Abstract

Due to its wide range of therapeutic indications approximately 2.5 million adults and children are currently receiving vitamin K antagonist (VKA) therapy in the US (Pengo et al., 2006). Bleeding is the major risk of anticoagulation, with an incidence of major hemorrhage in VKA-treated patients of 1.7-3.4% per year (Schulman et al., 2008). The 4-factor prothrombin complex concentrate (4F-PCC), which contains the human coagulation factors II, VII, IX and X together with the endogenous inhibitor proteins S and C, is indicated for the urgent reversal of acquired coagulation factor deficiency induced by VKA (e.g. warfarin or coumarin) therapy in adult patients with acute major bleeding. In contrast, the 3-factor prothrombin complex concentrates (3F-PCC), which contain factors II, IX, X and only minimal amounts of factor VII, are only indicated for the prevention and control of hemorrhagic episodes in hemophilia B patients. Nevertheless, the use of 3F-PCC for correcting hemostasis following warfarin overdose has been discussed (Imberti et al. 2011, Holland et al. 2009). However, the lack of factor VII in these 3F-PCC products has raised questions about efficacy in comparison to 4F-PCC (Sarode et al. 2012). To date, no studies have directly compared 3F-PCC vs. 4F-PCC regarding their efficacy for reversal of VKA anticoagulation.

Therefore, this study was conducted as a head-to-head comparison of 4F-PCC and 3F-PCC for effective reversal of VKA (coumarin) induced anticoagulation using an established rat model of acute bleeding (Dickneite et al. 2007).

Rats received an oral dose of 2.5 mg/kg phenprocoumon. At 15.75 hours post dosing, animals were treated with a single intravenous dose of saline, 4F-PCC (Beriplex® P/N, Kcentra®, CSL Behring) or 3F-PCC (Bebulin® VH and Profilnine® SD). Study endpoints included bleeding following tail clip, activated partial thromboplastin time (aPTT), and prothrombin time (PT). In addition, the plasma levels of vitamin K dependent coagulation factors were determined.

Acute coumarin anticoagulation of rats induced a rise in median bleeding time by ≥2 fold from an average of 823 to 1800 seconds (max. observation period) compared to untreated animals. In parallel, PT and aPTT were prolonged from 8.9 to 29.9 seconds and 14.5 to 25.5 seconds, respectively. Treatment with 4F-PCC was able to fully and statistically significantly reverse bleeding, achieving average bleeding times of 676 seconds. In parallel, the elevation in PT was reversed to 15.1 seconds. In contrast, the 3F-PCCs were not or only partially able to reduce coumarin induced bleeding with average bleeding times of 1398 and 1708 seconds post treatment. This also correlated with inferior reductions in PT which achieved minimum levels of 23.8 and 29.5 seconds. There was no reduction in aPTT seen for any treatment option.

In conclusion, this first direct comparison of 4F-PCC and 3F-PCCs for the reversal of VKA anticoagulation in a rat model of acute bleeding suggests that replenishment of all vitamin K-dependent coagulation factors including factor VII as achieved using a 4F-PCC may result in superior efficacy compared to the use of 3F-PCCs.

References

Dickneite G: Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation.

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Holland L, Warkentin TE, Refaai M, et al. Suboptimal effect of three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic INR due to warfarin overdose. Transfusion 2009;49:1171–7.

Imberti D, Barillari G, Biasioli C, et al. Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage. Blood Transfus 2011;9:148–55.

Pengo V, Pegoraro C, Cucchini U, IIiceto S. The management of oral anticoagulant therapy: the ISAM study. J Thromb Thrombolysis 2006;21:73-7

Sarode R, Matevosyan K, Bhagat R, Rutherford C, Madden C, Beshay JE. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage.J Neurosurg 116:491–497, 2012

Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: american college of chest physicians evidence-based clinical practice guidelines (8th edition). Chest 2008;13:257S-98S

Disclosures

Herzog:CSL Behring GmbH: Employment. Off Label Use: Non-clinical data on the use of 3F-PCC for reversal of VKA . Kaspereit:CSL Behring GmbH: Employment. Krege:CSL Behring GmbH: Employment. Niebl:CSL Behring GmbH: Employment. Schulte:CSL Behring GmbH: Employment. Dickneite:CSL Behring GmbH: Employment.

Author notes

*

Asterisk with author names denotes non-ASH members.