Letter to the Editor Henry G Watson* & James Ferguson *Department of Haematology Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Scotland AB25 2ZN Email: henrywatson@nhs.net Tel 00-44-1224-553394

Department of Emergency Medicine Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Scotland Email: j.ferguson@nhs.net Tel 00-44-1224-550506 Keywords: Intracranial haemorrhage, warfarin, prothrombin complex concentrate Word Count 675

We welcome the review of this common clinical problem and broadly agree with the conclusions arrived at by Leiblich and Mason1. One aspect of management that requires further investigation is the appropriate strategy for reversal of anticoagulation. Clinical studies consistently demonstrate that there is a higher incidence of intracranial haemorrhage (ICH) in patients who are anticoagulated with warfarin compared with controls who are not. Whilst there may be an increased risk of ICH, which is attributable to the indication for anticoagulation, there is a strong rationale to indicate that anticoagulation per se contributes to the increased bleeding risk in this group. As such, in the context of ICH in an anticoagulated patient there is a rationale, although little evidence, for reversal of anticoagulation. Our contention is that if anticoagulation is to be reversed then there is a strong rationale for achieving this as quickly and completely as possible. Although in the Swedish study, cited by Leiblich and Mason, the outcomes were apparently poorer for recipients of PCC compared with FFP it is highly likely that this observation resulted from clinical bias towards the use of PCC in patients with more severe head injury or in those perceived by the investigators to be at a higher risk of ICH than those given FFP or nothing2. In reality, prothrombin complex concentrates are likely to provide significant benefits over fresh frozen plasma for the rapid reversal of the anticoagulant effect of warfarin. PCCs are manufactured from pooled non-UK donor plasma, and subjected to two virus inactivation or removal steps while FFP is a single donor product which, at present in the UK, is still made from UK donor plasma with the attendant risks of vCJD transmission. FFP is blood group specific and the delay associated with determining blood group and thawing plasma for clinical use is not shared by PCC, which may be stored in a pharmacy, clinical areas or blood banks and is available for immediate release upon request. PCC requires about 10 minutes for re-constitution from its lyophilised state. The reversal of warfarin anticoagulation using coagulation factors is all about replacing the factors II, VII, IX and X, which are depleted by the action of warfarin. PCC contains all of these factors in a high concentration but no other procoagulant factors while FFP contains all the circulating prothrombotic factors in a dose of approximately 1u/ml. Although, this is subject to significant variation between units. To reverse an INR of >5 in a 70 Kg patient, based on manufacturers recommendations, would entail giving a dose of around 3000 units of PCC which would be delivered in a volume of 120-140 ml over between 18 and 40 minutes. The equivalent dose of FFP to deliver this dose of coagulation factors is around 3000 ml, which would predictably take hours to infuse and which would be more likely to be associated with circulatory overload. The only possible caveat of the use of PCC is that there have been reports of subsequent thrombotic events in recipients3. The role of PCC in these events is unclear as they are occurring in a group with a pre-existing risk of thrombotic events sufficient to warrant warfarin therapy. In addition, these patients may have had an additional acute prothrombotic event which resulted in the need for reversal. However, even bearing this small risk in mind, the prognosis for anticoagulant related ICH is so poor that this small risk is unlikely to detract from the overall potential benefit of reversal. Finally, a recent economic appraisal comparing the use of FFP and PCC within the UK healthcare system indicates that there is a cost benefit for the use of PCC as opposed to FFP in anticoagulated patients presenting with ICH4. In summary, although there are few good data to support rapid reversal of anticoagulation in patients on warfarin who sustain ICH, there is a strong rationale for this. We would suggest, in fitting with UK national guidelines5, that where reversal is considered appropriate this should be achieved using PCC as opposed to FFP for the reasons outlined above Conflict of interest declaration HGW received a lecture fee from CSL Behring in 2007 JF has no conflict of interest to declare References 1. Leiblich A & Mason S Emergency management of minor head injury in anticoagulated patients. Emerg Med J. 2011;28:115-118 2. Sjoblom L, Hardemark HG, Lindgren A et al Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke 2001;32:2567-2574 3. K?hler M, Hellstern P, Lechler E et al. Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates. Thromb Haemost. 1998;80(3):399-402. 4. Guest JF, Watson HG, Limaye S. Modelling the cost-effectiveness of prothrombin complex concentrate compared to fresh frozen plasma in emergency warfarin reversal in the UK. Clinical Therapeutics 2011 (in press) 5 .Baglin TP, Keeling DM, Watson HG; British Committee for Standards in Haematology. Guidelines on oral anticoagulation (warfarin): third edition -2005 update. Br J Haematol. 2006;132(3):277-85.

Conflict of Interest:

None declared