Kim Nagel

Comparing bleed frequency and factor concentrate use between haemophilia A and B patients

Summary.  Haemorrhagic manifestations in patients with haemophilia A and B are considered quite similar for comparable level of factor deficiency. We investigated the bleeding frequency and factor usage between HA and HB patients with comparable disease severities. We collected data on frequency of bleeds and factor concentrate utilization over 3 years, from January 2001 to December 2003. Information was gathered from home infusion logs recorded by patients or their parents, and treatment records from the Hemophilia Clinic or the Hospital Emergency Department. Data were available on 58 patients with severe HA (FVIII < 0.01 U mL−1), 10 with moderate HA (FVIII < 0.05 U mL−1), 15 with severe HB, and five with moderate HB who required treatment for episodic bleeds, postoperative haemostasis and for primary or secondary prophylaxis. The HA patients bled more frequently than HB patients (14.4 vs. 8.63 bleeds/patient/year), but used similar amounts of concentrate per year. HA patients underwent surgical procedures 3.2 times more frequently than HB patients to correct musculoskeletal complications. A total of 21 363 409 IU of recombinant FVIII was used by patients with HA (104 722 IU/patient/year) and 6 430 960 IU of recombinant factor IX, by patients with HB (107 182 IU/patient/year). The difference in factor concentrate usage is not statistically significant (P > 0.05). The decrease in bleed frequency in haemophilia B indicates that the conclusions from randomized trials of prophylaxis in HA may not be accurately applied to HB.

Parent health literacy and satisfaction with plain language education materials in a pediatric surgery outpatient clinic: a pilot study

BACKGROUND Although significant, the issue of health literacy (HL) among parents attending pediatric surgery outpatient clinics has received little attention. PURPOSE The objectives of this study are to determine the HL skills of parents attending the pediatric surgery outpatient clinic at McMaster Childrens Hospital and to describe parent satisfaction with plain language materials. METHODS This cross-sectional study was conducted at the pediatric surgery outpatient clinic at McMaster Childrens Hospital. Using convenience sampling for 4 months, parents were recruited and interviewed regarding their demographic status. The Newest Vital Sign tool was used to assess HL. Feedback on the plain language education material was received. RESULTS Seventy-nine individuals were recruited, with a recruitment rate of 62%. Seventy-one percent had adequate HL. English as a first language and Canada as the place of birth were significantly correlated with adequate HL (r = 0.367, P < .001; r = 0.259, P < .05). Parents reported satisfaction with the plain language material, regardless of their HL level. CONCLUSION Twenty-nine percent of parents showed inadequate HL, likely an underestimate owing to study limitations. Parents expressed satisfaction with the plain language material, emphasizing the need for clear, effective communication with patients and families. Future directions include evaluating staff knowledge of a universal precautions approach to health communication and the accessibility of plain language materials.

Neonatal central venous catheter thrombosis: diagnosis, management, and outcome.

Thrombotic occlusion of central venous catheters (CVCs) is a common problem in newborns. There is no guideline that systematically addresses the diagnosis, management, and prevention of this complication. The objective of this review is to establish evidence-based guidance for the management of CVC-related thrombosis. A comprehensive search of the scientific literature was conducted from 1948 to 2012. Twenty-six articles fulfilling four criteria – humans, neonates aged below 28 days, CVC insertion, and English language – were included for analysis. The incidence of thrombosis was 9.2% (308/3332). Singly inserted umbilical venous catheters (UVCs) and peripherally inserted central catheters accounted for over 80% of all CVCs. Frequently reported thrombotic sites were the hepatic vein, right atrium, and inferior vena cava. Symptoms included distal swelling of affected areas and thrombocytopenia. Increased length of catheter stay, infusion of blood products and malpositioned UVCs were identified as risk factors. The commonest diagnostic investigations to confirm thrombosis were echocardiography and ultrasonography. Spontaneous resolution may occur in UVC-related thrombosis, but this warrants close monitoring. Thrombolysis with urokinase alone or combined with low-molecular-weight heparin might be effective and well tolerated as treatment strategies. Prophylactic heparin increases the duration of catheter usability (P < 0.005, 95% confidence interval 0.35–0.81), decreases catheter occlusion, but may not uniformly prevent thrombosis. CVL-related thrombosis is an underreported complication because events in the majority occur silently. Currently, solid evidence-based recommendations for diagnosis and treatment are not possible. Well designed prospective studies are urgently required to establish a concrete investigational approach to CVC-related thrombosis and to institute safe therapeutic modalities.

Creatine monohydrate attenuates body fat accumulation in children with acute lymphoblastic leukemia during maintenance chemotherapy.

