factor X. Hirudin inhibited prothrombin activation suggesting that a conformational change may occur in prothrombin on binding to porcine endothelium, such that its catalytic centre is exposed with subsequent autocatalytic cleavages. If this in vitro observation of direct prothrombin activation is translated to the in vivo situation then this phenomenon may pose a non-immunological obstacle to pig to human xenotransplantation.
Jurd
K M
KM
Department of Haematology, Guy's and St Thomas' Trust, London, UK.
Gibbs
R V
RV
Hunt
B J
BJ
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D001777:Blood Coagulation / Q000276:immunology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D011516:Prothrombin / Q000276:immunology / Q000378:metabolism*; D013552:Swine; D014183:Transplantation, Heterologous / Q000009:adverse effects* / Q000276:immunology
D011516:Prothrombin