Continuing Education Activity

Prothrombin complex concentrate is derived from the cryoprecipitate supernatant of large plasma pools using ion-exchange chromatography. Initially developed for hemophilia, its role has shifted due to the availability of recombinant factors. Prothrombin complex concentrate is now indicated for the urgent reversal of acquired coagulation factor deficiency, specifically in patients experiencing warfarin-induced anticoagulation with major acute bleeding, such as intracerebral hemorrhage, or those requiring emergency surgery.

The Food and Drug Administration has approved prothrombin complex concentrate for use in these emergent settings, where rapid correction of coagulation is essential. This article reviews prothrombin complex concentrate's indications, mechanism of action, dosing, administration, monitoring, and associated adverse effects and contraindications. Understanding the pharmacologic properties of prothrombin complex concentrate allows healthcare professionals to administer it appropriately, ensuring effective management of anticoagulation reversal as part of an interprofessional team.

Objectives:

• Identify both the Food and Drug Administration–approved and off-label uses of prothrombin complex concentrate.

• Determine the appropriateness and dose of prothrombin complex concentrate based on the patient's international normalized ratio, clinical status, concurrent medications, and medical conditions.

• Assess the adverse effects associated with prothrombin complex concentrate administration.

• Implement effective coordination among interprofessional team members to enhance care delivery for patients who may benefit from prothrombin complex concentrate therapy.

Indications

Prothrombin complex concentrate (PCC) is produced using ion-exchange chromatography from the cryoprecipitate supernatant of large plasma pools, with antithrombin and factor XI removed beforehand.[1] Processing techniques involving ion exchangers allow for the production of either 3-factor PCC, such as factors II, IX, and X, or 4-factor PCC, such as factors II, VII, IX, and X.

PCC was initially developed initially as a treatment for hemophilia. However, the availability of recombinant replacement factors has made PCC a less preferred option for patients with this condition. PCC is now used as replacement therapy for congenital or acquired vitamin K deficiency or warfarin-induced anticoagulant effect, particularly in the emergent setting. Treatment with either oral or intravenous vitamin K or fresh frozen plasma was previously the standard vitamin K reversal treatment. The American College of Cardiology (ACC) published a consensus statement recommending the use of 4-factor PCC to reverse warfarin-induced bleeding.[2]

Food and Drug Administration–Approved Indications

Urgent warfarin reversal: The only Food and Drug Administration (FDA)-approved indication for PCC is the treatment of acquired coagulation factor deficiency secondary to warfarin-induced anticoagulation. These patients present with acute major bleeding, such as intracerebral hemorrhage, or have an urgent need for an invasive surgery or procedure.

Off-Label Uses

Reversal of direct oral anticoagulants: According to a recent statement by the ACC, PCC can be used to reverse the anticoagulant effects of direct oral anticoagulants, specifically factor Xa and direct thrombin inhibitors, when a more specific antidote is unavailable.[3] However, this is not an FDA-approved indication.

Congenital coagulation factor deficiency: PCC can be used prophylactically or therapeutically in patients with a congenital deficiency of vitamin K–dependent coagulation factors II, VII, IX, or X when purified specific coagulation factor products are unavailable. Although initially developed to treat hemophilia, PCC is rarely used due to the development of purified factor IX and recombinant factor IX. However, should the specific purified factor be unavailable, 4-factor PCC may be used.

Reduction of perioperative bleeding: Several multi-institutional studies have shown reduced perioperative bleeding and a decreased need for transfusion when 4-factor PCC is administered both prophylactically in patients with coagulopathy, as evidenced by a prolonged prothrombin time/international normalized ratio (PT/INR), and for the treatment of postoperative bleeding in patients with a normal coagulation profile.[4]

Massive transfusion: Some studies have shown improved INR reduction with a combination of PCC and fresh frozen plasma compared to fresh frozen plasma alone.[5] However, PCC does not contain factor V and may not be sufficient as a single agent in traumatic causes requiring massive transfusions.

Mechanism of Action

The coagulation cascade includes a series of reactions involving pro- and anticoagulant factors that result in hemostasis. The intrinsic and extrinsic pathways converge during the activation of factor X (factor Xa). Activated factors V and X produce thrombin. Different anticoagulation agents have different mechanisms of action. Apixaban and rivaroxaban inhibit factor Xa, whereas dabigatran inhibits thrombin. Warfarin inhibits the vitamin K–dependent synthesis of clotting factors II, VII, IX, and X and coagulation inhibitors proteins C and S.

