Patti Massicotte

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.

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.

A case series of 72 neonates with renal vein thrombosis Data from the 1-800-NO-CLOTS Registry

Neonatal renal vein thrombosis (RVT) is a well-recognized clinical entity which is associated with serious morbidity. However, current information regarding RVT has been restricted to case reports and small case series. In this study, it was our objective to describe patient demographics, clinical presentation, location and risk factors of RVT. For our study design, we looked at a case series of 72 neonates with RVT referred to the 1-800-NO-CLOTS consultation service between 9/1996 and 8/2001. Data on age, gender, associated conditions, prothrombotic disorders, family history, location of the thrombosis, diagnostic techniques, and treatment were prospectively recorded using a standardized form. Our results show that RVT affected males (65%, CI 52-76%) significantly more often than females (35%, CI 24-48%). Median age at presentation was 2 days (0-21 days). RVT was unilateral in 72% (left side: 67%,CI 49-81%; right side: 33%, CI 19-51%), and bilateral in 28%. The majority (83%) had at least one associated condition: Prematurity (54%), central venous lines (17%), a diabetic mother (13%), asphyxia (6%), infections (6%). Prothrombotic testing was performed in 21 neonates. Activated protein C resistance was found in 8 children (38%), other defects in three. This is the largest case series of neonatal RVT to date. Data from the study show that i) male infants are affected twice as often as females and ii) there appears to be a left-sided predominance of neonatal RVT. Neonatal RVT is only infrequently associated with the presence of a catheter as compared to thrombosis at other sites. The majority of infants have associated conditions with prematurity being most frequent. A small subset of neonates were screened for prothrombotic abnormalities and 50% of the children screened were positive.

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.

Decompressive Hemicraniectomy in Children With Severe Ischemic Stroke and Life-Threatening Cerebral Edema

Decompressive hemicraniectomy has been discussed as a treatment option that increases survival in adults with malignant stroke. This approach has not been studied extensively in children. From a prospective cohort, we identified 4 children who underwent decompressive hemicraniectomy for malignant infarctions with life-threatening cerebral edema within 72 hours of their stroke. All 4 children had different causes for their stroke and experienced severe cerebral edema with increasing intracranial pressure and an impending fatal outcome. Despite massive cerebral infarction, all patients were ambulant and able to speak at the time of follow-up. Although a limited experience, decompressive hemicraniectomy is a life-saving approach for malignant stroke in children.

Impact of Persistent Antiphospholipid Antibodies on Risk of Incident Symptomatic Thromboembolism in Children: A Systematic Review and Meta-Analysis

The aim of this study was to estimate the impact of antiphospholipid (aPL) antibodies on the risk of incident thromboembolism (TE; arterial and venous) in children via meta-analysis of published observational studies. A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1966 to 2010 was conducted using keywords in combination both as MeSH terms and text words. Two authors independently screened citations and those meeting the a priori defined inclusion criteria were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, TE type, and frequency of recurrence were abstracted. Heterogeneity across studies was evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using either fixed-effects or random-effects models. Of 504, 16 pediatric studies met the inclusion criteria. In total 1403 patients and 1667 population-based controls ≤18 years were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. Thus, data from arterial and venous TE were analyzed together. In addition, meta-regression analysis did not reveal statistically significant differences between site of TE, age at first TE, country, or publication year. A statistically significant association with a first TE was demonstrated for persistent aPL antibodies, with an overall summary ORs/CI of 5.9/3.6-9.7 (arterial 6.6/3.5-12.4; deep vein thrombosis 4.9/2.2-10.9). The present meta-analysis indicates that detection of persistent aPL is clinically meaningful in children with, or at risk for, TE and underscores the importance of pediatric thrombophilia screening programs.

Novel paediatric anticoagulants: a review of the current literature.

There are many limitations with respect to anticoagulants currently used in standard paediatric practice for prophylaxis and treatment of thrombosis: heparin, low-molecular-weight heparin, and warfarin. Factors such as pharmacokinetic and dosing variability are further exacerbated by properties of the immature haemostatic system of children. These shortcomings necessitate exploring alternative anticoagulants in the paediatric population. In this review, we discuss several promising direct thrombin inhibitors and factor Xa inhibitors, and synthesize relevant drug information and clinical experience from the limited available case reports, case series, and nonrandomized dose-finding trials published to date.

The Impact of Central Venous Catheters on Pediatric Venous Thromboembolism

The use of central venous catheters (CVCs) in children is escalating, which is likely linked to the increased incidence of pediatric venous thromboembolism (VTE). In order to better understand the specific risk factors associated with CVC-VTE in children, as well as available prevention methods, a literature review was performed. The overall incidence of CVC-VTE was found to range from 0 to 74%, depending on the patient population, CVC type, imaging modality, and study design. Throughout the available literature, there was not a consistent determination regarding whether a particular type of central line (tunneled vs. non-tunneled vs. peripherally inserted vs. implanted), catheter material, insertion technique, or insertion location lead to an increased VTE risk. The patient populations who were found to be most at risk for CVC-VTE were those with cancer, congenital heart disease, gastrointestinal failure, systemic infection, intensive care unit admission, or involved in a trauma. Both mechanical and pharmacological prophylactic techniques have been shown to be successful in preventing VTE in adult patients, but studies in children have yet to be performed or are underpowered. In order to better determine true CVC-VTE risk factors and best preventative techniques, an increase in large, prospective pediatric trials needs to be performed.