Paediatric Anticoagulant Guidelines Author: Bhavee Patel, Gareth Thomas Specialty: Paediatrics Date Approved: 18 th July 2012 Approved by: W&CH Quality & Safety Group Date for Review: June 2015
PAEDIATRIC ANTICOAGULANT GUIDELINES The purpose of these guidelines is to provide for safe and effective dosing and required monitoring of paediatric patients receiving anticoagulant therapy. It is not to determine which patients should receive anticoagulation; this remains a clinical decision which should be taken on an individual basis. HEPARIN Unfractionated heparin exerts its anticoagulant effect by acting at a number of points in the coagulation cascade. It has to be given intravenously, necessitating hospital stay, and therapy needs to be monitored using the aptt ratio (seconds). Unfractionated heparin can be reversed more reliably than low molecular weight heparin (LMWH). 1. Baseline labs: a. Baseline aptt, PT/INR, FBC with platelets prior to initiation of heparin. b. Notify consultant of any abnormal lab values. c. Consult Haematology if patient has baseline coagulopathy. 2. Dosing: a. Loading dose: (1) i. 75 units/kg intravenously over 20 minutes b. Maintenance dose: (1) (2) i. Infants less than 1 year: 28 units/kg/hour ii. Children greater than 1 year: 20 units/kg/hour iii. Start maintenance infusion immediately following loading dose 3. Monitoring: while receiving heparin a. Monitor patient for signs and symptoms of bleeding. b. Check aptt 4 hours after heparin loading dose and 4 hours after every change in infusion rate; may decrease to daily aptt once two consecutive measurements are within the therapeutic range. c. Daily FBC with platelets until stable then at least weekly. NB: If sample for aptt is being drawn from a line that has heparin running through it, extreme care should be taken. It is quite frequent for heparin to contaminate the sample 2
and results will not truly reveal systemic anticoagulation levels. Try to collect aptt from a different extremity than the one used for heparin therapy. 4. Dosing adjustments: (2) Rate Change aptt (seconds) Bolus (units/kg) Hold (minutes) (units/kg/hr) Repeat aptt <50 50 0 Increase by 20% 4 hours 50 59 0 0 Increase by 10% 4 hours 60 85 (target range) 0 0 0 24 hours 86 95 0 0 Decrease by 10% 4 hours 96 120 0 30 Decrease by 10% 4 hours >120 0 60 Decrease by 15% 4 hours 5. Treatment of overdose: reserve for patients with clinically significant bleeding episodes a. Administer protamine sulphate as follows (based on total amount of heparin received in last 2 hours): (3) Heparin Protamine Sulphate Dose (time since last dose, minutes) (per 100 units of heparin received) Less than 30 1 mg 30 60 500 750 micrograms 60 120 375 500 micrograms Greater than 120 250 375 micrograms Max Dose Infusion rate 50 mg Infuse over 10 minutes (max rate 5 mg/minute) 3
LOW MOLECULAR WEIGHT HEPARIN (LMWH) LMWH has a more specific effect against factor Xa and almost 100% bioavailability compared to unfractionated heparin. Hence, LMWH has both a more predictable antithrombotic effect with fewer bleeding complications. LMWH has a longer half-life compared to unfractionated heparin. 1. Baseline labs: a. Baseline aptt, PT/INR, FBC with platelet count, and serum creatinine prior to initial dose of LMWH for new patients. 2. Dosing in patients with normal renal function: (4) Drug Enoxaparin Age Prophylaxis Dosing (mg/kg/dose) Treatment Dosing (mg/kg/dose) Dosing interval Less than 2 months 0.75 1.5 Every 12 hours Greater than 2 months 0.5 1 Every 12 hours Max Dose 40 mg daily 3. Monitoring: a. Check anti-factor Xa 4 hours after second dose, platelets and serum creatinine. b. Monitor patient for signs and symptoms of bleeding. c. Check anti-factor Xa level 4 hours post subcutaneous dose with the 2 nd dose of any new regimen until 2 consecutive stable therapeutic levels are reached. d. Once stable therapeutic level is reached check anti-xa level weekly; twice weekly for patients with renal impairment. e. Usual ranges: (anti-factor Xa) (5) i. Prophylaxis: 0.1 0.4 units/ml ii. Treatment: 0.5 1 units/ml f. Check serum creatinine weekly if patient at increased risk of renal dysfunction. g. Check FBC with platelets weekly if patient considered at risk of heparin-induced thrombocytopenia. 4
