Prothrombin complex concentrate

Last updated

Prothrombin complex concentrate
Combination of
Factor II Blood clotting factor
Factor VII Blood clotting factor
Factor IX Blood clotting factor
Factor X Blood clotting factor
Clinical data
Trade names Kcentra, others
Other namesfactor IX complex
AHFS/Drugs.com Monograph
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]

Contents

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. PBB Protein PF4 image.jpg
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]

Related Research Articles

<span class="mw-page-title-main">Anticoagulant</span> Class of drugs

An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which help keep the bite area unclotted long enough for the animal to obtain blood.

<span class="mw-page-title-main">Coagulation</span> Process of formation of blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

<span class="mw-page-title-main">Warfarin</span> Anticoagulant medication

Warfarin is an anticoagulant used as a medication under several brand names including Coumadin. While the drug is described as a "blood thinner", it does not reduce viscosity but rather inhibits coagulation. Accordingly, it is commonly used to prevent blood clots in the circulatory system such as deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who have atrial fibrillation, valvular heart disease, or artificial heart valves. Less commonly, it is used following ST-segment elevation myocardial infarction (STEMI) and orthopedic surgery. It is usually taken by mouth, but may also be administered intravenously.

<span class="mw-page-title-main">Thrombin</span> Enzyme involved in blood coagulation in humans

Prothrombin is encoded in the human by the F2 gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin.

<span class="mw-page-title-main">Prothrombin time</span> Blood test that evaluates clotting

The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the extrinsic pathway and common pathway of coagulation. This blood test is also called protime INR and PT/INR. They are used to determine the clotting tendency of blood, in such things as the measure of warfarin dosage, liver damage, and vitamin K status. PT measures the following coagulation factors: I (fibrinogen), II (prothrombin), V (proaccelerin), VII (proconvertin), and X.

<span class="mw-page-title-main">Factor VII</span> Mammalian protein found in humans

Coagulation factor VII is a protein involved in coagulation and, in humans, is encoded by gene F7. It is an enzyme of the serine protease class. Once bound to tissue factor released from damaged tissues, it is converted to factor VIIa, which in turn activates factor IX and factor X.

<span class="mw-page-title-main">Factor X</span> Mammalian protein found in Homo sapiens

Coagulation factor X, or Stuart factor, is an enzyme of the coagulation cascade, encoded in humans by F10 gene. It is a serine endopeptidase. Factor X is synthesized in the liver and requires vitamin K for its synthesis.

<span class="mw-page-title-main">Factor V</span> Mammalian protein found in humans

Coagulation factor V, also less commonly known as proaccelerin or labile factor, is a protein involved in coagulation, encoded, in humans, by F5 gene. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Factor V deficiency leads to predisposition for hemorrhage, while some mutations predispose for thrombosis.

<span class="mw-page-title-main">Argatroban</span> Pharmaceutical drug

Argatroban is an anticoagulant that is a small molecule direct thrombin inhibitor. In 2000, argatroban was licensed by the US Food and Drug Administration (FDA) for prophylaxis or treatment of thrombosis in people with heparin-induced thrombocytopenia (HIT). In 2002, it was approved for use during percutaneous coronary interventions in people who have HIT or are at risk for developing it. In 2012, it was approved by the UK Medicines and Healthcare products Regulatory Agency for anticoagulation in people with heparin-induced thrombocytopenia Type II (HIT) who require parenteral antithrombotic therapy.

<span class="mw-page-title-main">Fresh frozen plasma</span> Liquid portion of whole blood

Fresh frozen plasma (FFP) is a blood product made from the liquid portion of whole blood. It is used to treat conditions in which there are low blood clotting factors or low levels of other blood proteins. It may also be used as the replacement fluid in plasma exchange. Using ABO compatible plasma, while not required, may be recommended. Use as a volume expander is not recommended. It is administered by slow injection into a vein.

<span class="mw-page-title-main">Rivaroxaban</span> Anticoagulant drug

Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication used to treat and prevent blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery. It is taken by mouth.

<span class="mw-page-title-main">Warfarin necrosis</span> Medical condition

Warfarin-induced skin necrosis is a condition in which skin and subcutaneous tissue necrosis occurs due to acquired protein C deficiency following treatment with anti-vitamin K anticoagulants.

<span class="mw-page-title-main">Dabigatran</span> Anticoagulant medication

Dabigatran, sold under the brand name Pradaxa among others, is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation. Specifically it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. It is used as an alternative to warfarin and does not require monitoring by blood tests. In a meta analysis of 7 different studies, there was no benefit of dabigatran over warfarin in preventing ischemic stroke; however, dabigatran were associated with a lower hazard for intracranial bleeding compared with warfarin, but also had a higher risk of gastrointestinal bleeding relative to warfarin. It is taken by mouth.

Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis. Pregnancy itself is a factor of hypercoagulability, as a physiologically adaptive mechanism to prevent post partum bleeding. However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.

Direct factor Xa inhibitors (xabans) are anticoagulants, used to both treat and prevent blood clots in veins, and prevent stroke and embolism in people with atrial fibrillation (AF).

<span class="mw-page-title-main">Vitamin K reaction</span> Medical condition

Vitamin K reactions are adverse side effects that may occur after injection with vitamin K. The liver utilizes vitamin K to produce coagulation factors that help the body form blood clots which prevent excessive bleeding. Vitamin K injections are administered to newborns as a preventative measure to reduce the risk of hemorrhagic disease of the newborn (HDN).

<span class="mw-page-title-main">Edoxaban</span> Anticoagulant medication

Edoxaban, sold under the brand name Lixiana among others, is an anticoagulant medication and a direct factor Xa inhibitor. It is taken by mouth.

<span class="mw-page-title-main">Apixaban</span> Anticoagulant medication

Apixaban, sold under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor Xa. Specifically, it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. It is used as an alternative to warfarin and does not require monitoring by blood tests or dietary restrictions. It is taken by mouth.

Prothrombin G20210A is a genetic condition that increases the risk of blood clots including from deep vein thrombosis, and of pulmonary embolism. One copy of the mutation increases the risk of a blood clot from 1 in 1,000 per year to 2.5 in 1,000. Two copies increases the risk to up to 20 in 1,000 per year. Most people never develop a blood clot in their lifetimes.

Direct thrombin inhibitors (DTIs) are a class of anticoagulant drugs that can be used to prevent and treat embolisms and blood clots caused by various diseases. They inhibit thrombin, a serine protease which affects the coagulation cascade in many ways. DTIs have undergone rapid development since the 90's. With technological advances in genetic engineering the production of recombinant hirudin was made possible which opened the door to this new group of drugs. Before the use of DTIs the therapy and prophylaxis for anticoagulation had stayed the same for over 50 years with the use of heparin derivatives and warfarin which have some well known disadvantages. DTIs are still under development, but the research focus has shifted towards factor Xa inhibitors, or even dual thrombin and fXa inhibitors that have a broader mechanism of action by both inhibiting factor IIa (thrombin) and Xa. A recent review of patents and literature on thrombin inhibitors has demonstrated that the development of allosteric and multi-mechanism inhibitors might lead the way to a safer anticoagulant.

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. 1 2 3 4 5 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. 1 2 3 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. 1 2 3 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. 1 2 3 "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. 1 2 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 (inactive 1 July 2024). PMID   9820837. S2CID   202659825.{{cite journal}}: CS1 maint: DOI inactive as of July 2024 (link)
  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. 1 2 3 "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. 1 2 "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