Prasad Mathew

Impact of Inherited Thrombophilia on Venous Thromboembolism in Children A Systematic Review and Meta-Analysis of Observational Studies

Background— The aim of the present study was to estimate the impact of inherited thrombophilia (IT) on the risk of venous thromboembolism (VTE) onset and recurrence in children by a meta-analysis of published observational studies. Methods and Results— A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2007 was conducted using key words in combination as both MeSH terms and text words. Citations were independently screened by 2 authors, and those meeting the inclusion criteria defined a priori were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, VTE type, and frequency of recurrence were abstracted. Heterogeneity across studies was evaluated, and summary odds ratios and 95% CIs were calculated with both fixed-effects and random-effects models. Thirty-five of 50 studies met inclusion criteria. No significant heterogeneity was discerned across studies. Although >70% of patients had at least 1 clinical risk factor for VTE, a statistically significant association with VTE onset was demonstrated for each IT trait evaluated (and for combined IT traits), with summary odds ratios ranging from 2.63 (95% CI, 1.61 to 4.29) for the factor II variant to 9.44 (95% CI, 3.34 to 26.66) for antithrombin deficiency. Furthermore, a significant association with recurrent VTE was found for all IT traits except the factor V variant and elevated lipoprotein(a). Conclusions— The present meta-analysis indicates that detection of IT is clinically meaningful in children with, or at risk for, VTE and underscores the importance of pediatric thrombophilia screening programs.

AAML03P1, a pilot study of the safety of gemtuzumab ozogamicin in combination with chemotherapy for newly diagnosed childhood acute myeloid leukemia: a report from the Children's Oncology Group.

The development of antigen‐targeted therapies may provide additional options to improve outcomes in children with acute myeloid leukemia (AML). The Childrens Oncology Group AAML03P1 trial sought to determine the safety of adding 2 doses of gemtuzumab ozogamicin, a humanized anti‐CD33 antibody‐targeted agent, to intensive chemotherapy during remission induction and postremission intensification for children with de novo AML.

Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.

α2‐Antiplasmin and its deficiency: fibrinolysis out of balance

Summary.  Fibrinolysis serves an important role in the process of coagulation, ensuring that clots that are formed in response to injury resolve after the injured tissue is repaired. Fibrinolysis occurs because the protein plasminogen is converted to the active serine protease plasmin by its activating molecules (primarily tissue plasminogen activator). One of the inhibitors of fibrinolysis is α2‐antiplasmin, which acts as the primary inhibitor of plasmin(ogen). Congenital deficiency of α2‐antiplasmin causes a rare bleeding disorder because of increased fibrinolysis. Despite the rare nature of this disorder, understanding of the actions of α2‐antiplasmin and the results of its deficiency has provided the opportunity for better understanding of the fibrinolytic system in both how it affects the risk of bleeding and its impact on other bodily systems. Here, we review the history of the discovery of α2‐antiplasmin, our understanding of its genetics and function, and our current knowledge of its congenital deficiency. We also discuss some of the current avenues of investigation into its impact on other diseases and physiological states.

Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from The Centers for Disease Control and Prevention’s (CDC) Universal Data Collection (UDC) project

Summary.  Lack of detailed natural history and outcomes data for neonates and toddlers with haemophilia hampers the provision of optimal management of the disorder. We report an analysis of prospective data collected from 580 neonates and toddlers aged 0–2 years with haemophilia enrolled in the Universal Data Collection (UDC) surveillance project of the Centers for Disease Control and Prevention (CDC). This study focuses on a cohort of babies with haemophilia whose diagnosis was established before the age of two. The mode of delivery, type and severity of haemophilia, onset and timing of haemorrhages, site(s) of bleeding, provision of prophylaxis with coagulation factor replacement therapy, and the role played by the federally funded Haemophilia Treatment Centers (HTC) in the management of these infants with haemophilia were evaluated. Seventy‐five per cent of haemophilic infants were diagnosed early, in the first month of life, especially those with a family history or whose mothers were known carriers; infants of maternal carriers were more likely to be delivered by C‐section. Involvement of an HTC prior to delivery resulted in avoidance of the use of assisted deliveries with vacuum and forceps. Bleeding from the circumcision site was the most common haemorrhagic complication, followed by intra‐ and extra‐cranial haemorrhages and bleeding from heel stick blood sampling. Eight per cent of the infants were administered factor concentrate within 24 h of birth; more than half were treated to prevent bleeding. This study highlights the significant rate and the sites of initial bleeding unique to very young children with haemophilia and underscores the need for research to identify optimal evidence‐based recommendations for their management.

Recombinant factor VIIa in management of spontaneous subcapsular liver hematoma associated with pregnancy.

BACKGROUND: Spontaneous subcapsular liver hemorrhage is a rare but life-threatening complication of pregnancy. Optimal management of an expanding hematoma or ruptured capsule has not been established. CASES: We report 3 patients with preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome with spontaneous subcapsular liver hematomas. The first 2 patients with ruptured liver hematomas experienced life-threatening hemorrhage. The third patient experienced uncontrollable vaginal bleeding, liver hemorrhage, and was in imminent danger of capsule rupture. Despite aggressive surgical intervention and traditional blood component therapy, adequate hemostasis could not be achieved in any of these patients. Recombinant factor VIIa was used to achieve hemostasis in all three patients. CONCLUSION: Recombinant factor VIIa is an effective adjunct in the treatment of preeclamptic patients with expanding or ruptured subcapsular liver hematoma.

