This site is intended for healthcare professionals
Oral Anticoagulation Reversal Learning Zone

Initiation of a fixed‐dose 4F-PCC protocol

Read time: 10 mins
Last updated:10th Nov 2020
Published:8th Oct 2020

Initiation of a fixed‐dose four‐factor prothrombin complex concentrate protocol

Fuh L, Goldstein JN, Hayes BD. J Thromb Thrombolysis. 2020 Jul;50(1):217-220. doi: 10.1007/s11239-019-01984-w.

  • A fixed-dose 4F-PCC protocol in patients requiring urgent warfarin reversal was evaluated
  • 17% of patients failed to achieve the target INR level
  • Of 63 patients, 11 were eligible to receive a supplemental dose. Only 2 patients received a second dose, suggesting that adequate haemostasis had been achieved
  • Fixed-dose 4F-PCC was given rapidly, with few dosing errors, suggesting that it is a reasonable approach for 4F-PCC administration

Patients requiring urgent warfarin reversal frequently receive a four-factor prothrombin complex concentrate (4F-PCC) dosing regimen based on weight and initial international normalised ratio (INR).

However, in emergency situations this method can lead to dosing delays and errors due to the length of time needed to obtain weight and INR information and the complexity of the calculation.

An alternative to this dosing regimen is a fixed-dose 4F-PCC strategy, which has previously been found to be safe and efficacious (Tomaselli et al., 2017; Klein et al., 2015; Varga et al., 2013), yet optimal dosing remains unclear. Doses of 1000, 1500, and 2000 units are effective for INR correction (Abdoellakhan et al., 2017; Wozniak et al., 2012; Khorsand et al., 2012; Kcentra™ Prescribing Information, 2013), however one study of patients with intracranial bleeding failed to achieve an INR of ≤ 1.5 with a fixed-dose strategy (Abdoellakhan et al., 2017).

Based on this research, Massachusetts General Hospital implemented a fixed-dose 4F-PCC strategy, using an initial dose of 1500 units.

In this retrospective single-centre study (N=63), the primary objective was to evaluate the frequency with which this initial fixed dose 4F-PCC protocol was inadequate for warfarin reversal, as defined by the need for supplemental dosing. The secondary objective included the time from order placement to 4F-PCC dose administration and cost.

As part of the protocol, the fixed-dose 4F-PCC utilised three 500-unit vials, expressed in exact factor IX units. INRs were drawn 30 minutes after the 4F-PCC dose was administered and if the initial fixed-dose 4F-PCC did not achieve INR goal, then the remainder of the standard weight- and INR-based dosing were given (Kcentra™ Prescribing Information, 2013).

For patients with central nervous system (CNS) bleeds, the target INR is ≤ 1.4, whereas all other indications target an INR < 2.

Evaluating the fixed-dose 4F-PCC protocol

For patients with central nervous system (CNS) bleeds, the target INR is ≤ 1.4, whereas all other indications target an INR < 2.


Table 1: Baseline characteristics of the 63 patients given the fixed-dose 4F-PCC protocol. CNS, Central nervous system.

The median time from 4F-PCC order placement to dose administration was 14 minutes and based on the INR following 4F-PCC administration:

  • Eleven patients (17%) were eligible to receive a supplemental dose based on failure to achieve their indication-specific INR goal
  • Two of these patients received the second dose, both with initial supratherapeutic INRs > 3.5.
  • Of the two patients who received a second dose, one patient with a subdural hematoma had an initial INR of 6 that dropped to 2.6 and the other had gastrointestinal hemorrhage with an initial INR of 20.8 that decreased to 3.9.

The fixed dose 4F-PCC protocol also provided an institutional cost savings of $107,729, based on average wholesale price, compared to the standard weight- and INR-based dosing.

Most patients that were given an initial fixed-dose 4F-PCC achieved their INR goals. Of patients who did not, most did not receive supplemental dosing suggesting that clinical providers felt adequate hemostasis had been achieved.

With administration rapidly after the decision to order, few dosing errors and high cost-savings, Fuh et al. suggests that a 1500 unit initial fixed-dose 4F-PCC protocol can provide efficient and effective warfarin reversal. However, patient monitoring is necessary if a supplemental dose is needed, particularly in those with initial INRs that are supratherapeutic.

Letter to the Editor in response to the clinical study by Fuh et al.

Mishra AK, Sahu KK, Siddiqui AD, George SV. J Thromb Thrombolysis. 2020 Feb;49(2):332-333. doi: 10.1007/s11239-019-02020-7.

Mishra et al., in a reply to the above publication by Fuh et al., have raised several questions regarding the results of this study.

They question the use of achieving target INR as the endpoint as both this and assessment of haemostatic efficacy are important to assess 4F-PCC as shown in the landmark Sarode et al. randomised control trial (Sarode et al., 2013).

These two criteria are significant, as the goal of administration of 4F-PCC is both the reversal of INR and improvement in morbidity and mortality. Notably, the rate of mortality was high (30%) in the Fuh et al. study while the prior Sarode et al. trial had reported a much lower mortality of 5.6% in the 4F-PCC arm and 4.6% in the fresh frozen plasma (FFP) arm (Sarode et al., 2013).

They also note that the number of CNS bleeds (76%) was high in this study and question whether mortality would have been lower if the distribution of bleeding aetiologies had been different. In the prior studies including 4F-PCC, the commonest type of bleeding reported has been gastrointestinal (Sarode et al., 2013; Kushimoto et al., 2017).

Mishra et al. strongly suggest that decisions on 4F-PCC administration should instead be based on the patient’s clinical presentation and baseline INR.


Abdoellakhan RA, Miah IP, Khorsand N, Meijer K, Jellema K. Fixed Versus Variable Dosing of Prothrombin Complex Concentrate in Vitamin K Antagonist-Related Intracranial Hemorrhage: A Retrospective Analysis. Neurocrit Care. 2017;26(1):64–69.

Kcentra [package insert], CSL Behring LLC. 2013. Kankakee, IL Accessed 1 April 2020.

Khorsand N, Veeger NJGM, van Hest RM, Ypma PF, Heidt J, Meijer K. An observational, prospective, two-cohort comparison of a fixed versus variable dosing strategy of prothrombin complex concentrate to counteract vitamin k antagonists in 240 bleeding emergencies. Haematologica. 2012;97(10):1501–1506.

Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med. 2015;33(9):1213–1218.

Kushimoto S, Fukuoka T, Kimura A, Toyoda K, Brainsky A, Harman A, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate for rapid vitamin K antagonist reversal in Japanese patients presenting with major bleeding or requiring urgent surgical or invasive procedures: a prospective, open-label, single-arm phase . Int J Hematol. 2017;106(6):777–786.

Sarode R, Milling TJ, Refaai MA, Mangione A, Schneider A, Durn BL, 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(11):1234–1243.

Tomaselli GF, Mahaffey KW, Cuker A, Dobesh PP, Doherty JU, Eikelboom JW, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042–3067.

Varga C, Al-Touri S, Papadoukakis S, Caplan S, Kahn S, Blostein M. The effectiveness and safety of fixed low-dose prothrombin complex concentrates in patients requiring urgent reversal of warfarin (CME). Transfusion. 2013;53(7):1451–1458.

Wozniak M, Kruit A, Padmore R, Giulivi A, Bormanis J. Prothrombin complex concentrate for the urgent reversal of warfarin. Assessment of a standard dosing protocol. Transfus Apher Sci. 2012;46(3):309–314.