Velma Marzinotto

The use of low molecular weight heparin in pediatric patients: a prospective cohort study.

OBJECTIVE Low molecular weight heparins (LMWHs) offer several advantages over standard anticoagulant therapy (unfractionated heparin/warfarin) including predictable pharmacokinetics, minimal monitoring, and subcutaneous administration. Our objective was to determine the safety and efficacy of LMWHs in children. METHODS A prospective cohort of children treated with the LMWH enoxaparin (Rhone Poulenc Rorer) was monitored at the Hospital for Sick Children, Toronto, Canada, from March 1994 until July 1997. RESULTS There were 146 courses of LMWH administered for treatment and 31 courses for prophylaxis of thromboembolic events (TEs). Clinical resolution of TEs occurred in 94% of children receiving therapeutic doses of LMWH, and 96% of children receiving prophylactic doses of LMWH had no symptoms of recurrent or new TEs. Major bleeding occurred in 5% of children receiving therapeutic doses. Recurrent or new TEs occurred in 1% and 3% of children receiving therapeutic and prophylactic doses of LMWH, respectively. CONCLUSION LMWH appears to be efficacious and safe for both management and prophylaxis of TEs. The results of this cohort study justify a randomized controlled trial comparing LMWH with standard therapy for the management of TEs in children.

Low-molecular-weight heparin in pediatric patients with thrombotic disease: A dose finding study

OBJECTIVE To compare low-molecular-weight preparations of heparin (LMWH) with standard heparin in children requiring anticoagulant treatment for thromboembolic disease. METHODS We treated 25 children who required heparin, but were at significant risk of bleeding, with LMWH (enoxaparin, Rhone-Poulenc Rorer). The median age was 4 years (range, newborn to 17 years), with nine infants less than 2 months of age. Fourteen children had a deep vein thrombosis or pulmonary embolism, nine had thrombotic complications in the central nervous system, and two had complex congenital heart disease, for which they received prophylaxis at a lower dosage (0.5 mg/kg given subcutaneously twice a day). The remaining 23 children received an initial dose of 1 mg/kg, every 12 hours subcutaneously, with subsequent doses adjusted to achieve a 4-hour anti-factor Xa level between 0.5 and 1.0 unit/ml. RESULTS Newborn infants had increased dose requirements; an average of 1.60 units/kg was required to achieve therapeutic heparin levels. For the remaining children, the initial dose of 1.0 mg/kg was sufficient. After the initial dose adjustment, LMWH was administered with twice-weekly monitoring. The median duration of therapy with LMWH was 14 days. Two children with previously documented gastrointestinal ulcers bled and required transfusion therapy. Therapy with LMWH was continued without further events. There were no new thrombotic events during the treatment with LMWH. The cost of administering LMWH compared with heparin was reduced by 30% because of decreased laboratory monitoring, blood sampling times, intravenous starts, and nursing time. Needle punctures were reduced with LMWH therapy by the placement of a subcutaneous catheter. CONCLUSION These results provide the basis for a randomized, controlled trial comparing LMWH with standard heparin in pediatric patients.

Heparin Therapy in Pediatric Patients: A Prospective Cohort Study

ABSTRACT: Current guidelines for heparin therapy in pediatric patients have been extrapolated from trials in adult patients without rigorous evaluation of efficacy and safety. We prospectively monitored consecutive pediatric patients receiving systemic doses of heparin over 10 mo at one institution using a predetermined nomogram to monitor maintenance therapy. Sixty-five consecutive children; 38 males and 27 females, received systemic doses of heparin. Thirty children had deep venous thrombosis and/or pulmonary embolism; 11 had arterial thrombi, most frequently after diagnostic angiography; and the remaining 24 received heparin prophylactically, for congenital heart disease. Twenty-nine (45%) of the 65 patients were less than 1 y of age and 22 (34%) were 10 y or older. Congenital heart disease was the predominant diagnosis under 1 y and deep venous thrombosis in older children. After a bolus dose of 50 U/kg, 39% of children (n = 30) achieved a minimal level activated partial thromboplastin time (APTT). Sixty-eight percent of children achieved a minimal level APTT by 24 h and 81% by 48 h. For all 65 children, APTT values were within the therapeutic range 43% of the time. APTT values outside the therapeutic range were twice as likely to be low as high. The average amount of heparin required to maintain therapeutic APTT values for children was 22 U/kg/h: 28 U/kg/h for infants <1 y and 20 U/kg/h for the rest. Bleeding was rare (2%) and mild. Documented recurrent thrombotic disease was more common (7%) with associated morbidity. In summary, a commonly used protocol for administration of heparin to children was rigorously evaluated and shown to provide insufficient amounts of heparin in the first days of treatment. Average requirements of heparin per kilogram per hour were determined and will form the bases of future studies.

