This section is intended to provide general information on products that may be indicated for use in patients with certain congenital or acquired bleeding disorders. Suggested treatment options are also included for patients on warfarin or direct oral anticoagulant (DOAC) when there is active bleeding or need for urgent/emergent invasive procedures.

Consult pharmacy services at your institution for information about drug availability, dosage and routes for administration. Any off-label use of products must be reviewed and determined by each institution. Consider consultation with hematologist or other specialist as appropriate for treatment options and dosing.

There are multiple factor concentrates available for use in treatment of patients with bleeding disorders. Selected factor concentrate products are listed below and may be available through Versiti Drug Distribution Services in Wisconsin and Illinois.

Management of Patients with Supratherapeutic INR

Warfarin Reversal

Warfarin mechanism of action: inhibits the synthesis of vitamin K-dependent clotting factors II, VII, IX, and X and the anticoagulant proteins C and S. Half-life: 20 to 60 hours (mean ~ 40 hours). Refer to package insert.

Therapeutic management of hypocoagulability due to warfarin is based on the INR and presence of active bleeding. Refer to Table 1.

Table 1: Suggested Management of Supratherapeutic INR

4-Factor Prothrombin Complex Concentrate (4F-PCC) (Kcentra®)

Indications:

Urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with acute major bleeding or need for urgent surgery or other invasive procedure.

Dosing:

• Fixed dosing of 1000-1500 units, found to be safe, effective, and more efficient for rapid reversal of Warfarin anticoagulation.
• Calculation based on INR result at presentation and body weight; typical dose for INR >6 is 50 units/kg body weight.

Comments:

Four-factor PCC should be used with caution in patients with chronic or advanced liver disease, and if used, conservative dosing applied since thromboembolic events have been identified.

Management of Patients on Direct Oral Anticoagulant (DOAC) Medication

Reversal Agents – See Table 2

Typically used in the setting of clinically relevant major or life-threatening bleeding or for emergent/urgent surgery or procedures.

Comments:

• If specific reversal agent is not available, 4F-PCC (i.e., 2000 units) may be an effective alternative for treatment of major bleeding associated with Factor Xa inhibitors.
• Plasma will NOT reverse the effects of these direct oral anticoagulant medications (DOAC).

Table 2: Direct Oral Anticoagulant Reversal Agents

References:

1. Tiede A, Collins P, Knoebl P, et al. International recommendations on the diagnosis and treatment of acquired hemophilia A. Haematologica. 2020;105(7):1791-1801. https://www.haematologica.org/article/view/9931
2. National Advisory Committee on Blood and Blood Products – NAC Statement on Fibrinogen Concentrate Use in Acquired Hypofibrinogenemia. V: 20210126. Available at: https://www.nacblood.ca/resources/guidelines/downloads/2021%20FC%20Statement%20Update20210310.pdf
3. Levy JH, Goodnough LT. How I use fibrinogen replacement therapy in acquired bleeding. Blood 2015; 125(9):1387-1393. https://doi.org/10.1182/blood-2014-08-552000
4. Cushing MM, Haas T, Karkouti K, Callum J. Which is the preferred blood product for fibrinogen replacement in the bleeding patient with acquired hypofibrinogenemia - cryoprecipitate or fibrinogen concentrate? Transfusion 2020; 60:S17-S23. https://doi.org/10.1111/trf.15614
5. MASAC Document 257 - Guidelines for Emergency Department Management of Individuals with Hemophilia and Other Bleeding Disorders. December 5, 2019. Available at: https://www.hemophilia.org/Researchers-HealthcareProviders/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/Guidelines-for-EmergencyDepartment-Management-of-Individuals-with-Hemophilia-and-Other-Bleeding-Disorders
6. Holbrook A, Shulman S, Witt DM et al. Evidence-based management of anticoagulant therapy. CHEST 2021;14(2): e152S - e184S. https://doi.org/10.1378/chest.11-2295
7. Tomaselli GF (Chair), Mahaffey KW (Vice chair). 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants. J Am Coll Cardiol 2020; 76(5): 594-622. https://doi.org/10.1016/j.jacc.2020.04.053
8. Rhoney DH, Chester KW, Darsey DA. Optimal dosage and administration practices for vitamin K antagonist reversal with 4-factor prothrombin complex concentrate. Clin Appl Thromb Hemost. 2020 Jan-Dec;26:1076029620947474. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573754/
9. Jansma B, Montgomery J, Dietrich S, et al. Emergent warfarin reversal with fixed-dose 4-factor prothrombin complex concentrate. Annals of Pharmacotherapy. 2020;54(11):1090–1095. https://pubmed.ncbi.nlm.nih.gov/32418445/
10. Huang, W-T, Cang WC, Derry KL et al. Four-factor prothrombin complex concentrate for coagulopathy reversal in patients with liver disease. Clin Appl Thromb Hemost 2017;23(8):1028-1035. https://journals.sagepub.com/doi/10.1177/1076029616668406
11. Drebes A., de Vos M., Gill S., et al. Prothrombin complex concentrates for coagulopathy in liver disease: single-center, clinical experience in 105 patients. Hepatology Communications. 2019;3:513-524. https://doi.org/10.1002/hep4.1293
12. O’Leary JG, Greenberg CS, Patton HM, Caldwell SH. AGA Clinical Practice Update: Coagulation in Cirrhosis. Gastroenterology 2019;157:34-43. https://www.sciencedirect.com/science/article/pii/S001650851935694X?via%3Dihub
13. Cuker A, Burnett A, Triller D, et al. Reversal of direct oral anticoagulants: Guidance from Anticoagulation Forum. Am J Hematology 2019;94(6):697-709. https://doi.org/10.1002/ajh.25475
14. Desaia NR, Cornutt D. Reversal agents for direct oral anticoagulants: considerations for hospital physicians and intensivists. Hospital Practice. 2019;47(3):113-122.

