A new gold standard treatment for the emergency correction of warfarin-induced coagulopathy
Submitting InstitutionUniversity of Sheffield
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences
Summary of the impact
As a result of University of Sheffield research in 1995-2002, a new gold
standard treatment for major bleeding on warfarin has been established,
ensuring the more effective treatment of tens of thousands of patients
requiring emergency anticoagulation reversal each year in the UK alone.
The treatment, using prothrombin complex concentrate (PCC) was
demonstrated to be superior to fresh frozen plasma (FFP), the standard
alternative at the time, and two PCCs have now been licensed for this
indication in the UK.
UK and international guidelines now recommend PCC over FFP.
Patients who experience venous thrombosis such as deep vein thrombosis
and pulmonary embolism, those with atrial fibrillation or who have metal
heart valves are anticoagulated with vitamin K antagonists, which in the
UK is primarily with warfarin. Approximately 1-2% of the population are on
warfarin at any time. Whilst warfarin is highly effective in preventing
thrombosis, its main adverse effect is bleeding. The annual risk of
bleeding is 1% for major bleeding requiring hospital admission and 0.3%
for fatal bleeding. Projected for the UK population over 10,000
individuals experience life threatening bleeding annually and in 3,000
cases this is fatal.
Up to the late 1990s the emergency management of anticoagulation reversal
was using fresh frozen plasma (FFP) which was widely available in all UK
hospitals. Researchers in the Department of Cardiovascular Science at the
University of Sheffield, led by Prof Michael Makris (1991 to present) and
Prof Eric Preston (NHS Consultant, Honorary Professor University of
Sheffield, now retired) became concerned that the standard treatment with
FFP was ineffective or poorly effective and set out to investigate whether
an alternative treatment with concentrates (used to treat patients with
haemophilia B) was superior. The research confirmed the poor efficacy of
FFP and demonstrated the superiority of prothrombin complex concentrate
(PCC) leading to a change in clinical practice in the management of
life-threatening bleeding in patients on warfarin. It was also
demonstrated that the vitamin K that was co-administered had to be given
intravenously for maximum efficacy.
In the first study (R1), the effect of FFP and PCC in patients with major
bleeding on warfarin who required emergency reversal was assessed. All 41
patients were treated in Sheffield at the Royal Hallamshire Hospital by
University of Sheffield staff. Patients with major bleeding were treated
with either FFP or PCC and the research showed that the correction of the
coagulopathy achieved by FFP was minor and insufficient for complete
reversal, whilst patients treated with PCC achieved very rapid complete
reversal of the coagulopathy. The paper concluded that "Clotting factor
concentrates are the only effective option where complete and immediate
correction of the coagulation defect is indicated in orally anticoagulated
patients with life or limb threatening haemorrhage".
In 2001 the University of Sheffield team collaborated with groups in
Aberdeen and Cambridge to show that vitamin K given with the PCC for
emergency warfarin reversal was more effective if given intravenously than
orally (R2). Approximately a third of the 64 patients studied in this work
were from Sheffield.
In 2002 a further study from Sheffield, of 42 patients with life
threatening bleeding on warfarin and who required immediate reversal,
showed that one of concentrates licensed at the time to treat patients
with haemophilia B, called Beriplex, was highly efficient and safe in
producing immediate reversal of the coagulopathy (R3).
References to the research
Authors working in Sheffield at the time are indicated in bold
R1) Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston
FE. (1997). Emergency oral anticoagulant reversal: the relative
efficacy of infusions of fresh frozen plasma and clotting factor
concentrate on correction of the coagulopathy. Thrombosis and Haemostasis.
The key paper that changed the management of reversal of warfarin
anticoagulation was carried out in Sheffield and published in 1997. PubMed
[Scopus 275 citations]
R2) Watson HG, Baglin T, Laidlaw SL, Makris M, Preston FE.
(2001). A comparison of the efficacy of response to oral and intravenous
vitamin K in reversal of over-anticoagulation with warfarin. British
Journal of Haematology. 115: 145-149
Another publication from Sheffield, Aberdeen and Cambridge demonstrated
that intravenous vitamin K was superior to oral vitamin K for the
emergency reversal of warfarin. [Scopus 82 citations]
R3) Preston FE, Laidlaw SL, Sampson B, Kitchen S. (2002). Rapid
reversal of oral anticoagulation with warfarin by a prothrombin complex
concentrate (Beriplex): efficacy and safety in 42 patients. British
Journal of Haematology. 116:619-624
A third publication demonstrated that a PCC called Beriplex used in
haemophilia was highly effective for the emergency reversal of warfarin.
[Scopus 125 citations].
Details of the impact
Patients with venous or arterial thrombosis or with prosthetic metal
heart valves are treated with warfarin anticoagulation. Approximately
600,000-1,200,000 patients are on warfarin in the UK at any time and
6,000-12,000 each year are likely to require emergency reversal of their
anticoagulation due to life-threatening bleeding. At the time of our
original research most patients with major bleeding on warfarin were
treated with fresh frozen plasma (FFP), whilst now the vast majority are
treated with prothrombin complex concentrate (PCC), based on our research
Impact on national and international clinical guidelines
National and international guidelines now recommend the use of PCC for
the management of life-threatening bleeding on warfarin.
