Updated to reflect use to replace coagulation factors in special populations when frozen plasma is not available or the risk/benefit ratio of frozen plasma is unfavorable NAC Statement on Reversal of Direct Oral Anticoagulants (last revision: October 2018) assimilated into this document with further revisions to incorporate latest evidence Addition of suggested dosing regimen using weight and INR based on randomized clinical trials and suggested pediatric dosing based on observational evidence Addition that adverse reactions to PCCs require mandatory report as per the Protecting Canadians from Unsafe Drugs Act (Vanessa's Law) Updated references, added links to the NAC Statement on Fibrinogen Concentrate Use in Acquired Hypofibrinogenemia where applicable, and further detailed risks associated with PCCs May 2014 Dosing recommendations and use of PCCs in elective situations revised Clarity improved around various recommendations June 2011 Addition of Beriplex as a licensed product Incorporation of two national audits of Octaplex, leading to revision of dosing recommendations V: 20220208 FINAL 5 | P a g eThe National Advisory Committee on Blood and Blood Products (NAC) is an interprovincial medical and technical advisory body to the provincial and territorial health ministries and the blood supplier Canadian Blood Services. Its mandate is to provide professional leadership in assisting and identifying, designing and implementing cost-effective blood utilization management initiatives for the optimization of patient care throughout Canada. Currently available four-factor prothrombin complex concentrates (PCCs) are human plasma derived products that have undergone solvent/detergent treatment and/or nanofiltration for viral, bacterial and parasite inactivation and/or removal. They contain the vitamin K dependent procoagulant factors -II, VII, IX and X as well as the vitamin K dependent natural anticoagulant factors Protein C and Protein S, manufactured with added heparin. The two currently available PCCs (Beriplex, Octaplex) are considered interchangeable in practice.# 
In 2008, NAC was approached by Canadian Blood Services and the Provinces to develop recommendations for appropriate use of PCCs as they became available in Canada. That led to the "NAC Statement on Recommendations for Use of PCCs", which underwent revisions in 2011 and 2014. Due to new evidence and changes in practice that have occurred since the last revision, a working group was convened in 2021 to revise and update the recommendations. The "NAC Statement on Reversal of Direct Oral Anticoagulants" published in 2018 has also been assimilated into this document.
The working group continues to advocate for the use of this product under the oversight of transfusion medicine services, directed by expertise in thrombosis/hemostasis/transfusion medicine, informed by the evolving medical literature, and in settings with access to appropriate diagnostic and treatment facilities for the identification and management of potential complications. These recommendations consider available literature, audit data and consensus opinion of the working group formed in 2021. Conflict of interest disclosures of the working group members are available on the NAC website (www.nacblood.ca).

# INDICATIONS Recommended Indications:
A. Rapid reversal of oral vitamin K antagonists (VKAs, e.g. warfarin) or deficiency of vitamin K dependent coagulation factors in patients with major bleeding - Major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) bleeding scale includes: 1.
 fatal bleeding; 2. symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, or intramuscular with compartment syndrome; 3. bleeding causing a fall in hemoglobin  20 g/L or leading to transfusion  2 units of red blood cells. - Critical bleeding following injury or surgical intervention also appropriately qualifies as major bleeding in this context. A. Treatment of bleeding in patients receiving direct factor Xa inhibitor anticoagulants -PCCs should only be considered in patients presenting with severe or life-threatening bleeding.
- Specific reversal agents for direct factor Xa inhibitors (including rivaroxaban, apixaban, and edoxaban), such as andexanet alfa, should be used, if available. At the time of writing, andexanet alfa is not currently approved by Health Canada. - There are no randomized trials published as of writing, evaluating the efficacy and safety of PCCs for treatment of direct factor Xa inhibitor associated bleeding. - The optimal dosing strategy is uncertain with 2000 IU (fixed dose) or 25-50 IU/kg (to a max 3000 IU) being the most commonly recommended dosing strategy. Other considerations for treatment: - Other adjunctive strategies include: holding medications that increase the risk of bleeding (e.g. antiplatelet agents), bleeding source control, and use of tranexamic acid (though tranexamic acid has not been studied in direct factor Xa inhibitor associated bleeding). - Inappropriate approaches to treatment of direct factor Xa inhibitor associated bleeding which are not to be used include: frozen plasma administration, vitamin K (unless concomitant vitamin K deficiency/antagonist is present), and recombinant factor VIIa. - In patients presenting for urgent surgery and/or an invasive procedure taking direct factor Xa inhibitor anticoagulants in whom clinically significant anticoagulant effect is suspected or demonstrated, if it is clinically appropriate to delay the surgery/procedure, then anticoagulants should be discontinued within an appropriate timeframe to ensure minimal residual anticoagulation. o If surgery cannot be delayed in an anticoagulated patient, consultation with expertise from thrombosis/hemostasis/transfusion medicine is strongly recommended to guide pre-procedural lab testing (including an anti-factor Xa level, if available, prior to proceeding especially if the direct factor Xa inhibitor has not been held for an appropriate time frame) and bleeding management. o Although an elevated INR is suggestive of direct factor Xa inhibitor presence, it cannot be used as a quantitative measure for the degree of anticoagulation, or alone provide guidance for administration of PCCs for surgical and/or invasive procedures. The INR may also be normal in patients who are fully anticoagulated. o At the time of writing, there is limited data regarding the efficacy and safety of PCCs for management of factor Xa inhibitor treated patients requiring urgent surgery. - NAC recommends that institutional/regional protocols be developed and implemented, including relevant laboratory testing and hemostatic management.
B. Use in bleeding/massive hemorrhage patients, when plasma is unavailable -Some smaller/remote health service providers may have challenges providing plasma in bleeding patients, given the lack of thawing devices or lack of stocking due to rarity of use. are only to be used for hemophilia patients with inhibitors as per the product monograph (control of spontaneous bleeding episodes, surgical interventions, and/or routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children older than 6 years of age).

