Guideline for the use of anti-thrombotic treatment in children

Including advice on venous thromboembolic disease (VTE) risk assessment, use of un-fractionated heparin, low molecular weight heparin, warfarin, thrombolysis and treatment of heparin induced thrombocytopenia

• Prevention of thrombosis
• Drug information
  • Unfractionated heparin
  • Low Molecular Weight Heparin (LMWH)
  • Vitamin K antagonists (Warfarin)
  • Direct Oral Anticoagulants (DOACs)
  • Heparin Induced Thrombocytopenia (HIT)
  • Thrombolysis
• Adolescent Risk assessment for Venous Thromboembolism (VTE) Form  
• Details of perioperative management of anticoagulation in patients who are taking oral anticoagulants
• Regional Anaesthesia and Anticoagulant Prophylaxis

Refer to specific Paediatric Cardiology Guidelines for patients with cardiac indications for anticoagulation

Aims of guideline

This guideline has been developed to promote a safe and consistent approach to the use of antithrombotic agents in children up to the age of 16 years. This includes the use of unfractionated heparin, low molecular weight heparin, vitamin K antagonists in particular warfarin new oral anticoagulants and fibrinolytic agents. It addresses starting treatment, potential toxicities and agents to reverse drug action and cover during surgery. It aims to provide a practical guide for medical and allied staff involved in the management of infants and children with thrombosis. It seeks to limit potential dangers of inappropriate use of these agents and optimise efficacy. It does not advocate use of novel therapies. It should have no adverse cost implications to the Trust.

This guideline should not replace specific departmental based protocols that already exist, such as protocols for cardiology/cardiac surgery patients.

This guideline uses anti-factor Xa (anti-FXa) assays for unfractionated heparin monitoring so in hospitals who use APTT monitoring an alternative protocol will be needed

Indications for anticoagulation

The list of indications for anticoagulant treatment is increasing and the ultimate decision to start a specific anticoagulant lies with the clinician. It is important to clearly define whether heparins (unfractionated or low-molecular weight heparin) or direct oral anticoagulants (DOACs) are being used for prophylactic or therapeutic purposes so the correct section of the protocol can be chosen and followed appropriately. Therefore, the indication, regime (prophylactic or therapeutic) and duration MUST always be clearly documented on the prescription chart and in the patient’s medical notes.

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Prevention of thrombosis (prophylactic)

Background

The frequency of venous thromboembolism (VTE) during childhood is estimated to be 0.7– 4.9 per 100 000 in the general population rising to 5-8 cases of symptomatic VTE per 10 000 hospital admissions. Frequency of VTE in adults is greater at 1 per 1000 of the general population and has been described in 15% of medical patients and up to 40% of surgical patients prior to the routine use of mechanical or chemical thromboprophylaxis.

VTE incidence in children is increasing due to a combination of improvements in medical care leading to improved survival with potentially prothrombotic conditions (such as malignancy and congenital cardiac defects) and an increased awareness of VTE in children, in addition to improved diagnostic techniques. There are 2 peaks in the incidence of VTE, 1 in infants less than 2 years old and the other at adolescence. In infants, VTE is most often associated with the use of central venous lines, sepsis, congenital disorders and malignancies. At adolescence, the physiology of the coagulation system matures and additional risk factors such as smoking, obesity, pregnancy, and oestrogen-containing oral contraceptives become relevant. There is a 2:1 preponderance of females among adolescents who develop VTE.

Historical Canadian registry data recorded significant morbidity, with a recurrence rate of 8% and a rate of postphlebitis syndrome of 12%. Mortality ranged from 2.2% to 8.4%. More recent data suggest a recurrence rate of approximately 20%, retrospective analysis has suggested risk factors for recurrence include TPN dependency, lack of thrombus resolution, thrombophilia and acute inflammation during the initial VTE. These risk factors have not been verified in prospective studies.

The team looking after the patient must consider the following: although the risk of VTE increases during adolescence compared to younger children, the absolute risk remains low compared to older adults; the evidence base to support the use of specific measures to reduce the risk of VTE in this age group is poor compared to adults; physical methods to reduce the risk of VTE will only be suitable in older and larger adolescents and should be used according to local protocols and experience; if an increased risk of bleeding is documented on the risk assessment- thromboprophylaxis with LMWH is relatively contraindicated; the use of LMWH outside of locally agreed specialty group protocols should always be discussed with a paediatric haematologist.