(6)(9) 4. Dose adjustment based on anti-factor Xa levels (achieves anti-factor Xa levels of 0.5 1): Anti-factor Xa (units/ml) Hold Less than 0.35 0 0.35 0.49 0 0.5 1 0 1.1 1.5 0 1.6 2 3 hours All doses until Greater than 2 anti-factor Xa is 0.5 units/ml Dose Titration Increase dose by 25% Increase dose by 10% Keep same dosage Decrease dose by 20% Decrease dose by 30% Decrease by 40% Time to repeat Anti-factor Xa Level 4 hours after next dose 4 hours after next dose Next day, then weekly (4 hours after dose) Before next dose Before next dose (confirm anti-factor Xa has decreased to less than 0.5 units/ml before giving new dose), then 4 hours after next dose Before next dose and every 12 hours until anti-factor Xa is less than 0.5 units/ml 5. Treatment of overdose: (7) a. Currently there is no product available for complete reversal of LMWH. However, protamine may provide partial reversal (maximum about 60%). b. Protamine sulphate may be given in a dose of 1 mg per 1 mg enoxaparin, in the first 4 hours after enoxaparin administration; where the dose of enoxaparin has exceeded 50 mg, an initial dose of 50 mg protamine sulphate would be appropriate. c. A second dose of 0.5 mg protamine sulphate per 1 mg enoxaparin may be given if bleeding continues 2 4 hours after first dose. d. Any decisions regarding the necessity and dose of subsequent protamine sulphate injections should be based on clinical response rather than measurement of antifactor Xa results. e. The healthcare professional should also consider that the amount of enoxaparin in the body drops to 50% after 8 hours and 33% or less after 12 hours. The dose of protamine sulphate should be adjusted depending on the length of time since enoxaparin was administered. f. Maximum protamine sulphate dose is 50 mg; rate not exceeding 5 mg/minute. 5
WARFARIN If a decision is made to initiate medium to long-term anticoagulation, warfarin is recommended. Timing of initiation of warfarin needs to be decided on an individual basis. Certain problems are associated with the use of warfarin in children. Sensitivity to warfarin changes during different phases of life, especially during infancy, because of varying concentrations of vitamin K dependent proteins in the body. Neonates, during the first month of life, are especially sensitive because of their relative deficiency of vitamin K, and therefore warfarin should be avoided in such patients if possible. However, formula fed infants are resistant to warfarin because of a high concentration of vitamin K in their diet. If anticoagulation is to be used in this group LMWH may be recommended. All cases should be discussed with a haematologist. In general, young children need more warfarin for each kilogram of body weight than older children and adults. Poor venous access, for INR checks, and non-compliance are added problems of anticoagulation in children. 1. Baseline labs: a. Baseline PT/INR prior to initiation of warfarin. (2)(8)(9) 2. Dosing nanogram to achieve INR 2 3: STAGE INR DOSE Day 1 1.0 1.3 0.2 mg/kg orally If liver failure or INR greater than 1.3 0.1 mg/kg orally 1.1 1.3 Repeat day 1 loading dose 1.4 1.9 50% of day 1 loading dose Days 2 4 2.0 3.0 50% of day 1 loading dose 3.1 3.5 25% of day 1 loading dose Omit dose until INR is less than 3.5 then Greater than 3.5 restart at 50% of previous dose If INR not greater than 1.5 on day 4 contact haematologist for help 6
1.1 1.3 Increase by 20% of dose 1.4 1.8 Increase by 10% of dose 1.9 3.1 No change 3.2 4.0 Decrease by 10% of dose Maintenance dose (day 5 onwards) 4.1 4.5 Decrease by 20% of dose Omit dose, check INR daily until INR less 4.6 8.0 than 4.5, then restart at 80% of previous dose Omit dose, patient needs clinical review and Greater than 8.0 assessment of whether reversal of anticoagulation is required For prosthetic valves to achieve INR 3.0 4.5: STAGE INR DOSE Maintenance dose (day 5 onwards) Less than 2.0 Increase by 20% of dose 2.0 2.8 Increase by 10% of dose 2.9 4.6 No change 4.7 5.1 Decrease by 10% of dose 5.2 6.0 Decrease by 20% of dose Omit dose, check INR daily if no bleeding or Greater than 6.0 minor bleeding than restart when INR less than 5.0 at 80% of previous dose Omit dose, patient needs clinical review and Greater than 8.0 assessment of whether reversal of anticoagulation is required 3. Monitoring: a. Daily INR until therapeutic for two consecutive days, then weekly. b. Monitor patient for signs and symptoms of bleeding. 7
