Continuing Education Activity

Prothrombin complex concentrate (PCC) comes from the process of ion-exchange chromatography from the cryoprecipitate supernatant of large plasma pools and after removal of antithrombin and factor XI. This agent's initial development was for hemophilia; however, with the availability of recombinant replacement factors, it no longer has a use in this setting. It is now used to replace congenital or acquired vitamin-K deficiency warfarin-induced anticoagulant effect, particularly in the emergent setting. The FDA-approved indication is for urgent reversal of acquired coagulation factor deficiency induced by warfarin-induced anticoagulation in patients presenting with major acute bleeding (intracerebral hemorrhage-ICH) or needing urgent invasive surgery or procedure. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, monitoring, and toxicity of prothrombin complex concentrate, so providers can direct patient therapy in treating conditions for which it is indicated, as part of the interprofessional team.

Objectives:

• Describe the mechanism of action of prothrombin complex concentrate.
• Review both the approved and off-label indications for using prothrombin complex concentrate.
• Summarize the adverse effects of prothrombin complex concentrate.
• Explain the importance of improving care coordination among the interprofessional team to enhance care delivery for patients who can benefit from therapy with prothrombin complex concentrate.

Indications

Prothrombin complex concentrate (PCC) comes from the process of ion-exchange chromatography from the cryoprecipitate supernatant of large plasma pools and after removal of antithrombin and factor XI.[1] Processing techniques involving ion exchangers allow for the production of either three-factor (i.e., factors II, IX, and X) or four-factor (i.e., factors II, VII, IX, and X) PCC. The initial development of this agent was for hemophilia; however, with the availability of recombinant replacement factors, it no longer has a use in this setting. It is now used as replacement therapy for congenital or acquired vitamin-K deficiency warfarin-induced anticoagulant effect, particularly in the emergent setting. The indications are listed below. 

1. Urgent reversal of acquired coagulation factor deficiency induced by warfarin-induced anticoagulation in patients presenting with major acute bleeding (intracerebral hemorrhage-ICH) or a need for urgent invasive surgery or procedure: This is the only FDA approved indication. Four factor PCC works to reverse a warfarin-induced major bleed in clinical practice. Treatment with either fresh frozen plasma (FFP) or oral/IV vitamin K was the cornerstone of vitamin-K reversal; however, the American College of Cardiology (ACC) published a consensus statement recommending using 4-factor PCC for the reversal of warfarin-induced bleeding.[2]
2. Reversal of Direct oral anticoagulants (DOAC) induced anticoagulation with major bleeding or requiring major surgery: PCC may be used to reverse DOAC induced anticoagulation when a more specific antidote is unavailable.[3] According to ACC Expert Consensus Decision Pathway on the Management of Bleeding Patients on Oral Anticoagulation, Statement PCC is recommended for both Xa inhibitors and direct thrombin inhibitors when antidotes are not available. However, this is not yet an FDA-approved indication. 
3. Treatment or prophylaxis of bleeding in congenital deficiency of any vitamin K-dependent coagulation factors (II, VII, IX, X) when purified specific coagulation factor products are unavailable. Although the initial development of PCC was for use in hemophilia, with the development of purified factor IX, and recombinant factor IX, PCC is now rarely used. However, in the rare event that purified factor is not available, 4-factor PCC may be used; this is also an off-label use of this agent.
4. Peri-operatively to decrease bleeding in patients not taking oral anticoagulants: 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 PT/INR) and for treatment of postoperative bleeding with a normal coagulation profile - this continues to be an off-label indication.[4]
5. Trauma setting with massive transfusion: Some studies have shown better INR reduction with PCC+ FFP compared to FFP alone.[5] It is important to remember that PCC does not contain factor V and may not be sufficient as a single agent in traumatic causes requiring massive transfusions. This application is also an off-label use of this agent.

Mechanism of Action

The coagulation cascade entails a series of reactions between pro- and anticoagulant factors resulting in hemostasis. The intrinsic and extrinsic pathways converge with the activation of factor X (factor Xa). Activated factor V and activated factor X produce thrombin. Warfarin inhibits vitamin K-dependent synthesis of clotting factors II, VII, IX, and X and anticoagulant factors protein C and protein S.

PCC contains factors II, IX, and X, and variable amounts of factor VII concentrate with a final overall clotting factor concentration approximately 25 times higher than in normal plasma.[6] To prevent the activation of these factors, PCC also contains heparin. PCC may also include the natural coagulation inhibitors protein C and protein S. PCC  helps replenish these factors.[7] 

Direct oral anticoagulation agents have a different mechanism of action: apixaban and rivaroxaban are inhibitors of factor Xa, and dabigatran inhibits thrombin. The mechanism of action of PCC in reversing anticoagulation with DOACs remains unestablished.

For several years, FFP and vitamin K were the preferred options for reversing anticoagulation. Prothrombin complex concentrate offers several advantages over FFP, most importantly, the small volume needed to reverse anticoagulation. PCC contains significantly higher amounts of the clotting factors compared to FFP; one dose of PCC equals 8 to 16 units of FFP. 

