Coagulation
Anticoagulants and procoagulants
4 factor PCC
Editorial Board Member: Mrigender Singh Virk, M.D.
Last staff update: 23 April 2024 (update in progress)
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PubMed Search: 4 factor PCC
Table of Contents
Definition / general | Essential features | Pathophysiology | Advantage over 3 factor PCC (3F PCC) | Brand names (U.S.) | Indications | Dosing | Dosage forms considerations | Example dosing calculation | Monitoring | Contraindications | U.S. boxed warning | Board review style question #1 | Board review style answer #1Cite this page: Alswied A, Conry-Cantilena K. 4 factor PCC. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/coagulation4factorPCC.html. Accessed May 6th, 2024.
Definition / general
- 4 factor prothrombin complex concentrate (4F PCC) is derived from plasma pools depleted of cryoprecipitate
- 4F PCC contains hemostatic levels of vitamin K dependent factors (II, VII, IX and X) and physiological amounts of coagulation inhibitory proteins, protein C and S
- Final formulation of 4F PCC may include heparin and antithrombin (ATIII) as specific clotting factor stabilizers to prevent activation
Essential features
- 4F PCC contains hemostatic levels of vitamin K dependent coagulation factors (II, VII, IX and X) and physiological amounts of coagulation inhibitory proteins, protein C and S
- 4F PCC is indicated for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist therapy in adult patients with
- Acute major bleeding (Kcentra only) or
- Need for an urgent surgery / invasive procedure (Kcentra and Balfaxar)
- Baseline and 30 minute postdose international normalized ratio (INR) levels, clinical response and signs of thromboembolism during and after treatment should be monitored
Pathophysiology
- 4F PCC contains the vitamin K dependent coagulation factors II, VII, IX and X, collectively referred to as the prothrombin complex, along with the antithrombotic proteins C and S
- During vitamin K antagonist therapy, a dose related deficiency of factors II, VII, IX and X may arise
- Anticoagulant action of vitamin K antagonists inhibits the carboxylation of glutamic acid residues in these factors, reducing both their synthesis and functionality
- Administration of 4F PCC elevates the levels of these coagulation factors and antithrombotic proteins in plasma (StatPearls: Prothrombin Complex Concentrate [Accessed 14 March 2024])
Advantage over 3 factor PCC (3F PCC)
- Key difference between 3F PCC and 4F PCC lies in the content of factor VII
- 3F PCC contains hemostatic levels of factor IX, varying levels of factors II and X and low levels of factor VII, whereas 4F PCC contains therapeutic levels of factors II, VII, IX, X and proteins C and S (Shock 2019;52:23)
Brand names (U.S.)
- Kcentra or Balfaxar
Indications
- U.S. Food and Drug Administration (FDA) approved use
- 4F PCC is indicated for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist therapy in adult patients with
- Acute major bleeding (Kcentra only) or
- Need for an urgent surgery / invasive procedure (Kcentra and Balfaxar)
- 4F PCC is indicated for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist therapy in adult patients with
- Off label use
- Life threatening hemorrhage associated with direct factor Xa inhibitor or direct thrombin inhibitor
- Perioperative coagulopathy
- Reversal of oral direct factor Xa inhibitors in patients requiring urgent procedures, in lieu of andexanet (factor Xa inhibitor reversal agent)
- References: FDA: Package Insert - Kcentra [Accessed 19 March 2024], FDA: Package Insert - Balfaxar [Accessed 19 March 2024], Transfus Med Rev 2021;35:96, Am J Emerg Med 2022;55:38
Dosing
- Weight based dose (dose is based on body weight up to but not exceeding 100 kg; for patients weighing > 100 kg, the maximum dose should not be exceeded)
Pretreatment INR 2 - < 4 4 - 6 > 6 Dose (units of factor IX/kg body weight) 25 35 50 Maximum dose (units of factor IX) Not to exceed 2,500 Not to exceed 3,500 Not to exceed 5,000
- Fixed dose protocols have been formulated using data from Kcentra studies, suggesting an initial dose of 1,000 - 2,000 units; repeat dosing is advised in cases of modest INR reversal (Cardiovasc Drugs Ther 2022;36:533)
Dosage forms considerations
- Each vial label indicates potency in terms of factor IX nominal strength (500 units or 1,000 units); this should be taken into consideration when patient dosing calculations are performed
- Kcentra: the potency of a 500 unit vial ranges from 400 to 620 units and for a 1,000 unit vial, it ranges from 800 to 1,240 units
- Balfaxar: the potency of a 500 unit vial varies from 400 to 640 units and for a 1,000 unit vial, it ranges from 800 to 1,280 units
- References: FDA: Package Insert - Kcentra [Accessed 19 March 2024], FDA: Package Insert - Balfaxar [Accessed 19 March 2024]
Example dosing calculation
- For a 70 kg patient with a baseline INR of 7.0, the required dose of 4F PCC would be 3,500 units of factor IX
- This calculation is based on an INR range above 6, where 50 units of factor IX per kg of body weight results in 3,500 units needed
