Four factor prothrombin complex concentrate (human): review of the pharmacology and clinical application for vitamin K antagonist reversal

Abstract

Vitamin K antagonists (VKAs) have been used for decades for the treatment and prophylaxis of thromboembolic events. Due to their wide range of therapeutic indications, they are the most prescribed oral anticoagulant worldwide. However, they are associated with bleeding complications due to their narrow therapeutic range, variability in individual dose responses and laboratory monitoring, and overdoses. Despite off-label use of 3-factor prothrombin complex concentrates and recombinant activated factor VII, until recently, vitamin K and plasma were the only recommended therapeutic options for reversing VKAs in the USA. In 2013, a 4-factor prothrombin complex concentrate (4F-PCC) was approved in the USA for VKA reversal in patients with bleeding or requiring emergency surgery and invasive procedure. Recent randomized controlled clinical trials have shown that 4F-PCC (Kcentra™) is non-inferior for hemostatic efficacy and superior for international normalized ratio correction as compared to plasma and has a similar safety profile.

Keywords::

• bleeding
• coagulopathy
• Kcentra™
• plasma
• prothrombin complex concentrate (human)
• vitamin K antagonist
• warfarin

Financial & competing interests disclosure

R Sarode is a consultant and advisor to CLS Behring and an advisor to Octapharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Four factor prothrombin complex concentrate (4F-PCC) contains clinically adequate amounts of vitamin K-dependent coagulant factors II, VII, IX and X, and anticoagulant proteins C and S.

• Clinical trials have demonstrated that 4F-PCC is superior to plasma for the reversal of vitamin K antagonists (VKAs) as regards international normalized ratio correction and noninferior to plasma in hemostatic efficacy and safety.

• 4F-PCC is rapidly infused in small volume and the action is prompt, which offers quick correction of international normalized ratio and rebalanced hemostasis for treating major bleeding or reducing the risk of bleeding during emergency surgery.

• The risk of thromboembolic complications is low, <1% (21 suspected cases in approximately 647,250 applications).

• 4F-PCC is processed through virus reduction and inactivation steps, and infection transmission due to 4F-PCC has not been reported.

• 4F-PCC is the standard of care for VKA reversal for acute major bleeding. According to the American college of chest physician guideline and the AABB, plasma is not indicated for VKA reversal when purified factor concentrates are available.

• Concomitant administration of intravenous vitamin K is necessary to sustain hemostatic levels of vitamin K-dependent factors.

Notes