prothrombin complex concentrate

{{Infobox drug

| type = combo

| component1 = Factor II

| class1 = Blood clotting factor

| component2 = Factor VII

| class2 = Blood clotting factor

| component3 = Factor IX

| class3 = Blood clotting factor

| component4 = Factor X

| class4 = Blood clotting factor

| tradename = Kcentra, others

| Drugs.com = {{Drugs.com|monograph|factor-ix-human-factor-ix-complex-human}}
{{drugs.com|monograph|factor-ix-recombinant}}

| MedlinePlus =

| DailyMedID = Kcentra

| pregnancy_AU =

| pregnancy_AU_comment =

| pregnancy_category =

| routes_of_administration = Intravenous

| ATC_prefix = B02

| ATC_suffix = BD01

| ATC_supplemental = {{ATC|B02|BD04}}

| biosimilars =

| legal_AU =

| legal_AU_comment =

| legal_BR =

| legal_BR_comment =

| legal_CA = Rx-only

| legal_CA_comment = {{harvnb|CSL Behring Canada|2019}}{{cite web | title=Blood health (non-cancer) |publisher=Health Canada | date=11 May 2018 | url=https://www.canada.ca/en/services/health/drug-health-products/drug-medical-device-highlights-2017/approved-drugs/blood-health-non-cancer.html | access-date=13 April 2024}}{{cite web | title=Regulatory Decision Summary for Rebinyn | website=Drug and Health Products Portal | date=29 November 2017 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS00310 | access-date=13 April 2024}}

| legal_DE =

| legal_DE_comment =

| legal_NZ =

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment = {{cite web | title=Beriplex P/N 250 IU - Summary of Product Characteristics (SmPC) | website=(emc) | date=27 January 2021 | url=https://www.medicines.org.uk/emc/product/6354/smpc | access-date=7 May 2023}}

| legal_US = Rx-only

| legal_US_comment = {{cite web | title=Kcentra (Prothrombin Complex Concentrate, Human) | website=U.S. Food and Drug Administration (FDA) | date=3 May 2023 | url=https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/kcentra | access-date=7 May 2023}}{{cite web | title=Balfaxar (prothrombin complex concentrate- human powder, for solution | work = DailyMed | publisher = U.S. National Library of Medicine | date=21 July 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68fa4f90-8b01-6498-4140-e0be5247c3fe | access-date=25 August 2023}}{{cite web | title=Balfaxar | website=U.S. Food and Drug Administration (FDA) | date=21 July 2023 | url=https://www.fda.gov/vaccines-blood-biologics/balfaxar | access-date=25 August 2023}}

| legal_EU = Rx-only

| legal_EU_comment = {{cite web |title=Active substance: human prothrombin complex |date=January 2017 |work=List of nationally authorised medicinal products |publisher=European Medicines Agency |id=EMA/45481/2017, PSUSA/00001638/201604 |url=https://www.ema.europa.eu/en/documents/psusa/human-prothrombin-complex-list-nationally-authorised-medicinal-products-psusa/00001638/201604_en.pdf}}

| legal_UN =

| legal_UN_comment =

| legal_status = Rx-only

| CAS_number = 37224-63-8

| CAS_supplemental =

| PubChem =

| IUPHAR_ligand =

| DrugBank = DB11330

| DrugBank2 = DB13152

| ChemSpiderID =

| UNII =

| KEGG =

| ChEBI =

| ChEMBL =

| synonyms = factor IX complex

}}

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(3-factor PCC) or, when also containing factor VII as does Kcentra, 4-factor PCC.{{cite book| vauthors = Wilson MD, Davis JE |chapter = Antithrombotic Reversal Agents | veditors = Perkins JC |title=Hematology/Oncology Emergencies |series=Emergency Medicine Clinics of North America |volume=3 |issue=3 |oclc=893676529 |date=2014|publisher=Elsevier |isbn=978-0-323-32029-0|page=720| chapter-url={{GBurl|rR04BAAAQBAJ|p=720}} }} It is used to treat and prevent bleeding in hemophilia B if pure factor IX is not available. It may also be used for reversal of warfarin therapy.{{cite book|title=British national formulary : BNF 69|date=2015|publisher=British Medical Association|isbn=978-0-85711-156-2|page=171|edition=69th |oclc=910448191}} It is given by slow injection into a vein.{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 978-92-4-154765-9 | author = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free |pages=259–60 |oclc=609852935}} Another product, activated prothrombin complex concentrate or FEIBA (Factor Eight Inhibitor Bypassing Agent), may be used for acquired hemophilia.{{cite journal |vauthors=Negrier C, Voisin S, Baghaei F, Numerof R, Novack A, Doralt JE, Romanov V, Gringeri A |title=Global Post-Authorization Safety Surveillance Study: real-world data on prophylaxis and on-demand treatment using FEIBA (an activated prothrombin complex concentrate) |journal=Blood Coagul Fibrinolysis |volume=27 |issue=5 |pages=551–6 |date=July 2016 |pmid=26829366 |pmc=4935538 |doi=10.1097/MBC.0000000000000525 }}

