Summary
During orthotopic liver transplantation (OLT) excessive bleeding is the main cause
of death and graft failure. The acute bleeding tendency that accompanies OLT, particularly
during the anhepatic period and after reperfusion of the graft, is due to the depletion
or functional abnormalities of several hemostasis components caused by the enhanced
activity of enzymes such as plasmin, trypsin and leukocyte proteases. We surmised
that enhanced proteolysis might also cause abnormalities of von Willebrand factor
(vWF), and that these abnormalities are implicated in the bleeding tendency that develops
during OLT. Therefore, the pattern of vWF proteolysis was studied with 16 patients
with chronic liver disease, in serial blood samples obtained before OLT, during the
anhepatic stage, after graft reperfusion and at the end of the surgical procedure.
vWF became markedly degraded during the anhepatic and reperfusion stages, as shown
by the partial loss of high molecular weight multimers, the relative decrease of the
intact 225 kD subunit and the increase of the native proteolytic fragments of 176
and 140 kD. Novel proteolytic fragments also became detectable. Using monoclonal antibody
epitope mapping, it could be demonstrated that some of the proteolytic fragments corresponded
in apparent molecular mass to those produced in vitro by incubating purified vWF with
plasmin or elastase, but other fragments could not be attributed to these proteases.
During the anhepatic and reperfusion stages there was a significant correlation between
the degree of vWF degradation and the total amount of blood components transfused
to replace blood losses. To evaluate whether or not vWF degradation could be controlled
by the administration of a broad-spectrum protease inhibitor such as aprotinin, 5
patients were given a bolus dose of 500,000 U before surgery followed by 100,000 U/h
during surgery, 5 were given a 2,000,000 U bolus followed by 500,000 U/h, and no aprotinin
was given to the remaining 6 patients. There were no differences in the patterns or
degrees of vWF degradation between patients treated with aprotinin or not. In conclusion,
there is a marked degradation of a key hemostasis protein during OLT. These alterations
may be of clinical significance, because they are correlated with the transfusion
requirements.
