1. Adam M. Spaulding Emergency Medicine Pharmacist Waterbury Hospital
Kcentra In-service
Adam M. Spaulding
Emergency Medicine Pharmacist
Waterbury Hospital

2. Prothrombin Complex Concentrates
Contain Vitamin K-dependent clotting factors
Made from pooled human plasma
Activated: Novoseven, FEIBA
Inactivated: Profilnine, Bebulin, Kcentra
Feiba has primarily inactivated factors 2, 9, 10. It has primarily activated factor 7. However, because FEIBA does not contain heparin nor ATIII, the contained factors have an increased tendency to become activated while in solution. For this reason, FEIBA is commonly thought of as being an activated PCC product.
Prothrombin Complex Concentrates (PCC) are a concentrated plasma product that contains clotting factors in varying amounts. Formulations can include 3 factor
products (II, IX and X) or 4 factor products (II, VII, IX and X). Dosing of PCC products is expressed as units of
factor IX [16]. The factors provided by PCC products are generally not activated and require activation by the
clotting cascade. There is one activated PCC (aPCC) product available, FEIBA, which contains activated Factor
VII and inactivated forms of Factors II, IX and X [17].

3. 4-F PCC (Kcentra) Contains clotting factors: II, VII, IX, X
All non-activated factors
Contains heparin and ATIII to keep non-activated
Contains proteins C and S and human albumin
Mimics natural milieu
Confers less risk of thrombosis
Inactive ingredients: sodium citrate, sodium chloride
Kcentra [package insert]. 2013

4. Clinical Use FDA indication: Un-labeled indications:
Emergent reversal of bleeding due to Vitamin K Antagonists
Emergent reversal of anticoagulation prior to emergent procedures
Un-labeled indications:
Emergent reversal of direct Xa inhibitors (+/- DTIs)
Bloodless surgery
Kcentra [package insert]. 2013

5. USA
Europe
Guyatt GH, Aki EA, Crowther M, et al. Executive Summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: 7S-47S.
Guyatt, et al. CHEST PMID:
Spahn et al. Critical Care PMID:

6. Dosing VKA reversal: Based on INR and weight (kg)
INR 2-4: 25units/kg
INR 4.1-6: 35units/kg
INR >6: 50units/kg
Direct Xa inhibitors: Empirically weight-based
Clinical presentation/history: 25-50units/kg
>1 dose not studied, not recommended and not approved at WH
Kcentra [package insert]. 2013
Spahn et al. Critical Care PMID:

7. Administration
Europe: given bedside via syringe (each vial pushed slowly over 2-3 minutes)
USA (and WH): Contents pooled in a bag and infused at 8.4mL/min (500mL/hr)
Follow by mL NS at same rate
MUST BE GIVEN WITH VITAMIN K
UK transfusion guidelines: Beriplex. JPAC. 2009
Kcentra [package insert]. 2013

8. “Advantages” over FFP: Practical and Theoretical
No checking blood groups or cross-matching
No waiting for blood to thaw
Less risk for viral transmission
No risk of TRALI
Less complications from volume overload
≤200mL vs mL
Reduce transfusion reactions?
Much quicker reversal of INR
Babilonia, et al. Thrombosis Journal PMID:

9. Sarode R, Milling TJ, Refaai MA, et al
Sarode R, Milling TJ, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128:
PMID:

10. PMID:

11. PMID:

12. Safety
Hanke, et al. Br J Anaest PMID:

13. PCC for NOACs (human studies)
Author, Year N
Study Design
Findings
Erenberg, 2011 12
• Dabigatran or rivaroxaban po x 2.5 d
• Treated with 3F-PCC bolus iv
• Measured PT and ETP over 24 hours
• PCC reversed PT, ETP in rivaroxaban
treated patients
• PCC did not reverse dabigatran
Marlu, 2012
10 Men
Dabigatran or rivaroxaban po x1
• Collected blood samples
• Treated blood (3-F PCC, rFVIIa, aPCC)
• Dabigatran – rFVIIa most effective
• Rivaroxaban - PCC most effective
Khoo, 2013 8
• Dabigatran+aPCC (FEIBA)
• Blood treated with aPCC
• aPCC reversed dabigatran
Dinklaar, 2013 9
• Rivaroxaban+ 3F-PCC
• PCC added to rivaroxaban-treated samples
• Coagulation assays performed
• PCC normalized thrombin generation
• Did not normalize PT w/ initial dose
• Dose of PCC required depended on type of assay
Korber, 2013 10
• Rivaroxaban + PCC/rFVIIa
• Blood samples treated with rivaroxaban
• Added PCC and rVIIa
• Performed clotting assays
• PCC had no effect on clotting tests
• rVIIa reversed PT and clotting factor time
Lazo-Langner A, Lang ES, Douketis J. Clinical review: clinical management of new oral anticoagulants: a structured review with emphasis on the reversal of bleeding complications. Critical Care 2013; 17:230.
Dabigatran
• Reversed with aPCC in 2/2 studies
Rivaroxaban
• Reversed with PCC in 3/4 studies
Lazo-Langner, et al. Critical Care PMID:

14. PCC for NOACs: Limitations in the literature
Many more animal studies than human studies
Human clotting factors behave differently in non-humans
Small “N”
Wide variability in study design
Different doses
Different species
Different outcomes (coagulation assays, bleeding time, blood loss)
Healthy volunteers
Reversal agents merely added to blood samples
Extrapolation to bleeding patients?
Outcomes include normalization of clotting tests as proxy for bleeding cessation**

15. Our protocol Restrictions for use at Waterbury Hospital
Kcentra Restrictions
Inclusion Criteria:
Treatment of life-threatening bleeding or major bleeding associated with hemodynamic instability in patients taking warfarin, rivaroxaban or apixaban (including those who present with intracranial hemorrhage and declining neurologic status)
Rapid correction of INR in patients receiving warfarin and who required immediate reversal for life-sustaining procedures (anticipated need within 8 hours)
Exclusion Criteria:
Known history of heparin-induced thrombocytopenia
Disseminated intravascular coagulation is suspected
Able to tolerate FFP volume and slower time of onset
Bleeding due to dabigatran (advise the physician over the phone)
Bleeding in the absence of an anticoagulant

16. Our Protocol
Ordering and dosing
Preparation
Administration

17. Ordering/Dosing Limited to ER, Neurology, Trauma surgery and ICU
STAT call to ED Pharmacist/Pharmacy
Doses will be rounded to the nearest 500 factor IX units by the verifying pharmacist
Use the rounding cheat sheet
Order must be re-entered
Pharmacist verifies appropriate indication, dose and that a concurrent order for Vitamin K exists
Only one dose of Kcentra can be ordered/patient

18. Dosing Cheat Sheet

19. Storage and Preparation
Kcentra Kit Contents
Contents list sheet
(10) Kcentra 500unit vials
(10) Manufacturer supplied 20mL diluents (SWFI)
(10) Mix2Vial transfer devices
(5) alcohol swabs
(4) 60mL syringes
Intravia 250mL empty bag
Premade label
Nominal potency will be used to calculate # of vials
Vials will be reconstituted with Mix2Vial transfer set provided
Multiple syringes will be pooled into a 250mL Intravia container
LOT numbers will need to be documented in the medical record*

20. Administration Administer within 4 hours of reconstitution
Dedicated line required for administration
2 separate lines preferable (one for Vitamin K)
Administered as an 500ml/hr
After infusion, the line needs to be flushed with NS
Replace Kcentra with cc bag NS and run at same rate
Need f/u INR 30 minutes after infusion

21. Cost $1.34 per unit ~$670 per vial (~500 units)
$6700 for 5,000 unit dose (max dose)
Unlike Genentech for alteplase, Kcentra is not reimbursed/replaced if the product is mixed, but not used
CMS offers NTAP program for Kcentra
If total costs of inpatient stay exceed the MS-DRG payment amount, NTAP attempts to pay the difference
Payment is NOT based on the dosage of Kcentra administered
Additional payments through NTAP are capped at $1,587.50

22. References
Kcentra [package insert]. King of Prussia, PA: CSL Behring; 2013.
Guyatt GH, Aki EA, Crowther M, et al. Executive Summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: 7S-47S. PMID:
Spahn DR, Bouillon B, Cerny V, et al. Management of bleeding and coagulopathy following major trauma: an updated European guidelines. Crit Care 2013; 17(2):R76. PMID:
Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee (JPAC). UK Transfusion Guidelines: Beriplex URL:
Babilonia K, Trujillo T. The role of prothrombin complex concentrates in reversal of target specific anticoagulants. Thrombosis Journal 2014;12:8. PMID:
Sarode R, Milling TJ, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128: PMID:
Hanke AA, Joch C, and Gorlinger K. Long-term safety and efficacy of a pasteurized nanofiltrated prothrombin complex concentrate (Beriplex® P/N): a pharmacovigilance study. Br J Anaest. 2013; 1-9. PMID:
Lazo-Langner A, Lang ES, Douketis J. Clinical review: clinical management of new oral anticoagulants: a structured review with emphasis on the reversal of bleeding complications. Critical Care 2013; 17:230. PMID:

23. Questions?