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, APTT, INR and renal function. 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. 
a. Obtain a 1mL syringe and pull the plunger back to the 0.3mL mark (this will allow for excess air to be expelled)
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
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) and inject the dose subcutaneously

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.

    a.       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.

    b.      Carefully depress the syringe plunger to expel excess drug until the bottom of the air-bubble is sitting level with the desired drug volume.

    c.       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.

    d.      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.

• Dose changes should be increased or decreased to the nearest whole number as per the LMWH dosing guidelines above

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.

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.

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.

References

1.       Low molecular weight heparin in pediatric patients with thrombotic disease: a dose finding study. Massicotte P, Adams M, Marzinotto V, Brooker LA and Andrew M. Journal of Pediatrics. 128(3): 313-318. 1996

2.       Low molecular weight heparin therapy in pediatric patients. Andrew M, Massicotte P and Brooker LA. Thrombosis in Oncology 1(2):2-5, 1998.

3.       Monagle P, Chan A, Goldenberg N, Ichord R, Journeycake J, Nowak-Gottl U, Vesely S. Antithrombotic therapy in neonates and children: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-based clinical practice guidelines. Chest. 141:e737-e801S. 2012.

4.       Preoperative vs postoperative initiation of low-molecular weight heparin

prophylaxis against venous thromboembolism in patients undergoing elective hip replacement.  Hull, RD. et al. Archives of Internal Medicine 159; 137-141, 1999.

5.       Central nerve block and thromboprophylaxis-is there a problem? (editorial) Checketts, MR and Wilsmith, JA. British Journal of Anaesthesia 82(2); 164-167. 1999.

6.       Epidural haematoma after rmoval of an epidural catheter in a patient receiving high-Dose enoxaparin. Yin, B. et al. British Journal of Anaesthesis 82(2):288-90. 1999.

7.       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

8.       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

9.       Recommendations for the development of a dedicated paediatric anticoagulation service. Newall F, Jones S, Bauman M, Bruce A, Massicotte P, Monagle P. Journal of Thrombosis and Haemostasis. 2014. (In press)

10.   Anticoagulation in Children. Newall F, Monagle P. Thrombosis Research. 130(2): 142-146. 2012.

11.   Recommendations for developing uniform laboratory monitoring of heparinoid anticoagulants in children. Newall F, Chan AK, Ignjatovic V, Monagle P. Journal of Thrombosis and Haemostasis. 10(1): 145-147. 2012

Revised November 2014 by the Clinical Haematology department