Comparing 3-PCC and 4-PCC warfarin reversal

Thrombin generation and thromboelastometry in monitoring the in-vitro reversal of warfarin: a comparison between 3-factor and 4-factor prothrombin complex concentrates

Spiezia L, Rossetto V, Campello E, Bulato C, Radu C and Simioni P
Blood Coagul Fibrinolysis. 2020;31(2):127–131.

• There are no current head-to-head comparisons of the efficacy and safety of three-factor and four-factor prothrombin complex concentrates (PCC) in anticoagulation reversal
• Spiezia et al. evaluated the in vitro efficacy of three-factor PCC (3-PCC) and four-factor PCC (4-PCC) in oral anticoagulant reversal with vitamin K antagonists (VKA) at different degrees of anticoagulation
• 3-PCC appears as effective as 4-PCC in oral anticoagulant reversal based on thrombin generation and thromboelastometry data, but is less effective according to international normalized ratio (INR) data

VKA anticoagulation is a common treatment for patients with atrial fibrillation, venous thromboembolism and prosthetic mechanical valves. However, every year, 3–7% of anticoagulated patients require urgent reversal of treatment due to life-threatening bleeding events or surgery (Libby et al., 2002).

Current ACCP guidelines suggest using PCC as the first-line treatment for VKA anti-coagulation reversal, with a target INR of less than 1.5 (Holbrook et al., 2012). In particular, guidelines recommend the use of 4-PCC rather than fresh frozen plasma (Holbrook et al., 2012).

Yet, there is still no consensus as to the efficacy of 3-PCC in VKA reversal. In a study by Holland et al. a dose of 50U/kg of 3-PCC in anticoagulated patients failed to achieve the target INR in more than half of patients (Holland et al., 2009). However, in a study by Imberti et al. 3-PCC was effective in reversing oral anticoagulant treatment in anticoagulated patients with intracranial haemorrhage (Imberti et al., 2011). Several in vitro studies have also demonstrated that despite a lack of efficacy in achieving the target INR, 3-PCC can restore normal thrombin generation and thrombus formation (Ogawa et al., 2011).

As haemostasis is the result of a balance between procoagulant and anticoagulant forces, INR is mainly a reflection of factor (F) VII activity and has no strict correlation with bleeding tendency. Spiezia et al. therefore suggest that PCC are more likely to stop bleeding via increased levels of FIX, FX and FII rather than FVII. Their hypothesis is supported by previous observations of recombinant FVIIa failing to stop wound bleeding despite correcting INR (Skolnick et al. 2010).

In this in vitro study, Spiezia et al. aimed to compare the lowest effective dose of three PCCs in achieving a target INR less than 1.5 as well as compare each PCC in normalising both thrombin generation and the thromboelastometry profile. Specifically, the team compared two 4-PCC, Octaplex and Beriplex (containing FII, FVII, FIX, FX) and one 3-PCC, Uman Complex (containing FIX, FII and FX).

Spiezia et al. initially enrolled six patients to determine the lowest effective PCC dose on INR, vitamin K clotting factors activity, thrombin generation and the thromboelastometry profile (Group A and B). Following this, the team enrolled 60 patients with atrial fibrillation, prior venous thromboembolism or a mechanical prosthetic cardiac valve - 40 with baseline INR 2.0 – 2.9 (Group C) and 20 with baseline INR 3.0 – 4.0 (Group D).  

Overall, Spiezia et al. found that 3-PCC was less effective in correcting INR than 4-PCC at higher degrees of anticoagulation:

• Independently of baseline INR, 4-PCC achieved target INR with a 0.5 U/mL dose
• 3-PCC achieved target INR with a 0.5 U/mL dose for INR 2.0–2.9 and a 1.5 U/mL dose for INR 3.0–4.0

No significant difference in thrombin generation and clotting time for both PCCs:

• Independently of baseline INR, a 0.5 U/mL dose restored normal thrombin generation
• Independently of the degree of anticoagulation, clotting time was normalised

Figure 1: The difference in thrombin generation and EXTEM clotting time at baseline and after PCC addition

Looking at coagulation factors, Spiezia et al. found:

• A lowered increase in FII activity with 3-PCC compared to 4-PCC (P<0.05)
• FVII activity remained unchanged
• A lowered increase of FIX activity with 3-PCC compared to 4-PCC (P<0.05)

The results obtained by Spiezia et al. suggest that 3-PCC could be considered as effective as 4-PCC in reversing oral anticoagulant treatment if looking at thrombin generation and clotting time data, but not when looking at INR data.

Further studies are needed to confirm these results, address the clinical implications of their in vitro findings and determine a definite link between bleeding risk and a normal thrombin generation and/or thromboelastometry profile after reversal therapy.

The authors suggest that, until then, only INR data should be taken into consideration when identifying the efficacy of oral anticoagulant treatment reversal after PCC administration, as recommended by the guidelines.

References

Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, et al. Evidence-based management of anticoagulant therapy. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 SUPPL.):e152S–e184S.

Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion. 2009;49(6):1171–1177.

Imberti D, Barillari G, Biasioli C, Bianchi M, Contino L, Duce R, et al. Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage. Blood Transfus. 2011;9(2):148–155.

Ogawa S, Szlam F, Ohnishi T, Molinaro RJ, Hosokawa K, Tanaka KA. A comparative study of prothrombin complex concentrates and freshfrozen plasma for warfarin reversal under static and flow conditions. Thromb Haemost. 2011;106(6):1215–1223.

Skolnick BE, Mathews DR, Khutoryansky NM, Pusateri AE, Carr ME. Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood. 2010;116(5):693–701.

Sullivan M, Simon G, Spertus J, Russo J. A survey of oral vitamin K use by anticoagulation clinics. Arch Intern Med. 2002;162(16):1893–1896.