Additional Resources:

1. National Hemophilia Foundation https://www.hemophilia.org/
2. National Organization of Rare Diseases https://rarediseases.org/rare-diseases/acquired-hemophilia/
3. Treat the Bleed (website) Canada https://treatthebleed.org/

Medication Package Inserts

1. Kogenate^®FS (Bayer) https://www.kogenatefs.com/home/prescribing-information
2. Hemofil M (Takeda) https://www.shirecontent.com/PI/PDFs/HEMOFILM_USA_ENG.pdf
3. ELOCTATE (Bioverativ Therapeutics) https://products.sanofi.us/Eloctate/Eloctate.pdf
4. JIVI^® (Bayer HealthCare LLC) https://labeling.bayerhealthcare.com/html/products/pi/Jivi_PI.pdf
5. DDAVP (Desmopressin) Injection https://products.sanofi.us/ddavp_iv/ddavp_iv.pdf
6. BeneFIX^® (Pfizer) http://labeling.pfizer.com/showlabeling.aspx?id=492
7. Rixubis^® (Shire) https://www.shirecontent.com/PI/PDFs/RIXUBIS_USA_ENG.pdf
8. Alprobix (Bioverativ Therapeutics/Sanofi US) https://products.sanofi.us/Alprolix/alprolix.html
9. Kcentra^® package insert. CSL Behring, Marburg Germany, October 2018. https://labeling.cslbehring.com/PI/US/Kcentra/EN/Kcentra-Prescribing-Information.pdf
10. Humate-P^® (CSL Behring) https://labeling.cslbehring.com/PI/US/Humate-P/EN/Humate-P-Prescribing-Information.pdf
11. Wilate^® (Octapharma) https://www.wilateusa.com/wp-content/uploads/2019/10/20190923_pil_18x_USA_26.pdf
12. Vonvendi^® (Takeda) https://www.shirecontent.com/PI/PDFs/VONVENDI_USA_ENG.pdf
13. FEIBA (Takeda) https://www.shirecontent.com/PI/PDFs/FEIBA_USA_ENG.pdf
14. NovoSeven^®RT https://www.novo-pi.com/novosevenrt.pdf
15. Obizur (Baxalta US) https://www.shirecontent.com/PI/PDFs/OBIZUR_USA_ENG.pdf
16. Thrombate III (Grifols) https://www.thrombate.com/documents/51038104/51038282/THROMBATE+-+PI/fce61957-3696-4aff-b6c6-b09d4225cae3
17. RiaSTAP^® (CSL Behring) http://cslbehring.vo.llnwd.net/o33/u/central/PI/US/RiaSTAP/EN/RiaSTAP-PrescribingInformation.pdf
18. Fibryga^® (Octapharma) https://www.fibrygausa.com/why-fibryga/#hcp Package insert at: https://www.fibrygausa.com/wp-content/uploads/2021/03/20201222_pil_347_11.07_US_en.pdf
19. C1 esterase inhibitor, Berinert^® (CSL Behring) https://labeling.cslbehring.com/PI/US/Berinert/EN/BerinertPrescribing-Information.pdf
20. Protein C, Ceprotin^® (Shire) https://www.ceprotin.com/Contents/PDFs/ceprotinhcp_usa_eng.pdf
21. Bristol-Myers Squibb Company. Coumadin (warfarin sodium) tablets package insert. Princeton, NJ: Bristol-Myers Squibb Company; December 2019.
22. Andexanet Alfa (Alexion Pharmaceuticals, Inc.) https://andexxa.com/
23. Praxbind (Idarucizumab) (Boehringer Ingelheim Pharmaceuticals, Inc.) https://www.praxbind.com/idarucizumab/what-is-praxbind Package insert at: https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Praxbind/Praxbind.pdf