Review of Anticoagulant Drugs in Paediatric Thromboembolic Disease

18th Expert Committee on the Selection and Use of Essential Medicines (21 to 25 March 2011)

Section 12: Cardiovascular medicines 12.5 Antithrombotic medicines

September 2010

Prepared by:

Fiona Newall Anticoagulation Nurse Manager/ Senior Research Fellow Royal Children’s Hospital/ The University of Melbourne Melbourne, Australia

1 Contents

Intent of Review Review of indications for antithrombotic therapy in children Venous thromboembolism Arterial thrombeombolism Anticoagulant Drugs Unfractionated heparin Mechanism of action and pharmacology Dosing and administration Monitoring Adverse events Formulary Summary recommendations Vitamin K antagonists Mechanism of action and pharmacology Dosing and administration Monitoring Adverse events Formulary Summary recommendations Low Molecular Weight Heparins Mechanism of action and pharmacology Dosing and administration Monitoring Adverse events Formulary Summary recommendations ??Novel anticoagulants Summary

2 1. Intent of Review To review the indications for anticoagulant therapies in children. To review the epidemiology of thromboembolic events in children. To review the literature and collate the evidence regarding dosing, administration and monitoring of anticoagulant therapies in childhood. To review the safety of anticoagulant therapies and supervision required To give recommendations for the inclusion of anticoagulants on the WHO Essential Medicines List

2. Review of indications for antithrombotic therapy in children Anticoagulant therapies are given for the prevention or treatment of venous and/or arterial thrombosis. The process of ‘development haemostasis’, whereby the proteins involved in coagulation change quantitatively and qualitatively with age across childhood, essentially protects children against thrombosis(1-5). For this reason, insults such as immobilization are unlikely to trigger the development of thrombotic diseases in children. Even if inherited genetic predisposition is present in children, they are unlikely to develop a thrombosis until adulthood(2). As a result, the epidemiology of thromboembolic disease differs between children and adults, with the majority of thrombotic events diagnosed in children being iatrogenic (2, 6-8).

However, this finding likely reflects the state of this disease in developed countries, where advanced surgical and medical approaches are used to treat and palliate life- threatening conditions. There is very little evidence reporting the prevalence of thromboembolic diseases in developing countries. A Medline search using key words, “thrombosis or stroke”, ‘developing countries’ and limited to humans, the English language and all children identified 20 articles: of these, only 1 actually included episodes of thromboembolic disease in children(9). As such, recommendations for the management of thromboembolic disease in childhood are very much limited to tertiary paediatric populations in developed countries.

Venous Thromboembolism (VTE) The risk factor most frequently identified as the leading contributor of VTE in childhood is the placement of central venous access devices(6, 8). Other conditions associated with the development of VTE in childhood include malignancy, vascular malformations, trauma or surgery (8, 10-12). The reported incidence of VTE in children ranges from 0.07/10,000 Canadian children in the community to 5.3- 8.0/10,000 children admitted to tertiary hospitals(8, 10). Children who develop spontaneous VTE are likely to be adolescents with some form of inherited or acquired thrombophilia (8, 10). The rate of inherited and acquired thrombophilia conditions varies depending upon the ethnic origin of a population. For example, the prevalence of thrombophilia in childhood is significantly higher in mainland Europe than in Australian and North American studies investigating VTE in childhood (8, 10, 13).

Demonstrating the significant underlying health problems associated with VTE in childhood, the all-cause mortality associated with a concomitant diagnosis of VTE in one study population was 8.4%, with 15% of children who survived to discharge having significant VTE-related morbidity at follow-up (8).

3 Arterial Thromboembolism (ATE) Similar to VTE, ATE is unlikely to occur in healthy children. No registry data reporting the incidence of ATE in healthy children is available. For hospitalized children however, ATE occurs with a similar prevalence to VTE. A 2-year prospective registry of ATE in an Australian tertiary paediatric centre identified an incidence of 8.5/10,000 hospital admissions (7). Children presenting with ATE usually have multiple pre-disposing factors present, including placement of intra- arterial devices, vascular malformations, surgery and congenital heart disease (7). One subset of patients presenting with ATE are children with Arterial Ischaemic Stroke AIS). In children, AIS may develop secondary to congenital heart disease due to right-to-left shunts, or seemingly unprovoked(6, 14, 15).

Arterial thromboembolism in childhood is associated with significant morbidity and mortality. The only prospective registry of ATE in childhood determined a direct ATE-related mortality rate of 9%, with 49% of children who survived to discharge being diagnosed with long-term physiological deficits associated with their ATE(7)

3. Anticoagulant Drugs Unfractionated heparin (UFH) a. Mechanism of action and pharmacology Unfractionated heparin is a heterogeneous glycosaminoglycan with a molecular weight ranging from 3000 to 30,000 kD (16-21). Whilst UFH used for clinical purposes was initially isolated from the livers of pigs and dogs, the majority of commercial UFH preparations currently available are isolated from porcine intestinal mucosa or bovine lung (19). The majority of UFH binding occurs due to electrostatic attraction, however the binding of UFH to antithrombin (AT) is highly specific and dependent upon a unique pentasaccharide sequence located on ‘high affinity’ UFH molecules (22, 23). ‘High affinity’ UFH fractions with a molecular weight greater than 5000Da are able to inhibit thrombin and factor Xa, whilst UFH fractions with a molecular weight of less than 5000Da preferentially promote inhibition of factor Xa only(20, 24, 25). In the presence of UFH, AT’s inhibition of coagulation serine proteases increases approximately 1000-fold(26). In addition, UFH increases the intravascular release of tissue factor pathway inhibitor (TFPI) (27-36). Three to ten minutes following the injection of UFH, TFPI release from the vascular endothelium increases in a dose and concentration dependent fashion(34). Between one third and one half of the thrombin inhibition achieved following the administration of UFH in vivo is attributable to TFPI (30). b. Dosing and administration of UFH Few randomized controlled trials of UFH dosing, route of administration or duration of therapy have been conducted in paediatric populations. The majority of evidence available is based upon a handful of cohort studies in children at risk of thrombosis or who have been diagnosed with a thrombosis.

Original research studies reporting evidence related to the dosing, administration and/or monitoring of UFH in children was identified from a Medline search (1950- 2009). The key word was ‘Heparin’, and the search was limited to ‘Administration

4 and Dosing’, ‘English Language’, ‘Humans’ and ‘All Child’ (0-18years). 281 papers identified. 20 papers provided details regarding unfractionated heparin dosing and/or monitoring in children. Studies reporting the use of UFH for the maintenance of vascular catheters were excluded. Table 1 summarises the studies identified.

