Patricia Massicotte

Antithrombotic Therapy in Neonates and Children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

This chapter about antithrombotic therapy in neonates and children is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs, and Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading, see Guyatt et al in this supplement, pages 123S-131S). In this chapter, many recommendations are based on extrapolation of adult data, and the reader is referred to the appropriate chapters relating to guidelines for adult populations. Within this chapter, the majority of recommendations are separate for neonates and children, reflecting the significant differences in epidemiology of thrombosis and safety and efficacy of therapy in these two populations. Among the key recommendations in this chapter are the following: In children with first episode of venous thromboembolism (VTE), we recommend anticoagulant therapy with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1B]. Dosing of IV UFH should prolong the activated partial thromboplastin time (aPTT) to a range that corresponds to an anti-factor Xa assay (anti-FXa) level of 0.35 to 0.7 U/mL, whereas LMWH should achieve an anti-FXa level of 0.5 to 1.0 U/mL 4 h after an injection for twice-daily dosing. In neonates with first VTE, we suggest either anticoagulation or supportive care with radiologic monitoring and subsequent anticoagulation if extension of the thrombosis occurs during supportive care (Grade 2C). We recommend against the use of routine systemic thromboprophylaxis for children with central venous lines (Grade 1B). For children with cerebral sinovenous thrombosis (CSVT) without significant intracranial hemorrhage (ICH), we recommend anticoagulation initially with UFH, or LMWH and subsequently with LMWH or vitamin K antagonists (VKAs) for a minimum of 3 months (Grade 1B). For children with non-sickle-cell disease-related acute arterial ischemic stroke (AIS), we recommend UFH or LMWH or aspirin (1 to 5 mg/kg/d) as initial therapy until dissection and embolic causes have been excluded (Grade 1B). For neonates with a first AIS, in the absence of a documented ongoing cardioembolic source, we recommend against anticoagulation or aspirin therapy (Grade 1B).

Pulmonary thromboembolism in children

Pulmonary thromboembolism (PTE) is uncommonly diagnosed in the pediatric patient, and indeed often only discovered on autopsy. The incidence of pediatric PTE depends upon the associated underlying disease, diagnostic tests used, and index of suspicion. Multiple risk factors can be found including: peripartum asphyxia, dyspnea, haemoptysis, chest pain, dehydration, septicemia, central venous lines (CVLs), trauma, surgery, ongoing hemolysis, vascular lesions, malignancy, renal disease, foreign bodies or, uncommonly, intracranial venous sinus thrombosis, burns, or nonbacterial thrombotic endocarditis. Other types of embolism can occur uncommonly in childhood and need to be recognized, as the required treatment will vary. These include pulmonary cytolytic thrombi, foreign bodies, tumor and septic emboli, and post-traumatic fat emboli. No single noninvasive test for pulmonary embolism is both sensitive and specific. A combination of diagnostic procedures must be used to identify suspect or confirmed cases of PTE. This article reviews the risk factors, clinical presentation and treatment of pulmonary embolism in children. It also highlights the current diagnostic tools and protocols used to evaluate pulmonary embolism in pediatric patients.

Berlin Heart EXCOR Pediatric ventricular assist device Investigational Device Exemption study: Study design and rationale

BACKGROUND Currently, there are no Food and Drug Administration-approved devices available that can provide long-term mechanical circulatory support to smaller children with severe heart failure as a bridge to heart transplant (HT). In recent years, the Berlin Heart EXCOR Pediatric ventricular assist device (VAD) has emerged as a potential treatment option. Systematic data on the safety and efficacy of the EXCOR are limited. METHODS The Investigational Device Exemption (IDE) clinical study is designed to evaluate the safety and probable benefit of the EXCOR to support regulatory review of the device under the Humanitarian Device Exemption regulation. The study design and rationale are reviewed in light of the well-described challenges inherent in small population studies. RESULTS The Berlin Heart EXCOR IDE clinical study is a prospective, multicenter, single-arm, clinical cohort study. Children aged 0 to 16 years with severe heart failure (Interagency Registry for Mechanically Assisted Circulatory Support profile 1 or 2) due to 2-ventricle heart disease and actively listed for HT comprise the primary study cohort. The control population is a propensity-matched retrospective cohort of children supported with extracorporeal membrane oxygenation, the only bridge device available to smaller children before the EXCOR. The primary efficacy end point is survival to heart transplantation or recovery. The primary safety end point is the incidence of serious adverse events as defined by pediatric Interagency Registry for Mechanically Assisted Circulatory Support criteria. The study will enroll a total of 48 subjects in 2 cohorts based on body surface area (cohort 1 <0.7 m(2), cohort 2 0.7-1.5 m(2)) and is powered to show safety superiority to a prespecified performance goal of 0.25 serious adverse events per day of support. Children ineligible for the primary cohort will still have access to the device in a third compassionate-use cohort where adverse event data will be collected for additional safety characterization of the device. CONCLUSION The Berlin Heart IDE clinical study will be the first bridge-to-HT VAD study designed exclusively for children. It is anticipated that the study will provide important information on the safety and efficacy of the Berlin Heart EXCOR Pediatric in children while providing valuable lessons into the design and conduct of future VAD studies in children.