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

Prothrombin complex concentrate came into medical use in the 1960s.{{cite book| vauthors = Besa EC | chapter = Clinical Aspects of Transfusion Therapy |title=Hematology |date=1992 |publisher=Lippincott Williams & Wilkins |isbn=978-0-683-06222-9 |oclc=1175934487|page=276| chapter-url ={{GBurl|rR04BAAAQBAJ|p=720}} }} It is on the World Health Organization's List of Essential Medicines.{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06 | hdl-access=free }}{{cite book | vauthors = ((World Health Organization)) | year = 2015 | title = 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) | publisher = World Health Organization | location = Geneva | author-link = World Health Organization | hdl = 10665/189763 | id = WHO technical report series |volume=994 | hdl-access=free | isbn = 978-92-4-120994-6 | issn = 0512-3054 | page=510 }} It is made from human plasma.{{cite web|title=Factor IX (Human), Factor IX Complex (Human)|url=https://www.drugs.com/monograph/factor-ix-human-factor-ix-complex-human.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20170924045854/https://www.drugs.com/monograph/factor-ix-human-factor-ix-complex-human.html|archive-date=24 September 2017}} Recombinant factor IX is also available in a stand-alone preparation.{{cite web|title=Factor IX (Recombinant)|url=https://www.drugs.com/monograph/factor-ix-recombinant.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20170924093004/https://www.drugs.com/monograph/factor-ix-recombinant.html|archive-date=24 September 2017}}

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.{{cite book|title=Austria-Codex|at=Cofact|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2015|language=de}} Other uses include a deficiency of one of the included clotting factors, either congenital or due to liver disease, and hemophilia. Several guidelines, including those from the American College of Chest Physicians, recommend prothrombin complex concentrate for warfarin reversal in people with serious bleeding.{{cite web|title=ACCP 2012 guidelines: 'Evidence-Based Management of Anticoagulant Therapy, Section 9.3 Treatment of Anticoagulant-Related Bleeding'|url=http://journal.publications.chestnet.org/article.aspx?articleid=1159453|archive-url=https://archive.today/20130703233657/http://journal.publications.chestnet.org/article.aspx?articleid=1159453|url-status=dead|archive-date=2013-07-03|work=Chest}}{{cite journal |author=((Haemostasis and Thrombosis Task Force for the British Committee for Standards in Haematology)) |title=Guidelines on oral anticoagulation: 3rd edition |journal=Br J Haematol |volume=101 |issue=2 |pages=374–387 |date=May 1998 |doi=10.1046/j.1365-2141.1998.00715.x |pmid=9609538 }}{{cite journal | vauthors = Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM | title = Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis | journal = The Medical Journal of Australia | volume = 181 | issue = 9 | pages = 492–7 | date = November 2004 | doi = 10.5694/j.1326-5377.2004.tb06407.x | pmid = 15516194 | s2cid = 3035209 }}{{cite journal | vauthors = Palareti G | title = A guide to oral anticoagulant therapy. Italian Federation of Anticoagulation Clinics | journal = Haemostasis | volume = 28 | pages = 1–46 | year = 1998 | issue = Suppl 1 | pmid = 9820837 | doi = 10.1159/000054103 | s2cid = 202659825 |url=https://karger.com/pht/article-abstract/28/Suppl.%201/1/155259/A-Guide-to-Oral-Anticoagulant-Therapy?redirectedFrom=fulltext| url-access = subscription }}

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.{{cite journal | vauthors = Levy JH, Douketis J, Steiner T, Goldstein JN, Milling TJ | title = Prothrombin Complex Concentrates for Perioperative Vitamin K Antagonist and Non-vitamin K Anticoagulant Reversal | journal = Anesthesiology | volume = 129 | issue = 6 | pages = 1171–1184 | date = December 2018 | pmid = 30157037 | pmc = 6234087 | doi = 10.1097/ALN.0000000000002399 }}

Contraindications

File:PBB Protein PF4 image.jpg.]]

