Update on the mechanism of action and future of activated prothrombin complex concentrates

Activated prothrombin complex concentrates (aPCCs) are an established treatment for bleeding in patients with inhibitors. These products are derived from prothrombin complex concentrates, purified from human plasma with dedicated activation steps included in their manufacturing process. Despite these activation steps, the majority of the prothrombin complex proteins remain as zymogens, with only a relatively small content of activated coagulation enzymes. Among these, the order of concentration based on activity units is the following: factor VIIa to factor Xa to thrombin to factor IXa. Studies in various in vitro and in vivo model systems indicate that the mechanism of action of aPCCs is primarily based on an enzyme-substrate complex consisting of factor Xa and prothrombin. These findings are complemented by others showing that prothrombin is a major procoagulant that is capable of triggering hemostasis under physiologic and pathophysiologic conditions. Despite the findings of the mechanism of action, aPCCs have a long history of successful clinical use, with established dosing regimens, and a relatively low risk of thromboembolic complications compared with other treatment options for patients with inhibitors.