Written by: Mediware Consulting and Analytics on Tuesday, May 6, 2014 Posted in: Blood Management

The Rise of Designer Blood Products 4 Factor PCCs

Blood factor concentrates are not new, but most U.S. physicians are only vaguely familiar with them.  Single or multiple blood factor concentrates were originally developed to treat patients with congenital clotting deficiencies, such as hemophilia A or B.

Although some of these clotting factors are made with recombinant technologies (such as recombinant factor VIIa), most are derived by extracting and purifying clotting factors from pooled plasma.  The post-HIV concern with this approach was that these clotting factor extracts come from pooled plasma from hundreds or thousands of donors, but the EU and now the FDA feel that pooled blood products are “safe” using mini-pool testing techniques to screen for transmissible diseases along with pathogen inactivation methods such as solvent- detergent technology.  The latest iteration of these concentrated blood factors include a combination of clotting factors designed to treat acquired clotting deficiencies from vitamin K antagonist drugs (warfarin/ Coumadin®).  These so-called four factor prothrombin complex concentrates (4F-PCCs) contain therapeutic doses of clotting factors II, VII, IX and X.  Previously available in Europe, the FDA has now approved a 4F-PCC (KCentra®) with the specific indication for the urgent reversal of vitamin K antagonist (VKA) drugs in adults with acute major bleeding.  Most recently,  Kcentra® was also approved for the urgent reversal of VKA drugs in adults needing urgent surgery or an invasive procedure. There is also active investigation on the use of 4F-PCCs as part of a management strategy for patients with bleeding on novel oral anticoagulant drugs (NOACs) such as rivaroxaban, apixaban and dabigatran1.

Sarode published a head to head study comparing safety and efficacy of a 4F-PCC (Beriplex®) to plasma (the standard of care) in patients on VKAs with an acute major bleed2.  This RCT looked at hemostatic efficacy at 24 hours (rated as excellent/good/none), time to INR correction, plasma levels of clotting factors, and adverse effects.  Overall, the 4F-PCC patients did as well or better than the plasma patients:

  • 4F-PCC was non-inferior to plasma for hemostatic efficacy at 24 hours (71% vs. 68%);
  • 4F-PCC was superior to plasma in INR reversal at 30 min post-treatment (62% vs. 10%);
  • 4F-PCC had a faster increment of FII, VII, IX, X and proteins C and S than plasma;
  • 4F- PCC had a much lower volume delivered (100 vs. 820 mL).

Of equal importance, safety endpoints were generally similar between the 4F-PCC and plasma groups and consistent with patients experiencing acute major bleeding.  Significantly, fluid overload and pulmonary edema were the most frequent adverse events, and all fluid overload events possibly related to treatment occurred in the plasma group.  This is of particular importance since transfusion associated circulatory overload (TACO) is now the leading serious transfusion related adverse event, with an incidence of 5- 6% and a mortality rate of 1- 2%3.

Given the results of this study, it should be clear that 4F-PCC will become the treatment of choice in bleeding patients on VKAs who require a rapid, low volume reversal strategy, such as patients with intracranial bleeding.  Of note, plasma is no longer indicated for the reversal of VKAs in Europe given the widespread availability of 4F-PCCs along with safety concerns for plasma. The U.S. leads the world in a number of areas of medicine, but we continue to lag behind Europe and Canada in transfusion safety.  The arrival of 4F-PCCs gives us another tool to improve patient care in a select group of patients.

Selected References

1. Levy JH, Faraoni D, Spring JL, Douketis JD, Samama CM. Managing new oral anticoagulants in the perioperative and intensive care unit setting. Anesthesiology. 2013;118(6):1466–74. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23416382. Accessed November 14, 2013.

2. Sarode R, Milling TJ, Refaai M a, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128(11):1234–43. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23935011. Accessed November 12, 2013.

3. Alam A, Lin Y, Lima A, Hansen M, Callum JL. The prevention of transfusion-associated circulatory overload. Transfus. Med. Rev. 2013;27(2):105–12. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23465703. Accessed December 2, 2013.