Prothrombin complex concentrate

Prothrombin complex concentrate
Combination of
Factor IIBlood clotting factor
Factor VIIBlood clotting factor
Factor IXBlood clotting factor
Factor XBlood clotting factor
Clinical data
Trade namesKcentra, others
Other namesfactor IX complex
AHFS/Drugs.comMonograph
Monograph
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank

Prothrombin complex concentrate (PCC), also known as factor IX complex, sold under the brand name Kcentra among others, is a combination medication made up of blood clotting factors II, IX, and X[9](3-factor PCC) or, when also containing factor VII as does Kcentra, 4-factor PCC.[10] It is used to treat and prevent bleeding in hemophilia B if pure factor IX is not available.[9][11] It may also be used for reversal of warfarin therapy.[11] It is given by slow injection into a vein.[9] Another product, activated prothrombin complex concentrate or FEIBA (Factor Eight Inhibitor Bypassing Agent), may be used for acquired hemophilia.[12]

Common side effects include allergic reactions, headache, vomiting, and sleepiness.[9][13] Other serious side effects include blood clots which may result in a heart attack, stroke, pulmonary embolism, or deep vein thrombosis.[13] Antibodies may form after long term use such that future doses are less effective.[11]

Prothrombin complex concentrate came into medical use in the 1960s.[14] It is on the World Health Organization's List of Essential Medicines.[15][16] It is made from human plasma.[13] Recombinant factor IX is also available in a stand-alone preparation.[17]

Medical uses

Prothrombin complex concentrate reverses the effects of warfarin and other vitamin K antagonist anti-coagulants and is used in cases of significant bleeding in people with a coagulopathy. It is also used when such a person must undergo an emergency operation.[18] Other uses include a deficiency of one of the included clotting factors, either congenital or due to liver disease, and hemophilia.[18] Several guidelines, including those from the American College of Chest Physicians, recommend prothrombin complex concentrate for warfarin reversal in people with serious bleeding.[19][20][21][22]

For rapid anticoagulation reversal for surgery, four-factor prothrombin complex concentrate reduces international normalized ratio (INR) and decreases bleeding during surgery when compared with administration of fresh frozen plasma. No differences in thromboembolic event was found.[23]

Contraindications

Platelet factor 4 can cause heparin-induced thrombocytopenia.

The package insert states that prothrombin complex concentrate is contraindicated in patients with disseminated intravascular coagulation, a pathological activation of coagulation,[24] because giving clotting factors would only further fuel this process. However, if the PCC is given because factor levels are low, it can restore normal coagulation. As PCC products contain heparin, they are contraindicated in patients with heparin-induced thrombocytopenia.[24]

Chemistry

Prothrombin complex concentrate contains a number of blood clotting factors. Typically this includes factor II, IX, and X.[9] Some versions also contain factor VII, protein C, and protein S.[10][24] Heparin may be added to stop early activation of the factors.[10]

History

The US Food and Drug Administration (FDA) announced its approval in 2013.[25] The FDA approved Kcentra's orphan drug status in December 2012.[25][26]

Society and culture

Economics

In the United States a dose of prothrombin complex concentrate costs about US $3200[27] though one study described the cost as $11 650.[28] The Australian National Blood Authority sets Prothrombinex (500 IU) at around AUD$327. [29]

Brand names

A number of different formulations are available globally.[30]

