• Warfarin- Information for Clinicians
• Warfarin Management
• Home INR Monitoring Program
• Low Molecular Weight Heparin (LMWH) – Information for Clinicians
• Aspirin- Information for Clinicians

Warfarin- Information for Clinicians

Warfarin is the generic name for the most commonly used oral anticoagulant. Warfarin is a Vitamin K antagonist, making it sensitive to changes in diet, medications and level of wellbeing. Infants and children respond to warfarin differently to adults and as a result, management by a dedicated paediatric anticoagulant service is recommended. Anticoagulant therapy management by dedicated services is associated with improved clinical outcomes for patients.  

There are 2 brands of warfarin commercially available. It is not advisable to use different brands interchangeably or use generic options.

Both brands of warfarin colour-code their tablets. The following table describes the availability of tablet strengths and their corresponding colour.

Warfarin Management

The Clinical Haematology department manages warfarin therapy for over 150 children around Victoria, Tasmania and some parts of New South Wales and South Australia. The majority of children require warfarin for primary thromboprophylaxis, usually in the setting of complex congenital heart disease, with most of these children likely to require lifelong anticoagulation. The RCH Clinical Haematology department is the largest provider of dedicated anticoagulant management to children in Australia and has demonstrated excellent outcomes with respect to keeping children taking warfarin safe and well.

Anticoagulation Clinic Outcomes 2004

The Clinical Haematology department has established robust education processes and services to improve the quality of warfarin management for children. The key principles employed by the service are individualized management, point-of-care INR monitoring, robust education and frequent evaluation.

Coaguchek S validation 2004

CoaguChek XS Validation 2009

Home INR Monitoring Program

In 2003, the Clinical Haematology department extended its service through the establishment of a Home INR Monitoring program, where parents/older patients were taught to perform their own INR tests using the INR  monitors in their homes.

The Home INR Program has capacity to manage up to 100 children on warfarin. This is based on our current supply of CoaguChek XS^TM Monitors.

Entry into the Home INR Monitoring program is restricted to families and children who:

• Reside in Victoria
• Require warfarin for more than 12 months.
• Have English Language proficiency
• Have been on warfarin therapy for more than three months

Due to the time required for training families, it is not feasible or cost-effective to train families and supply all the consumables for home monitoring if the child only requires warfarin for a short period.

As the training program is conducted in group format, engaging interpreters to support families with limited English is not feasible.

The warfarin knowledge requirements for families of children commencing on the Home INR program is quite extensive. The education provided to families during the training supplements previous education they a have received through the Haematology Department. To ensure that families have an established understanding of warfarin therapy a child must have been on warfarin for more than three months before they are eligible to commence home monitoring. By this time, the child's warfarin therapy should be stable and the family has become more confident with day-to-day management of warfarin. Families may not commence home INR monitoring as soon as their child has been on warfarin for 3 months. Capacity within the program must allow new participants to start.

Home INR program_education 2006

Patient warfarin education review 2005

Validated Warfarin Education program

Low Molecular Weight Heparin (LMWH) – Information for Clinicians

In neonates and children, the Low Molecular Weight Heparin of choice is "Enoxaparin" (Clexane) as this is the only LMWH available in Australia that has had paediatric dose-finding studies. All RCH patients requiring LMWH therapy should be referred to the Clinical Haematology Department.

 Indications

Low Molecular Weight Heparins are used for the prophylaxis or treatment of deep vein thrombosis. The decision to use LMWH instead of standard heparin or warfarin will depend upon the clinical scenario and individual patient factors such as risk of bleeding or availability of venous access.

 Dose Availability     

^{S  = dose available in pre-filled syringe.
G = graduated syringe}

Administration of LMWH

1.Weigh patient and obtain a baseline FBE. The prescribed dose should be calculated according to Table 1, depending upon the patient's weight and whether LMWH is indicated for the treatment or prevention of thrombosis.

Table 1. Recommended LMWH dosing for infants and children

2.LMWH is administered via subcutaneous route. This can be achieved by either by rotating injection sites or by injecting into an insuflon^TM catheter.

Direct subcutaneous injection should be given into a subcutaneous tissue skinfold of the abdomen or the upper-outer aspect of the thigh. The skinfold should be held throughout the injection. After removal of the needle, do not rub the site. Rather, place firm, even pressure to the site of injection for 1-5 minutes. This aids in minimizing the size of the bruise that may develop at the injection site.

Injection via an insuflon^TM catheter  can be performed in infants and children with sufficient subcutaneous tissue. Whilst there is no evidence regarding a minimum weight at which an insuflon^TM catheter can be used to administer LMWH, is it advisable to avoid using insuflon^TM catheters in most premature neonates and infants less than 3kg. There are reported cases of premature neonates requiring blood transfusions secondary to haemorrhaging into a subcutaneous space following the repeated injection of LMWH into an insuflon^TM catheter.

* LMWH can cause irritation of the subcutaneous tissues following injection via either method. This irritation usually passes within 5 minutes. Some children find the application of ice for 3-5 minutes prior to the injection being given minimizes this irritation.

