Chapter A17: Prothrombin Complex Concentrates and Direct Oral Anticoagulant Antidotes

INTRODUCTION

Prothrombin complex concentrate (PCC) is a lyophilized powder that ­consists of coagulation factors II, VII, IX, and X in addition to other factors and additives. Prothrombin complex concentrates come in two forms, activated and nonactivated. Activated PCCs (aPCCs) are typically used to treat hemophilia, and formulations consist of a mixture of nonactivated and activated factors. Nonactivated factors require activation by the other cofactors to function in the coagulation cascade. In the United States, nonactivated PCCs are available in both four-factor and three-factor formulations (4F-PCC and 3F-PCC, respectively). Prothrombin complex concentrates are also widely available in Europe, Asia, and Australia. In addition to clotting factors, 4F-PCC contains heparin and antithrombotic factors C and S.¹³ Three-­factor PCC contains only small amounts of factor VII and heparin.¹⁶ Although some direct oral anticoagulants (DOACs) now have a reversal agent, PCCs are still used to attempt rapid reversal of DOAC-induced coagulopathy.

With dabigatran, the first of the DOACs, the need for a definitive reversal agent became apparent after adverse effects and fatalities were reported. The manufacturer of dabigatran developed idarucizumab, a monoclonal antibody, as a result.^83,84 Similarly, with the rising use of the oral Xa inhibitors, andexanet alfa (Andexxa), a recombinant modified human Factor Xa was recently approved.

PROTHROMBIN COMPLEX CONCENTRATES

History

Prothrombin complex concentrates were initially used for the treatment of patients with hemophilia A. This iteration of PCC is referred to as 3F-PCC because it contains a lower concentration of factor VII compared with 4F-PCC to limit thrombogenic complications. 3F-PCC is approved for the treatment of hemophilia A, but it was used off label to reverse warfarin-induced coagulopathy before the approval of 4F-PCC in the United States. The use of 4F-PCC became routine when consensus guidelines recommended their use to reverse warfarin-associated coagulopathy. Four Factor-PCC was approved for use in the United States in 2013 solely for the purpose of reversing warfarin-associated coagulopathy, but it is routinely used for other indications.

Pharmacology

Prothrombin complex concentrates contain the coagulation factors that are inhibited by vitamin K antagonists (VKAs) such as warfarin. These factors include factors II, VII, IX, and X. They also include proteins C and S. Kcentra (a 4F-PCC) is manufactured from pooled United States sourced plasma. Other countries used pooled regionally sourced plasma. It is then purified, heat treated, nanofiltered, and lyophilized to produce concentrated factors II, VII, IX, and X and proteins C and S (Table A17–1). Nonactivated PCCs also contain antithrombin, albumin, heparin, sodium chloride, and sodium citrate.⁴⁴ Three Factor-PCCs contain factors II, IX, and X. In addition, a small amount of factor VII is included. This decreased dose of factor VII is thought to limit thrombogenic complications in patients with hemophilia. The ­manufacturing process is similar to that of 4F-PCC and therefore contains factors C and S and ...