Risk Assessment

Risk assess all children either 12 yrs or older or if they are post pubertal. It is recommended that all patients should be periodically re-assessed during their inpatient stay as VTE risk may change. Re-assessment after at least 48 to 72 hours is recommended.

If the patient is older than their 16th birthday follow the Leeds Teaching Hospitals VTE prevention guidelines for adults.

If younger than their 16th birthday complete the risk assessment and follow the recommendations.

There is inadequate evidence base to guide risk assessment in children who are prepubertal or < 12 yrs. Discussion with one of the paediatric haematology team is welcomed regarding individual cases.

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Adolescent Risk assessment for Venous Thromboembolism (VTE)

• Adolescent Risk assessment for Venous Thromboembolism (VTE) Form  

Prophylactic antithrombotic interventions

In all at-risk patients, ALWAYS : -

Consider general measures to reduce the risk of VTE:

• Maintain adequate hydration
• Mobilise early
• Remove central venous catheters as soon as possible
• Consider withholding the combined oral contraceptive pill for 4 weeks before planned surgery and advise alternative measures if stopped

Consider specific measures to reduce the risk of VTE:

• Anti-embolism stockings on the ward for surgical patients. Consider intermittent pneumatic compression (IPC) device for surgery.

Please note no paediatric sizes of anti-embolism stockings or intermittent pressure compression boots are available. Use only in larger patients and those weighing >40 kg. Standard size calf intermittent pressure compression boots are effective in those with a calf circumference of up to 43 cm.

Poorly fitted or worn stockings could produce a tourniquet effect and increase the risk of thrombosis. The top must not be rolled down. They should be removed daily for hygiene and skin inspection purposes.

Contraindications include massive leg oedema or pulmonary oedema (congestive heart failure), severe peripheral vascular disease or neuropathy, any local condition which could be exacerbated by the intermittent pressure compression boots (eg, dermatitis, recent skin graft/poor tissue viability, leg wound infection), and extreme leg deformity.

• Thromboprophylaxis with low molecular weight heparin (LMWH)

VTE Prophylaxis in COVID-19 Pneumonia
Children 12 years and older admitted to a ward with covid-19 pneumonia should be prescribed prophylactic LMWH (details according to this protocol) unless contraindicated (link to LMWH section). Consider prophylaxis in younger children if additional risk factors present.

Drug information

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Unfractionated heparin

Unfractionated heparin (or standard heparin) is the original form of heparin used in clinical practice. It contains molecules of varying size and efficacy therefore its bioavailability and anticoagulant effect are unpredictable. Intensive monitoring is therefore required. It can be given by the intravenous or subcutaneous routes but for effective anticoagulation in children it is generally administered by continuous intravenous infusion after a loading bolus dose.

Contraindications

Heparin-induced thrombocytopenia (HIT)

Patients who consume large amounts of alcohol, who are sensitive to the drug, who are actively bleeding or who have haemophilia or other bleeding disorders, severe liver disease (including oesophageal varices), purpura, severe hypertension, active tuberculosis or increased capillary permeability.

The rare occurrence of skin necrosis in patients receiving heparin contra-indicates the further use of heparin either by subcutaneous or intravenous routes because of the risk of thrombocytopenia.

Because of the special hazard of post-operative haemorrhage heparin is contra-indicated during surgery of the brain, spinal cord and eye, in procedures at sites where there is a risk of bleeding, in patients that have had recent surgery, and in patients undergoing lumbar puncture or regional anaesthetic block.

The relative risks and benefits of heparin should be carefully assessed in patients with a bleeding tendency or those patients with an actual or potential bleeding site eg. hiatus hernia, peptic ulcer, neoplasm, bacterial endocarditis, retinopathy, bleeding haemorrhoids, suspected intracranial haemorrhage, cerebral thrombosis or threatened abortion.

In patients receiving heparin for treatment rather than prophylaxis, locoregional anaesthesia in elective surgical procedures is contraindicated because use of heparin may be very rarely associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis.