The American College of Chest Physicians produces evidence-based guidelines for the management of antithrombotic therapy every 3 years. Within this volume of work there is a chapter dedicated to Antithrombotic therapy in children. For each recommendation regarding dosing and administration of UFH, the grade of evidence associated with that recommendation is listed. Due to the lack of well-designed randomized controlled trials generating evidence regarding optimal dosing, administration and monitoring, the bulk of these recommendations has a Grade 2 level of evidence(6).

5 Author/date Study design Study population (incl. N) Age Distribution Dosing recommendation Monitoring

Ekert Cohort study Haemolytic Uraemic 15 days to 8.5 yrs - UFH administered from day of diagnosis - UFH effect measured using aPTT. 1973(37) Syndrome (n=9); - Loading doses of 100-400units/kg - aPTT demonstrated significant intra- and Disseminated Intravascular - Infusion doses to maintain aPTT 1.5-2.5 inter-individual variation, both within Coagulopathy (N= 8); times normal. disease groups and between groups. Purpura fulminans (n=1) - Duration of Rx: HUS (7days); DIC (8 - 1 cerebral haemorrhage and 1 major days); PF (23 days) bleeding from renal biopsy site – both fatal. 4 ‘minor’ bleeding events (no a priori definitions were given). Freed, Double-blinded n=161 1-34 years - 100-150unit/kg UFH bolus versus No recommendation Keane and RCT Children and young adults (median 11yrs) placebo. Rosenthal undergoing cardiac All patients > - In children < 10yrs of age, 100units/kg 1974(38) angiography. 10kg UFH significantly reduced the rate of cool, pulseless extremities following cardiac angiography compared to placebo (p=0.003). McDonald Prospective N=15 25 weeks - Bolus of 50-100units/kg followed by - UFH concentration measured using anti- 1982(39) cohort study Infants (term and preterm) gestation, day 1 to infusion rate of 10-20units/kg/hr Xa assay with documented venous or 28 month old term - UFH effect measured using Laidlaw arterial thromboembolism baby. Whole Blood Clotting Time - r2 of anti-Xa and WBCT was 0.47 - Good clinical outcome for 14 of 15 infants. One child required amputation of digits - Used mathematical equations, not pharmacokinetic methods, to determine UFH clearance in infants. This suggested infants had increased clearance compared to adults. von Kries, Cohort study of N=10 Gestational ages - UFH and AT was mixed and continuously - UFH effect measured using thrombin Stannigel ‘heparin Newborn infants with ranged from 30- infused in 5% glucose clotting time. and Gobel activated Disseminated Intravascular 40 weeks. - Doses ranged from 20-40 units/kg/day of - Study did not evaluate the method of 1985(40) antithrombin Coagulopathy and life- No details re age AT and 50-500units/kg/day UFH. monitoring. (AT) threatening illness who had at time of UFH. - Authors concluded that 40units/kg/day of concentrate” poor UFH response or low AT and 200units/kg/day UFH achieved the newborns AT levels. best thrombin clotting time for treatment benefit

6 Author/date Study design Study population (incl. N) Age Distribution Dosing recommendation Monitoring

Netz et al Prospective N= 120 No age ranges UFH dose = 100units/kg - UFH effect measured by ACT 1987(41) cohort study Infants and children given. Patients were divided into: - ACT demonstrated UFH response requiring cardiac -infants with cyanotic heart disease (25) differed between infants and children, angiography -infants with acyanotic heart disease (25) regardless of heart disease -children with cyanotic heart disease (25) - ACT demonstrated UFH response -children with acyaontic heart disease (45) differed between cyanotic and acyanotic heart disease, regardless of age. - No multivariate analyses were conducted to determine the independent impact of age and cyaonotic heart disease upon UFH response - 100 unit/kg UFH caused a 3-fold increase in ACT values within 15mins of UFH, this reduced to 2-fold increase by 60mins post bolus. Andrew at al Prospective n=65 (Male = 38) <1 year= 29 Mean dose according to age: - UFH effect measured using aPTT 1994(42) cohort Venous thrombosis n=38 1-10yrs =14 <1year 28units/kg/hr - aPTT therapeutic in 68% of patients by Arterial thrombosis n=11 >10yrs= 22 >1year 20-22units/kg/hr 24hrs and 81% of patients by 48 hrs Congenital heart disease following UFH initiation. prophylaxis n=24 - Therapeutic aPTT levels achieved in 43% of tests Grady, Prospective n=36 1 month – 50 or 100 units/kg bolus - UFH effect measured using ACT Eisenberg cohort Children undergoing cardiac 19.5years - 50units/kg bolus increased ACT to and Bridges angiography. 209±52secs versus ACT of 270±57 secs 1995(43) following a 100units/kg bolus. - ACT >200seconds prevented significant increase in thrombin activity, as measured by fibrinopeptide A. Saxena et al Quasi- N=366 17days to 11 - 50 units/kg vs 100units/kg. No information re anticoagulant therapy 1997(44) experimental Children undergoing cardiac years - Arterial thrombosis rate was 9.8% and monitoring was provided. angiography 9.3% respectively. - Likelihood of thrombosis related to increased number of vascular access attempts (p<0.001), absence of back bleed at the end of procedure (p<0.001) and increased duration of procedure (p<0.01).

7 Author/date Study design Study population (incl. N) Age Distribution Dosing recommendation Monitoring

- Based on clinical criteria, the authors conclude that 50units/kg is as efficacious as 100units/kg. Codispoti et RCT of 13 in each arm - “Standard” UFH dose was 300units/kg. - UFH concentration was measured using al 2001(45) standard UFH - Interventional UFH dose was an automated protamine titration assay. therapy for individualized based on an automated - UFH effect was measured using thrombin Cardio- protamine titration assay generation and fibrinolysis. pulmonary -Higher UFH doses were given to the - Thrombin generation (p=0.02) and bypass versus intervention group versus the standard fibrinolysis (p=0.05) was reduced more individualized therapy group (p<0.001). significantly in the intervention versus approach - Blood loss and transfusion requirements control group. lower in intervention vs control group (p=0.05) Chan et al In vitro spiking 10 donors were used to 2 to 13 years 0.25units/mL spiked into plasma pools - UFH effect measured using thrombin 2002(46) of pooled make up each of the 3 age- generation. plasma from related plasma pools - Thrombin generation demonstrated UFH cord, children inhibits thrombin to a greater degree in and adults plasma pools from children compared to adults. - Proportionately more thrombin-alpha2M complexes were formed in plasmas from children and newborns compared to that of adults Massicotte Multi-centre LMWH = 36 4 months to 17.7 - UFH dosing not prescribed as standard No measures of UFH effect were reported. et al international UFH/VKA = 40 years practice at each study site was used. 2003(47) RCT of - 12.5 % rate of major bleeding reported in UFH/VKA UFH/VKA arm versus 5.65% in LMWH versus LMWH arm (ns). for venous (No details provided as to whether these thrombosis events occurred on UFH or VKA therapy). Nankervis et Prospective 12 neonates on veno-arterial Age range not Mean UFH infusion rate 42.2±10.9 - UFH effect measures using ACT and anti- al 2007(48) cohort study extracorporeal membrane given. units/kg/hr (range 20-69.5unitskg). Xa assay. oxygenation - mean ACT = 167 ±20 seconds. - mean anti-Xa assay = 0.73±0.19units/mL - poor correlation between ACT and UFH dose and ACT and anti-Xa assay

