191FM.7 PROTOCOL FOR OVER-ANTICOAGULATION WITH WARFARIN

High International Normalised Ratio (INR), patient not bleeding • If INR ≥5 and <8, omit warfarin for 1 - 2 days. • If INR ≥8, stop warfarin until INR <5, give 1 to 5 mg phytomenadione orally (vitamin k). Use Konakion MM Paediatric®. Note this is unlicensed. • Occasional patients with INR ≥8 and a very high risk of thrombosis may be more safely managed without phytomenadione - seek senior advice. Restart warfarin, if still required, once INR <5, consider cause of raised INR and adjust maintenance dose. • Oral phytomenadione will have an effect within 16 - 24 hours.

Non-major bleeding INR 5.0 or greater • Omit warfarin. • Give 1 to 3 mg phytomenadione by IV bolus. Note: 1 to 5 mg phytomenadione by mouth may be more appropriate in the community or in some inpatients (e.g. if no IV access, depending on how significant the bleed is). If anticoagulation is to be stopped, consider 5 – 10 mg phytomenadione orally or IV (larger dose to be used if there is a plan for no further anticoagulation). • Restart warfarin, if still required, once INR <5.

INR less than 5 • A clinical decision needs to be made as to whether lowering the INR is required. If this is the case, consider giving IV phytomenadione 1 - 3 mg and modifying warfarin dose. Omit warfarin • General haemostatic measures • For oral cavity bleeding consider tranexamic acid 250 mg/5 ml mouthwash (unlicensed) – 5 to 10 ml 8 hourly. • Consider cause of bleeding (especially if INR in therapeutic range). • Repeat INR following day • See note above regarding patients at very high thrombotic risk.

Major/life-threatening haemorrhage (e.g. CNS/major GI) The definition recommended by the International Society on Thrombosis and Haemostasis (ISTH) defines major bleeding as fatal bleeding; symptomatic bleeding in a critical area or organ such as intracranial, intraspinal, intraocular resulting in vision changes, retroperitoneal, intraarticular, pericardial, or intramuscular with compartment syndrome; bleeding causing a fall in haemoglobin level of 2 - g/dL or more; and/or bleeding leading to transfusion of two or more units of whole blood or red cells. • Emergency reversal in major bleeding is with 25 - 30 units/kg prothrombin complex concentrate (PCC) (Beriplex®) and 5 mg IV phytomenadione. • Fresh frozen plasma (FFP) produces suboptimal anticoagulation reversal and should not be used. • Give the 5 mg phytomenadione IV immediately, (do not wait for INR result) then Beriplex®. • See below for dosing and administration of Beriplex®. • Note that in the context of serious haemorrhage any delay in administration increases the risk of morbidity and death and is unacceptable – do NOT wait for the INR result before reversing the anticoagulation.

Guideline 191FM.7 1 of 4 Uncontrolled if printed Administration of Beriplex® (Prothrombin Complex Concentrate) • Beriplex® (PCC) consists of the vitamin K-dependent coagulation factors II, VII, IX and X. • Beriplex® is derived from plasma. It is not blood group specific. • Beriplex® rapidly replaces the above coagulation factors that are depleted by warfarin and corrects the INR. • Beriplex® is available in the Blood Transfusion laboratory. • Beriplex® does not require the authorisation of a haematologist.

Prior to administration: • Discuss with consultant or registrar. Haematology consultant is not required to authorise, however advice can be sought if necessary. • Gain patient consent as Beriplex® is a blood product

Dosing • Dose: 25 – 30 units/kg rounded to the nearest 500 units. • Note Beriplex® is available in 250-, 500- and 1000-unit vials. • Note: The dosing on the Beriplex® SPC differs and is based on INR ranges. However, please follow dosing as below:

Dosing table Weight Total Dose (units) <60 kg 1500 60 – 75 kg 2000 76 – 90 kg 2500 >90 kg 3000

