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. 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.
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. 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.
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.
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:
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:
The significant contraindications to PCC include the following:
Other contraindications relevant to some institutions:
The monitoring parameters are as follows:
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).
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 improving patient outcomes through interprofessional collaboration between physicians, nurse practitioners, and pharmacists. Pharmacists can be a great resource in this setting, guiding physicians concerning dosing and indications for administration.
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