Cautions

In patients with advanced renal or hepatic disease, a reduction in dosage may be necessary. The risk of bleeding is increased with severe renal impairment.

Patients with present or previous thrombocytopenia.

Although heparin hypersensitivity is rare, it is advisable to give a trial dose in patients with a history of allergy. Caution should be exercised in patients with known hypersensitivity to low molecular weight heparins.

Heparin side-effects

1. Bleeding - reported in 1.5% (95% confidence interval [CI], 0.0 to 8.3%) of children treated for deep-vein thrombosis (DVT)/pulmonary embolism (PE).
2. Heparin-induced thrombocytopenia (HIT) - case reports described in cases from 3 months upwards. Cardinal features are thrombocytopenia (or a 50 % drop in platelet count) +/- thrombosis 6-10 days after heparin started. Onset may be more rapid if previously exposed to heparin. Laboratory tests (Coagulation laboratory tel 65620, or National Blood Service via blood bank 23398) can confirm the diagnosis but action should be taken on the basis of clinical suspicion. A high index of suspicion is required to diagnose HIT in children, as many patients in the neonatal intensive care unit /paediatric intensive care unit who are exposed to heparin have multiple potential reasons for thrombocytopenia and/or thrombosis. Primary treatment is to stop heparin and use argatroban as an alternative to heparin if prolonged anticoagulation is required (see table 4).
3. Heparin-induced osteoporosis - described in only three case reports in children. However, given the convincing relationship between heparin and osteoporosis in adults, the long-term use of heparin in children should be avoided when other alternative anticoagulant agents are available.
4. Skin necrosis - stop heparin immediately if occurring
5. Hyperkalaemia - determine if it is necessary to continue treatment with heparin, if yes then treat the hyperkalaemia as per guidelines in the BNF for children.

Doses (Table 1)
Bolus doses of 75 to 100 units/Kg result in therapeutic APTT values in 90% of children. Bolus doses are not needed if intravenous heparin is replacing low molecular weight heparin. For patients changing to unfractionated heparin from LMWH, start unfractionated heparin instead of LMWH at the time the next dose of LMWH was due.(Also please see guidance for surgery). Maintenance heparin doses are age-dependent, with infants (up to 2 months of age, corrected for gestational age) having the highest requirements (average dose, 28 units/Kg/hr), and children over 1 year of age having lower requirements (average dose, 20 units/Kg/hr). The doses of heparin required for older children are similar to the weight-adjusted requirements in adults (ie. 18 units/Kg/hr).

Therapeutic range
The therapeutic effect of heparin can be monitored using the anti-FXa level or activated partial thromboplastin time (APTT). The recommended therapeutic range for the treatment of venous thromboembolism in adults is an anti-FXa level of 0.35 to 0.7 Units/mL or an APTT that reflects a heparin level by protamine titration of 0.2 to 0.4 units/mL .
We are now recommending use of the anti FXa level for monitoring of unfractionated heparin as it has a number of advantages compared with the APTT. There is no difference in clinical end points, bleeding or thrombosis if anti-FXa assays are used. The therapeutic range is generally achieved more rapidly with anti-FXa assays after fewer blood tests. It is used in many of the children’s hospitals in the UK and extensively in the USA.

Table 1

Protocol for initial anticoagulation with unfractionated heparin (UFH) in children*

*Anti FXa levels on ICE
Tab Haematology; tab anticoagulants (under Specialist Coagulation); select Anti Factor Xa Level

Heparin in renal impairment
Patients with a creatinine clearance of less than 30mL/min should have their anti-FXa level checked every 12hours

Reversal of Heparin Therapy
As in adults, if anticoagulation with heparin needs to be discontinued for clinical reasons, stopping the heparin infusion will usually suffice because of the rapid clearance of heparin. However, the half-life of heparin in high concentrations following an overdose is significantly longer than if levels are within the therapeutic range. If an immediate effect is required, intravenous protamine sulphate rapidly neutralizes heparin activity by virtue of its positive charge. The dose of protamine sulphate required to neutralize heparin is based on the amount of heparin received in the previous 2 hrs (See table 2).