8 Author/date Study design Study population (incl. N) Age Distribution Dosing recommendation Monitoring

- strong correlation between anti-Xa and UFH dose (r2=0.75) - Authors concluded the ACT was NOT a reliable indicator of UFH effect and the anti-Xa assay increased during time on ECMO, suggesting UFH effect may accumulate. Baird et al Retrospective Children requiring ECMO Median age 3days - Mean UFH dose= 45± 21 units/kg - UFH effect measured using ACT 2007(49) review of (duration ranged from 6-134 (IQR 1-52 days) - Survivors (49±20units/kg/hr) received - Mean ACT 227±50 secs. Extracorporeal hours) higher UFH doses than non-survivors - Modest correlation between UFH dose Membrane (39±22units/kg/hr) (p<0.001). and ACT (r=0.48 survivors; 0.42 non- Oxygenation at survivors). a single - All survivors had shorter ECMO times institution (171± 24 hours versus 197±166 hours, p= between 1980- 0.017) 2001 - ACT not predictive of survival (p=0.36) Kuhle et al Prospective Children >36 weeks Age data not Mean dose 25.3± 8.4 units/kg/hr - UFH effect measured using aPTT, anti- 2007(50) cohort study gestational given Xa and TCT. age and ≤18 years of age - No assay demonstrated strong correlation admitted with UFH dose. to the critical care unit and - ‘Agreement’ between APTT and aXa requiring therapeutic occurred in <33% of cases. doses of UFH for ≥12h - Based on the assumption that the anti-Xa is the ‘gold standard’ method for UFH monitoring, the authors concluded the aPTT was a poor option for UFH monitoring Guzzetta et RCT of Infants requiring CPB who Infants in - Intervention group received significantly - UFH effect measured using surrogate al 2008(51) standard UFH were < 6 mo of age intervention were higher UFH doses than control 597± 22 vs measures: Prothrombin Fragments 1.2, or UFH titrated older than control 1080± 392units; p<0.001) fibrinopeptide A, βTG, FV, FVIII. to HEPCON group (114± - No difference in the mean protamine dose - Authors concluded that use of the Hepcon during Cardio- 29days vs 138±27 in each arm (control= 4.0±0mg/kg; resulted in greater suppression of Pulmonary days; p= 0.04) intervention=3.9±1.9 mg/kg; P< 0.84). haemostasis than standard UFH dosing Bypass regimen. Ignjatovic et In vitro UFH Plasma pools consisting of at < 1 year UFH spiked in concentration of 0.1, 0.3, - UFH effect measured using aPTT, anti- al 2006 (52) spiking study least 15 donors were 1-5 years 0.5, 0.7, 1.0 units/mL Xa, anti-IIa

9 Author/date Study design Study population (incl. N) Age Distribution Dosing recommendation Monitoring

prepared according to the 6-10 years - An anti-Xa assay of 0.35 to 0.7 units/mL age-ranges list in next 11-16 years resulted in aPTT ranges of 82-177secs in column infants < 1 yr to 55-118 in adults (p<0.05). Ignjatovic et Prospective 167 patients (96 male) Mean age = 2.2 UFH dosing ranged from 10units/kg/hr - UFH effect measured using aPTT and al 2006 (53) observational Paediatric Intensive Care ±3.1 years (range infusion to 100units/kg bolus dose anti-Xa assay. study Unit 2 days to - In vivo response of aPTT to UFH is age- Haemodialysis unit 13.5 years). dependent. Cardiac angiography - aPTT values correlating to an anti-Xa assay of 0.35 to 0.7 units/mL were >180seconds. - aPTT values correlating with anti-Xa assay of 0.35 to 0.7units/mL demonstrated clinically significant variance. Ignjatovic et Prospective Children admitted to the UFH dose of 10units/kg/hour to - UFH effect measured using 3 different al 2007(54) observational Padiatric Intensive Care Unit 25units/kg/h (± bolus) within the previous anti-Xa assay kits. study or Haemodialysis unit 6 h - anti-Xa assay kits with exogenous requiring UFH therapy antithrombin or Dextran Sulphate produce difference anti-Xa results compared to the modified assay that contained neither. - The addition of AT or DS to anti-Xa kits generates non-physiological results. Newall et al Prospective N=85 54 (64%) < 1yr. UFH infusions of >10units/kg/hr. - UFH effect measured using aPTT, anti- 2009(55) observational Patiens < 16years Remaining UFH doses ranged from 12.1 to Xa, anti-IIa, and thrombin generation. study of UFH in patients analysed 15.1units/kg/hour. - Antithrombin levels decreased compared PICU setting. according to age to age-related norms in children up to 11 (1-5,6-10, 11- years of age. 16years) - anti-Xa and anti-IIa showed a trend to lower levels in younger children despite similar UFH doses. - thrombin generation showed a trend for increased thrombin inhibition in older children. -in vitro AT supplementation did not correct the age-related differences in anti- Xa or ETP. Table 1. Summary of Studies Investigating UFH Dosing, Administration and Monitoring in Infants and Children

10 c. Monitoring of UFH Monitoring of UFH is necessary due to its relatively narrow therapeutic window. Sub- therapeutic levels of UFH are associated with an increased risk of thrombus development, propagation or recurrence, whilst supra-therapeutic UFH levels are associated with a significant bleeding risk (56). Despite the enormous energy and funding that has been invested in the development of laboratory assays that will inform clinicians regarding UFH therapy, all assays currently available share two common limitations: first, the heterogeneity of UFH has prohibited the development and utilization of one method suitable for measuring UFH effect universally; second, measures of UFH effect in vitro are yet to mirror UFH effect in vivo. As such, the results generated aim to correlate with the goal of thrombosis treatment or prevention, and do not measure the primary goal of therapy

Table 2 summarises the 3 assays commonly used to monitor UFH therapy. The gold standard method for measuring UFH concentration in plasma is Protamine titration. In 1954, Refn and Vestergaard reported a method for protamine titration to determine UFH concentration, which is still used today(57), although a micro-method has been published that allows this assay to be performed using one fifth of the original plasma volume(58). Recommendations for UFH therapy from the American College of Chest Physicians (ACCP) suggest target APPT ranges for UFH therapy reflect heparin concentrations of 0.2 – 0.4 IU/ml by protamine titration or 0.35 to 0.7 IU/m by anti- Xa assay(56). The APTT range corresponding to these concentrations of UFH must be determined on an institutional basis due to the high level of variability observed between APTT reagents(59). Protamine titration produces reliable and reproducible results, however it is not a convenient assay for the conventional management of UFH as it is not readily automated(60). This has resulted in many laboratories using the anti-Xa assay as a surrogate measure of UFH concentration. The anti-Xa assay facilitates the measurement of UFH’s AT-catalysed inhibition of Xa(59-66) and is broadly used to guide the determination of therapeutic APTT ranges in the clinical management of UFH(56). The anti-Xa assay is easy to perform, automated and experiences minimal interference from biological variables, however it is more expensive than the commonly used APTT and may not be available in smaller laboratories(60). Prior to performing an anti-Xa assay, each laboratory must create a normal curve for UFH using a pool of normal plasma spiked with varying amounts of UFH. To this plasma pool, known quantities of Xa are added, and after a period of incubation, the amounts of residual Xa are measured(59).

