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 pathogen-reduced, lyophilized concentrate containing four vitamin K-dependent clotting factors (II, VII, IX, X) along with proteins C and S, primarily used for rapid reversal of vitamin K antagonists in patients with major bleeding or requiring urgent surgery. 1

Composition and Characteristics

• 4F-PCC contains therapeutic amounts of coagulation factors II (prothrombin), VII, IX, and X, as well as proteins C and S, obtained from pooled human plasma 1
• Unlike 3-factor PCCs (which contain mainly factors II, IX, and X with negligible factor VII), 4F-PCCs contain all four vitamin K-dependent coagulation factors 1
• 4F-PCCs are free of viral contaminants due to pathogen reduction and inactivation processes during manufacturing 1
• The product is stored as a lyophilized powder at room temperature, allowing for rapid reconstitution and infusion in emergency situations 1
• Per unit volume, 4F-PCCs contain approximately 25 times the concentration of vitamin K-dependent factors compared to plasma (25 U/mL vs. 1 U/mL) 1

Clinical Applications

FDA-Approved Indication

• Rapid reversal of vitamin K antagonist (VKA) anticoagulation (e.g., warfarin) in patients with major bleeding or requiring urgent surgical/invasive procedures 1
• Dosing for VKA reversal is based on INR and body weight:
  • 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) 1

Off-Label Uses

• Reversal of direct oral anticoagulants (DOACs), particularly factor Xa inhibitors (apixaban, rivaroxaban, edoxaban, betrixaban) when specific reversal agents like andexanet alfa are unavailable 1
• Management of trauma-induced coagulopathy 2
• Treatment of bleeding after cardiopulmonary bypass 2
• Management of coagulopathy in liver failure 2

Advantages Over Fresh Frozen Plasma (FFP)

• Does not require ABO blood group compatibility testing 1
• Can be rapidly reconstituted and administered (infusion time of 20-30 minutes vs. hours for FFP) 1
• Requires significantly smaller volume for administration (less risk of volume overload) 1
• Contains approximately 25 times the concentration of coagulation factors compared to plasma 1
• Associated with fewer adverse reactions such as transfusion-associated circulatory overload (TACO) or transfusion-related acute lung injury (TRALI) 1
• More effective in rapidly normalizing INR in patients on vitamin K antagonists 3

Clinical Efficacy

• In VKA reversal, 4F-PCC can correct INR to 1.4 or less in nearly 100% of patients within 30 minutes post-administration 1
• Associated with reduced requirements for packed red blood cell transfusions compared to FFP 1
• For intracranial hemorrhage in patients on warfarin, 4F-PCC results in significantly faster INR reversal and decreased progression of hemorrhage compared to plasma 1
• When used for VKA reversal, 4F-PCC should always be administered with intravenous vitamin K to prevent later increases in INR 1

Safety Profile

• Main safety concerns include risk of thromboembolic events, allergic reactions, and heparin-induced thrombocytopenia 1
• Thromboembolic event rates range from 0-18% (mean 2.5%) in clinical studies 3
• When used for factor Xa inhibitor reversal at doses of 25-50 IU/kg, thromboembolic rates appear to be low (approximately 2.1%) 4
• Long-term pharmacovigilance data shows thromboembolic events occur at a rate of approximately 1 per 9,963 standard infusions 5
• Hypersensitivity reactions are rare (approximately 1 per 64,485 standard infusions) 5
• No confirmed cases of viral transmission related to 4F-PCC use have been reported 5

Dosing Considerations

• For VKA reversal: Weight-based dosing according to INR (25-50 U/kg) 1
• For factor Xa inhibitor reversal: Lower doses (25 U/kg) may provide similar hemostatic effectiveness to higher doses (50 U/kg) with potentially lower thromboembolic risk 6
• Maximum dose is typically capped at 5,000 units 1

Important Clinical Considerations

• 4F-PCC should be administered as soon as possible after diagnosis of major bleeding in anticoagulated patients to improve outcomes 1
• For intracranial hemorrhage, rapid reversal of anticoagulation with 4F-PCC is recommended to limit hematoma expansion 1
• When used for VKA reversal, 4F-PCC should always be co-administered with intravenous vitamin K to prevent rebound increases in INR 1
• Patients should be monitored for signs of thromboembolic complications after administration 1