Prothrombin Complex Concentrate

Aka: Prothrombin Complex Concentrate, Prothrombin Drug Combination, PCC, Beriplex, Octaplex, Kcentra, Cofact

1. Indications
   1. First-line management of life threatening Hemorrhage in unstable patients on Anticoagulants (e.g. Warfarin)
   2. Given as part of Massive Hemorrhage protocol (along with pRBC and Platelets), replacing the FFP component
2. Contraindications
   1. Disseminated Intravascular Coagulation
   2. Heparin-Induced Thrombocytopenia
3. Mechanism
   1. Concentrated extract from fresh-frozen plasma (factors are at 25 fold higher concentration than FFP)
   2. Each PCC vial contains 500 units of Factor IX (equivalent to two 200-250 cc units/bags of FFP)
4. Dosing
   1. Dose calculated for weight up to a maximum of 100 kg
   2. Prothrombin Complex Concentrate ( PCC, 4 factor preferred)
      1. Reversal of Rivaroxaban (Xarelto) or Apixaban (Eliquis) with acute major bleeding
         1. Dose: 50 Units/kg (up to 5000 units) every 24 hours until bleeding stabilized
      2. Reversal of Vitamin K Antagonists (e.g. Warfarin) with acute major bleeding
         1. Coadminister Vitamin K
         2. Dose based on Factor IX units
         3. Pre-dose INR 2 to 4
            1. PCC 25 units/wtKg up to 2500 units Factor IX
         4. Pre-dose INR 4 to 6
            1. PCC 35 units/wtKg up to 3500 units Factor IX
         5. Pre-dose INR >6
            1. PCC 50 units/wtKg up to 5000 units Factor IX
5. Precautions
   1. Do not give after 6-7 hours from onset of Hemorrhage (paradoxically increases risk of bleeding)
   2. Limit PCC to a maximum of 2 doses
   3. PCC lasts for less than one day
      1. Vitamin K should be given concurrently for a sustained effect
6. Disadvantages (compared with FFP)
   1. Cost is $4500 (twenty times that of the $250 FFP dose)
      1. Limit use to life-threatening bleeding events
      2. Cost limits emergency availability at smaller, rural medical centers
7. Advantages (compared with FFP)
   1. Twice as fast as FFP in Coagulopathy reversal
      1. Time to reversal 5.7 hours (compared with 11.8 hours for FFP)
      2. PCC is a single dose every 24 hours (compared with multiple doses of FFP)
   2. Half the adverse effects of FFP
      1. Adverse event rate 9.7% (compared with 19.5% for FFP)
      2. Similar rate of thromboembolic complications (VTE) as with FFP (despite more rapid Coagulopathy reversal)
      3. Lower rate of transfusion and Allergic Reactions compared with FFP
         1. No risk of Transfusion-Related acute lung injury (TRALI)
         2. Anaphylactoid reactions may still occur
   3. Much less volume required
      1. PCC volumes are 0.1 to 0.15 Liters compared with 1 to 2 Liters FFP
      2. Fluid Overload does not occur with PCC, but occurs in 6-7% of patients given FFP
   4. Better outcomes (variable)
      1. PCC treated patients required only half of Blood Products transfused (compared with FFP per Hickey study)
         1. PCC group required 1.4 units pRBC
         2. FFP group required 3.2 units pRBC
      2. However, another study demonstrated no better outcomes with PCC (Sarode study)
         1. PCC study demonstrated no better bleeding control (despite faster INR correction)
         2. Mortality in the PCC group (10 patients died) was double the FFP group (5 patients died) at 45 days
         3. Sarode (2013) Circulation 128(11): 1234-43 [PubMed]
   5. Faster preparation and infusion times
      1. PCC
         1. Does not require thawing
         2. Infuses in 25 minutes
      2. FFP
         1. Thaws in 20 min (45 C water bath) to 45 min (37 C water bath)
         2. Infuses in 30-120 minutes
         3. FFP must be used within 4 hours of thawing
   6. References
      1. Hickey (2013) Circulation 128(4): 360-4 [PubMed]
8. Components
   1. Factor II
   2. Factor VII (present only in four factor PCC)
   3. Factor IX
   4. Factor X
   5. Protein C (not present in all formulations)
   6. Protein S (not present in all formulations)
   7. Heparin (to prevent factor activation)
9. Formulations: Prothrombin Complex Concentrate
   1. PCC3 - Three factor (II, IX, X)
   2. PCC4 - Four factor (II, VII, IX, X)
      1. Kcentra (U.S., 2013)
      2. Octaplex
      3. Beriplex
10. Adverse Effects
    1. Headache
    2. Nausea or Vomiting
    3. Hypotension
    4. Arthralgias
    5. Thromboembolism (e.g. CVA, MI)
       1. Identified in initial studies
       2. Subsequent study found no difference in clot formation when compared with FFP
          1. Milling (2016) Ann Emerg Med 67(1): 96-105 +PMID:26094105 [PubMed]
11. References
    1. Arora and Menchine in Herbert (2013) EM:Rap 13(12): 1-2
    2. Franchini (2010) Blood Transfus 8(3): 149–154 [PubMed]