Significant association with location of central venous line placement and risk of venous thrombosis in children

Venous thromboembolic events (VTE) in children are frequently associated with central venous lines (CVL). Identifying risk factors related to CVL management could potentially minimize CVL-related thrombotic complications. The objectives of the study were to assess whether CVL location, type, size, and duration of placement are associated with the incidence of VTE in children. The study was a prospective, multicentre cohort study in a general pediatric population requiring CVL. Data on CVL characteristics were documented prospectively using standardized case report forms. Outcome assessments were by i) clinical monitoring for symptomatic VTE which were confirmed by appropriate objective test, or ii) screening by venography at study exit. Among 158 children, 21 (13%) hadVTE. The incidence of VTE was increased with femoral CVL (32%) and subclavian CVL (27%) compared to brachial CVL (12%) and jugular CVL (8%; p = 0.01). The incidence of VTE was independent of CVL type (peripherally inserted central catheters, untunneled CVL, tunneled exteriorized CVL, subcutaneous ports; p = 0.90), and CVL size (CVL diameter, p = 0.42; number of CVL lumen, p = 0.58). The incidence of VTE did not increase with duration of CVL placement: 0-5 days (17% VTE), 6-20 days (19%), 21-35 days (10%), and 36-50 days (11%, p = 0.68). The incidence of CVL-relatedVTE may be reduced by preferred placement of CVL in brachial or jugular veins. The choice of CVL type and size does not significantly influence the risk of VTE. Short-term CVL are associated with a similar risk of VTE as longer-term CVL.

Systemic thromboembolism in children Data from the 1-800-NO-CLOTS Consultation Service

Thromboembolism (TE) has recently been recognized as a clinical entity in children. Determining the clinical characteristics of pediatric TE is an important first step in dealing with this new disorder. The paper summarizes 1776 consecutive children with systemic TE referred to 1-800-NO-CLOTS telephone consultation service. 1-800-NO-CLOTS is a free consultation service for clinicians managing pediatric TE. Patient information was collected immediately using standardized forms. In children with systemic TE, infants under one year of age (47%) including neonates (26%) represented the largest distinct pediatric age group. Age-related differences were seen in TE locations, associated conditions, and risk factors. However, venous TE was the most frequent manifestation (74%). Neonates and children with cardiac disorders were more likely to have an arterial TE than a venous TE Beyond the neonatal period, venous TE associated with a central line is more likely to occur than arterial TE. Children with ALL were 5.7 times more likely to have a venous TE than an arterial TE. TE were infrequent in otherwise healthy children with 90% of children having at least one risk factor. Central catheters were the single most common risk factor associated with TE, present in 2/3 of children. Ultrasound was most frequently employed for diagnosis of TE. Finally, there was marked heterogeneity in treatment of children with TE. In children, neonates form the largest single group with TE. TE usually occur only in the presence of one or more risk factors with catheters being the single most important factor.

Urgent Clinical Challenges in Children With Ischemic Stroke Analysis of 1065 Patients From the 1-800-NOCLOTS Pediatric Stroke Telephone Consultation Service