The APTT can best be described as a non-specific measure of the intrinsic and common pathways of the coagulation system(67). Clinical trials of UFH therapy investigating mode of delivery(68), duration of therapy(69) and dose(70) determined that a heparin concentration of 0.2-0.4 units/ml by protamine titration that correlated to an APTT of 1.5 to 2.5 times normal values produced desirable UFH safety and efficacy outcomes(71, 72). As a result, most advisory bodies recommend therapeutic APTTs be determined by correlating APTT results with therapeutic UFH levels as measured by anti-Xa assay (0.35-0.7 IU/ml) or protamine titration (0.2-0.4 IU/ml)(56). However, the APTT is sensitive to changes in coagulation factors, inhibitors to coagulation factors, and pre-analytical variables such as difficult venous bleed, delayed mixing with citrate solution and delayed time to laboratory processing (59, 61, 73, 74). As a result, the APTT lacks specificity for UFH therapy(75). Despite these limitations, the APTT continues to be widely utilized in UFH management.

11 In paediatric populations, baseline APTT levels are increased compared with adult normative values and alter with age. This likely reflects quantitative, and possibly qualitative, developmental differences in various haemostatic parameters. Whilst clinical trials confirmed the need for substantive prolongation of the APTT, anti-Xa and/or protamine titration assays for the effective management of thromboembolic disease in adults, such trials have not been conducted in paediatric populations. As such, the defined laboratory parameters that suggest UFH is likely to be safe and efficacious in adult patients remain as yet untested in paediatrics. What is abundantly clear however is that unfractionated heparin appears to elicit variable effect in infants and children, compared to adults (52, 53, 76, 77). Use of either a protamine titration assay range of 0.2 to 0.4 unit/mL or an anti-Xa assay range of 0.35 to 0.7 units/mL results in a 3 to 4-fold increase in APTT prolongation than that observed in adults(76, 77). Whether titrating UFH therapy to achieve an APTT in excess of 200 seconds in a child would produce improved therapeutic outcomes without significantly increasing haemorrhagic risk is not known.

12 Assay Common Uses Advantages Disadvantages APTT - Coagulation screening - Low cost. - Prolonged APTT does not mean effective anticoagulation assay - Easy to perform - Wide variability in reagent sensitivity F-Clot - Therapeutic UFH - broadly available - Non-physiological measure of UFH effect monitoring Anti-Xa - Calibration of APTT - Direct measure of UFH - Not as broadly available as APTT. reference ranges. inhibition of Xa. - Costs more than the APTT. F-Ch - Therapeutic UFH - Easy to perform. - Some variability in reagent sensitivity. monitoring. - Does not measure other mechanisms of UFH effect (eg. Anti- IIa). Protamine - Not used clinically. - Only assay that directly measures - Not broadly available. - Used by reference UFH concentration. - Automated methods have not been validated for management Titration laboratories. - Inexpensive. of therapeutic UFH and manual methods labour intensive. Q Table 2. Summary of Assays Used to Monitor UFH Therapy. Key: F-Clot = Functional, Clot based assay; F-Ch = Functional, Chromogenic assay; Q = quantitative assay

13 d. UFH-related Adverse events Bleeding As with all studies reporting bleeding outcomes of anticoagulant therapy, determining the true incidence of clinically significant bleeding from UFH trials is complicated by the lack of consistency in defining bleeding events. As a result, a broad range of major bleeding events associated with UFH therapy have been reported, ranging from 1% to 56% of patients receiving UFH therapy (69, 78-81). Generally, bleeding rates reported with UFH therapy increase in the presence of individual risk factors, significantly prolonged or increased monitoring assays (APTT, anti-Xa assay) and method of administration(81).

In the only prospective cohort study of UFH therapy in paediatrics, no major bleeding events were observed(82). However, this finding must be viewed in context of the relatively low rate of therapeutic anticoagulation reported in the study (68% at 24 hours) and the likelihood of patients who did not have a therapeutic APTT being subtherapeutic. In the only randomised controlled trial of therapeutic anticoagulation that has been conducted in children, (the REVIVE study) low molecular weight heparin therapy was compared to UFH and VKA for the treatment of venous thromboembolic events(47). The REVIVE study reported a major bleeding rate of 12.5% in the UFH/VKA arm of the study(47). A recent retrospective cohort study of children receiving UFH in a paediatric intensive care unit setting determined that 24% of children exposed to UFH development major bleeding(83). Whilst alarming, this result must be tempered by the very broad definition of major bleeding used within the study.

Heparin-Induced Thrombocytopaenia (HIT) Heparin Induced Thrombocytopaenia II (HIT II) is an immune-mediated adverse reaction to UFH that occurs in less than 3% of patients exposed to heparin for 5 or more days(84). Diagnosis of HIT II is complicated by the lack of any a definitive diagnostic test to confirm the presence of an immune reaction to UFH. There are two methods of testing for HIT II: functional assays (platelet aggregation/ Serotonin- release assay) and immuno-assays (PF4 ELISA)(85). Both methods offer a high negative predictive value (i.e. rule out HIT II) however their positive predictive value is moderate(85).

There have been no prospective studies to determine the incidence of HIT in paediatrics. There are a number of case reports which highlight the paediatric-specific nature of this adverse-drug reaction, but their methods of confirming the diagnosis of HIT and management of the adverse reactions are inconsistent. Platelet aggregation studies have been frequently used to investigate the prevalence of HIT in children exposed to UFH (86). Whilst such assays do measure reactivity of platelets to heparin, this reactivity does not necessarily indicate the presence of an immune reaction to heparin and cannot be used to confirm the diagnosis of HIT alone. One tertiary paediatric centre conducted a retrospective audit of all suspected cases of HIT in that centre(87). Despite 15% of children admitted to that centre being exposed to UFH, only four cases of suspected HIT were identified across a 2-year period. This finding confirms the suspicion of many paediatric haematologists that HIT occurs with significantly less frequency in children than in adults.