Administration • Beriplex® requires reconstitution using the contents of the pack with each vial (water for injection, vial of powder and double ended needle). • See Appendix 1 for instructions. Instructions also contained within each pack. • Once reconstituted infuse via slow intravenous bolus. For patients ≥70 kg, infuse at rate of 8 ml/min. For patients <70 kg infuse at a rate of 0.12 ml/kg/min. • Beriplex® should not be mixed with any drug, diluent or solution. • Monitor heart rate (HR) before and during infusion – NB HR may be elevated due to major bleeding. • Record the batch number of each vial administered on the drug chart. • Repeat coagulation screen 10 - 30 minutes after completion of infusion.

Cautions and side effects Full details of cautions, side effects and contra-indications are available in the Beriplex® summary of product characteristics (SPC), available at www.medicines.org.uk/emc. • Discontinue injection immediately if there are any signs of serious allergic or anaphylactic reactions. • There is a risk of thrombosis formation or disseminated intravascular coagulation – monitor. • Due to the potential for thromboembolic complications, closer monitoring of patients with a history of coronary heart disease, myocardial infarction or liver disease, those patients who are postoperative and those patients generally at risk of thromboembolic events.

Contra-indications • Known hypersensitivity to any of the components of Beriplex® (PCC). • Risk of thrombosis, angina pectoris or recent myocardial infarction (exception: life-threatening haemorrhages following overdoses of oral anticoagulant therapy and before induction of fibrinolytic therapy). • Known history of heparin-induced thrombocytopenia (HIT).

Guideline 191FM.7 2 of 4 Uncontrolled if printed The following should take place once bleeding is controlled: • Consider cause for bleeding on therapeutic anticoagulant, particularly if not supra-therapeutic i.e. INR in range) – always investigate possibility of underlying cause (e.g. unsuspected renal or GI tract pathology). • Review compliance with medication and factors that may contribute to poor control. • Review ongoing anticoagulation. − Consider risks and benefits of ongoing anticoagulation − Choice of anticoagulant, − Dosing and monitoring arrangements

References 1. BCSH Guidelines on oral anticoagulation with warfarin – fourth edition, BJH 2011 https://b-s-h.org.uk/guidelines/guidelines/oral-anticoagulation-with-warfarin-4th-edition/ 2. Kanaka KA, Szlam F, J Thromb Haemost 2010; 8: 2589-91 3. Oxford Haemophilia and Thrombosis Centre Protocols for Outpatient Oral Anticoagulation with Vitamin K Antagonists 4. Beriplex SPC. Available at Beriplex P/N 1000 IU - Summary of Product Characteristics (SmPC) - (emc) (medicines.org.uk) Last updated 29/1/21, accessed on 5/3/21

See also: Guideline 83FM Peri-operative Bridging of Warfarin Therapy in Adult Patients undergoing Elective Surgery or Invasive Procedures Guideline 192 Guideline for the use of Fresh Frozen Plasma (FFP) and Cryoprecipitate - BHT users only Guideline 222 Adult and Paediatrics Injectables Policy Guide - BHT users only

Title of Guideline Protocol for Over-anticoagulation with Warfarin Guideline Number 191FM Version 7 Effective Date May 2021 Review Date May 2024 Original Version Published November 2004 Approvals: Medicines Check (Pharmacy) 5th March 2021 Clinical Guidelines Group 20th April 2021 Author/s Haematology Consultants SDU(s)/Department(s) responsible Haematology for updating the guideline Pharmacy Uploaded to Intranet 28th May 2021 Buckinghamshire Healthcare NHS Trust

Guideline 191FM.7 3 of 4 Uncontrolled if printed

Appendix 1 Reconstitution and Administration of Beriplex®

Watch the demonstration on how to reconstitute Beriplex® at: http://cslbehring.vo.llnwd.net/o33/u/cs/uk//Mix2Vial/index.htm

Guideline 191FM.7 4 of 4 Uncontrolled if printed