- To determine the volume to administer, the potency of the vial must be considered; in the case of a vial containing 30 units/mL of factor IX, 117 mL would be the appropriate amount (3,500 U divided by 30 U per mL equals 117 mL)
- References: FDA: Package Insert - Kcentra [Accessed 19 March 2024], FDA: Package Insert - Balfaxar [Accessed 19 March 2024]
Monitoring
- Baseline and 30 minute postdose INR levels, clinical response and signs of thromboembolism during and after treatment should be monitored
Contraindications
- Anaphylaxis or severe systemic reaction to PCC or any component of the formulation
- Known allergy to heparin or history of heparin induced thrombocytopenia
- Immunoglobulin A (IgA) deficiency, with known antibodies against IgA (Balfaxar)
- Disseminated intravascular coagulation (Kcentra)
- References: FDA: Package Insert - Kcentra [Accessed 19 March 2024], FDA: Package Insert - Balfaxar [Accessed 19 March 2024]
U.S. boxed warning
"Arterial and venous thromboembolic complications:
Patients being treated with vitamin K antagonist therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing vitamin K antagonists should be weighed against the potential risks of thromboembolic events, especially in patients with history of a thromboembolic event. Resumption of anticoagulation should be evaluated if the risk of thromboembolic events outweighs the risk of acute bleeding.
Both fatal and nonfatal arterial and venous thromboembolic complications have been reported with prothrombin complex concentrate in clinical trials and postmarketing surveillance. Monitor patients receiving prothrombin complex concentrate for signs and symptoms of thromboembolic events.
Prothrombin complex concentrate was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris or severe peripheral vascular disease within the prior 3 months. Prothrombin complex concentrate may not be suitable in patients with thromboembolic events in the prior 3 months."
Patients being treated with vitamin K antagonist therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing vitamin K antagonists should be weighed against the potential risks of thromboembolic events, especially in patients with history of a thromboembolic event. Resumption of anticoagulation should be evaluated if the risk of thromboembolic events outweighs the risk of acute bleeding.
Both fatal and nonfatal arterial and venous thromboembolic complications have been reported with prothrombin complex concentrate in clinical trials and postmarketing surveillance. Monitor patients receiving prothrombin complex concentrate for signs and symptoms of thromboembolic events.
Prothrombin complex concentrate was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris or severe peripheral vascular disease within the prior 3 months. Prothrombin complex concentrate may not be suitable in patients with thromboembolic events in the prior 3 months."
Board review style question #1
A 73 year old man on warfarin for atrial fibrillation presented with severe abdominal pain. Imaging studies reveal an intraperitoneal hemorrhage. The decision is made to reverse the anticoagulation urgently. The medical team debates between using a 3 factor prothrombin complex concentrate (PCC) and a 4 factor PCC.
Based on the composition of prothrombin complex concentrates, which of the following best describes the difference between 3F PCC and 4F PCC in the context of reversing warfarin induced anticoagulation?
- 3F PCC contains hemostatic levels of factor IX, varying levels of factors II and X and low levels of factor VII, whereas 4F PCC contains therapeutic levels of factors II, VII, IX, X and proteins C and S
- 3F PCC contains therapeutic levels of factors II, VII, IX and X, while 4F PCC contains hemostatic levels of factors II, IX and X, with low levels of factor VII
- 3F PCC contains therapeutic levels of factors VII, IX and X, while 4F PCC contains varying levels of factors II, IX and X, with low levels of factor VII
- Both 3F PCC and 4F PCC contain therapeutic levels of factors II, VII, IX and X but only 4 factor PCC contains proteins C and S
Board review style answer #1
A. 3F PCC contains hemostatic levels of factor IX, varying levels of factors II and X and low levels of factor VII, whereas 4F PCC contains therapeutic levels of factors II, VII, IX, X and proteins C and S. This makes 4F PCC a more suitable option for reversing warfarin induced anticoagulation due to its broader range of coagulation factors.
Answer B is incorrect because it inaccurately states that 3F PCC contains therapeutic levels of factor VII and 4F PCC contains low levels of factor VII.
Answer C is incorrect because it inaccurately describes the composition of both 3F PCC and 4F PCC. 3F PCC does not contain therapeutic levels of factor VII and 4F PCC does not contain low levels of factor VII. Instead, 4F PCC contains therapeutic levels of all 4 factors (II, VII, IX and X) and proteins C and S.
Answer D is incorrect because it states that both 3F PCC and 4F PCC contain therapeutic levels of factors II, VII, IX and X, which is inaccurate.
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Reference: 4 factor PCC
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Reference: 4 factor PCC
