Margaret Adams

Outcome of pediatric thromboembolic disease : A report from the Canadian Childhood thrombophilia Registry

The outcome for children with deep vein thrombosis (DVT) and pulmonary embolism (PE) is unknown. An understanding of morbidity and mortality of DVT/PE is crucial to the development of rational treatment protocols. The Canadian Childhood Thrombophilia Registry has followed 405 children aged 1 mo to 18 y with DVT/PE for a mean of 2.86 y (range, 2 wk to 6 y) to assess outcome. The all-cause mortality was 65 of 405 children (16%). Mortality directly attributable to DVT/PE occurred in nine children (2.2%), all of whom had central venous line–associated thrombosis. Morbidity was substantial, with 33 children (8.1%) having recurrent thrombosis, and 50 children (12.4%) having postphlebitic syndrome. Recurrent thrombosis and postphlebitic syndrome were more common in older children, although deaths occurred equally in all age groups. The incidence of recurrent thrombosis and postphlebitic syndrome are likely underestimated because of difficulties in diagnosis, especially in younger children. The significant mortality and morbidity found in our study supports the need for international multicenter randomized clinical trials to determine optimal prophylactic and therapeutic treatment for children with DVT/PE.

Central venous catheter related thrombosis in children: Analysis of the Canadian Registry of Venous Thromboembolic Complications

BACKGROUND Central venous lines (CVLs) are frequently associated with deep venous thrombosis (DVT) in children; however, little is known about the epidemiologic characteristics or outcome of CVL-related DVT. METHODS The Canadian Childhood Thrombophilia Registry monitored 244 consecutive patients with objectively diagnosed CVL-related DVT for a median duration of 24 months (range 3 months to 7 years). RESULTS The incidence of CVL-related DVT was 3.5 per 10,000 hospital admissions. CVL-related DVTs were more frequent in the upper venous system. Ultrasonography or echocardiography were the most commonly used diagnostic tests (n = 183 patients). Venograms were performed on 82 (34%) patients. A variety of therapies were used. Thirty-nine children had pulmonary emboli, but most were not investigated for pulmonary emboli. Nine (3.7%) children died as a consequence of their thromboembolic disease. Recurrent DVT occurred in 16 (6.5%) children, and postphlebitic syndrome occurred in 23 (9.5%) children. CONCLUSION Currently no uniform guidelines exist for the prevention and management of CVL-related DVT in children. The frequency and clinical consequences of CVL-related DVTs justify controlled trials of primary prophylaxis in children requiring central venous access.

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.

Delay to Diagnosis in Acute Pediatric Arterial Ischemic Stroke

Background and Purpose— For the clinician, the diagnosis of arterial ischemic stroke (AIS) in children is a challenge. Prompt diagnosis of pediatric AIS within 6 hours enables stroke-specific thrombolytic and neuroprotective strategies. Methods— We conducted a retrospective study of prospectively enrolled consecutive cohort of children with AIS, admitted to The Hospital for Sick Children, Toronto, from January 1992 to December 2004. The data on clinical presentation, symptom onset, emergency department arrival, neuroimaging and stroke diagnosis were recorded. The putative predictors of delayed diagnosis were selected a priori for analysis. Results— A total of 209 children with AIS were studied. The median interval from symptom onset to AIS diagnosis was 22.7 hours (interquartile range: 7.1 to 57.7 hours), prehospital delay (symptom onset to hospital arrival) was 1.7 hours (interquartile range: 49 minutes to 8.1 hours), and the in-hospital delay (presentation to diagnosis) was 12.7 hours (interquartile range: 4.5 to 33.5 hours). The initial assessment was completed in 16 minutes and initial neuroimaging in 8.8 hours. The diagnosis of AIS was suspected on initial assessment in 79 (38%) children and the initial neuroimaging diagnosed AIS in 47%. The parent’s help seeking action, nonabrupt onset of symptoms, altered consciousness, milder stroke severity, posterior circulation infarction and lack of initial neuroimaging at a tertiary hospital were predictive delayed AIS diagnosis. Conclusion— In the diagnosis of AIS, significant prehospital and in-hospital delays exist in children. Several predictors of the delayed AIS diagnosis were identified in the present study. Efforts to target these predictors can reduce diagnostic delays and optimize the management of AIS in children.

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.