Table 2

Reversal of Heparin with protamine

Hypersensitivity reactions to protamine sulphate may occur in patients with known hypersensitivity reactions to fish, or in those previously exposed to protamine therapy or protamine-containing insulin therapy.

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Low Molecular Weight Heparin (LMWH)

Low molecular weight heparin preparations consist of heparin molecules that lie within a narrow range of low molecular weights. The greater uniformity and small sizes lead to greater bioavailability after subcutaneous administration and a more predictable anticoagulant effect. No monitoring of therapeutic levels is required in adults however in children limited monitoring is still suggested. Reversal of LMWH is difficult therefore in cases where rapid reversal of anticoagulation may be required unfractionated heparin is preferred.

Tinzaparin is the recommended standard LMWH for therapeutic anticoagulation in all children and young people in Leeds Children’s Hospital.

Tinazaparin is also the recommended LMWH for prophylactic anticoagulation in children <12 years old or <50 kg body weight.

Enoxaparin is the recommended LMWH for prophylactic anticoagulation in patients 12 years or older and 50kg or heavier, pre-filled syringes should be prescribed.

Cautions
As for unfractionated heparin

Side effects
As for unfractionated heparin

Prescribing

Check coagulation screen, full blood count, renal and liver function before starting LMWH.

Renal impairment and liver impairment:
The use of unfractionated heparin may be a preferable option in renal or liver dysfunction.
If low molecular weight heparin is used consider reducing dose, increasing the frequency of monitoring anti-FXa levels and adjusting dose accordingly. Patients with a creatinine clearance of less than 30mL/min should receive an initial 50% dose reduction. The anti-FXa level should be measured after the first dose, further monitoring and dose modifications should follow the suggested guidance.

Switching from UFH to LMWH

When switching from UFH to LMWH if the anti-FXa level is in range then the first dose of LMWH should be given 2 hours after stopping the UFH infusion. If outside range consult paediatric haematology registrar or consultant for advice.

Administration:
Small doses of LMWH need to be measured with a 1mL syringe.
If a subcutaneous device for administration (Insuflon™) is used, the need to flush the dead space will depend on the size of the patient and the dose to be given. This should be discussed with your ward pharmacist. Use of such devices not infrequently leads to inaccurate administration so if there is a failure to achieve therapeutic anti-FXa levels consider using separate injections.

Monitoring/Therapeutic range
Therapeutic doses of LMWH are extrapolated from adult data and are based on anti-FXa levels.

Therapeutic: An anti-FXa level of 0.50 to 1.0 units/mL in a sample taken 4 hrs following a subcutaneous injection. (In general, peak anti-FXa levels occur 2 to 6 hrs following a subcutaneous LMWH injection).

Prophylactic: An anti-FXa level of 0.1-0.3 units/ml in a sample taken 4 hrs following a subcutaneous injection. This however should not be measured routinely. In clinical conditions or patients where prophylactic efficacy of LMWH is questioned such as patients with liver or renal impairment, it is advised to seek advice from a haematologist with experience in coagulation.

Treatment of LMWH-induced bleeding
Equimolar concentrations of protamine sulphate neutralize the anti-factor IIa activity but result in only partial neutralization of the anti-FXa activity. Therefore full reversal of LMWH may not be achieved. However if urgent reversal is indicated protamine may be used. Seek advice from on call Paediatric Haematology consultant.

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Vitamin K antagonists (Warfarin)

Warfarin (and other vitamin K antagonists) can be used for long term anti-coagulation of children. Achieving a therapeutic INR can be difficult especially in young children. The largest cohort study (319 patients) found that to maintain a target INR of 2 to 3, infants required an average of 0.33 mg/kg warfarin and teenagers required 0.09 mg/kg warfarin. The warfarin dose should only exceed 10 mg daily with caution, however in exceptional patients this dose may be required.

Anti-coagulation ideally should always be initiated with heparin which results in an immediate effect. Introduction of warfarin without heparin cover can cause coumarin induced skin necrosis and a transient hyper coagulable state. Local consensus is to introduce warfarin one day after heparin is started. Heparin can be stopped when two INR results greater than 2.0 are achieved on successive days providing the APTT is not above the therapeutic range. On occasions warfarin can be introduced as a single agent but a cautious approach with a slow escalating regimen must be adopted, warfarin must not be introduced in a rapid loading regime in the absence of heparin.