The package insert states that prothrombin complex concentrate is contraindicated in patients with disseminated intravascular coagulation, a pathological activation of coagulation,{{cite web | title=Kcentra- prothrombin, coagulation factor vii human, coagulation factor ix human, coagulation factor x human, protein c, protein s human, and water kit | work = DailyMed | publisher = U.S. National Library of Medicine | date=22 October 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eee1afb8-324c-42e4-8bf0-f0c9da5e6d42 | access-date=21 April 2020}} 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.

Chemistry

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

History

The US Food and Drug Administration (FDA) announced its approval in 2013.{{cite press release | title=CSL Behring Receives FDA Approval of Kcentra for Urgent Warfarin Reversal in Patients with Acute Major Bleeding | publisher=CSL Behring | date=29 April 2013 | url=https://newsroom.csl.com/2013-04-29-CSL-Behring-Receives-FDA-Approval-of-Kcentra-TM-for-Urgent-Warfarin-Reversal-in-Patients-with-Acute-Major-Bleeding | access-date=7 May 2023}} The FDA approved Kcentra's orphan drug status in December 2012.{{cite press release |url=https://newsroom.csl.com/CSL-Behrings-Kcentra-R-Receives-FDA-Approval-For-Use-In-Warfarin-Reversal-In-Patients-Undergoing-Surgery |title=CSL Behring's Kcentra Receives FDA Approval For Use In Warfarin Reversal In Patients Undergoing Surgery |publisher=CSL Behring|date=13 December 2013|url-status=live|archive-url=https://web.archive.org/web/20161006060102/http://www.cslbehring.com/newsroom/Kcentra-Earns-FDA-Approval-for-Use-in-Patients-Undergoing-Surgery?tabSelections=1255923338766¤tPage=1|archive-date=6 October 2016|access-date=5 October 2016 }}

Society and culture

= Economics =

In the United States a dose of prothrombin complex concentrate costs about US $3200{{cite journal |vauthors=Fasanya C, Arrillaga A, Caronia C, Rothburd L, Japhe T, Hahn Y, Joseph P, Reci D, Eckardt P |title=Use of Andexanet Alfa for Factor Xa Inhibitor Reversal in US Verified Trauma Centers: A National Survey |journal=Clin Appl Thromb Hemost |volume=30 |issue= |pages=10760296241238013 |date=2024 |pmid=38494906 |pmc=10946067 |doi=10.1177/10760296241238013 }} though one study described the cost as $11 650.{{cite journal |vauthors=Irizarry-Gatell VM, Bacchus MW, De Leo EK, Zhang Y, Lagasse CA, Khanna AY, Harris NS, Zumberg MS |title=The use of andexanet alfa vs. 4-factor prothrombin complex concentrates in the setting of life-threatening intracranial hemorrhage |journal=Blood Coagul Fibrinolysis |volume=35 |issue=3 |pages=94–100 |date=April 2024 |pmid=38358898 |doi=10.1097/MBC.0000000000001279 }} The Australian National Blood Authority sets Prothrombinex (500 IU) at around AUD$327. {{Cite web |title=What Blood Products are Supplied |work=National Product Price List |publisher=Australian National Blood Authority |url=https://blood.gov.au/national-product-price-list |access-date=2024-01-18 }}

=Brand names=

A number of different formulations are available globally.{{cite book| vauthors = Miller RD, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Cohen NH, Young WL |title=Miller's Anesthesia|date=2014|publisher=Elsevier |isbn=978-0-323-28011-2|page=1892|edition=8th |chapter=63. Patient Blood Management: Autologous Blood Procurement, Recombinant Factor Vila Therapy, and Blood Utilization § Prothrombin Complex Concentrates |chapter-url={{GBurl|L2ckBQAAQBAJ|pg=RA1-PA91}} |oclc=892338436}}