# ADVERSE EVENTS AND RISKS
- PCC use may be associated with an increased risk of thrombosis and should be used with caution in patients with recent thrombotic events (i.e. venous thromboembolism, myocardial infarction, ischemic stroke, systemic embolism) and DIC. o Risks of thrombosis reported with PCC use in VKA reversal range from 1.4% to 4.2% across studies in systematic reviews. o The risk of thrombosis after VKA reversal with PCC has not been shown to be higher than after VKA reversal with plasma. o If the decision is to use the product off-label in patients with liver dysfunction and DIC, please consult the product monograph for further recommendations (e.g. the need for antithrombin levels or replacement). - PCCs also contain heparin, which can lead to/or exacerbate HIT.
- Other reported reactions can be found in the product monograph, and may include formation of inhibitor antibodies for one or more of the factors, and anaphylactic reactions.
- The Protecting Canadians from Unsafe Drugs Act (Vanessa's Law) introduces amendments to the Food and Drugs Act that mandates reporting of serious adverse drug reactions. This act came into effect December 16th, 2019, applies to purified plasma protein products, and includes the reporting of serious anticoagulant-related bleeds by hospitals. o Serious adverse reactions include those that require in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is life-threatening, or results in death. o Regulations for mandatory reporting of serious adverse drug reactions apply to all hospital facilities. Any patient or staff member is eligible to submit a severe adverse drug reaction report. Facility/regional policies should be consulted to ensure reporting per local protocol as reporting is not explicitly in the domain of transfusion medicine services. For more information, please consult Health Canada.

# DOSING, ADMINISTRATION & MONITORING
There is significant variability in the dosing used for PCCs across Canada and in the literature.
- The working group felt that there was insufficient published evidence to indicate one dosing regimen for VKAs as superior to another and recommends following local policy with monitoring for efficacy. o Some of the variability in practice and literature stems from different target INRs for various clinical indications and whether or not weight-based and/or INR-based dosing was deemed important by local clinical groups. - The expert consensus recommendation is to target a local INR of 1.5 or less for VKA reversal.
- This is based on the fact that an INR of 1.5 or less has evolved to be the standard of practice across Canada. However, no data clearly supports a relationship between the surrogate outcome of lowering the INR and reduced bleeding in this situation.
- Normal hemostasis does not require 100% factor levels. Although the product monographs recommend correcting factor levels to normal, an INR of 1.5 is likely equivalent to vitamin-K dependent factor levels of at least 30-50% which are adequate for hemostasis. Administration:
- Must be administered intravenously, where medications shall not be added directly to the administration set that contains a blood component or another product. - Should be administered by slow IV infusion (for example: 1000 IU over 5 minutes); or as per product monograph. o Health Canada has approved adult infusion rate recommendations based on the product monograph, though observational literature and experience at Canadian hospitals suggest more rapid infusion rates (such as 1000 IU over 5 minutes) are safe. - Preferentially should be infused through peripheral IV access. Caution should be exercised when infusing centrally and it is prudent to use product monograph recommended infusion rates when administered through a central line.
Vitamin K for VKA Reversal:
- The expert working group recommends IV Vitamin K administration for VKA reversal. When Vitamin K is used as an alternative, the injectable formulation, which can be given orally or intravenously, is preferred. Oral vitamin K has a slower onset of action than IV vitamin K. Intramuscular and subcutaneous routes of Vitamin K administration are not recommended. - Clinicians should not be hesitant to prescribe IV vitamin K as it does not produce the inability to resume oral anticoagulation ("warfarin resistance") when used at appropriate doses. Further, if warfarin resistance is encountered in a rare patient, there are alternative anticoagulants that can be used. - For patients receiving VKAs with INRs of >4.5 but <10 without clinically significant bleeding, the ASH Guidelines for Management of Venous Thromboembolism suggests using temporary cessation of VKAs alone without the addition of vitamin K.

# Post dose monitoring in VKA Reversal:
Since dose effect is not universally applicable, efficacy of dosing in VKA reversal must be determined using the surrogate marker INR post PCC administration.
- If correction to an INR <1.5 has not been achieved and there is insufficient time to wait for Vitamin K to take effect, a subsequent dose of PCC guided by the post-infusion INR may be required if the patient continues to demonstrate clinical bleeding.