A. The current UK guideline on the use of FFP published by the British
Committee for Standards in Haematology (BCSH) states that for reversal of
warfarin "FFP has only a partial effect, is not the optimal treatment, and
should never be used for the reversal of Warfarin in the absence of severe
bleeding". The evidence supporting this statement in the guideline is our
publication of 1997 (R1). (S1)
B. The current UK guideline on the management of patients on warfarin
published by the BCSH recommends "All hospitals managing patients on
warfarin should stock a licensed four factor prothrombin complex
concentrate. Emergency anticoagulation reversal in patients with major
bleeding should be with 25-50µ/kg for factor prothrombin complex
concentrate....... Fresh frozen plasma produces suboptimal anticoagulation
reversal and should only be used if prothrombin complex concentrate is not
available." This guideline lists our 1997 reference (R1) as showing
"Complete and rapid correction of the coagulopathy is more rapidly
achieved with PCC than FFP Makris et al 1997" (S2)
C. The use of PCC rather than FFP in patients on warfarin is also
recommended by a 2013 guideline on the management of bleeding in patients
on antithrombotic agents (S3). This is the BCSH guideline on
anticoagulation reversal for all the different anticoagulant drugs.
D. In the UK, at the Dudley Group of Hospitals, the policy for reversal
of warfarin in patients with intracranial or major bleeding recommends use
of PCC and quotes our study R1 to support this recommendation (S4)
E. The French national guidelines on the management of major bleeding in
patients on vitamin K antagonists, such as warfarin, recommend the use of
PCC rather than FFP and quote our study R1 as demonstrating the
superiority of PCC over FFP (S5)
F. The Italian national guidelines produced by the Italian Society for
Transfusion Medicine and Immunohaematology working party also recommend
the use of PCC over FFP for treatment of major bleeding on vitamin K
antagonists and use all 3 of our studies R1, R2 and R3 to support this
Impacts on the economy and commerce
PCCs were introduced 40 years ago to treat haemophilia B. Initially we
used them off-label in our research to treat warfarin related bleeding.
PCCs are no longer used to treat haemophilia B.
In the last 7 years, however, two international pharmaceutical companies,
Octapharma and CSL Behring, have brought concentrates to the market for
use in emergency reversal of warfarin (Octaplex and Beriplex
respectively). Beriplex, the product licensed in the UK in 2007, was the
product first shown by us in 2002 (R3) to be safe and effective. CSL
Behring referenced our publications (R1, R3) in the clinical section of
their license dossier submitted to the European Medicines Agency (S7).
In the Australian Public Assessment Report for Human Prothrombin Complex
Concentrate it is stated that our publication R3 was included in the
Beriplex license application as supportive evidence (S8).
Octapharma and CSL Behring have sold more than 20 million units of
Octaplex/Beriplex in the UK in 2012 (S9).
In 2012 CSL Behring has sold in excess of 300 million units of Beriplex
internationally (S7). In April 2013, the US Food and Drug Administration
approved KCentra™, the first US FDA-approved 4- Factor prothrombin complex
concentrate for urgent warfarin reversal in patients with acute bleeding,
This is the US name for Beriplex and has enabled CSL Behring to access a
new and very large market with the concentrate (S10).
Sources to corroborate the impact
(S1) O'Shaughnessy DF, Atterbury C, Bolton Maggs P, et al. Guidelines for
the use of fresh frozen plasma, cryoprecipitate and cryosupernatant.
British Journal in Haematology 2004; 126: 11-28.
(S2) Keeling D, Baglin T, Tait C et al. Guidelines on oral
anticoagulation with warfarin - fourth edition. British Journal of
Haematology 2011; 154:311-324
(S3) Makris M, van Veen JJ, Tait CR, Mumford AD, Laffan M. Guideline on
the management of bleeding in patients on antithrombotic agents. British
Journal of Haematology 2013; 160:35-46
(S5) Pernod G, Godier A, Gozalo C et al. French clinical practise
guidelines on the management of patients on vitamin K antagonists in at
risk situations (overdose, risk of bleeding, and active bleeding).
Thrombosis Research 2010; 126:e167-e174
(S6) Liumbruno G, Bennordello F, Lattanzio A, et al. Recommendations for
the use of antithrombin concentrates and prothrombin complex concentrates.
Blood Transfusion 2009; 7:325-334
(S7) Email from Head of Commercial Operations CSL Behring, on 11th June
2013 confirms use of Sheffield research findings in EMA application.
(S9) Email from Director of Serious Hazards of Transfusion (SHOT) on 11th
June 2013 confirms sales data.
Page 43 of the CSL financial report corroborates availability of Beriplex
in the US, under the name KCentra.