Corticosteroids are an important component of the treatment of acute lymphoblastic leukemia (ALL), with known significantly negative effects on bone and muscle. Creatine monohydrate (CrM) supplementation may be an adjunctive therapeutic strategy to attenuate some of these adverse effects.

Diagnosis and treatment of intracranial hemorrhage in children with hemophilia.

Intracranial hemorrhage (ICH) is a significant complication for children with hemophilia. Identifying risk factors may allow us to establish clinically relevant guidelines for the diagnosis and management of ICH. The purpose of this review is to nucleate evidence from the available literature on the incidence, risk factors, presentation, treatment, and outcomes of ICH that can be utilized to develop a clinically useful framework for the diagnosis and management of hemophiliac patients with the condition. An electronic MEDLINE and EMBASE literature search was undertaken using the key words ‘intracranial hemorrhage and hemophilia’ and setting limits as: Last 10 years and Review or Randomized Controlled Trial (RCT) or Clinical Trial, or Practice Guidelines. Following review of all articles using predetermined search words and criteria, 31 were retrieved with sufficient data to address our objectives. An algorithm is presented for the management of children (≥3 years–18 years) with hemophilia and suspected ICH. A standardized approach to ICH may reduce unnecessary exposure to radiation via computed tomography scan in a select group of children. Currently there is limited scientific evidence to recommend a diagnostic and therapeutic algorithm for neonates with hemophilia.

Evaluation of the use of low-molecular-weight heparin in neonates: a retrospective, single-center study.

Controversies exist over the currently recommended guidelines for the use of low-molecular-weight heparin (LMWH) in neonates. We retrospectively studied 30 neonates treated with LMWH and found a poor therapeutic response to recommended doses as measured by anti-Xa levels. Sixty percent of the study participants required their doses to be increased because of subtherapeutic anti-Xa levels during the initial course of their treatment. The mean starting enoxaparin dose was 1.53 ± 0.38 mg/kg. The mean enoxaparin dose, once therapeutic anti-Xa levels had been achieved, was 1.86 ± 0.50 mg/kg. Preterm and term infants required doses of 2.06 ± 0.61 mg/kg and 1.67 ± 0.26 mg/kg, respectively, to achieve therapeutic anti-Xa levels. In summary, our results suggest that higher initial doses are required to achieve therapeutic anticoagulation in neonates.

Spontaneous neonatal arterial thromboembolism: infants at risk, diagnosis, treatment, and outcomes.

Neonatal spontaneous arterial thromboembolism is a rare phenomenon with a high risk of morbidity and mortality. Currently, there is little information regarding common risk factors, diagnostic strategies, therapeutic interventions, and outcomes of this condition. The objective was to nucleate the best evidence regarding the disorder in order to facilitate early detection and treatment recommendations and document adverse outcomes. Web of Science, PubMed, Medline, CINAHL, Cochrane Databases, DARE, and OVID databases were searched using the following keywords: ‘arterial’ AND ‘thrombus’ OR ‘thrombosis’ OR ‘thromboembolism’ OR ‘embolism’ AND ‘spontaneous’ AND ‘at birth’ OR ‘newborn’ OR ‘neonatal’ OR ‘fetal’ AND ‘umbilical cord’ OR ‘umbilical wall necrosis’ AND ‘coagulation abnormality’ OR ‘placenta bits’ OR ‘ischemic limbs’. The search yielded 172 articles, all of which were case series or single case descriptions. Twenty-seven met inclusion criteria, with a total of 53 newborns and 30 newborn pathology reports. Ultrasound was the preferred method of diagnosis and thromboembolic locations varied with the most common site being umbilical, resulting in embolism and vascular compromise. Treatment interventions and drug dosages were not standardized and ranged from use of anticoagulants to surgery and hyperbaric oxygen. The reported mortality rate was 32.8%. Recurring etiological features facilitated identification of possible sequences of events contributing to the disorder. The literature lacks empirical evidence to affirm causes and predisposing risk factors for timely diagnosis and effective treatment of spontaneous neonatal arterial thromboembolism. Further research is needed to clearly establish the causes and the efficacy of specific treatment options.

Neonatal and infant pulmonary thromboembolism: a literature review.

Pulmonary thromboembolism (PTE) is rare in neonates and infants; however evidence suggests it is underdiagnosed. The primary objective is to conduct a scientific review to determine if the presentation, diagnosis, treatment and outcomes of neonates and infants with PTE are consistent across studies. Secondly, to develop an algorithm to establish the diagnosis and management of the condition based on current information. Two authors searched the literature independently using existing databases and verified that identical articles were assembled. Infants aged less than 1year with PTE were included and further categorized into neonates 28 days or less and infants 29 days to 1 year or less. Forty-five articles with 157 cases (121 neonates; 36 infants) were identified with PTE. All of the reports were descriptive and neither randomized controlled trials nor prospective or case–control studies were identified. The reports are sub-classified into cases of pulmonary air embolism (PAE) with a higher mortality rate and patients with PTE. Diagnostic and treatment strategies varied widely and were individually case-based, dependent on clinical findings, which influenced patient outcomes. Scientific data to guide an evidence-based, diagnostic and treatment approach to PTE is limited because of the absence of rigorous clinical trials. Large scale, multicenter collaborative studies are required to firmly establish the management of PTE in this population.

