What is the role of aprotinin in minimizing blood loss during liver transplantation?

Updated: Apr 19, 2019
  • Author: Vanessa A Olcese, MD, PhD; Chief Editor: Ron Shapiro, MD  more...
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Aprotinin is a serine protease inhibitor that prevents the lysis of fibrinogen by inhibiting plasmin, kallikrein, and leukocyte elastase, which are 3 proteases involved in fibrinolysis. This serves to decrease platelet aggregation and increase both the activated partial thromboplastin time (aPTT) and activated clotting time.

A randomized, double-blinded, placebo-controlled study of 137 liver transplantation subjects given high-dose and regular-dose aprotinin demonstrated significantly lower (60%) blood loss and packed red blood cell (PRBC) transfusion volume when compared with control subjects. [22] No increase in thrombotic complications was reported.

In this study, a large dose of aprotinin (ie, 2 million kallikrein inhibitor units [KIU]) was administered as the initial dose, and additional smaller doses of 500,000 KIU/h were administered during surgery. Additional studies have demonstrated that lower aprotinin doses (500,000 KIU initially and 150,000-200,000 KIU/h) are not different from large doses in terms of reduced blood loss or morbidity. [23, 24]

However, other studies have not reported a benefit with aprotinin use. Therefore, the precise role of aprotinin remains undefined. Currently, aprotinin is available only via a limited-access protocol.

Fergusson et al and the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study investigators reported an increased risk for death with the use of aprotinin compared with tranexamic acid or aminocaproic acid in high-risk cardiac surgery. [25] Despite modest evidence that aprotinin was actually the more effective hemostatic agent—reducing the risk of massive postoperative hemorrhage as well as the requirement for postoperative transfusion of blood products at 30 days—aprotinin increased the risk of death by greater than 50%.

This increased risk led the investigators to terminate the trial early and conclude that the strong negative mortality trend associated with the use of aprotinin compared to other antifibrinolytics precluded its use in high-risk cardiac surgery. The increase in mortality seen with aprotinin has been postulated as secondary to its superiority as an antifibrinolytic agent; perhaps it alters the delicate balance between procoagulant and anticoagulant mediators in a way that is not yet appreciated (ie, through off-target effects). [25, 26]

A small meta-analysis of the use of aprotinin in orthotopic liver transplantation (OLT) patients did not demonstrate a negative effect on postoperative outcomes. [27] Nevertheless, the important lessons learned leading up to and after the BART study should caution against the further use of aprotinin outside the setting of a carefully conducted prospective clinical trial.

Prior to the BART study, although several prospective observational epidemiological studies pointed toward an increased mortality risk associated with aprotinin use, other meta-analyses did not detect this association, leading to the continued usage of aprotinin, as meta-analyses are felt to be superior to observational studies. The recent experience with aprotinin in cardiac surgery suggests that pooling data from many small trials that were not designed to study mortality may not be the best way to draw meaningful conclusions.

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