Worldwide, an increasing number of patients are taking oral anticoagulants; this is largely driven by the ageing population with increasing numbers of persons with atrial fibrillation, and for whom anticoagulation is the mainstay of treatment.
Traditionally, warfarin has been the main anticoagulant used, but in the last five years, four direct-acting oral anticoagulants (DOACs) have been introduced. The currently licensed DOACs inhibit thrombin, in the case of dabigatran, or inhibit factor Xa, in the case of rivaroxaban, apixaban and edoxaban. Despite the rapid uptake of DOACs in many countries, warfarin remains the most commonly used oral anticoagulant worldwide.
The most frequent adverse event of oral anticoagulant therapy is bleeding. In the case of warfarin, major bleeding requiring hospital admission occurs in 1% per year, while fatal bleeding is observed in 0.3% per year.1 Overall, the DOACs have the same number of bleeding complications as warfarin, but the distribution of bleeds is significantly different. DOACs are associated with fewer intracranial haemorrhages and more gastrointestinal bleeds.2
Reversal of bleeding
Warfarin exerts its action by inhibiting the production of the active vitamin K-dependent clotting factors II, VII, IX and X, as well as protein C and protein S. Warfarin is monitored with the International normalised ratio (INR) test, with the majority of patients being maintained in the 2.0–3.0 range. As the INR increases, the risk of bleeding is also higher.3 When faced with a patient with life-threatening bleeding, such as intracranial bleeding, the anticoagulant effect needs to be reversed as soon as possible.
International recommendations for the management of this scenario suggest the use of 5–10mg of intravenous vitamin K and intravenous prothrombin complex concentrate (PCC).3 When vitamin K is given intravenously, it significantly improves the coagulopathy within six to eight hours by allowing the production of active factors II, VII, IX and X. While waiting for the vitamin K effect, PCC is able to immediately replace the missing clotting factors.1 PCCs contain factors II, IX, X and variable amounts of factor VII.
Four-factor PCCs contain factor VII whereas 3-factor PCCs do not. It is generally believed that 4-factor PCC is more effective in reversing the warfarin anticoagulation, especially in patients with an INR of >4.0.4 The effect of PCC in reversing the warfarin-induced coagulopathy is so reproducible and reliable that our practice is to give the PCC and proceed to surgery, if necessary, without waiting for confirmation that the prolonged INR has been corrected.
Fresh frozen plasma versus PCC
Despite the clear guideline advice to use PCC for the immediate correction of the coagulopathy, many centres continue to use fresh frozen plasma (FFP). FFP contains all the clotting factors but in a very dilute form. It has to be administered slowly, in large volume, has to be thawed before use, and has to be of the appropriate blood group. In contrast, PCC volume is small, can be given quickly, requires no thawing and is not blood group-specific.1 In a recent report analysing data from two randomised trials, Refaai and colleagues showed a much higher risk of fluid overload with FFP when compared to PCC.5
Four-factor PCCs have been the standard care of treatment of warfarin reversal associated with major bleeding in Europe for almost 20 years, but they were only recently licensed in the USA following the randomised trial of Sarode and colleagues that confirmed the superiority of PCC.6 The superiority of PCC over FFP has also been demonstrated in patients on warfarin who require emergency surgery.7
There are some concerns around the possibility of PCC inducing thrombosis but, in reality, this risk is small and actually no higher than the risk when using FFP.8 Another important issue is that not all thrombotic events in PCC-treated patients are secondary to the PCC, because these patients are individuals with a high risk of thrombosis, and which is why they were on warfarin in the first place.
Many of these thromboses tend to occur a week or later after PCC administration. Provided the observed bleeding is life- or limb-threatening, we believe that the optimal treatment is with intravenous vitamin K and 4-factor PCC.3,9
The introduction of DOACs into clinical practice is rapidly changing the field and they are often preferred to warfarin due to their oral intake without any monitoring. Furthermore, DOACs have fewer drug interactions than warfarin and their short half-lives allow easier elective peri-operative management. One reason for some reluctance to commence a DOAC is the lack of a reversal agent.
Very recently, a specific antidote for dabigatran was licensed but has not been used extensively or reported on. Clinical trials are ongoing with the specific factor Xa reversal agents and none of these are licensed or available for use outside of clinical trials.