1. Quick administration: The large amount of FFP takes much longer to infuse, whereas PCC can be administered over a few minutes and provides immediate reversal in life-threatening bleeding.
2. Safe in heart failure: PCC can be safely administered in patients with cardiac or renal impairment who may be unable to tolerate large volumes of plasma.
3. FFP requires procurement from the blood bank and thawing before administration, factors that lead to delays in administration and anticoagulation reversal.
4. PCC is leukocyte-free and less likely to cause infusion reactions.[8]
5. Antibodies associated with causing transfusion-related acute lung injury (TRALI, defined as new acute lung injury that developed during or within 6 hours of transfusion of one or more units, not attributable to another ALI risk factor)  - a significant cause of death after transfusion) are removed from PCC during the manufacturing process; therefore, PCC is associated with minimal risk compared to FFP.[9][10]
6. PCC products have a lower risk of viral transmission since they undergo viral inactivation.[7]

Administration

PCC exists in two varieties: 3-factor PCC and 4-factor PCC. The 3-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. Experts have stated that 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, extent and location of bleeding, and clinical status of the patient.  The approximate dosing required described below should achieve the normalization of INR  (less than or equal to 1.2) within 1 hour of treatment.

Bleeding/perioperative Prophylaxis of Bleeding During Vitamin K Antagonist Therapy 

INR: 2 to less than 4: 25 units/kg; maximum dose: 2500 units

INR: 4 to 6: 35 units/kg; maximum dose: 3500 units

INR: greater than 6: 50 units/kg; maximum dose: 5000 units

Repeat or subsequent dosing is not recommended.  In patients weighing greater than 100 kg, the recommendation is to exceed the maximum dose.

Life-threatening Major Bleed With a Non-Warfarin Anticoagulant

Recommendations are to administer 50 units/kg, with an additional 25 units/kg if the patient meets all the following criteria:

• Bleeding is life-threatening
• The specific antidote is not available (e.g., adexanet alfa for apixaban)
• 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 (3 to 5 half-lives) can be extended if renal impairment is present and sufficient to prolong the half-life of the medication.

It is also recommended to administer vitamin K along with PCC when used for reversal of VKA anticoagulation; this results from the long half-life of warfarin requiring sustained reversal that only vitamin K can provide.[11]

Adverse Effects

• Immediate allergic reactions
• Heparin-induced thrombocytopenia (if the preparation contains heparin)
• Thromboembolic complications like pulmonary embolism, stroke, myocardial infarction, and deep venous thrombosis - today's PCC formulations differ vastly from those used in the 1980s and have a lower thrombosis risk. Current PCC formulations contain coagulation inhibitors such as heparin, antithrombin, protein C, protein S, and protein Z, which may contribute to this lower risk. The main risk factor for developing thrombosis is the accumulation of factor II, which can occur with large or frequent dosing.[12]

Contraindications

Significant Contraindications

• History of DIC (disseminated intravascular coagulation)
• Angina, myocardial infarction, peripheral vascular disease, or stroke in the last three months
• Thromboembolic disease event history in the previous three months
• Known anaphylactic or severe systemic reactions to prothrombin complex concentrate, albumin hypersensitivity, heparin hypersensitivity, plasma protein hypersensitivity
• Heparin-induced thrombocytopenia (HIT)
• Labor, obstetric delivery, pregnancy: PCC effect on the fetus is unknown - it is not recommended to use PCC in pregnant patients or during labor unless clearly indicated and benefits outweigh the risk
• Breastfeeding: It is unknown if PCC gets excreted in breast milk - it may be used only if benefits clearly outweigh the risks; suspend breastfeeding while receiving PCC
• Hepatitis, infection: there is a risk of viral transmission as with all other blood products - although this risk is significantly lower in PCC compared to FFP[13]

Other Relevant Contraindications

• Acidosis; pH of less than 7.10
• Temperature below 96 degrees Fahrenheit
• Platelet count less than 50000/mm^3
• Patients with non-survivable acute injuries or illness

Monitoring

• INR (baseline and 30 minutes post-dose)
• Prothrombin time (PT), activated partial thromboplastin time (PTT), fibrinogen
• Signs and symptoms of thromboembolism during and after administration of PCC

Toxicity

Higher doses of PCC can increase the risk of thromboembolism. There is no known antidote. Postmarketing surveillance reports angioedema, bronchospasm, and other severe thromboembolic complications (e.g., myocardial infarction, transient ischemic attack, and arterial thrombosis).[14]

Enhancing Healthcare Team Outcomes

Prothrombin complex concentrate is a newer biological agent and is not yet widely available. It may be used as a medium to reverse bleeding and improve patient outcomes through interprofessional collaboration between clinicians (MDs, DOs, NPs, PAs), nursing staff, and pharmacists. Pharmacists can be an excellent resource in this setting, guiding clinicians concerning dosing and indications for administration and answering team members' questions about the medication. This type of interprofessional team coordination can result in more effective therapy when using PCC when indicated, producing improved outcomes. [Level 5]