Accidental UFH Overdose Given the many different preparation of UFH available (see formulary), accidental overdose of UFH is a significant risk. There is no universally recognized mechanism to aid in the correct identification of different strength vials. For infants especially, confusing a 50 unit/5mL vial with a 5000 unit/5mL vial can easily occur as the only difference between the two is the colour of the writing on the vial. Great care therefore needs to be paid when preparing all UFH infusions or bolus doses. e. Formulary of UFH Unfractionated heparin is prepared by many pharmaceutical companies. The strength and volume of vials varies significantly and as previously mentioned, there is no consistent approach to packaging UFH doses. Available strengths range from 5 units/1mL to 500 units/mL.

f. UFH Summary recommendations (i) UFH is an affordable medication and the laboratory assays available to monitor it are readily available and affordable. Of the available assays suitable for monitoring UFH therapy, the aPTT, whilst having acknowledged limitations, is certainly the most affordable option. (ii) Age-specific dosing of UFH is required. All dosing decisions need to be reviewed in light of laboratory-based monitoring to optimize treatment outcomes. Evidence-based guidelines for UFH dosing and administration are best taken from the ACCP Antithrombotic Therapy guidelines(6). Many of the clinical recommendations listed within these guidelines however may not reflect the patient demographics common to developing nations. (iii) None of the laboratory assays currently available for UFH monitoring demonstrate strong correlation with protamine titration – the gold standard method of determining UFH concentration. As a result, all laboratory assay results should be considered in light of the patient’s clinical condition and prognosis.

Vitamin K antagonists (VKAs) a. Mechanism of action and pharmacology Warfarin, phenprocoumon and acenocoumarol are Vitamin K antagonists. Bacteria in the gut are responsible for the reduction of Vitamin K to Vitamin K epoxide. This is absorbed in the intestine and converted to available Vitamin K by an enzyme known as Vitamin K epoxide reductase. Clotting factors II, VII, IX and X need this enzyme to become functional. Vitamin K Antagonists exert ther action by inhibiting Vitamin K epoxide reductase, reducing the amount of Vitamin K available to synthesise the Vitamin K dependent clotting factors (88, 89, 90 10). Antagonism of Vitamin K, or a deficiency of this vitamin results in effective anticoagulation of the patient (90, 91). Therapeutic doses of VKA drugs reduce the availability of functional Vitamin K dependent clotting factors by approximately 30% (90). Upon oral ingestion, VKAs are absorbed rapidly from the GI tract and bind firmly to plasma albumin (92). The

15 VKA are primarily metabolised by the liver, raising significant clinical implications for patients with hepatic dysfunction due to their reduced ability to clear the drug (89, 91, 93).

The anticoagulant state produced by VKAs is dependent upon clearance of functional clotting factors from the body. Factor VII has the shortest half-life of all the Vitamin K dependent clotting factors and it is the first factor affected by the initiation of VKA therapy. Factor II (prothrombin) has a much longer half-life and levels of Factor II do not decrease until day five to six of therapy. The reduction in circulating Factor VII levels is not thought to be as significant in producing an antithrombotic state as the reduction in Factor II (92). Although certain coagulation studies may become prolonged after two to three days of therapy, achievement of functional anticoagulation is not fully achieved until day five to six of therapy (90).

b. Dosing and administration The dose response relationship of VKA therapy is influenced by both genetic and environmental factors. Genetic resistance to VKAs has been reported in human and animal models. Environmental factors such as coexisting disease states, concomitant medications, and diet also influence VKA response (89, 91, 92). Medications such as aspirin and non-steroidal anti-inflammatories, although not directly influencing VKAs, do increase the risk of bleeding secondary to VKA therapy by disrupting normal platelet function (92). The response to VKA therapy can fluctuate significantly secondary to changes in the factors described previously. Patients receiving VKAs must be closely monitored in order to prevent adverse events such as haemorrhage or progressive thromboembolic disease, which are directly related to “over” and “under” anticoagulation respectively (89).

Original research studies reporting evidence related to the dosing, administration and/or monitoring of VKA therapy in children was identified from a Medline search (1950-2009). Three searches were conducted:

i). “Warfarin”: limited to ‘Administration and Dosing’, ‘English Language’, ‘Humans’ and ‘All Child’ (0-18years). Seventeen papers were identified, but of these only seven papers provided details regarding warfarin dosing and/or monitoring in children. ii). “Phenprocoumon”: limited to ‘Administration and Dosing’, ‘English Language’, ‘Humans’ and ‘All Child’ (0-18years). Eight papers were identified, however no papers provided details regarding phenprocoumon dosing and/or monitoring in children. iii). “Acenocoumarol”: limited to ‘Administration and Dosing’, ‘English Language’, ‘Humans’ and ‘All Child’ (0-18years). Twenty-one papers were identified, however only two papers provided details regarding acenocoumarol dosing and/or monitoring in children.

Table 3 summarises the evidence generated by these studies.

16 Author/date Study design Study population (incl. N) Age Distribution Dosing recommendation Monitoring

Bradley et al Comparative N= 28 Mean age = 7.9 - Mean warfarin dose = - No monitoring data reported 1985(94) Cohort study Children with proshetic years 0.16mg/kg/day. - Haemorrhage risk 22/100 pt years on warfarin vs of warfarin heart valves. - Mean aspirin/dipyridamole doses 0/100 pt years on Aspirin/Dipyridamole. and Aspirin/ = 6.1 and 1.9 mg/kg/day, - Thrombosis risk 0/100 patient years on warfarin vs dipyridamole respectively 12/100 pt years on ASA/Dip. - Authors concluded that warfarin is better than Aspirin/Dipyridamole for prosthetic valve prophylaxis as the morbidity and mortality outcomes of thrombosis were worse than those associated with bleeding. Doyle et al Retrospective Retrospective n=26 Not specified Warfarin Loading Dose = Warfarin monitored using the Prothrombin time 1988(95) and Prospective n=15 0.2mg/kg/day for 2 days prospective cohorts Thrombosis = 6 Prosthetic valve = 6 CHD (other) = 7 Andrew et al Prospective n=115 (68 males) < 1 year (19) Mean warfarin dose (mg/kg±SD): - Warfarin monitored using the INR 1994(96) cohort 2° prophylaxis = 56 1-5 years (33) <1year = 0.32 ± 0.05mg/kg - Mean INR frequency = 4 tests/mth 1° prophylaxis = 59 6-10 years (20) 11-18 years = 0.09 ± 0.01mg/kg - Target therapeutic range (2.0 – 3.0) Achievement = Venous thrombosis = 64 11-18 years (43) 46% (n=101) Congenital Heart Disease =67 Tait et al Prospective n=45 (27 males) 9 months to 18 Median warfarin dose mg/kg/day - Warfarin monitored using the INR 1996(97) cohort Main indication: CHD years (IQR): - Mean INR frequency was every 3 weeks < 2yrs 0.14 (0.11-0.19) - TTR Achievement 2-5yrs 0.11 (0.09-0.13) - TTR 2.0 – 3.0: 62% 6-10yrs 0.09 (0.07 – 0.1) - TTR 3.0 – 4.0: 39% 11-18yrs 0.08 (0.07-0.09) Cheung & Retrospective n= 35 (23 male) Mean age 8.4 ± - Warfarin Target INR 1.5 to 2.5 - Warfarin monitored using the Prothrombin time Leung cohort DVT = 2 5.8 years (range: - Mean warfarin dose (mg/kg±SD): expressed as INR. 1998(98) CHD = 33 0.4 to 19.7 years). 0–2 years = 0.14±0.05 - Frequency of testing not specified 2–5 years = 0.13±0.04 - TTR Achievement not specified 5–10 years = 0.09±0.04 10–18 years = 0.07±0.03 Streif et al Prospective n=319 (180 males) <1 year 43 - Mean warfarin dose (mg/kg±SD): - Warfarin monitored using the INR. 1999(99) cohort Secondary prophylaxis=41% 1-6 years 123 <1year = 0.33±0.2 - Mean No. of INR tests/month ± SD; TTR%±SD

