Platelet preserving effects of the antifibrinolytic drug Aprotinin as potential contributor to its mode of action as hemostatic agent in cardiac surgery

This project will study the mode of action of aprotinin, a commonly used drug to prevent or treat bleeding complications in cardiac surgery. Aprotinin has a long clinincal history, but was suspended from clinical use between 2007 and 2012. However, in 2012 this suspension was lifted by the European Medicines Agency, and Nordic Pharma reintroduced aprotinin, specifically for use during complex cardiac surgery.

Despite decades of clinical use, little is known on the mode of action of this drug. Nordic Pharma and the UMCG think that a better understanding of how exactly the drug contributes to reduction of blood loss will lead to a more rational and more effective approach to its use. As cardiac surgery is frequently accompanied by substantial blood loss, and as it has been well established that blood transfusions in these patients are associated with an increased risk for complications and poor outcome, every clinical intervention that can reduce blood loss is of direct benefit for the patient, and will reduce healthcare costs due to the reduction of complications.

They will study the mode of action of aprotinin in a laboratory setting, and also study the hypothesis that aprotinin next to inhibitory effects on the system that breaks down blood clots, also has beneficial effects on blood platelets. The effects is hypothesised to be absent in tranexamic acid, a competitor drug that will also be studied.

The project will provide in-depth mechanistic detail in the mode of action of aprotinin in the setting of cardiac surgery. Importantly, the experiments will take concomitant antiplatelet therapy and the profound lytic environment of blood which is present in patients on a heart-lung machine into account. They will thus provide detail of the mode of action of aprotinin in situations mimicking the blood compartment of patients undergoing cardiac surgery.

Results:

The study was designed to better understand the mode of action of a drug for better use in the clinic.

This was done in collaboration with Nordic pharma with  in vitro studies.

We have demonstrated that the effects of Aprotinin on intrinsic coagulation activation do not occur with TXA, another clinically used antifibrinolytic drug. Our results may thus improve the clinical management of patients undergoing complex surgical procedures or other clinical situations in which major blood loss is expected. We have published our findings in a peer-reviewed journal and have presented data on an international conference. Together with Nordic Pharma, we plan to summarise all data on the mode of action of Aprotinin in a review that will be submitted to an international peer-reviewed journal. Such a document is intended to inform clinicians using antifibrinolytic drugs in clinical practice.