PCC contains factors II, IX, and X and variable amounts of factor VII. The administered product contains clotting factor concentrations approximately 25 times higher than in normal plasma.[6] PCC also contains heparin to prevent early factor activation and may also include proteins C and S.[7] 

The mechanism of action of PCC in reversing anticoagulation with direct oral anticoagulants remains unestablished. Fresh frozen plasma and vitamin K were previously the preferred options for reversing anticoagulation. However, PCC offers several advantages over fresh frozen plasma, which are listed below.

• Volume required: PCC contains significantly higher amounts of clotting factors compared to fresh frozen plasma; one dose of PCC equals 8 to 16 units of fresh frozen plasma.
• Quick administration: PCC can be administered for a few minutes, immediately reversing life-threatening bleeding. In contrast, the relatively large volume of fresh frozen plasma takes longer to infuse.
• Safe in heart failure: PCC can be safely administered to patients with cardiac or renal impairment who may be unable to tolerate large volumes of plasma.
• Faster to use: Fresh frozen plasma requires procurement from the blood bank and thawing before administration, which delays administration.
• Reduced adverse reaction risk: PCC is leukocyte-free and less likely to cause infusion reactions.[8] Antibodies associated with transfusion-related acute lung injury are removed from PCC during manufacturing.[9][10] PCC products also have a lower risk of viral transmission as they undergo viral inactivation.[7]

Pharmacokinetics

Absorption: As PCC is administered intravenously, its bioavailability is directly proportional to the dose.

Distribution: After a single intravenous infusion, PCC was found to be distributed similarly to endogenous proteins, resulting in a rapid and sustained increase in the plasma levels of factors II, VII, IX, and X, and proteins C and S.

Metabolism: After a single intravenous infusion of PCC, factor II had the longest half-life (59.7 hours), whereas factor VII had the shortest (4.2 hours) among healthy individuals.

Elimination: After a single intravenous infusion, PCC was found to be eliminated in a manner similar to that of endogenous proteins.

Administration

Available Dosage Forms and Strengths

PCC is available in 2 forms—3-factor PCC and 4-factor PCC. Three-factor PCC contains factors II, IX, X, and little or no factor VII. In all the indications listed above, 4-factor PCC is the preferred choice. In cases where 4-factor PCC is unavailable, 3-factor PCC with recombinant factor VII is an acceptable alternative.

PCC dosing products are expressed as units of factor IX. Individualized dosing is based on the severity of the disorder, the extent and location of bleeding, and the patient's clinical status. The approximate dosing described below should achieve a normal INR (≤1.2) within 1 hour of treatment.

PCC is available as 500-unit (400- to 620-unit) vials and 1000-unit vials of lyophilized concentrate for reconstitution. 

Adult Dosage

Bleeding during vitamin K antagonist (warfarin) therapy: 

• INR 2-4: 25 units/kg; maximum dose: 2500 units
• INR 4-6: 35 units/kg; maximum dose: 3500 units
• INR >6: 50 units/kg; maximum dose: 5000 units

Repeat or subsequent dosing is not recommended. Patients weighing over 100 kg should not be administered more than the maximum dose.

Bleeding during non-warfarin anticoagulation therapy:

Clinicians should administer 50 units/kg, with an additional 25 units/kg if the following criteria are met:

• The bleeding is life-threatening.
• A specific antidote, such as andexanet alfa for apixaban, is unavailable.
• The patient presents within 3 to 5 half-lives of the drug (half-life is around 12 hours for apixaban and 5 to 9 hours for rivaroxaban). This window can be extended if renal impairment is present and sufficient to prolong the medication's half-life.

Clinicians should also administer vitamin K with PCC to reverse vitamin K antagonist anticoagulation. This step is necessary due to the long half-life of warfarin requiring sustained reversal that only vitamin K can provide.[11]

Specific Patient Populations

Pregnancy considerations: The effect of PCC on the fetus is unknown; PCC should not be administered in pregnant patients or during labor unless indicated, and the benefits outweigh the risks.

Breastfeeding considerations: The presence of PCC in breast milk has not been established. However, breastfeeding should be suspended for patients receiving PCC.

Pediatric patients: The safety and effectiveness of PCC have not been assessed in pediatric patients.

Older patients: There is no evidence that PCC administration to older adults differs in safety or effectiveness from that in other populations, regardless of formulation.

