Regular ArticleThromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy
Introduction
Major bleeding occurs at an annual rate of 1-3% in patients treated with vitamin K antagonists (VKA)[1]. The most feared bleeding complication is intracranial bleeding with a mortality rate as high as 50% within 30 days[2]. Early reversal of the VKA effect appears to limit the growth of an intracerebral hematoma[3], [4], the size of which seems to be related to the mortality[5]. Rapid reversal is also needed before urgent surgery to provide adequate peri- and postoperative hemostasis.
The options available for reversal of VKA are vitamin K, plasma, prothrombin complex concentrates (PCC; factors II, VII, IX and X) and recombinant activated factor VII (rFVIIa). Vitamin K reverses VKA only after 12–24 hours [6]. Plasma transfusion for full reversal of VKA takes an average of 30 h[7], and it is associated with a risk of volume overload[6], and occasionally with transfusion related acute lung injury[8] . In Europe, there is a widespread use of PCC for the reversal of VKA, whereas in the United States only 3-factor PCCs (factors II, IX and X) are available. One reason for the limited use of PCC might be the fear of thromboembolic complications, which mainly were described in cases with hemophilia and inhibitors[9]. There is limited experience from rFVIIa in the reversal of VKA[10], and it has been associated with an increase in arterial thromboembolism when used in non-hemophilic patients[11].
The occurrence of thromboembolic complications after treatment with PCC in patients with hemophilia and inhibitors[9] is probably related to supra-normal levels of vitamin K dependent coagulation factors. Most published case series with PCC for reversal of VKA were too small to estimate the risk for thromboembolism. Four cohorts with approximately 100 patients each have reported an incidence of 0-2%. These studies focused mainly on the efficacy of PCC in achieving hemostasis and lowering the International Normalized Ratio (INR).
The aim of our study was to prospectively assess the occurrence of thromboembolic complications in patients treated with 4-factor-PCC for the reversal of warfarin coagulopathy and to assess the clinical effect of PCC treatment.
Section snippets
Study population
The Coagulation Unit at Karolinska University Hospital in Stockholm, Sweden provides advice on management of bleeding and thrombotic problems for approximately half of the country, including consultations on urgent warfarin reversal with PCC, which formed the basis for our study population. Our study had a prospective cohort design. Patients were eligible for inclusion if they were to receive PCC for emergency reversal of warfarin either due to bleeding or need for emergency surgery or invasive
Patient population
Between February 2002 and October 2010 we included 210 patients, but in 35 cases there was another indication than warfarin reversal for using PCC and in 15 cases there was no documentation that the patients had received PCC. In addition, an unknown number has been missed since the physician on call did not always register the eligible cases. The baseline characteristics of the remaining 160 patients are shown in Table 1. Most of the patients (65.2%) were managed at 3 tertiary referral
Discussion
We are here reporting results from a large cohort of patients treated with PCC for the urgent reversal of warfarin coagulopathy, both in the setting of warfarin-associated bleeding and in non-bleeding patients on warfarin and in need of emergency surgery. Our main finding is the low – but not absent – risk of thromboembolic events and the high efficacy of PCC in this setting.
In our population, 6% of the patients treated with PCC for warfarin reversal were adjudicated to have sub-optimal
Conflict of interest statement
Sam Schulman has received honoraria for advisory boards for Octapharma and CSL Behring. The other authors have no conflict of interest to declare.
Acknowledgement
Doris Näslin, the research nurse at the Coagulations Center of Karolinska University Hospital assisted in the collection and organization of patients’ medical notes.
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Both authors SS and MH contributed equally to the study.