What is 4-factor prothrombin complex concentrate (4F-PCC)?

4-Factor Prothrombin Complex Concentrate (4F-PCC)

4-Factor Prothrombin Complex Concentrate (4F-PCC) is a plasma-derived concentrate containing therapeutic amounts of four vitamin K-dependent coagulation factors: Factor II (prothrombin), Factor VII, Factor IX, and Factor X, along with small amounts of proteins C and S. 1

Composition and Characteristics

• Content: Contains all four vitamin K-dependent coagulation factors (II, VII, IX, X) and small amounts of proteins C and S 1
• Formulation: Available as a lyophilized powder that can be rapidly reconstituted in a small volume at bedside
• Administration: Does not require ABO blood type matching 1
• Concentration: Contains approximately 25 times (25 U/mL) the concentration of vitamin K-dependent factors compared to plasma (1 U/mL) 1

FDA-Approved Indications

4F-PCC is FDA-approved for:

• Urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (e.g., warfarin) therapy in adult patients with acute major bleeding 1
• Urgent reversal of vitamin K antagonist therapy for patients needing urgent surgery/invasive procedures 1

Dosing for Warfarin Reversal

Dosing is based on INR and body weight 1:

• INR 2 to <4: 25 U/kg
• INR 4 to 6: 35 U/kg
• INR >6: 50 U/kg
• Maximum dose: 5,000 units (capped at 100 kg body weight)

Off-Label Uses

4F-PCCs are increasingly used off-label for:

1. DOAC Reversal: Used for reversal of direct oral anticoagulants (DOACs), particularly factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) when specific reversal agents are unavailable 1

   • Efficacy for DOAC reversal appears to be around 80% with thromboembolism rates up to 4% 1
   • Typically dosed at 25-50 IU/kg for DOAC reversal 1

2. Other Clinical Scenarios:

   • Trauma-induced coagulopathy 2
   • Post-cardiopulmonary bypass bleeding 2
   • Coagulopathy in liver failure 2
   • Perioperative bleeding management 3

Advantages Over Fresh Frozen Plasma

• Faster administration (no thawing required)
• Smaller volume (20 mL vs. 225-300 mL per unit of plasma)
• No need for ABO compatibility testing
• Lower risk of transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI) 1
• More rapid INR correction (1.4-1.9 within 1 hour vs. 2.2-12 with FFP) 4

Safety Considerations

• Thromboembolism risk: The main safety concern is thromboembolic events, with reported rates of 0-18% (mean 2.5%) 4
• Risk factors for thromboembolism include:
  • Repeated dosing (due to accumulation of factor II, which has a 60-hour half-life) 1, 3
  • Pre-existing thrombotic risk factors
  • Higher doses

Differences from 3-Factor PCC

• 3-factor PCCs contain little or no Factor VII 1
• 4F-PCCs are preferred for warfarin reversal due to complete factor replacement 1

Clinical Efficacy

• For warfarin reversal: Superior to plasma for rapid INR correction 4
• For DOAC reversal: Partially corrects thrombin generation, but effect depends on circulating DOAC concentrations 1
• Meta-analyses show reduced mortality compared to no treatment (OR 0.41) and similar or slightly reduced mortality compared to FFP (OR 0.64) 4

Important Considerations in Clinical Use

• Should be administered along with vitamin K when used for warfarin reversal 1
• For DOAC reversal, specific reversal agents (andexanet alfa for factor Xa inhibitors, idarucizumab for dabigatran) are preferred when available 1
• Fixed dosing (2000 IU) may be as effective as weight-based dosing for DOAC reversal with potentially lower total dose 1
• Optimal timing for invasive procedures after PCC administration depends on the specific clinical scenario and bleeding risk 1

4F-PCC represents an important tool in the management of anticoagulant-associated bleeding and urgent reversal of anticoagulation, particularly when specific reversal agents are unavailable or when rapid correction of coagulopathy is required.