Adverse Effects

Adverse reactions associated with PCC administration include the following:

• Immediate allergic reactions
• Procedural pain and catheter site-related reaction 
• Asthenia
• Postoperative wound complication
• Heparin-induced thrombocytopenia (if the preparation contains heparin)
• Thromboembolic complications, such as pulmonary embolism, stroke, myocardial infarction, and deep venous thrombosis; modern PCC formulations contain coagulation inhibitors such as heparin, antithrombin, protein C, protein S, and protein Z, which may contribute to their lower thrombosis risk compared to formulations used in the 1980s. The main risk factor for developing thrombosis is the accumulation of factor II, which can occur with large or frequent dosing.[12]
• Hypotension or hypertension
• Headache
• Fever
• Nausea, vomiting, and diarrhea
• Anemia
• Abdominal pain
• Hypokalemia
• Dysuria
• Fluid overload
• Tachycardia and atrial fibrillation
• Pleural effusion, pulmonary edema, respiratory distress, dyspnea, and hypoxia 
• Skin lacerations, contusions, and hematoma

Drug-Drug Interactions

Alteplase, bivalirudin, and dabigatran are known to have synergistic effects with PCC and are contraindicated. Tranexamic acid enhances the effects of PCC through pharmacodynamic synergy. Coadministration is contraindicated due to an increased risk of thrombosis.

Apixaban, argatroban, dalteparin, enoxaparin, heparin, reteplase, rivaroxaban, and tenecteplase are contraindicated for patients receiving PCC, as these drugs cause pharmacodynamic antagonism.

Contraindications

Significant contraindications to PCC administration include:

• History of disseminated intravascular coagulation
• Angina, myocardial infarction, peripheral vascular disease, or stroke within the past 3 months
• Thromboembolic disease event history in the previous 3 months
• Known anaphylactic or severe systemic reactions to prothrombin complex concentrate
• Known hypersensitivity to albumin, heparin, or plasma protein
• Heparin-induced thrombocytopenia
• Labor, obstetric delivery, or pregnancy
• Breastfeeding
• Hepatitis infection [13]

Other relevant contraindications to PCC administration include:

• Acidosis (pH <7.1)
• Temperature <96 °F
• Platelet count <50000/mm³

Box Warning

Patients receiving vitamin K antagonist therapy typically have conditions that make them prone to thromboembolic events. When deciding to reverse vitamin K antagonist treatment, it is important to weigh the benefits against the risks of thromboembolic events, especially in patients with a history of such events. Anticoagulation should be resumed with caution, prioritizing it as soon as the risk of thromboembolic events surpasses the risk of acute bleeding.

In clinical trials and postmarketing reports, PCC has been associated with fatal and non-fatal arterial and venous thromboembolic complications. Patients receiving PCC should be monitored for signs or symptoms of thromboembolic events. In addition, PCC may not be appropriate for patients who have experienced thromboembolic events within the past 3 months.

Warning/Precautions

• Thromboembolic risk/complications
• Transmissible infectious agent: PCC is derived from human blood, which carries a risk of transmitting infectious agents, including viruses such as hepatitis and HIV, Creutzfeldt-Jakob disease or its variant.

Monitoring

Clinicians should monitor patients receiving PCC for the following:

• INR levels (baseline and 30 minutes post-dose) [14]
• PT, activated partial thromboplastin time, and fibrinogen levels
• Signs and symptoms of thromboembolism during and after administration

Toxicity

Higher doses of PCC are associated with an increased risk of thromboembolism, and no specific antidote exists. Postmarketing surveillance reports angioedema, bronchospasm, and other severe thromboembolic complications, including myocardial infarction, transient ischemic attack, and arterial thrombosis.[15]

Enhancing Healthcare Team Outcomes

PCC is a relatively newer biological agent that is not yet widely available. It is often used to reverse bleeding in critical situations, and its successful administration requires close interprofessional collaboration among clinicians, pharmacists, and nursing staff. Pharmacists play a crucial role by advising on the appropriate dosing and indications for PCC use and addressing any medication-related concerns within the healthcare team.

Nurses are essential in monitoring patient parameters, including INR, thromboembolism symptoms, and other vital indicators during and after PCC administration, in accordance with hospital protocols. This coordinated interprofessional approach ensures that PCC therapy is used effectively and safely, ultimately improving patient outcomes in critical bleeding scenarios.