Contraindications
Local bleeding point, severe hypertension, bacterial endocarditis (relative contraindication).
Pregnancy

Cautions
Recent surgery, hepatic impairment, renal impairment

Side-effects
Bleeding
Hypersensitivity, skin necrosis

Doses

Introduction of Warfarin in children (target INR range 2 to 3) - For paediatric cardiology indications for warfarin see their local guidelines (appendix 1). Heparin can be stopped when two INR results greater than 2.0 are achieved on successive days providing the APTT is not above the therapeutic range.

Initiation of warfarin should be guided by the protocol below and prescribed on eMeds. See later for guidance on management after discharge.

Long term follow up of paediatric patients on warfarin
All children on long-term management of warfarin will need to be referred to a warfarin clinic or to a doctor who is able to manage the warfarin treatment. Plans for outpatient management on discharge should be considered at the point of initiating warfarin and early referral is important allow adequate time for outpatient arrangements to be put into place.

Leeds Children’s Hospital has a paediatric outpatient warfarin clinic which is a pharmacist-led telephone clinic for paediatric patients who have been started on anticoagulant therapy with warfarin and discharged home. The service is aimed at paediatric patients under the care of a LTHT consultant and runs Monday to Friday. Since the clinic is a telephone only clinic, the location of planned INR testing must be considered. (eg, at their local hospital, at their GP surgery, at home or at LTHT). Consultant Paediatricians must ensure that these arrangements are in place before referring patients to the children’s warfarin clinic.

If a patient requires warfarin therapy after their sixteenth birthday they will need to be referred to their local adult anticoagulant service.

For further information on the Children’s Warfarin Clinic including patient information leaflets and how to refer - see information on Leeds Health Pathways (http://nww.lhp.leedsth.nhs.uk/referral_info/detail.aspx?ID=294).

Management of raised INR

Treatment of Warfarin-induced bleeding

Major bleeding (limb or life threatening):

1. Stop warfarin
2. Exclude local cause of bleeding.
3. Ensure there is no other coexisting coagulopathy such as disseminated intravascular coagulation, if this is present consult paediatric haematology consultant on call.
4. If immediate reversal required, give prothrombin complex concentrate (factors II, VII, IX and X) 25-50 units/Kg or (if no concentrate available) fresh frozen plasma 15mL/Kg. (Available through blood bank 23398). The prothrombin complex concentrate should completely reverse the warfarin effect. Recheck the coagulation screen following infusion.
5. Give phytomenadione (vitamin K1) by slow intravenous injection at a dose of 50-100 microgram/Kg up to age 12 years, 5-10mg above age 12 years. Vitamin K alone will only be effective 6 hours after administration.

No bleeding or minor bleeding

INR greater than 8:

1. Stop warfarin, restart when INR less than 5.
2. If other risk factors for bleeding consider low dose of vitamin K

Child under 12 years: no specific dosing guidance published. Consider 5-10microgram/Kg vitamin K by slow intravenous injection or 50-100 microgram/kg vitamin K using the intravenous preparation orally. Repeat vitamin K if INR remains too high after 24 hours.

Child above 12 years: 500 microgram by slow intravenous injection or 5 mg orally. For partial reversal give smaller oral doses of vitamin K 0.5-2.5mg, using the intravenous preparation orally. Repeat vitamin K if INR remains too high after 24 hours.

INR 6-8: no bleeding or minor bleeding – stop warfarin, restart when INR less than 5.

INR less than 6: Depending on target range and reason for raised INR, reduce dose or stop warfarin, restart when INR less than 5.

When restarting warfarin following vitamin K administration the response to warfarin may be affected for several days and should be considered when dose adjusting.

Unexpected bleeding at therapeutic levels – assess for local/systemic source of blood loss and coexisting coagulopathy or thrombocytopenia.

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Direct Oral Anticoagulants (DOAC)

Rivaroxaban is a DOAC licensed for use in children aged from from full-term neonates (following at least 10 days of oral feeding and weighing at least 2.6 kg). Rivaroxaban is approved for the treatment and prevention of recurrence of venous thromboembolism following at least 5 days of parenteral anti-coagulation with heparin.

