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Fixed-dose 4-factor prothrombin complex concentrate: we don’t know where we’re going if we don’t know how to get there

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Abstract

4-Factor Prothrombin Complex Concentrate (4F-PCC) is the standard-of-care intervention in patients with major bleeding taking oral vitamin K antagonists. Despite growing clinical experience with 4-FPCC, the optimal dosing strategy remains unclear. In balancing efficacy, safety, and cost of this treatment, many institutions have adopted a low, fixed-dose regimen, with average doses lower than that in the package insert. The fixed-dose 4F-PCC strategy is supported by the available observational studies and case reports; however, the current body of literature is highly heterogenous. The purpose of this narrative review is to address the advantages and shortcomings with clinical use of fixed-dose 4F-PCC, as well as limitations of the available literature. The heterogeneity of the current literature should guide future studies to support or refute this potentially life-saving intervention.

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References

  1. Frontera JA, Lewin JJ 3rd, Rabinstein AA, Aisiku IP, Alexandrov AW, Cook AM, del Zoppo GJ, Kumar MA, Peerschke EI, Stiefel MF, Teitelbaum JS, Wartenberg KE, Zerfoss CL (2016) Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 24(1):6–46. https://doi.org/10.1007/s12028-015-0222-x

    Article  PubMed  CAS  Google Scholar 

  2. Kcentra (PC (2013) Concentrate (human)). CSL Behring, Marburg

    Google Scholar 

  3. Tomaselli GF, Mahaffey KW, Cuker A, Dobesh PP, Doherty JU, Eikelboom JW, Florido R, Hucker W, Mehran R, Messé SR, Pollack CV, Rodriguez F, Sarode R, Siegal D, Wiggins BS (2017) 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants. A report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 70(24):3042–3067. https://doi.org/10.1016/j.jacc.2017.09.1085

    Article  PubMed  Google Scholar 

  4. Yasaka M, Sakata T, Minematsu K, Naritomi H (2002) Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication. Thromb Res 108(1):25–30

    Article  PubMed  Google Scholar 

  5. Yasaka M, Oomura M, Ikeno K, Naritomi H, Minematsu K (2003) Effect of prothrombin complex concentrate on INR and blood coagulation system in emergency patients treated with warfarin overdose. Ann Hematol 82(2):121–123. https://doi.org/10.1007/s00277-002-0568-y

    Article  PubMed  CAS  Google Scholar 

  6. Yasaka M, Sakata T, Naritomi H, Minematsu K (2005) Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res 115(6):455–459. https://doi.org/10.1016/j.thromres.2004.09.002

    Article  PubMed  CAS  Google Scholar 

  7. van Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk ME, Schouten TJ, Ploeger B, Strengers PF (2006) Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: an open, prospective randomized controlled trial. Thromb Res 118(3):313–320. https://doi.org/10.1016/j.thromres.2005.08.005

    Article  PubMed  CAS  Google Scholar 

  8. Junagade P, Grace R, Gover P (2007) Fixed dose prothrombin complex concentrate for the reversal of oral anticoagulation therapy. Hematology 12(5):439–440. https://doi.org/10.1080/10245330701448529

    Article  PubMed  CAS  Google Scholar 

  9. Khorsand N, Veeger NJ, Muller M, Overdiek JW, Huisman W, van Hest RM, Meijer K (2011) Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy. Transfus Med 21(2):116–123. https://doi.org/10.1111/j.1365-3148.2010.01050.x

    Article  PubMed  CAS  Google Scholar 

  10. Khorsand N, Veeger NJ, van Hest RM, Ypma PF, Heidt J, Meijer K (2012) An observational, prospective, two-cohort comparison of a fixed versus variable dosing strategy of prothrombin complex concentrate to counteract vitamin K antagonists in 240 bleeding emergencies. Haematologica 97(10):1501–1506. https://doi.org/10.3324/haematol.2012.063701

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Wozniak M, Kruit A, Padmore R, Giulivi A, Bormanis J (2012) Prothrombin complex concentrate for the urgent reversal of warfarin. Assessment of a standard dosing protocol. Transfus Apher Sci 46(3):309–314. https://doi.org/10.1016/j.transci.2012.03.021

    Article  PubMed  Google Scholar 

  12. Varga C, Al-Touri S, Papadoukakis S, Caplan S, Kahn S, Blostein M (2013) The effectiveness and safety of fixed low-dose prothrombin complex concentrates in patients requiring urgent reversal of warfarin. Transfusion 53(7):1451–1458. https://doi.org/10.1111/j.1537-2995.2012.03924.x

    Article  PubMed  CAS  Google Scholar 

  13. Hirri HM, Green PJ (2014) Audit of warfarin reversal using a new Octaplex reduced dose protocol. Transfus Apher Sci 51(2):141–145. https://doi.org/10.1016/j.transci.2014.08.024