A cross-sectional study of catheter-related thrombosis in children receiving total parenteral nutrition at home

We performed a cross-sectional evaluation of deep vein thrombosis (DVT) related to the use of central venous lines (CVLs) in all pediatric patients receiving home total parenteral nutrition at our institution (N = 12). All children (5 months to 17 years of age) were examined with bilateral upper limb venography. All CVLs were flushed daily with heparin (200 units). At the time of evaluation, 49 CVLs had been placed in the 12 children. Of the 39 CVLs removed, 27 (66%) were blocked; venograms had not been previously obtained except of one child. Eight children had clinical evidence of superficial collateral circulation in the upper portion of the chest and the upper extremities; five had intermittent symptoms of superior vena cava obstruction. On venography, 8 of the 12 children had extensive evidence of DVT; two were unilateral and six bilateral. Five children were treated with warfarin (0.12 to 0.28 mg/kg per day) to achieve an international normalized ratio of 1.4 to 1.8. Neither bleeding nor further CVL-related DVT has occurred. We conclude that the risk of CVL-related DVT in children requiring home total parenteral nutrition is high, and that venography should be performed early in the event of CVL blockage. A multicenter, controlled trial assessing optimal warfarin therapy in this patient population is indicated.

Home monitoring of warfarin therapy in children with a whole blood prothrombin time monitor

We prospectively evaluated a capillary whole blood prothrombin time (PT) monitor (Biotrack, Ciba Corning) in an outpatient pediatric anticoagulation clinic (40 clinic patients) and in age-matched healthy subjects (30 control subjects). Subsequently, 23 children requiring warfarin therapy were placed on a home program (home patients) using the PT monitor; their parents were trained and the results followed by clinic staff. The PT results were reported as internationalized normalized ratios (INRs). The laboratory and PT-monitor INR values were similar for the clinic patients and the control subjects (y = 0.76x + 0.38; r = 0.93; p < 0.001). The accuracy of the PT monitor (the difference between INR values and the laboratory INR) was best at an INR of 2.5 to 3.5; 90% of paired INR values were within 0.8 INR units. The average duration of monitoring for home patients was 13 months (range, 2 to 60 months). They had an average of 3 dose measurements (range, 1 to 11 measurements) and 1.8 dose changes (range, 0.6 to 4.5 changes) per month. Of the 599 measurements, 63% were within the therapeutic range, similar to those for clinic patients; the dose requirements were also similar. There was 1 significant bleeding event, a subdural hematoma in a patient with an INR of 4.1, and 1 catheter-related thrombotic event with an INR of 1.2; both children recovered. Of the 23 families, one discontinued home monitoring because of parental discomfort, 2 children died of their primary disease, 6 completed warfarin therapy, and 14 remain on the home program. We conclude that the whole blood PT/INR monitor is safe and offers practical advantages to children requiring anticoagulation.

Capillary Whole Blood Monitoring of Oral Anticoagulants in Children in Outpatient Clinics and the Home Setting

Abstract. A whole blood prothrombin time/international normalized ratio (PT/INR) monitor (CoaguChek, Roche Diagnostics Corp., Indianapolis, IN) was assessed in children for its accuracy, reliability, safety, and acceptance by health care personnel and patients families. The PT/INR values measured by the CoaguChek monitor showed an excellent correlation with PT/INR values measured by the Hospital for Sick Children (HSC) laboratory (r= 0.96) and Hamilton Civic Hospitals Research Centre (HCHRC) laboratory (r= 0.92) in clinic patients and a close correlation with PT/INR values measured by the HSC laboratory (r= 0.76) and HCHRC laboratory (r= 0.74) in patients at home. Reduced correlation in the home setting did not adversely affect clinical management. The whole blood PT/INR monitor is safe and accurate for children requiring oral anticoagulation therapy in either the outpatient clinic or home setting.

