Prothrombin complex concentrate in the reduction of blood loss during orthotopic liver transplantation.

Patients with end stage liver disease frequently develop clothing disorders as
a result of decreased synthetic capacity of the liver. It is assumed that
patients with end stage liver disease, due to decreased coagulation factors and
disturbed coagulation tests, have an increased bleeding risk. This is reflected
in prolonged prothrombin time (PT) and activated partial thromboplastin time(
APTT), and in a increased risk for bleedingcomplications during orthotopic
liver transplantation (OLT). Preoperative PT and INR however, do not predict
bleeding risk and the risk of transfusion during OLT.
In the past years, there has been a decrease in blood loss and transfusion
requirements due to improvements in surgical techniques and a restrictive
transfusion policy. Nevertheless, there is a substantial risk for bleeding
during OLT and severe bleeding complications still occur.
Transfusion products like red blood cells (RBC), platelet concentrates, fresh
frozen plasma clotting factors (FFP) and fibrinogen have not led to a further
decrease in blood loss during OLT. Transfusion complications are well described
in literature, and are mainly caused by volume overload by these high volume
transfusion products. In particular, transfusion of multiple units can result
in a volume overload in a already hyperdynamic circulation due to portal
hypertension, resulting in more bleeding. It has been proven in clinical
studies that a restrictive transfusion policy decreases blood loss during OLT.
The fact that transfusion products are not contributing in decreasing blood
loss has probably more to do with the hemodynamics, the hemostatic effect thus
disappears to the background.
Cofact (prothrombin complex concentrate), in contrast to transfusion products
mentioned above, is a low-volume mixture of 4 procoagulants, among which
prothrombine. We expect that pre-oprative intravenous administration of Cofact
will decreases per operative and postoperative blood loss and transfusion
requirements. Also we want to investigate the safety of Cofact in regards to
thrombotic complications in this patient group.

To investigate in a randomized controlled trial, whether giving Cofact
pre-operatively can reduce the bloodloss and transfusion requirements during
orthotopic liver transplantation. Also we investigate the safety of Cofact in
this patient population.

Because of difficulty in assessing the total volume of blood loss during
orthotopic liver transplantation (for example because of ascites admixture), we
have chosen the transfusion of RBC as primary objective.

A multicentre double-blinded placebo controlled randomized trial.

Intravenous administration of Cofact to the studygroup during induction of
anesthesia.

Because Cofact consist of procoagulants, there is a theoretical risk for
thrombotic complications. Clinical studies, however, dont confirm this risk.
Also, patients will go preoperatieve thromboelastography to exclude
hypercoagulability. Patients that show hypercoagulability will be excluded.

The risk for transmittable infectious diseases cannot fully be excluded because
Cofact is made out of human plasma. The risk for transmittance is minimalized
by testing and screening the donor for past exposure to certain viruses.
By testing donors for the presence of certain current viral infection, en by
inactivation and elimination of certain viruses, the risk for transmission is
further reduced.

The total duration of hospital stay and course is mostly similar to patients
undergoing liver transplantation and not participating in this study. The
exception lies in a electrocardiogram study at day 3 and 7 post-operatively.
This study has minimal discomfort for patient, a few electrodes are placed of
patients body and he/she has to lie still for a few minutes. This extra study
is being performed in eye of patient safety. The polyclinic follow-up is the
same as with other liver transplantation patients.

There is a small risk for allergic or anafylactic reaction to the study product
Cofact. In case of such an event, treatment with Cofact will be ceased
immediately. A severe anafylactic reaction can lead to shock and can be
lifethreatening. There is expertise in every participating centre to manage and
treat such an event.