4. The above tables are intended as guidance only and do not replace the clinical experience and judgement of the practitioner involved in the dosing and prescribing of warfarin. The practitioner must consider: a. Not only the current result but previous results. b. Changes to diet or recent medication e.g. antibiotics. c. That changes made in the dose will not fully reflect on the INR until day 3 or 4. NB: In difficult cases call the consultant haematologist 5. The following tables list commonly used drugs that are known to interact with the anticoagulant effect of warfarin, where possible alternative agents that do not significantly interact should be chosen. If this is not possible the anticoagulant clinic or nurse should be contacted to be made aware that an interacting medicine has been started or stopped. Arrangements should then be made for the patient to have an INR test within 4 7 days or for the warfarin dose to be adjusted. NB: This is not intended to be a comprehensive list of drug interactions with warfarin Common drugs used in the Health Board which: (10) a. Will increase the effects of warfarin: Aspirin Ciprofloxacin Metronidazole Miconazole Vitamin E Azithromycin Clarithromycin Fluconazole Levothyroxine Cephalosporins Erythromycin Itraconazole Omeprazole Cranberry juice has been documented as enhancing the effects of warfarin b. Will decrease the effects of warfarin: Rifampicin Sucralfate Barbiturates Carbamezapine Vitamin K c. Have variable effects on warfarin: Cholestyramine Phenytoin Oestrogens Progestogens 8
6. Discharge a. Anticoagulant treatment booklets should be issued to children or their parents/carers/guardians, and are available from the pharmacy department. b. Ensure that accurate information is shared with out-patient clinic or GP. NB: Anticoagulation clinic available in Neath Port Talbot Hospital (requires referral letter) c. Make arrangements for the patient to have his/her INR checked within seven days of discharge (three days if an interacting drug is being stopped or started). (11)(12) 7. Treatment of overdose: a. If INR in therapeutic range and patient bleeding: i. Investigate source of bleeding. ii. Consider risk/benefit of stopping warfarin. b. If INR less than 6.0 but more than 0.5 units above target value: i. Reduce dose as per protocol above. c. If INR 6.0 8.0, no bleeding or minor bleeding: i. Stop warfarin. ii. Restart when INR less than 5.0. d. If INR greater than 8.0, no bleeding or minor bleeding: i. Stop warfarin. ii. Give phytomenadione (vitamin K) 15 30 micrograms/kg by slow intravenous injection ( Konakion MM) or 5 mg by mouth (Konakion MM Paediatric). iii. For partial reversal of anticoagulation give smaller oral doses of phytomenadione (vitamin K) e.g. 0.5 2.5 mg using Konakion MM Paediatric. iv. Repeat dose of phytomenadione (vitamin K) if INR still too high after 24 hours. NB: large doses of phytomenadione (vitamin K) may completely reverse the effects of warfarin and make re-establishment of anticoagulation difficult e. In cases of non-life threatening haemorrhage: 9
i. Where anticoagulation can be suspended, give slow intravenous injection of phytomenadione (vitamin K) (Konakion MM) 250 micrograms/kg over 3 5 minutes. ii. Where rapid re-anticoagulation is desirable e.g. valve replacements, give prothrombin complex concentrate (factors II, VII, IX and X) dose to be advised by haematologist. Dissolve in water for injection as per manufacturer s guidance, using aseptic technique and the provided transfer device. Administer over 10 minutes. See local protocol for further details on administration. iii. Monitor INR for at least 48 hours post overdose and to determine when to restart normal therapy. f. In cases of life or limb threatening haemorrhage, including intracranial haemorrhage: i. Stop warfarin treatment. ii. Give slow intravenous injection of phytomenadione (vitamin K) (Konakion MM) 250 micrograms/kg over 3 5 minutes. iii. Give prothrombin complex concentrate (factors II, VII, IX and X) dose to be advised by haematologist. Dissolve in water for injection as per manufacturer s guidance, using aseptic technique and the provided transfer device. Administer over 10 minutes. See local protocol for further details on administration. iv. Discuss with consultant haematologist. v. Repeat INR within 1 hour of giving PCC consider further dose if INR greater than 1.5 and patient still bleeding. vi. Consider risk/benefit of recommencing warfarin. 10