Contraindications
Active bleeding, significant risk for major bleeding, hepatic disease associated with coagulopathy and clinically relevant bleeding risk, antiphospholipid syndrome.

Cautions
Renal impairment (see manufacturers information), concomitant treatment with potent cytochrome P450 inhibitors, active cancer or cancer treatment, neonates with hyperbilirubinemia (due to sodium benzoate excipient in liquid)

Doses

<12kg - see manufacturer information SmPC (Summary of Product Characteristics) see link or BNFc
12kg - <30kg - 5mg TWICE daily
30kg - <50kg - 15mg ONCE daily
>50kg - 20mg ONCE daily

The first dose of rivaroxaban should be given 0-2hrs before the time of the next scheduled LMWH dose or at the time of discontinuing unfractionated heparin infusion

Treatment of bleeding

There is no reversal agent for rivaroxaban licensed in children. The half-life of rivaroxaban varies with age and ranges from 5 to 9 hours in adolescents and young adults to down to 1.9 and 1.6 h in children aged 0.5-< 2 years and less than 0.5 years, respectively. Please refer to the adult guideline on Leeds Health Pathways: Management of Bleeding in Patients on Direct Oral Anticoagulants (DOACs)

Converting from Vitamin K Antagonists (VKA) to Rivaroxaban

VKA treatment should be stopped and Rivaroxaban therapy should be initiated once the INR is ≤ 2.5.
When converting patients from VKAs to Rivaroxaban, INR values will be falsely elevated after the intake of Rivaroxaban. The INR is not valid to measure the anticoagulant activity of Rivaroxaban, and therefore should not be used

Converting from Rivaroxaban to Vitamin K antagonists (VKA)

Children who convert from Rivaroxaban to VKA need to continue Rivaroxaban for 48 hours after the first dose of VKA. After 2 days of co-administration an INR should be obtained prior to the next scheduled dose of Rivaroxaban. Co-administration of Rivaroxaban and VKA is advised to continue until the INR is ≥ 2.0. Once Rivaroxaban is discontinued INR testing may be done reliably 24 hours after the last dose (see above and section 4.5).

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Heparin Induced Thrombocytopenia (HIT) and Protocol for the Use of Argatroban in Paediatric Patients

(Please also see adult Heparin Induced Thrombocytopenia guidelines)

If heparin induced thrombocytopenia is considered, please consult paediatric haematology consultant on call.

Argatroban, a synthetic L-arginine derivative, is a direct thrombin inhibitor that binds reversibly to thrombin. Argatroban exerts its anticoagulant effect independently of antithrombin and inhibits fibrin formation; activation of coagulation factors V, VIII and XIII; activation of protein C; and platelet aggregation. Argatroban is capable of inhibiting the action of both free and clot-associated thrombin. It does not interact with heparin-induced antibodies.

Use of Argatroban is unlicensed in children, minimal dosage data exists in children, and this guidance is extrapolated from adult experience. Refer to Medicines Compendium for further information.
Check coagulation screen before Argatroban administration

Contraindications to Argatroban

Argatroban is contraindicated in;

• Patients with uncontrolled bleeding.
• Patients who have hypersensitivity to Argatroban or to any of the excipients.
• Patients with severe hepatic impairment.

Dosage and administration of Argatroban

• Therapy with Argatroban is monitored using the activated partial thromboplastin time (APTT).
• Before commencing Argatroban, discontinue heparin therapy and check baseline APTT (activated partial thromboplastin time).
• Check patient’s weight.
• Assess liver function; patients with moderate hepatic impairment should receive lower starting doses of Argatroban.

Initial Dosage of Argatroban

• The initial dosage in paediatric patients (without hepatic impairment) in HIT type II is 0.75 microgram/kg/min, administered as a continuous IV infusion. No dosage adjustments in renal impairment.
• In paediatric patients with moderate hepatic impairment an initial dose of 0.2 microgram/kg/min is recommended. The APTT should be monitored closely and the dosage should be adjusted as indicated clinically. Argatroban is contra-indicated in patients with severely impaired liver function
• Dilute Argatroban to give a final concentration of 1mg/mL, with sodium chloride 0.9% or glucose 5%.
• Check APTT 2 hours after starting infusion, then adjust rate to achieve therapeutic range using the dose adjustment table below.
• Argatroban infusion must not be stopped to check the APTT.