    Article  PubMed  CAS  Google Scholar 

  14. Klein L, Peters J, Miner J, Gorlin J (2015) Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med 33(9):1213–1218. https://doi.org/10.1016/j.ajem.2015.05.017

    Article  PubMed  Google Scholar 

  15. Abdoellakhan RA, Miah IP, Khorsand N, Meijer K, Jellema K (2017) Fixed versus variable dosing of prothrombin complex concentrate in vitamin K antagonist-related intracranial hemorrhage: a retrospective analysis. Neurocrit Care 26(1):64–69. https://doi.org/10.1007/s12028-016-0248-8

    Article  PubMed  CAS  Google Scholar 

  16. Astrup G, Sarangarm P, Burnett A (2017) Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis. J Thromb Thrombolysis. https://doi.org/10.1007/s11239-017-1586-x

    Article  Google Scholar 

  17. Dentali F, Marchesi C, Giorgi Pierfranceschi M, Crowther M, Garcia D, Hylek E, Witt DM, Clark NP, Squizzato A, Imberti D, Ageno W (2011) Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 106(3):429–438. https://doi.org/10.1160/th11-01-0052

    Article  PubMed  CAS  Google Scholar 

  18. Khorsand N, Kooistra HA, van Hest RM, Veeger NJ, Meijer K (2015) A systematic review of prothrombin complex concentrate dosing strategies to reverse vitamin K antagonist therapy. Thromb Res 135(1):9–19. https://doi.org/10.1016/j.thromres.2014.11.019

    Article  PubMed  CAS  Google Scholar 

  19. Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, Goldstein JN (2013) 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 128(11):1234–1243. https://doi.org/10.1161/circulationaha.113.002283

    Article  PubMed  CAS  Google Scholar 

  20. Goldstein JN, Thomas SH, Frontiero V, Joseph A, Engel C, Snider R, Smith EE, Greenberg SM, Rosand J (2006) Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 37(1):151–155. https://doi.org/10.1161/01.str.0000195047.21562.23

    Article  PubMed  Google Scholar 

  21. Mangram A, Oguntodu OF, Dzandu JK, Hollingworth AK, Hall S, Cung C, Rodriguez J, Yusupov I, Barletta JF (2016) Is there a difference in efficacy, safety, and cost-effectiveness between 3-factor and 4-factor prothrombin complex concentrates among trauma patients on oral anticoagulants? J Crit Care 33:252–256. https://doi.org/10.1016/j.jcrc.2016.02.018

    Article  PubMed  CAS  Google Scholar 

  22. Canadian Blood Services (2008) National advisory committee on blood and blood products: recommendations for use of Octaplex in Canada. Canadian Blood Services, Ottawa

    Google Scholar 

  23. Canadian Blood Services (2011) National Advisory committee on blood and blood products: recommendations for use of Prothombin Complex Concentrates in Canada. Canadian Blood Services, Ottawa

    Google Scholar 

  24. Canadian Blood Services (2014) National Advisory committee on blood and blood products: recommendations for use of Prothombin Complex Concentrates in Canada. Canadian Blood Services, Ottawa

    Google Scholar 

  25. Gorlin J, Kinney S, Fung MK, Tinmouth A (2017) Prothrombin complex concentrate for emergent reversal of warfarin: an international survey of hospital protocols. Vox Sang 112(6):595–597. https://doi.org/10.1111/vox.12539

    Article  PubMed  CAS  Google Scholar 

  26. Zemrak WR, Kelley E, Kovacic NL, Mooney DM, Morris JG, MacVane CZ, Rosenblatt JA (2016) Thrombotic complications following the administration of high-dose prothrombin complex concentrate for acute warfarin reversal. Am J Emerg Med 34(8):1736.e1731–1736.1733. https://doi.org/10.1016/j.ajem.2015.12.069

    Article  Google Scholar 

  27. Fixed versus variable dosing of 4-factor prothrombin complex concentrate for emergent warfarin reversal. https://ClinicalTrials.gov/show/NCT03064035. Accessed 15 Dec 2017

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Authors and Affiliations

  1. Department of Pharmacy, HonorHealth John C. Lincoln Medical Center, 250 E. Dunlap, Phoenix, AZ, 85020, USA

    Scott T. Hall & Kyle C. Molina

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  1. Scott T. Hall
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  2. Kyle C. Molina
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Correspondence to Kyle C. Molina.

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Hall, S.T., Molina, K.C. Fixed-dose 4-factor prothrombin complex concentrate: we don’t know where we’re going if we don’t know how to get there. J Thromb Thrombolysis 46, 50–57 (2018). https://doi.org/10.1007/s11239-018-1653-y

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  • DOI: https://doi.org/10.1007/s11239-018-1653-y

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