Anticoagulants in pediatric cerebral sinovenous thrombosis: a safety and outcome study.

Clinical trials are lacking in pediatric cerebral sinovenous thrombosis (CSVT). Neonates and children increasingly receive anticoagulant therapy (ACT) based on adult studies. Safety data for ACT in pediatric CSVT are scant and urgently needed. The objective was to assess the safety and outcome of ACT in pediatric CSVT.

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.

The Relationship of Antiphospholipid Antibodies to Thromboembolic Events in Pediatric Patients with Systemic Lupus Erythematosus: A Cross-Sectional Study

The purpose of this study was to evaluate pediatric patients with systemic lupus erythematosus (SLE) to determine 1) the incidence of thrombosis, 2) the incidence of antiphospholipid antibodies, and 3) whether there is an association between the presence of antiphospholipid antibodies and thrombosis. We performed a cross-sectional cohort study in 59 consecutive SLE patients who had been managed at rheumatology clinics in two pediatric hospitals. A history, questionnaire, and chart review were completed by the study nurse blinded to laboratory results. Only the thrombotic events that could be substantiated by review of radiographic tests were accepted. The presence of antiphospholipid antibodies was determined by prospective analysis for a lupus anticoagulant and anticardiolipin antibodies on two separate occasions at least 3 mo apart. Patients were considered to be positive if one or more tests were positive on both occasions. Thirteen thrombotic events occurred in 10 of the 59 patients(17%). Fourteen patients (24%) were classified as positive for lupus anticoagulant, and 19 patients (27%) were classified as positive for anticardiolipin antibodies. A significant relationship between the presence of a lupus anticoagulant and a thrombotic event was shown: odds ratio 28.7(95% confidence interval 4.03-138.2, p < 0.001). A nonsignificant trend was seen for the presence of an anticardiolipin antibody and a thrombotic event: odds ratio 2.12 (95% confidence interval 0.71-22.8,p = 0.08). We conclude that in pediatric patients with SLE:1) a significant proportion of patients have thrombotic events,2) a significant proportion of patients have antiphospholipid antibodies, and 3) there is a significant relationship between the presence of a lupus anticoagulant and thrombotic events.

A multicenter study of the treatment of childhood chronic idiopathic thrombocytopenic purpura with anti-D

We evaluated the effects of the intravenous administration of anti-D, an immune globulin directed at the D antigen on erythrocytes that is purified from plasma from sensitized persons, on patients with idiopathic thrombocytopenic purpura. To determine the most effective dose, the duration of response, and the side effects of this therapy in children, we performed a multicenter cohort study of escalating doses of intravenously administered anti-D in children aged 1 to 18 years with chronic idiopathic thrombocytopenic purpura, defined as idiopathic thrombocytopenic purpura persisting for more than 6 months with a platelet count of less than 50 x 10(9) cells/L. Twenty-five Rh-positive children received increasing doses of anti-D as follows: day 1, 25 micrograms/kg; day 2, 25 micrograms/kg; day 7, 35 micrograms/kg; day 14, 45 micrograms/kg; and day 21, 55 micrograms/kg. Administration of anti-D was stopped after day 21 or when the platelet count rose to greater than 150 x 10(9) cells/L or the hemoglobin level was 100 gm/L. Platelet count was less than 50 x 10(9) cells/L in all children before treatment. A response was defined as an increase in the platelet count to more than 50 x 10(9)/L and a doubling of the pretreatment platelet count. Of 25 children, 23 (92%) had responses by day 7 of the initial treatment protocol. Eighteen children (72%) had platelet counts greater than 150 x 10(9) cells/L by day 7 after two doses of anti-D. Median duration of response was 5 weeks (range 1 to 24 weeks). Average drop in hemoglobin level was 13.7 gm/L; in one child (a nonresponder) hemoglobin value fell to less than 100 gm/L. No other untoward side effects were seen. Of the 23 children who responded, 21 were retreated with one dose of anti-D when platelet counts returned to baseline values of less than 50 x 10(9) cells/L; all but three of the children who underwent retreatment showed a response the second time. Sixteen children continued to receive intermittent anti-D therapy after completion of the study, and all continued to have excellent responses. We conclude that anti-D is a safe, effective, and relatively inexpensive therapy for childhood chronic idiopathic thrombocytopenic purpura.

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.