17 Primary prophylaxis =59% 6-13 years 74 1-6 years = 0.15±0.1 <1 year = 8.1±5.5; 37±16 CHD n=114 13-18 years 112 6-13 years = 0.13±0.06 1-6 years = 5.7±3.4; 45±18 Non-CHD n=155 13-18 years = 0.09±0.05 6-13 years = 4.6±4.0; 54±18 Fontan n=50 13-18 years = 3.8±3.0; 53±19 Newall et al Prospective n= 94 (44 Males) < 1yr 7 - no recommendation regarding - Warfarin monitored using the INR 2004(100) cohort CHD n=67 1-5yrs 13 warfarin dose/kg - Mean No. of INR tests/month; TTR % CVL prophylaxis n=15 6-10yrs 23 < 1 year 6.8; 49.2 Ischaemic Stroke n=3 11-15yrs 24 1-5 years 3.9; 61.5 Arterial thrombosis n=2 >15yrs 27 6-10 years 2.6; 66.9 Venous thrombosis n=7 11-15 years 2.6: 65.7 >15 years 1.8; 62.4 Soper et al Retrospective n=26 (16 males) Median age - No recommendation regarding - Warfarin monitored using the INR 2006(101) Case Series Fontan circulation n =14 6.4years (range warfarin dose/kg/ - Median No. INR tests/mth; TTR % for total Prosthetic valve n =7 3.1 to 18.1 years) population = 1.9–2.1; 76-79% Kawasaki disease n =2 Cardiomyopathy n =1 Other n =3

Author/date Study design Study population (incl. N) Age Distribution Dosing recommendation Monitoring

Bonduel et Prospective n=93 (54 males) 2mth-1year = 19 Acenocoumarol doses: - Acempcoumarol monitored using the INR al 2003(102) cohort 1-5 years = 27 2mth-1 year = 0.2 mg kg-1 - Median No. of INR tests/mth; TTR% Primary prophylaxis n=21 6-10 years =20 1-5 years = 0.09 mg kg-1 2months-1 year = 3; 40 Secondary prophylaxis n=72 11-18 years =27 6-10 years = 0.07 mg kg-1 1-5 years = 2; 57 Venous thrombosis n= 66 11-18 years = 0.06 mg kg-1 6-10 years = 2; 70 Pulmonary embolism n = 5 Median (range) = 11-18 years = 2; 63 CHD n= 22 5.1 years (0.2-18) Woods et al Retrospective n=31 (12 male) Age range 5mths Acenocoumarol Mean dose = - Acenocoumarol monitored using the Prothrombin 1986(103) cohort – 16 years. 1.5mg/day (0.71-2mg/day) time expressed as INR CHD with prosthetic heart - TTR 72% valves - Monthly monitoring assays. Table 3. Summary of Studies Investigating VKA Dosing, Administration and Monitoring in Infants and Children

18 c. VKA Monitoring The effect of warfarin therapy is measured by the Prothrombin Time (PT). This measurement is achieved by combining the plasma of the anticoagulated patient with thromboplastin derived from rabbit or human brain (and later recombinant thromboplastins), and measuring elapsed time until clot formation. The PT is measured in seconds, with the usual normal range being between 12-16 seconds. In 1982 the World Health Organisation recommended that the INR be used to report the PT to ensure consistency and reliability (90). This ratio is determined by assigning each thromboplastin used in performing a PT a sensitivity index (ISI), which is used to interpret the PT result generated. The INR in a non-warfarinised, healthy adult should be between 0.9-1.1.

Regular blood monitoring of adults and children receiving warfarin is imperative to the safe and effective use of this agent (11, 96, 99, 104-106). The literature supports the current understanding that children receiving warfarin require more frequent monitoring than their adult counterparts due to the complexity of their underlying medical conditions (107). The gold standard method for monitoring warfarin therapy is a venous INR. In the subgroup of paediatric patients likely to be warfarinised, the ability to use the gold standard method of testing is significantly challenged due to poor venous access relative to the frequency of testing required (107).

The advent of point-of-care INR monitoring using a drop of capillary whole blood has provided a safe and reliable alternative to venous INR monitoring in children(100, 107-112). Many of the commercially available capillary INR monitors have had validation studies performed in children, and have been shown to perform equally well when used within institutional settings or by patients in their homes. d. VKA-related adverse events Bleeding The literature suggests that although more difficult to control in children, warfarin produces a similar risk of bleeding in children as in adults (0.5-6.5% risk of major bleeding per year of therapy)(88, 96). As warfarin therapy is likely to be initiated in children with significant underlying pathologies, the presentation of a bleeding event is likely to occur at a site of injury or weakness, rather than at an unaffected site (113). In the Sixth ACCP guidelines for Antithrombotic therapy in children, Monagle et al report the approximate bleeding rates for children receiving warfarin, as minor or serious events (104). Twenty percent will develop a minor bleeding event (eg. bruising, epistaxis, bleeding from cuts etc) per patient year. The annual rate of serious bleeding is proportional to intensity of therapy, (114, 115) with children who have mechanical heart valves (target INR 2.5-3.5) having a higher risk (<3.2%) than all other warfarinised children (target INR 2.0-3.0) in whom the major bleeding rate is 1.7% (104). Osteoporosis Of recent years, there has arisen concern regarding the long term effects of warfarin on bone mineral density (BMD), particularly in children. A component of warfarin induced embryopathy is deformity in bone development (116). Bone growth requires Vitamin K dependent proteins (osteocalcin), which, like the coagulant proteins produced by the liver, are antagonised by warfarin. No prospective data has been published on this potential adverse event in children. A paper was presented at an

