Background. Delayed xenograft rejection is characterized by platelet a
ctivation and fibrin deposition and is thought to occur independently
of complement activation. We have therefore investigated the potential
for xenogeneic endothelial cells (EC) to regulate the conversion of p
rothrombin to thrombin, a central component of the final common pathwa
y of coagulation and all important platelet agonist. Methods and Resul
ts. Quiescent porcine aortic EC (PAEC) were found to convert high leve
ls of human prothrombin to thrombin (0.234+/-0.019 IU/ml) when compare
d with human aortic EC (0.017+/-0 IU/ml, 30-min time point, chromogeni
c assay; P<0.001). PAEC activation by human complement resulted in com
parable levels of thrombin generation, Prothrombin conversion by PAEC
as determined by generation of F1+2 (1.909+/-0.119 nmol/L) and formati
on of thrombin-antithrombin III complexes (125.611+/-6.373 mu g/L) was
significantly greater than the matched human aortic EC values (F1+2:
1.539+/-0.03 nmol/L, P<0.001; thrombin-antithrombin III: 1.833+/-0.104
mu g/L, P<0.001), Sequential analysis of prothrombin activation by PA
EC indicated generation of the intermediate meizothrombin followed by
autolytically accelerated thrombin formation. Subsequent experiments e
stablished important cross-species' incompatibilities with respect to
porcine thrombomodulin interaction with human thrombin and protein C i
n that PAEC had, a reduced capacity to generate activated human protei
n C in vitro. Conclusion. These observations indicate a potentially im
portant molecular barrier involving blood coagulation that may impact
on the planned clinical application of porcine transgenic organs.