Dose-finding and pharmacokinetics of therapeutic doses of tinzaparin in pediatric patients with thromboembolic events.

In children, there is an increasing off-label use of low molecular weight heparin (LMWH). However, there is an absence of information on dosing and pharmacokinetics of LMWH over all age groups. The objectives of the current study were to determine i) the once daily dose required to achieve anti-Xa levels of 0.5-1.0 IU/mL, ii) the pharmacokinetics and iii) preliminary safety data using tinzaparin. The study took the form of a single centre open-label Phase II study performed in 35 children requiring anticoagulation for treatment of thromboembolism. Age groups studied were: 0- < 2 months; 2 months- < 1 year; 1- < 5 years; 5- < 10 years; 10-16 years. Both population pharmacokinetic analysis using nonlinear mixed-effect modeling techniques and model-independent pharmacokinetic methods were employed. Results showed a relationship of age and dose requirements, clearance, time to peak anti-Xa level and volume of distribution. Younger children required an increased dose, cleared tinzaparin more rapidly, had anti-Xa levels peak earlier and had an increased volume of distribution. Younger children were more likely to be below target range than older children,with up to 75% of children < 1 year being below the target anti-Xa level. Four recurrences and one major bleed occurred. In conclusion, there is an inverse relationship of age on dose requirements related to volume of distribution, clearance and time to peak anti-Xa. Children < 5 years likely require dose adjustment samples to be drawn 2-3 hours post injection. Infants require anti-Xa levels to be monitored at least twice monthly.

Heparin-Bonded Central Venous Catheters Do Not Reduce Thrombosis in Infants With Congenital Heart Disease: A Blinded Randomized, Controlled Trial

Background. Infants with congenital heart disease who require central venous lines are at increased risk of thrombosis. Heparin-bonded catheters provide protection from thrombotic events in some children. However, heparin-bonded catheters may not be as effective in infants ≤1 year old because of other potential risk factors (smaller vessel size, longer duration of catheter use). No studies have assessed the benefit of heparin-bonded catheters in such specific high-risk populations. The objective of this study was to assess the efficacy of heparin-bonded catheters for preventing thrombosis in infants aged ≤1 year with congenital heart disease. Study Design. This study was designed as a randomized, controlled, blinded single-center trial. Infants ≤1 year old with congenital heart disease requiring a central venous line for clinical care were randomly assigned to receive either a heparin-bonded catheter or a standard non–heparin-bonded catheter. Catheters were visually indistinguishable. The primary outcome was incidences of both silent and clinically noticeable thrombosis confirmed by ultrasound. Ultrasounds were reviewed by a blinded central adjudication committee. Interim analysis was performed after enrollment of 97 patients. Results. Eighty-seven patients were evaluable (41 of the patients were female). Thrombotic events occurred in 17 (42.5%) of 40 patients in the non–heparin-bonded catheter group and in 21 (44.7%) of 47 patients in the heparin-bonded catheters group. The study was stopped when the interim analysis showed convincing evidence for no difference between groups over the alternative hypothesis of 50% risk reduction. Conclusions. Infants with congenital heart disease are at significant risk of both silent and clinically identified thrombosis. There seems to be no advantage in using heparin-bonded catheters in infants ≤1 year of age.

The Use of Low Molecular Weight Heparin in Pediatric Patients: Review of A Single Institution Experience • 761

The Use of Low Molecular Weight Heparin in Pediatric Patients: Review of A Single Institution Experience • 761

MONITORING PEDIATRIC ORAL ANTICOAGULANT PATIENTS AT HOME WITH PROTIME MICROCOAGULATION SYSTEM. 895

MONITORING PEDIATRIC ORAL ANTICOAGULANT PATIENTS AT HOME WITH PROTIME MICROCOAGULATION SYSTEM. 895