Pharmacokinetics of recombinant and plasma-derived factor VIII products in paediatric patients with severe haemophilia A

A review of current literature and factor VIII (FVIII) product inserts was conducted to determine if the half-lives of available recombinant and plasmaderived FVIII products are comparable in paediatric patients. There is widespread pharmacokinetic data for FVIII use in adults, but this data cannot be applied to paediatric patients due to several significant physiological differences. Specifically, ADVATE, Kogenate FS and Xyntha demonstrate three variable pharmacokinetic trends, which include a lower areaunder-the-curve, a higher clearance rate and a lower half-life [1–3]. Paediatric pharmacokinetic studies are available for ADVATE, Kogenate FS and Xyntha (Table 1). However, each FVIII product defines their age groups differently when reporting pharmacokinetic data (Table 1), thereby making it difficult to compare their half-lives. Moreover, there is no paediatric pharmacokinetic data for any of the plasma-derived products, thus excluding possible comparisons with recombinant-derived products. Currently, there is strong evidence that reducing the number of bleeds in young children is vital in the prevention of haemophilic arthropathy [4]. Also, clinical trials with paediatric patients demonstrate that tailoring dosing frequency to an individual’s half-life can have clinically significant outcomes in terms of bleeding prevention [5]. For this reason, we recommend that future research involve defining uniform age groups that every FVIII product will adhere to when reporting pharmacokinetic data. A recent focus on the management of haemophilia A is the manufacture of FVIII products with prolonged half-lives. BAX 855, a PEGylated form of Baxter’s rFVIII product ADVATE, recently demonstrated improved pharmacokinetic parameters compared to ADVATE in preclinical studies [6]. Furthermore, N8GP, a recombinant FVIII with a site-directed glycoPEGylation was recently evaluated with regard to safety and pharmacokinetic parameters in 26 patients [7]. The patients were all previously treated men, age ≥18, with severe haemophilia A. Results of the trial showed a clearance of 0.0179 dL h 1 kg , and a mean terminal half-life of 19.0 h [7]. As these new products have the potential to significantly improve prophylactic treatment regimens in patients with haemophilia A, it is only a matter of time before we can expect to see pharmacokinetic studies conducted in the paediatric population. Therefore, we recommend that each new product report its pharmacokinetic

Do children with central venous line (CVL) dysfunction have increased risk of symptomatic thromboembolism compared to those without CVL-dysfunction, while on cancer therapy?

BackgroundThromboembolism (TE) and infection are two common complications of central venous line (CVL). Thrombotic CVL-dysfunction is a common, yet less studied, complication of CVL. Two retrospective studies have reported significant association of CVL-dysfunction and TE. Recent studies indicate association of CVL-related small clot with infection. Infection is the most common cause of non-cancer related mortality in children with cancer. We and others have shown reduced overall survival (OS) in children with cancer and CVL-dysfunction compared to those without CVL-dysfunction. Despite these observations, to date there are no prospective studies to evaluate the clinical significance of CVL-dysfunction and it’s impact on the development of TE, infection, or outcome of children with cancer.Study designThis is a prospective, analytical cohort study conducted at five tertiary care pediatric oncology centers in Ontario. Children (≤ 18 years of age) with non-central nervous system cancers and CVL will be eligible for the study. Primary outcome measure is symptomatic TE and secondary outcomes are infection, recurrence of cancer and death due to any cause. Data will be analyzed using regression analyses.DiscussionThe overall objective is to delineate the relationship between CVL-dysfunction, infection and TE. The primary aim is to evaluate the role of CVL-dysfunction as a predictor of symptomatic TE in children with cancer. We hypothesize that children with CVL-dysfunction have activation of the coagulation system resulting in an increased risk of symptomatic TE. The secondary aims are to study the impact of CVL-dysfunction on the rate of infection and the survival [OS and event free survival (EFS)] of children with cancer. We postulate that patients with CVL-dysfunction have an occult CVL-related clot which acts as a microbial focus with resultant increased risk of infection. Further, CVL-dysfunction by itself or in combination with associated complications may cause therapy delays resulting in adverse outcome.This study will help to identify children at high risk for TE and infection. Based on the study results, we will design randomized controlled trials of prophylactic anticoagulant therapy to reduce the incidence of TE and infection. This in turn will help to improve the outcome in children with cancer.