While waiting for the widespread availability of the specific antidotes, a number of guidelines on the management of DOAC-related bleeding have been published.9,10 Because DOACs have relatively short half-lives of 12–16 hours, pharmacological reversal may not always be necessary. Provision of supportive care while the levels of the anticoagulant are reducing over time will often be sufficient. The measurement of the specific concentration of the anticoagulant, if available, can be helpful, especially in confirming that the level is low.11
Dabigatran, but not the Xa inhibitors, can be dialysed out if the facilities for its rapid set-up are available; in practice, this is not a realistic possibility for most hospitals. If more rapid reversal is required, this can only be achieved with the use of activated or non-activated PCCs.
A large number of publications have reported on the use of PCC to reverse DOACs. Most publications centre around the in vitro and ex vivo reversal or the use of animal models of bleeding. Very few case reports of the use of PCC to reverse DOAC-related bleeding in humans have been published, and these reports suffer from publication bias.
The laboratory studies involve the addition of exogenous PCC to anticoagulated samples and measuring either the prothrombin time or activated partial thromboplastin time or, more commonly, thrombin generation to demonstrate improvement in the results. There are many ways of performing thrombin generation and the results of even similar experiments are not always consistent.
There are a large number of reports of PCC use in animal bleeding models, with many animals and many models used. In general the results show that PCCs do, at least partially, reverse the coagulopathy and reduce the bleeding. Their success appears to be greater for the Xa than the IIa inhibitors.
Human data on the use of PCC to reverse DOACs can be subdivided in that from non-bleeding human volunteers who take the DOAC and then receive the PCC, or a limited number of uncontrolled case reports where bleeding humans receive PCC. There are many unanswered question on the use of PCC to reverse DOAC-related bleeding but, for now, they appear to be the best widely available drugs that we have.12
It is often assumed that when specific reversal agents for the IIa and Xa inhibitors are introduced, there will no longer be a role for PCC for DOAC reversal; but we believe that this is a premature assumption. Experience suggests that any newly introduced drug with a limited sales market will be very expensive and certainly much more expensive than PCC. A further advantage of PCC is where the patient’s history is unreliable as to what DOAC is being taken, because PCCs are at least partially effective in the reversal of all DOACs.
- Makris M, van Veen JJ, Maclean R. Warfarin anticoagulation reversal: management of the asymptomatic and bleeding patient. J Thromb Thrombolysis 2010;29:171–81.
- Sherwood MW et al. Gastrointestinal bleeding in patients with atrial fibrillation treated with rivaroxaban or warfarin: ROCKET AF trial. J Am Coll Cardiol 2015;66:2271–81.
- Keeling D et al. Guidelines on oral anticoagulation with warfarin – fourth edition. Br J Haematol 2011;154:311–24.
- Morgan Jones G et al. 3-factor versus 4-factor prothrombin complex concentrate for warfarin reversal in severe bleeding: A multicenter retrospective, propensity-matched pilot study. J Thromb Thrombolysis 2015; Dec 31[Epub ahead of print].
- Refaai MA et al. Increased risk of volume overload with plasma compared with four-factor prothrombin complex concentrate for urgent vitamin K antagonist reversal. Transfusion 2015;55:2722–9.
- Sarode R 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;128:1234–43.
- Goldstein JN et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet 2015;385:2077–87.
- Milling TJ et al. Thromboembolic events after vitamin K antagonist reversal with 4-factor Prothrombin Complex Concentrate: exploratory analyses of two randomized, plasma controlled studies. Ann Emerg Med 2016;67:96–105.
- Makris M et al. Guideline on the management of bleeding in patients on antithrombotic agents. Br J Haematol 2013;160:35–46.
- Kaatz S, Crowther M. Reversal of target specific oral anticoagulants. J Thromb Thrombolysis 2013;36:195–202.
- Kitchen S et al. Measurement of non-coumarin anticoagulants and their effects on tests of haemostasis: Guidance from the British Committee for Standards in Haematology. Br J Haematol 2014;166:830–41.
- Makris M. Prothrombin complex concentrate for non-vitamin K oral anticoagulant reversal: good enough for now? J Thromb Haemost 2014;12:1425–7.