Dose Adjustments of argatroban infusion

• Dose adjustment may be required to attain the target APTT 50-90 secs
• In the case of an APTT greater than 90 seconds, the infusion should be discontinued until the APTT is within the desired range (typically within 2 hours of discontinuation of infusion), and the infusion restarted at half of the previous infusion rate. The APTT should then be rechecked after 2 hours.
• The maximum recommended dose is 10 microgram/kg/min. The maximum recommended duration of treatment is 14 days, although there is limited clinical experience of administration for longer periods.

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Thrombolysis

Tissue plasminogen activator – tPA (Alteplase) is a fibrinolytic drug which acts as a thrombolytic agent by activating plasminogen to form plasmin, which degrades fibrin and so breaks up thrombi.

In paediatric patients, tPA is the agent of choice. The reason for this preference is its fibrin specificity, low immunogenicity, the existence of a US food and drug administration warning regarding urokinase and evidence of improved clot lysis in vitro compared to urokinase and streptokinase. However increased in vitro clot lysis by tPA has not been demonstrated in clinical trials in children.

In a review of thrombolysis in paediatric patients, there was success rate of 64% in 413 children (described as complete resolution), whilst 21% of children had no response. In a review of thrombolysis in neonates, reported overall patency rates ranged from 39% to 86.5% for children with aortic thrombosis and cardiac disease.

Administration of thrombolytic therapy is advised for children with limb-threatening or organ-threatening arterial thrombosis who fail to respond to initial heparin therapy and have no contraindications. The decision to use tPA should be made by the multi-disciplinary consultant team involved and the haematology consultant on-call should be made aware of the decision to use thrombolysis as soon as possible for guidance on dose, duration and monitoring of therapy.

Contraindications
Conditions that increase the risk of major bleeding during thrombolytic therapy are considered contraindications and are listed below. These contraindications are not absolute or evidence-based and in every individual clinical situation, the relative risks of thrombolytic therapy must be weighed against potential benefits;

1. Major surgery within 7 to 10 days
2. Active bleeding
3. Central nervous system surgery/ischaemia/trauma/haemorrhage within 30days
4. Prematurity and recent intra-ventricular haemorrhage
5. Seizures within 48hours
6. Inability to maintain platelets count greater than 50 x 109/L
7. Inability to maintain fibrinogen greater than 1g/L
8. Uncontrolled hypertension

Side effects

Bleeding, nausea and vomiting. Reperfusion can cause cerebral and pulmonary oedema. Hypotension (elevation of legs or reducing the rate can control this), allergic reactions and anaphylaxis. Back pain, fever and convulsions.

Preparation for starting thrombolysis

1. The patient must be on the paediatric intensive care unit (PICU) or High Dependency Unit (HDU), in paediatric cardiac theatres or the paediatric cardiac catheter laboratory.
2. Measure baseline Full blood count (FBC), prothrombin time (PT), activated partial thromboplastin time (APTT), Fibrinogen and D-dimer levels. tPA requires fibrin as a co-factor for the activation of plasminogen, therefore the patient requires adequate fibrinogen levels.
3. Notify blood bank and have one unit of packed red blood cells, fresh frozen plasma/ Octaplas and cryoprecipitate available at short notice.
4. In neonates or patients with recent head trauma consider cranial ultrasound or Head CT scan prior to initiating therapy to confirm/exclude intracranial haemorrhage.
5. Maintain fibrinogen level greater than 1g/L with cryoprecipitate.
6. Maintain platelets count greater than 50 x 109/L
7. Stop warfarin, non-steroidal anti-inflammatory drugs (NSAIDs), anti-platelet agents and therapeutic heparin.
8. Administer FFP/Octaplas 10mL/Kg, unless the patient is volume restricted
9. Start heparin infusion at 10unit/Kg/hr, once clotting screen is normal.