3. Administration of LMWH Doses less than 10mg   For patients prescribed doses less than 10mg, a special request can be made to pharmacy to have 10mg/0.5mL syringes prepared. These syringes are prepared by an external contractor under sterile conditions. They have a 10-day expiry from the date of preparation. A minimum of 24 hours notice is required to request these syringes via pharmacy. Families then need to be taught how to discard the unnecessary volume contained in the pre-prepared syringes

4. Administration of enoxaparin doses between 10mg and 20mg: 
For patients prescribed doses less than 20mg but greater than or equal to 10mg, the 20mg/0.2mL preparation of enoxaparin should be used. 
Clexane syringes recently had a 'safety lock' added which obscures the syringe graduations between 0.1 and 0.2mL on the  graduated syringes (see table above). 
a. Obtain a clean 1mL syringe and pull the plunger back to the 0.3mL mark
b. Remove the needle cap from the enoxaparin 20mg/0.2mL syringe and squirt the contents into the top of the 1mL syringe
c. Attach a 25G or 27G needle to the end of the syringe and inject the dose subcutaneously
d. Push the syringe up to desired dose, squirting out the excess volume. (e.g. if the dose is 15mg, push the syringe up to the 0.15mL mark)

5. Administration of 20-40mg doses of LMWH. The 20mg and 40mg pre-filled syringes are ready for immediate use and are not graduated. This means they should only be dispensed when the entire contents of that syringe equals the prescribed dose. The full contents of the syringe should be administered. When injecting directly (i.e. not via an insuflon^TM catheter), the air bubble should not be expelled to avoid loss of the drug into the syringe's dead-space. For injections into insuflon^TM catheters, the air-bubble should be expelled from the syringe to prevent repeated air instillation into site.

6. Preparation and administration of doses from graduated syringes (60mg, 80mg, 100mg, 120mg, 150mg)
Patients to whom Clexane in graduated syringes is dispensed must be taught how to expel the unnecessary volume of drug from the syringe. The volume to be injected should be measured precisely according to the dosage recommended.

1. Point the needle of the syringe towards the ground and gently tap the glass. An air-bubble should settle above all liquid in the syringe.
2. Carefully depress the syringe plunger to expel excess drug until the bottom of the air-bubble is sitting level with the desired drug volume.
3. Inject the prescribed dose into patient, ensuring the air-bubble remains behind the drug volume to be injected. This ensures no drug is 'lost' within the dead-space of the syringe.
4. For injections into indwelling devices such as an insuflon^TM,  air should be expelled from the syringe to prevent repeated air instillation into site.

7. Timing of commencement of therapy (especially post-procedural) should be individualised.

8. Duration of therapy is determined on an individualised basis, based upon indication for treatment.

Monitoring of LMWH therapy in infants and children

Recent evidence demonstrates infants and children achieve highly variable dose-response to clexane. As a result, blood monitoring is vital to ensure achievement of minimum therapeutic levels and to avoid of excessive anticoagulation.

1. LMWH therapy is monitored using an anti-factor Xa assay (anti-Xa).

2. The therapeutic range for LMWH administered to treat a thrombosis, or as bridging therapy around a procedure in patients usually prescribed oral anticoagulant therapy, is 0.5 to 1.0 units/mL.

3. The therapeutic range for LMWH administered to prevent a thrombosis is 0.3 to 0.5 units/mL.

4. The anti-Xa assay requires collection of a precise volume of venous or arterial blood into a coagulation (citrate) specimen collection tube. Under-filled or over-filled specimen collection tubes will produce unreliable results. If incorrectly filled specimen tubes are sent to the Core Laboratory, a request for a repeat collection will be necessary. The APTT assay will be completely normal in patients therapeutically anticoagulated with LMWH.

5. LMWH can accumulate in the body over time, especially in infants and children. For this reason, ongoing anti-Xa measurement is essential even once the optimal LMWH dosing strategy has been determined. We recommend performing 1-2 weekly anti-Xa assays on patients who have achieved steady-state anticoagulation using LMWH and who have no significant intercurrent illnesses. For children who have an intercurrent illness and who require ongoing LMWH therapy, more frequent measurement of the anti-Xa assay may be needed. Please consult the Clinical Haematology department for advice in these situations.

6. Nomogram for adjustment of LMWH therapy

Table 2 outlines dose adjustments required for a given anti-Xa result in patients requiring an anti-Xa assay between 0.35 to 0.7 units/mL. 

Table 2. Nomogram for dose adjustment of LMWH therapy. This nomogram assumes there is no bleeding.

 Precautions

1. Avoid the use of aspirin as this can increase the risk of bleeding.
2. Avoid intramuscular injections and arterial punctures, if possible.

 Adverse Events

The major adverse event related to treatment with LMWH is bleeding. If a patient on LMWH develops a major bleed, withhold further doses and seek an urgent Haematology consult. Rarely, LMWH therapy can cause alopecia. The extent of hair loss can vary greatly. All cases of LMWH-related alopecia have resolved upon cessation of therapy.