References

  1. ^ CSL Behring Canada 2019
  2. ^ "Blood health (non-cancer)". Health Canada. 11 May 2018. Retrieved 13 April 2024.
  3. ^ "Regulatory Decision Summary for Rebinyn". Drug and Health Products Portal. 29 November 2017. Retrieved 13 April 2024.
  4. ^ "Beriplex P/N 250 IU - Summary of Product Characteristics (SmPC)". (emc). 27 January 2021. Retrieved 7 May 2023.
  5. ^ "Kcentra (Prothrombin Complex Concentrate, Human)". U.S. Food and Drug Administration (FDA). 3 May 2023. Retrieved 7 May 2023.
  6. ^ "Balfaxar (prothrombin complex concentrate- human powder, for solution". DailyMed. U.S. National Library of Medicine. 21 July 2023. Retrieved 25 August 2023.
  7. ^ "Balfaxar". U.S. Food and Drug Administration (FDA). 21 July 2023. Retrieved 25 August 2023.
  8. ^ "Active substance: human prothrombin complex" (PDF). List of nationally authorised medicinal products. European Medicines Agency. January 2017. EMA/45481/2017, PSUSA/00001638/201604.
  9. ^ a b c d e World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 259–60. hdl:10665/44053. ISBN 978-92-4-154765-9. OCLC 609852935.
  10. ^ a b c Wilson MD, Davis JE (2014). "Antithrombotic Reversal Agents". In Perkins JC (ed.). Hematology/Oncology Emergencies. Emergency Medicine Clinics of North America. Vol. 3. Elsevier. p. 720. ISBN 978-0-323-32029-0. OCLC 893676529.
  11. ^ a b c British national formulary : BNF 69 (69th ed.). British Medical Association. 2015. p. 171. ISBN 978-0-85711-156-2. OCLC 910448191.
  12. ^ Negrier C, Voisin S, Baghaei F, Numerof R, Novack A, Doralt JE, et al. (July 2016). "Global Post-Authorization Safety Surveillance Study: real-world data on prophylaxis and on-demand treatment using FEIBA (an activated prothrombin complex concentrate)". Blood Coagul Fibrinolysis. 27 (5): 551–6. doi:10.1097/MBC.0000000000000525. PMC 4935538. PMID 26829366.
  13. ^ a b c "Factor IX (Human), Factor IX Complex (Human)". The American Society of Health-System Pharmacists. Archived from the original on 24 September 2017. Retrieved 8 December 2016.
  14. ^ Besa EC (1992). "Clinical Aspects of Transfusion Therapy". Hematology. Lippincott Williams & Wilkins. p. 276. ISBN 978-0-683-06222-9. OCLC 1175934487.
  15. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06.
  16. ^ World Health Organization (2015). The selection and use of essential medicines. Twentieth report of the WHO Expert Committee 2015 (including 19th WHO Model List of Essential Medicines and 5th WHO Model List of Essential Medicines for Children). Vol. 994. Geneva: World Health Organization. p. 510. hdl:10665/189763. ISBN 978-92-4-120994-6. ISSN 0512-3054. WHO technical report series.
  17. ^ "Factor IX (Recombinant)". The American Society of Health-System Pharmacists. Archived from the original on 24 September 2017. Retrieved 8 December 2016.
  18. ^ a b Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Cofact.
  19. ^ "ACCP 2012 guidelines: 'Evidence-Based Management of Anticoagulant Therapy, Section 9.3 Treatment of Anticoagulant-Related Bleeding'". Chest. Archived from the original on 3 July 2013.
  20. ^ Haemostasis and Thrombosis Task Force for the British Committee for Standards in Haematology (May 1998). "Guidelines on oral anticoagulation: 3rd edition". Br J Haematol. 101 (2): 374–387. doi:10.1046/j.1365-2141.1998.00715.x. PMID 9609538.
  21. ^ Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM (November 2004). "Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis". The Medical Journal of Australia. 181 (9): 492–7. doi:10.5694/j.1326-5377.2004.tb06407.x. PMID 15516194. S2CID 3035209.
  22. ^ Palareti G (1998). "A guide to oral anticoagulant therapy. Italian Federation of Anticoagulation Clinics". Haemostasis. 28 (Suppl 1): 1–46. doi:10.1159/000054103. PMID 9820837. S2CID 202659825.
  23. ^ Levy JH, Douketis J, Steiner T, Goldstein JN, Milling TJ (December 2018). "Prothrombin Complex Concentrates for Perioperative Vitamin K Antagonist and Non-vitamin K Anticoagulant Reversal". Anesthesiology. 129 (6): 1171–1184. doi:10.1097/ALN.0000000000002399. PMC 6234087. PMID 30157037.
  24. ^ a b c "Kcentra- prothrombin, coagulation factor vii human, coagulation factor ix human, coagulation factor x human, protein c, protein s human, and water kit". DailyMed. U.S. National Library of Medicine. 22 October 2018. Retrieved 21 April 2020.
  25. ^ a b "CSL Behring Receives FDA Approval of Kcentra for Urgent Warfarin Reversal in Patients with Acute Major Bleeding" (Press release). CSL Behring. 29 April 2013. Retrieved 7 May 2023.
  26. ^ "CSL Behring's Kcentra Receives FDA Approval For Use In Warfarin Reversal In Patients Undergoing Surgery" (Press release). CSL Behring. 13 December 2013. Archived from the original on 6 October 2016. Retrieved 5 October 2016.
  27. ^ Fasanya C, Arrillaga A, Caronia C, Rothburd L, Japhe T, Hahn Y, et al. (2024). "Use of Andexanet Alfa for Factor Xa Inhibitor Reversal in US Verified Trauma Centers: A National Survey". Clin Appl Thromb Hemost. 30: 10760296241238013. doi:10.1177/10760296241238013. PMC 10946067. PMID 38494906.
  28. ^ Irizarry-Gatell VM, Bacchus MW, De Leo EK, Zhang Y, Lagasse CA, Khanna AY, et al. (April 2024). "The use of andexanet alfa vs. 4-factor prothrombin complex concentrates in the setting of life-threatening intracranial hemorrhage". Blood Coagul Fibrinolysis. 35 (3): 94–100. doi:10.1097/MBC.0000000000001279. PMID 38358898.
  29. ^ "What Blood Products are Supplied". National Product Price List. Australian National Blood Authority. Retrieved 18 January 2024.
  30. ^ Miller RD, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Cohen NH, Young WL (2014). "63. Patient Blood Management: Autologous Blood Procurement, Recombinant Factor Vila Therapy, and Blood Utilization § Prothrombin Complex Concentrates". Miller's Anesthesia (8th ed.). Elsevier. p. 1892. ISBN 978-0-323-28011-2. OCLC 892338436.

Further reading