Recommended INR based on Indication (13) Indication Target INR Length of Therapy Arterial Ischaemic Stroke + cardioembolic stroke or vascular dissection Minimum 6 weeks CVL (on long-term TPN) 2 2.5 First 3 months after CVL inserted CVL related Thrombosis (Treatment) 2 3 (2.5) 3 months then prophylactic doses Recurrent Thromboembolism Idiopathic 2 3 (2.5) Indefinite 3 months or removal of Secondary 2 3 (2.5) precipitating factors Central Splanchnic Venous Thrombosis (CSVT) without intracranial haemorrhage (ICH) in children 2 3 (2.5) 3 6 months Venous Thromboembolism (VTE) in children greater than 2 months of age Idiopathic 2 3 (2.5) 6 months Secondary 2 3 (2.5) 3 months Dilated Cardiomyopathy (Prophylaxis) 2 3 (2.5) Chronic Fontan Surgery (Prophylaxis) 2 3 (2.5) Kawasaki with coronary aneurysms 2 3 (2.5) Prosthetic Heart Valves (Biological) 2 3 (2.5) 3 12 months Prosthetic Heart Valves (Mechanical) 3.0 4.5 Chronic Pulmonary Hypertension Unknown Discuss with Cardiologists for exceptions 11
References 1. BNF for Children. London : BMJ Group, Pharmaceutical Press, and RCPCH Publications Ltd, 2010-2011. pp. 148-149. 2. Great Ormond Street Hospital for Children NHS Trust. Anticoagulation in Neurovascular Disorders. Great Ormond Street Hospital for Children NHS Trust Web Site. [Online] 1.1, 12 November 2009. [Cited: 1 March 2011.] http://www.gosh.nhs.uk/clinical_information/clinical_guidelines/cmg_guideline_00033. 3. BNF for Children. London : BMJ Group, Pharmaceutical Press, and RCPCH Publications Ltd, 2010-2011. p. 154. 4. BNF for Children. London : BMJ Group, Pharmaceutical Press, and RCPCH Publications Ltd, 2010-2011. p. 150. 5. British Committee for Standards in Haematology. Guideline on the Investigation, Management and Prevention of Venous Thrombosis in Children. British Committee for Standards in Haematology Guidelines. [Online] 2010. [Cited: 3 March 2011.] http://www.bcshguidelines.com/documents/bcshchildhoodvtefinaldec2010.pdf. 6. Monagle, P, et al. 2001, Antithrombotic Therapy in Children. Chest, Vol. 119, pp. S344-70. 7. sanofi aventis. Clexane Forte Syringes. electronic Medicines Compendium (emc). [Online] 20 December 2010. [Cited: 4 March 2011.] http://www.medicines.org.uk/emc/medicine/10054/spc/clexane+forte+syringes/. 8. Alder Hey Children's NHS Foundation Trust. Warfarin Prescription Sheet. 9. Jilma, Bernd, Kamath, Sridhar and Lip, Gregory Y H. 2003, ABC of antithrombotic therapy: Antithrombotic Therapy in Special Circumstances. II - In Children, Thrombophilia, and Miscellaneous Conditions. BMJ, 11 January 2003, Vol. 326, pp. 93-96. 10. BNF for Children. London : BMJ Group, Pharmaceutical Press, and RCPCH Publications Ltd, 2010-2011. pp. 837-838. 11. Goldshield. Warfarin 1 mg tablets B.P. electronic Medicines Compendium (emc). [Online] 20 August 2010. [Cited: 7 March 2011.] http://www.medicines.org.uk/emc/medicine/23642/spc/warfarin+1mg+tablets+b.p./. 12. BNF for Children. London : BMJ Group, Pharmaceutical Press, and RCPCH Publications Ltd, 2010-2011. pp. 592-593. 13. Monagle, Paul, et al. 2008, Antithrombotic Therapy in Neonates and Children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, Vol. 133, pp. 887S - 968S. 12
Directorate of Women & Child Health Checklist for Clinical Guidelines being Submitted for Approval by Quality & Safety Group Paediatric Anticoagulant Guidelines Title of Guideline: Paediatric In-Patient Warfarin chart Name(s) of Author: Bhavee Patel Paediatric Pharmacist Dr Gareth Thomas Consultant Paediatric Neurologist Chair of Group or Committee supporting submission: Issue / Version No: 1 Next Review / Guideline Expiry: 2 years Details of persons included in consultation process: Brief outline giving reasons for document being submitted for ratification The guidelines have been trialled with great success across the Health Board Recently, we have had a significant number of patients with VTE who have required Clexane and Warfarin for treatment. However, there have been no clear guidelines across the Health Board for their use in paediatrics. Additionally, we have been using the adult warfarin chart when prescribing warfarin. Name of Pharmacist (mandatory if drugs involved): Please list any policies/guidelines this document will supercede: Bhavee Patel None Keywords linked to document: Anticoagulation, Heparin, Clexane, Warfarin Date approved by Directorate Quality & Safety Group: July 2012 File Name: Used to locate where file is stores on hard drive * To be completed by Author and submitted with document for ratification to Clinical Governance Facilitator 13