Background and Purpose— Clinical trials are lacking in pediatric stroke. As a result, physicians caring for children with stroke face significant challenges. The patient characteristics and specific nature of clinical challenges facing practicing clinicians can inform the design of and priorities for developing relevant clinical trials. Methods— Physicians consulted the 1-800-NOCLOTS toll-free pediatric stroke telephone consultation service on children (birth to 18 years) with ischemic stroke. Pediatric neurologist or hematologists provided telephone consultation and documented caller and patient characteristics, antithrombotic treatments and callers’ questions for entry into a computerized database. Children referred from January 1, 1995 to January 1, 2004, comprised the study cohort. Results— Stroke consults were completed on 1065 children located predominantly in the United States (76%). Children had arterial ischemic stroke (AIS; 679; 64%) or cerebral sinovenous thrombosis (CSVT; 386; 36%) and were 54% male and 16% neonates. Risk factors and antithrombotic agents (none, aspirin, warfarin, and heparins) differed by stroke type. In 60% of patients, callers had not initiated antithrombotic therapy. Callers’ questions for both stroke types usually concerned treatment selection (83%), but for AIS, questions more frequently (P<0.0001) concerned the selection and interpretation of etiological investigations. Conclusions— Research is urgently needed in pediatric stroke to provide direction for management in “real-life” settings. Research efforts should address the unique challenges within different stroke types and include observational studies addressing investigation of the child with AIS. For AIS and CSVT, randomized controlled trials investigating the efficacy of antithrombotic treatment are urgently needed.

Childhood Acute Myelomonocytic Leukemia (aml-m4) Presenting as Catastrophic Antiphospholipid Antibody Syndrome

: The authors describe a 15-year-old girl presenting with a cerebral ischemic stroke as the first manifestation of catastrophic antiphospholipid antibody syndrome secondary to acute myeloid leukemia (AML). Despite treatment with anticoagulants, therapeutic plasma exchange, and chemotherapy, the patient developed multiorgan thromboses and failure, eventually culminating in death. This unusual presentation of AML has not been previously described in children. Clinical features of antiphospholipid antibody syndrome and current knowledge regarding its association with malignancies are reviewed.

Thrombophilia and pregnancy complications

The implications of currently available data on the association of gestational vascular complications with thrombophilia are presented in this consensus report. Screening is recommended for women with the following previous complications: fetal loss including three or more first trimester loss, two or more second trimester loss, or any stillbirth; early, severe or recurrent preeclampsia and severe intrauterine growth restriction. Maternal antithrombotic therapy is currently evaluated in women with thrombophilia and previous complications.

Thromboprophylaxis of central venous lines in children with cancer: The first steps taken on the long road ahead

Approximately one third of children with malignancy and central venous lines develop catheter‐related thrombosis, with the reported sequelae including death, pulmonary embolism, chylothoraces, superior vena cava syndrome and post‐thrombotic syndrome. These complications prompt the design and completion of randomized, controlled trials to determine a safe and efficacious therapy to prevent these thromboses. The authors Ruud et al. have presented a well‐designed, randomized, controlled trial which demonstrates the lack of utility of using low‐dose warfarin to prevent catheter‐related thrombosis in children with central lines and acute lymphoblastic leukaemia. The difficulties with warfarin in children are again demonstrated in this study.

Thrombophilia risk is not increased in children after perinatal stroke

Perinatal stroke causes cerebral palsy and lifelong disability. Specific diseases are definable, but mechanisms are poorly understood. Evidence suggests possible associations between arterial perinatal stroke and prothrombotic disorders, but population-based, controlled, disease-specific studies are limited. Understanding thrombophilia in perinatal stroke informs pathogenesis models and clinical management. We conducted a population-based, prospective, case-control study to determine the association of specific perinatal stroke diseases with known thrombophilias. Children with idiopathic magnetic resonance imaging-classified neonatal arterial ischemic stroke (NAIS), arterial presumed perinatal ischemic stroke (APPIS), or fetal periventricular venous infarction (PVI) were recruited. Standardized thrombophilia evaluations were performed after 12 months of age on stroke cases and controls, including quantified proteins C and S, antithrombin, factors VIII/IX/XI, fibrinogen, lipoprotein(a), homocysteine, lupus anticoagulant, anticardiolipin antibodies and genotyping of factor V Leiden (FVL), factor II G20210A (FII), and methylenetetrahydrofolate reductase C677T. A total of 212 children were studied: 46 with NAIS, 34 with APPIS, 55 with PVI, and 77 controls (male, 53%; median age, 4.8 years). Of 14 parameters, no differences were observed in 12, including all common thrombophilias. Mean prothrombin time was shorter in arterial strokes (P < .001). Rates of antiphospholipid antibodies were low, comparable to those in controls, and resolved on repeat testing. FVL and FII rates were comparable to population norms. Total number of possible abnormalities did not differ between cases and controls. Our prospective, population-based, controlled, disease-specific study suggests minimal association between perinatal stroke and thrombophilia. This does not exclude the possibility of disordered coagulation at the time of stroke but suggests testing in childhood is not indicated.