LMWH Antidote

The antidote for LMWH is Protamine sulphate. This reverses most, but not all, of the effects of LMWH. The dose of protamine sulphate given is dependent upon the dose of LMWH administered and the time of administration. If protamine is given within 8 hours of the LMWH then a maximum neutralizing dose is 1mg Protamine/100units (or 1mg) of LMWH given in the last dose.  If more than 8 hours have passed since the dose of LMWH was given, administer 0.5mg Protamine per 1mg (100units) of LMWH given. Protamine is administered by slow IV infusion (over 10 mins) to avoid a hypotensive reaction.  

Protamine is a medication that requires a high level of caution when being prescribed and administered. Outside cardiac surgery and ICU, consultant or fellow approval is required for the use of protamine- do not allow this to lead to delayed administration in the case of bleeding. Contact the appropriate senior person immediately.

Special note regarding with-holding LMWH prior at time of procedures:

As with other anticoagulant medications, consideration must be given to the management of LMWH prior to invasive procedures such as lumber punctures and surgery. At the Royal Children's Hospital it is recommended that prior to any spinal or epidural procedure, 2 doses of LMWH be omitted. For example, if a patient is to have a lumber puncture on Tuesday morning, they should miss their dose of LMWH the night prior to, and morning of, the lumbar puncture. Please contact the Clinical Haematology department for advice on management around such procedures.

 References

1. Hirsh J. Low molecular weight heparins. Monograph. Decker Periodicals Inc., Hamilton, Ontario, Canada.
2. Massicotte P, Adams M, Marzinotto V, Brooker LA and Andrew M. Low molecular weight heparin in pediatric patients with thrombotic disease: a dose finding study. J Ped 128(3): 313-318.
3. Massicotte P. Low molecular weight heparin therapy in children. J Ped, in press.
4. Andrew M, Massicotte P and Brooker LA. Low molecular weight heparin therapy in pediatric patients. Thrombosis in Oncology 1(2):2-5, 1998.
5. Monagle P, Chalmers E, Chan A, deVeber G, Kirkham F, Massicotte P, et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:887S-968S.
6. Hull, RD. et al. Preoperative vs postoperative initiation of low-molecular weight heparin
prophylaxis against venous thromboembolism in patients undergoing elective hip replacement.  Archives of Internal Medicine 159; 137-141, 1999.
7. Checketts, MR and Wilsmith, JA. Central nerve block and thromboprophylaxis-is there a
problem? (editorial) British Journal of Anaesthesia 82(2); 164-167. 1999.
8. Yin, B. et al. Epidural haematoma after rmoval of an epidural catheter in a patient receiving high-Dose enoxaparin. British Journal of Anaesthesis 82(2):288-90. 1999.
9. Dosing and monitoring of Enoxaparin (LMWH) therapy in children. Ignjatovic V, Najid S, Newall F, Summerhayes R, Monagle P. British Journal of Haematology. 149: 734-738.  2010
10. The in vitro response to Low Molecular Weight Heparin (LMWH) is not age-dependent in children. Ignjatovic V, Newall F, Summerhayes R, Monagle P. Thrombosis and Haemostsis. 103: 855-856. 2010

Aspirin- Information for Clinicians

Aspirin is a medication only available for oral administration. Tablets are available in enteric and non-enteric coating. Dispersible tablets are also available. For infants and small children it may be necessary to either crush tablets or use a dispersible tablet and administer the aspirin in liquid form. These guidelines are for the use of aspirin for its antiplatelet activity.

Indications

Aspirin is commonly used in patients with cardiac disease and those with a history of arterial stroke. There are also certain indications for the use of Aspirin in pregnancy. It is more commonly used in patients with or at risk of arterial thrombosis.

Administration and Maintenance of Aspirin

1. Aspirin is commenced only when patients are permitted oral intake.
2. Commence Aspirin 3-5mg/kg/day to a maximum of 100mg.
3. Continue aspirin therapy as clinically indicated. For primary and secondary prophylaxis at least 3 months therapy is recommended.

Therapeutic monitoring is not required.

Precautions

A significant association between Reyes Syndrome and the ingestion of aspirin by children with influenza-like illness or chicken pox has been reported in the literature. Parents should be educated regarding the risk of developing Reyes Syndrome secondary to aspirin therapy. It should be clearly explained that aspirin therapy must be stopped in the presence of fever and/or chicken pox or measles. Paracetamol is permitted in this scenario.

Aspirin's mechanism of action is irreversible platelet inactivation. Once therapeutic doses are taken, antiplatelet effect remains for the lifespan of the platelet population which is 7-10 days. Patients scheduled to undergo surgical procedures should in general, stop aspirin 7-10 days prior to surgery. Peri-operative Aspirin therapy may increase the risk of peri-operative bleeding.

For women taking aspirin during pregnancy, therapy is often continued until 36-38 weeks gestation. The timing of cessation of aspirin therapy is the decision of the primary physician.

The concurrent use of non-steroidal anti-inflammatory medications and Aspirin is not recommended.

Aspirin should be taken after food.

Adverse Effects

Patients on aspirin therapy are at a slightly increased risk of bleeding and bruising. Usually this is not significant. If a patient develops significant bleeding or bruising whilst on aspirin, referral to a Haematology department is recommended.