Route of administration
tPA can be given systemically or through a catheter in close proximity to the thrombus. Catheter directed thrombolysis can be extremely effective and allows low dose tPA to reach the site of action immediately.

Dose of systemic thrombolysis

• There is no consensus on the ideal dose of tPA. High dose tPA (0.5mg/Kg/hour) is associated with serious complications (10-40% major bleeding)
• At Leeds Children’s Hospital, tPA is usually started at 0.1mg/Kg/hour as a continuous intravenous infusion. The dose is increased by 0.1mg/Kg/hour every 3 to 4 hours according to assessment of efficacy and bleeding, up to a maximum of 0.6mg/Kg/hour. Care must be taken with older children at the higher dosage ranges.
• Duration of treatment will be clinically assessed considering the relative risks and benefits of continuation

Dose of local thrombolysis

• Catheter direct thrombolysis; tPA dose of 0.01mg/Kg/hour to 0.05mg/Kg/hour

Monitoring

• Monitor the response to thrombolytic therapy by measuring FBC, PT, APTT, fibrinogen and D-dimers 2 hours after onset of tPA and 2hours after a dose increase. Ensure the results are obtained and responded to before the next increment in tPA infusion rate is implemented. Once the dose does not change monitor every 6 hours until infusion is stopped.
• In order to reduce the risks of bleeding maintain the fibrinogen concentration at 1g/L or higher, using cryoprecipitate transfusions.
• Maintain the platelet count at greater than 50 x 109/L, using platelet transfusions.
• In a case of life-threatening bleeding while on thrombolysis, stop infusion and discuss with haematology consultant immediately.

Precautions during thrombolysis

• Avoid intramuscular injection
• Use minimal handling
• Avoid invasive procedures
• Bleeding at sites of venous or arterial puncture is not unusual but should alert physician to the possibility of more significant bleeding and prompt assessment of risks of continuing thrombolytic therapy

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Details of perioperative management of anticoagulation in patients who are taking oral anticoagulants

Specific guidance is available from the on call Paediatric Haematology Consultant. Please also refer to adult guidance on Leeds Health Pathways – ‘Guidelines for the perioperative management of warfarin in patients undergoing elective procedures’. ‘Guidelines for the perioperative management of DOACs in patients undergoing elective procedures’. Advice available in these guidelines will need specific paediatric interpretation.

Please refer to paediatric cardiology guidelines, if cardiac indication for anticoagulation.

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Regional Anaesthesia and Anticoagulant Prophylaxis

1. The use of LMWH thromboprophylaxis in patients at risk is not a contraindication to the performance of neuraxial anaesthesia in the absence of a coagulopathy. Timing must be carefully planned in relation to LMWH administration.
2. In patients on prophylaxis, the placement of a needle or epidural catheter, or removal or repositioning of the catheter should occur at least 12 hours after standard prophylactic LMWH doses.
3. If a bloody tap occurs during needle or catheter placement, LMWH should be delayed for 24 hours.
4. In patients with indwelling catheters, it is recommended that the first dose of LMWH should be given at least 12 hours after surgery, rather than immediately postoperatively.
5. In children on once daily dose thromboprophylaxis the removal of the epidural should be at least 10-12 hours after the last dose of LMWH.
6. Those on twice daily dose the removal of the epidural catheter should be at least 8 hours (2 half-lives) after the last dose.
7. In children on once or twice daily dose thromboprophylaxis, the next dose of LMWH should be given at least 4 hours after the removal of the epidural catheter.
8. In patients with an epidural indwelling catheter, on LMWH thromboprophylaxis, concomitant treatment with drugs that affect haemostasis (eg, NSAIDs) or antiplatelet medication should be used with caution.
9. Any patient with an epidural infusion presenting significant leg weakness should have the epidural infusion stopped, and no further LMWH until recovery. If there is no recovery of leg strength within 4 hours, a MRI scan should be performed to exclude spinal hematoma.

Nonneuraxial Blocks
Bleeding may be the most serious complication of nonneuraxial regional techniques in the anticoagulated patient. Therefore in high-risk procedures, the same guidelines as for neuraxial blocks regarding timing of LMWH and performance of the regional anesthesia technique, including insertion and removal of plexus catheters, should be applied.