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 for replacement therapy of 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 acute major 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) and oral/IV vitamin K was the cornerstone of vitamin-K reversal; however, the American College of Cardiology (ACC) published a consensus statement recommending the use of 4-factor PCC for 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 not available. Although 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),[4]and for treatment of postoperative bleeding with a normal coagulation profile - this continues to be an off-label indication.
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.

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 contain the natural coagulation inhibitors protein C, and protein S. PCC  helps replenish these factors.[7] 

The 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 the reversal of 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 hence a delay in anticoagulation reversal.
4. PCC is leukocyte free and less likely to cause infusion reactions.[8]
5. Antibodies associated with causing transfusion-related lung injury (TRALI - a significant cause of death after transfusion) are removed from PCC during the manufacturing process; therefore, PCC is associated with minimal risk as compared to FFP.[9][10]
6. PCC products have a lower risk of viral transmission since they undergo viral inactivation.[7]

PCC exists as 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 case 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 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.

1. Bleeding/perioperative prophylaxis of bleeding during vitamin K antagonist therapy: 

INR: 2 to less than 4: 25 units/kg; maximum dose: ,500 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.

 2. 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 is because of the long half-life of warfarin requires sustained reversal that only vitamin K can provide.

Adverse effects associated with PCC include the following:

1. Immediate allergic reactions
2. Heparin-induced thrombocytopenia (if the preparation contains heparin)
3. 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.

The significant contraindications to PCC include the following:

• 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

Other contraindications relevant to some institutions:

• 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