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Evaluating high-dose 4F-PCC for WICH reversal

Read time: 10 mins
Last updated:31st Oct 2023
Published:20th Jul 2020

High-Dose 4-Factor Prothrombin Complex Concentrate for Warfarin-Induced Intracranial Haemorrhage

Merchan C, Ahuja T, Raco V, Lewis A Neurohospitalist. 2020;10(1):16–21. DOI:

  • The ideal dosing strategy of 4-factor prothrombin complex concentrate (4FPCC) after warfarin-induced intracranial haemorrhage (WICH) is unknown
  • Merchan et al. compared the safety and efficacy of the standard 4FPCC dosing strategy (SD) with the NYU Langone Health institutional high-dose (HD) strategy for patients with WICH
  • A high-dose 4FPCC may be more effective at lowering international normalized ratio (INR) and preventing bleed expansion in patients with WICH, while maintaining a similar safety profile

Anticoagulation with warfarin, a widely used oral vitamin K antagonist, increases the risk of intracranial haemorrhage (ICH) by 3-fold (Rosand et al., 2004; Garcia-Rodriguez et al., 2013). As haematoma volume has been shown to be a predictor of mortality and functional outcome after ICH (6), rapid reduction of haematoma expansion is essential.

4FPCC has previously been shown to be effective in the rapid reversal of INR and the reduction of haematoma expansion (Sarode et al., 2013; Huttner et al., 2006) and has consequently become the recommended first-line therapy for the urgent reversal of WICH (Frontera et al., 2016). However, the ideal target INR to prevent haematoma expansion is unknown.

To balance the risks and benefits of 4FPCC, the Neurocritical Care Society guidelines recommend that dosing be based on bodyweight, INR and PCC type (Frontera et al., 2016). However, because the optimal dosing strategy is unknown, institutional strategies are varied. As a result, some hospitals adhere to 4FPCC package insert recommendations, while others utilise alternative strategies (Rivosecchi et al., 2016; Astrup et al., 2018; Pereira et al., 2018).

Prior to 2015, the NYU Langone Health institutional protocol recommended dosing based on pre-dose INR and bodyweight according to Kcentra package guidelines (Kcentra packet insert, 2013), however this strategy is not specific to WICH (Sarode et al., 2013). This led to concerns that standard dosing could delay INR reversal, hamper neurosurgical intervention, lead to worse functional outcomes and increase mortality rates. Consequently, NYU Langone Health developed a high-dose (HD) 4FPCC strategy for the urgent reversal of WICH.

In this single-centre retrospective review study, Merchan et al. sought to compare the safety and efficacy of the standard (SD) 4FPCC Kcentra package dosing strategy with their high dose 4FPCC institutional guideline for patients with WICH. The study compared an SD group of 30 patients and an HD group of 18 patients using electronic health records of patients who received Kcentra for spontaneous or traumatic intracranial bleeds while on warfarin.

For the primary outcome, Merchan et al. compared the percentage of patients who achieved an INR ≤ 1.3 after the administration of 4FPCC. The secondary outcomes included assessing haematoma expansion, 3-month modified Rankin Score (mRS) to assess neurologic status, occurrence of thrombotic events within 7 days of 4FPCC administration and hospital discharge or death.


Figure 1: The proportion of patients achieving primary and secondary outcomes

While Merchan et al. observed that high dose 4FPCC had a greater effect in achieving an INR ≤ 1.3, maintaining an INR of ≤ 1.3 and preventing haematoma expansion, their results were not statistically significant.

There were also no changes seen in neurologic status at discharge or three months following discharge. However, due to a median premorbid mRS of four out of a maximum of six, there was limited potential to assess the effect of HD 4FPCC on neurologic outcome. Administration of HD 4FPCC also had no effect on the rate of thromboembolic events, with one thrombotic event, deep vein thrombosis, overserved in each group.

Notably, while the median high dose was 2,000 units, this was comparable to the Abdoellakhan et al. study that observed a significantly higher proportion of patients achieving INR ≤ 1.5 with a 4FPCC high-dose of 1,750 units compared to a low-dose of 1,000 units (P=0.01) (Abdoellakhan et al., 2017).

This study by Merchan et al. is the first to look at an aggressive HD strategy to treat WICH stratified based on both INR and an assessment of whether or not a patient has a life-threatening condition While HD 4FPCC did not demonstrate a statistically significant decrease in INR or reduction in haematoma expansion, the trend in INR and haematoma expansion favoured the HD over SD regimen while maintaining a similar safety profile.

Due to the limited nature of this single-centre retrospective study, larger studies are needed to fully evaluate the impact of HD 4FPCC on haematoma expansion, functional outcomes, and mortality.


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