19 international conference in 1999 suggesting longterm warfarin therapy may influence the BMD in growing children (117). Due to concerns raised in this paper, further research was conducted in an Australian paediatric centre, revealing 94% of children taking long term warfarin had BMD results below their age-related mean, with one third recording a BMD score two standard deviations below the mean (118). The authors acknowledge that confounding variables exist as to the cause of this reduced BMD, notably the prevalence of congenital heart disease in this population. In the adult literature, conflicting reports exist as to the relationship between warfarin and reduced bone density (119, 120). e. VKA Formulary No suspension formulation of VKAs is available. All presentations are in tablet form. Coumadin: 1mg/ 2mg/ 5mg Marevan: 1mg/ 3mg/ 5mg Phenprocoumon: (not available in Australia and i’m not sure what the presentations available internationally are) f. Summary recommendations for VKAs Vitamin K antagonists have been shown to produce safe and effective anticoagulation in children in both retrospective and prospective cohort studies. Due to the lack of randomized trials in this area however, data is lacking regarding optimal dosing strategies and target therapeutic ranges for listed indications in children. As such, the bulk of recommendations regarding VKA therapy in children have been extrapolated from adult evidence. A summary of these recommendations can be found in the ACCP Recommendations for Antithrombotic Therapy in Children(6).

More evidence is available regarding the optimal dosing and monitoring of warfarin and acenocourmarol in children than phenprocoumon. Choice between warfarin and acenocoumarol should be made based upon geographical availability and experience. Both require monitoring using a prothrombin time reported as an INR. Given the lack of paediatric-specific evidence regarding optimal treatment intensity and duration, extrapolation from adult indications and practice is common. Vitamin K antagonists are inexpensive drugs and the monitoring assays used to measure treatment efficacy are affordable when venous blood collection is performed. The infrastructure required to support point-of-care monitoring of VKA therapy is more costly.

20 Low Molecular Weight Heparins a. Mechanism of action and pharmacology Low Molecular Weight Heparins are prepared by chemically or enzymatically altering UFH chains to isolate the region containing the unique pentasaccharide sequence required for binding to antithrombin(121). As a result, LMWHs experience less competitive plasma binding compared to UFH and elicit a more predictable anticoagulant response(6, 121, 122). Due to their reduced chain-length, LMWHs are unable to bind simultaneously to antithrombin and thrombin, meaning thrombin inhibition is not possible(121). Rather, LMWH preparations produce the bulk of their anticoagulant effect by potentiating the antithrombin-mediated inhibitor of factor X(121).

This chemical alteration results in LMWHs having a longer half-life and reduced reversibility compared to UFH(6). As a result, LMWHs are commonly used in patients with less acute risk of haemorrhage and for whom prompt reversibility is unlikely to be necessary. b. Dosing and administration

Original research studies reporting evidence related to the dosing, administration and/or monitoring of LMWH therapy in children was identified from a Medline search (1950-2009). The key search term was “Low Molecular Weight Heparin” with resultant articles limited to ‘Administration and Dosing’, ‘English Language’, ‘Humans’ and ‘All Child’ (0-18years). Eight papers provided details regarding low molecular weight heparin dosing and/or monitoring in children. These are summarized in Table 4.

21 Author/date Study design Study population (incl. N) Age Distribution Dosing recommendation Monitoring

Hofmann et Retrospective N=79 children 2 weeks to 19 - LMWH doses of 45-100 units/kg/day - LMWH monitored using the “Coacute” al 2001(123) cohort study years. required to achieve prophylactic anti-Xa levels anti-Xa assay used (Chromogenix), Primary thromboprophylaxis of 0.2-0.4 units/mL. containing exogenous antithrombin. post surgery or trauma = 62 - No patient receiving the above regime Venous thrombosis = 13 developed a new thrombosis. - LMWH doses of 200-500units/kg/day 78% had LMWH for < 2 required to achieve therapeutic anti-Xa levels wks of 0.5-1.0 IU/mL. Enoxaparin or nadroparin - Clinical outcomes all improved in children were used. given LMWH following lytic therapy, regardless of whether lytic therapy resulted in complete thrombus resolution or not. -Patients given LMWH following UFH demonstrated either complete (n=6), partial (n=2) or no re-occlusion (n=4). Strater et al Quasi- N= 135 children post first Age range 6 - Aspirin dose = 4 mg/kg per day. - LMWH measured using an anti-Xa 2001(124) experimental episode of ischaemic stroke. months to 18 - LMWH dose = 1 to 1.5 mg/kg per day assay with target range 0.2-0.4units/mL. design Aspirin n=49 years - 9.6% of children had a recurrent stroke – - No data given re whether this was comparing LMWH n=86 there was no difference in incidence rate achieved in the arm allocated LMWH Aspirin and Follow up 8-48 months between Aspirin and LMWH arms. treatment. LMWH Chan et al In vitro 10 donors were used to 2 to 13 years 0.25units/mL spiked into plasma pools - LMWH effect measured using Thrombin 2002(125) spiking of make up each of the 3 age- generation. pooled plasma related plasma pools - Thrombin generation demonstrated from cord, LMWH inhibits thrombin to a greater children and degree in plasma pools from cord blood adults compared to children and adults. - More thrombin-alpha2M complexes were formed in plasma from children and newborns compared to adults Massicotte Dose finding N=24 3 months to 16 - Children > 5 kg require 30units/kg (SC), - LMWH monitored using an anti-Xa et al study of years. twice daily assay. 2003(126) LMWH - Children < 5 kg require 50units/kg (SC), - Dosing changes made using a nomogram primary twice daily. to reflect an anti-Xa assay of 0.1-0.3 prophylaxis of units/mL

22 Author/date Study design Study population (incl. N) Age Distribution Dosing recommendation Monitoring

VTE related to CVLs Massicotte Multi-centre 36 in LMWH arm 4 months to 17.7 -.A nomogram was used to adjust LMWH - LMWH effect was measured using an et al international 40 in UFH/VKA arm years doses to achieve an anti-Xa level between anti-Xa assay 4 hours post a morning dose 2003(47) RCT of 0.50 and 1.0 units/ml. on either Day 1 or 2 of treatment. UFH/VKA vs Reviparin was LMWH used. -major bleeding occurred in 5.6% of patients - Once TTR anti-Xa achieved, tests were LMWH for in the LMWH arm. repeated monthly. VTE - Anti-Xa assay were within TTR for 75% of test points. Massicotte Multi-centre N=186 2 months to 16.8 - Treatment arm received 30units/kg for - LMWH effect measured using anti-Xa et al international years. infants and children >3 months of age and 50 assay. 2003(127) RCT of Children having CVL units/kg if < 3 months of age, twice daily - Mean (range) anti-Xa results in LMWH LMWH vs insertion. - Control group received no anticoagulation. arm: 0.136 (0.025–0.550) units/ml. Placebo for N=92 reviparin - Study was underpowered, but found no prevention of N=94 standard care significant difference in rate of CVL-related CVL-related thrombosis between the 2 arms (14.1% vs thrombosis 12.5% (OR=1.15; 95% CI 0.42, 3.23). Kuhle et al Single centre, N=35 Age groups: -Younger children required increased doses of - LMWH was monitored using an anti-Xa 2005(128) open label, - 0-2 months Tinzaparin compared to older children. assay. phase II study. - 2 month-1 year - Younger children cleared Tinzaparin more - Infants required anti-Xa monitoring at - 1-5 years rapidly and had increased volume of least twice monthly. - 6-10 years distribution compared to older children. - Younger children achieved earlier peaks - 11-16 years - Up to 75% of <1yrs olds had subtherapeutic in anti-Xa activity compared to older anti-Xa assays children. Schobess et Open label N=80 Age range 3 - LMWH Dose given was 1mg/kg BD for 7- - LMWH monitored using an anti-Xa al 2006(129) pilot safety months to 18 14 days after which patients were stratified to assay. study Infants and children with years receive once daily (1.5mg/kg) or BD (1 mg/kg - Target anti-Xa assay 4 hours post dose = venous thrombosis. BD) dosing. 0.5-0.8units/mL Outcome measures: Post Thrombotic Syndrome, 6.3% of patients developed Post Thrombotic 3 patients required dose adjustments recurrent thrombosis, Syndrome. based on sub- or supra-therapeutic anti-Xa bleeding and death. 4 children developed recurrent thrombosis. levels. Table 4. Summary of Studies Investigating LMWH Dosing, Administration and Monitoring in Infants and Children

23 c. Monitoring Low molecular weight heparin therapy is monitored using the anti-Xa assay. The therapeutic range for LMWH management of thromboembolic disease is an anti-Xa assay between 0.5 and 1.0 unit/mL(6, 121, 122, 130). An anti-Xa range of 0.3 to 0.5 units/mL is considered an acceptable range for the prevention of thromboembolic disease(6, 121, 122, 130). The anti-Xa assay can be purchased as a test kit from a number of providers and is performed via an automated coagulation analyser.

The anti-Xa assay requires venous collection into a citrate containing tube. There are currently no point-of-care devices validated for use in monitoring LMWH therapy. Recent evidence has demonstrated that LMWH has a less consistent dose-response profile in children compared to adults(122, 131). As a result, ongoing monitoring of LMWH therapy is necessary even once steady-state therapy appears to have been achieved. Given the increased expense of anti-Xa monitoring compared to the APTT assay, and the fact that not all institutions are able to perform this assay, consideration must be given to the availability of monitoring prior to choosing a LMWH as a therapeutic option. d. Adverse events Bleeding Major bleeding is the most serious potential adverse event associated with LMWH therapy in children. Rates of LMWH-related major bleeding range from 0.7% to 5.6% in children(47, 122), with one study including only neonate participants reporting a major bleeding rate of 10.8%(132). Bleeding is more commonly reported in infants and children who have had recent injury or surgery(6). Other There is no paediatric-specific data regarding the potential association between LMWH preparations and heparin induced thrombocytopaenia, osteoporosis or allergy. e. Formulary Paediatric dose-finding and pharmacokinetic studies have been conducted for Enoxaparin, Tinzaparin and Reviparin.

Australia Enoxaparin: 20mg/0.2mL; 40mg/0.4mL; 60mg/0.6mL*; 80mg/0.8mL*; 100mg/1.0mL*; 120mg/0.8mL*; 150mg/1.0mL* (*graduated syringes) Dalteparin: 2500units/0.2mL; 5000units/0.2mL; 7500units/0.75mL; 10,000 IU/mL; 12500units/0.5mL; 15000units/0.6mL; 18000units/0.72mL Danaparoid: 750units/0.6mL f. Summary recommendations Low Molecular Weight Heparin preparations provide an attractive alternative to UFH and VKA, both of which require frequent blood monitoring. That being said, LMWH still require venous blood collection for anti-Xa monitoring even once therapeutic levels have been achieved. This is due to the fact that children have a less predictable dose-response to LMWH preparations than adult patients. As such, access to anti-Xa monitoring is essential.

Low molecular weight heparin preparations and the anti-Xa assays required to monitor them make choosing LMWHs a more expensive option than either UFH or VKAs.

4. Summary

Anticoagulant therapies are reportedly being used with increased frequency in paediatric practice(2). This likely reflects advances made in tertiary care of acute and chronic illnesses in infants and children, and as such is a statistic that reflects developed countries more than developing countries. The bulk of evidence-based recommendations for the use of anticoagulant therapies in children are specific for children with complex conditions requiring access to highly technical and expensive therapies(6). Table 5 presents summarises the clinical indications for anticoagulant therapy in children presented in the ACCP 2008 recommendations into 21 discrete categories(6). Of the indications within this list, only 10 indications are likely to be encountered within health services in developing countries (these have been indicated using an “*”). Of these 10 indications, consideration still needs to be given to the availability of monitoring assays to ensure the safety and efficacy of treatment provided.

Given the breadth of options available for achieving anticoagulant therapy in children even without considering novel antithrombotic agents now becoming available, clinicians face significant challenges in deciding upon the best course of treatment. Without doubt, anticoagulant therapies such as UFH and VKAs offer clinicians in developing countries significant advantages including:

i). A greater body of evidence with respect to paediatric-specific dosing and monitoring ii). Increased affordability of both the drug and monitoring assays Whilst these therapies certainly have the common limitation with respect to an unpredictable dose-response profile, significant literature is available to guide clinicians with respect to optimization of these therapies in children.

Indications for Antithrombotic Management Deep Vein Thrombosis: Central Venous Line- (CVL) and Non-Central Venous Line Related* Veno-Occlusive Disease Prophylaxis Neonatal Renal Vein Thrombosis* Primary Antithrombotic Prophylaxis for CVLs Primary Prophylaxis for Blalock-Taussig Shunts Primary Prophylaxis for Fontan Surgery Primary Prophylaxis for Stage I Norwoods Primary Prophylaxis for Glenn or BCPS Primary Prophylaxis for Endovascular Stents Primary Prophylaxis for Dilated Cardiomyopathy* Primary Pulmonary Hypertension* Biological Prosthetic Heart Valves* Mechanical Prosthetic Heart Valves* Ventricular Assist Devices (VADs) and Extra-Corporeal Membranous Oxygenation (EMCO) Therapy of Arterial Thrombosis* Arterial Catheter Prophylaxis Primary Prophylaxis for Venous Access related to Haemodialysis Use of UFH or LMWH for Haemodialysis Kawasaki Disease* Cerebral Sinovenous Thrombosis (CSVT) and Arterial Ischaemic Stroke (AIS)* Purpural Fulminans*

Table 5. Summary List of Indications for Antithrombotic Therapy in children. Adapted from(6).

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