Haemostatic efficacy and safety of bolus and continuous infusion of recombinant factor VIIa are comparable in haemophilia patients with inhibitors undergoing major surgery - Results from an open-label, randomized, multicenter trial

Bolus infusion (BI) recombinant factor VIIa (rFVIIa) administration is safe and effective in the surgical management of haemophilia patients with inhibitors but has not been compared directly with continuous infusion (CI). We conducted an open-label, randomized, multicenter trial comparing the efficacy and safety of rFVIIa administered by BI or CI for the surgical management of haemophilia A or B patients with inhibitors to FVIII or FIX. Safety was compared with that of a control group of non-inhibitor patients receiving FVIII or FIX concentrates for major surgery. All inhibitor subjects received an initial bolus dose of 90 microg/kg rFVIIa and were then randomly assigned to BI (n = 12) or CI (n = 12). The BI group received 90 microg/kg rFVIIa every two hours (h) during surgery through day 5, then every four hours for days 6-10. The CI group received 50 microg/kg/h rFVIIa through day 5, then 25 mg/kg/h for days 6-10. The control group (n = 12) received FVIII or FIX per institutional protocols. Twenty-two major surgeries included orthopedic procedures on the knee (n = 13), hip (n = 3), and abdominal/pelvis procedures (n = 4). One patient with an autoimmune FVIII inhibitor randomized to the BI arm was excluded from efficacy analysis. Haemostatic efficacy of rFVIIa in each group was comparable: effective in 8/11 and 9/12 subjects in the BI and CI arms, respectively, and ineffective in three subjects in each arm. Serious adverse events were related to continued or increased bleeding. In conclusion, haemostatic efficacy and safety of BI and CI of rFVIIa are comparable for the surgical management of haemophilia subjects with inhibitors.

Pain and Distress from Bone Marrow Aspirations and Lumbar Punctures

OBJECTIVE To compare the efficacy of 3 different pharmacologic regimens to relieve pain and distress in children with cancer undergoing bone marrow aspirations (BMAs) and lumbar punctures (LPs). DESIGN Retrospective cohort study with crossovers for some patients. PATIENTS AND METHODS The pain and distress ratings of patients undergoing BMAs (n = 73) and LPs (n = 105) were examined in a comparison of 3 different interventions: (1) a topical eutectic mixture of lidocaine and prilocaine (EMLA cream), (2) oral midazolam and EMLA cream, or (3) propofol/fentanyl general anesthesia. The choice of the intervention depended on patient/parent request. A validated faces pain scale was completed by the child or parent following each BMA or LP. The faces pain scale includes ratings of the severity of pain (from 0 = none to 5 = severe) and ratings of how frightened (from 0 = not scared to 5 = scared) the child was prior to each procedure. Comparisons of the pain and distress ratings were made among all patients for their first procedure and also within individual patients who had received >1 of the 3 interventions. Independent comparisons between the first treatments received by each patient were analyzed using Kruskal–Wallis tests. Comparisons of different crossover treatments received by individual patients were analyzed using Wilcoxon tests. RESULTS For all first procedures, mean ± SD pain and distress ratings during LPs were significantly lower when propofol/fentanyl was used (n = 43; 0.4 ± 1.0 and 1.4 ± 1.7) versus either EMLA (n = 29; 2.4 ± 1.7 and 2.9 ± 1.9) or midazolam/EMLA (n = 33; 2.4 ± 1.8 and 2.7 ± 1.8), respectively. Pain and distress ratings during BMAs were also significantly lower with propofol/fentanyl (n = 29; 0.5 ± 1.0 and 1.2 ± 1.7) versus EMLA (n = 21; 3.5 ± 1.6 and 3.3 ± 1.8) or midazolam/EMLA (n = 23; 3.3 ± 1.5 and 3.0 ± 1.9), respectively. When data were analyzed within each patient, these differences were also present. CONCLUSIONS Children receiving propofol/fentanyl general anesthesia experienced significantly less procedure-related pain and distress than did those receiving either EMLA or oral midazolam/EMLA.

Recombinant activated factor VII for haemophilia patients with inhibitors undergoing orthopaedic surgery: a review of the literature

Summary.  Arthropathy is prevalent in patients with haemophilia and inhibitors and is a major source of pain and disability, significantly reducing quality of life. Recombinant activated factor VII (rFVIIa; NovoSeven®) is one of the treatments available for acute life‐threatening bleeding episodes in haemophilia patients with inhibitors. It has also been used successfully in a range of orthopaedic surgical procedures in these patients. This is a review of published data on elective orthopaedic procedures in haemophilia patients with inhibitors under cover of rFVIIa from January 2002 to November 2006. Articles were retrieved from MEDLINE using specified search parameters. Twelve articles covering a total of 80 orthopaedic procedures were identified. In the vast majority of cases, rFVIIa provided safe and effective haemostatic cover during orthopaedic surgery with no bleeding complications. There was variation in the administered dose, although the majority of patients were treated with 90 μg kg−1 bolus followed by either continuous infusion or bolus infusion. Of those cases reporting bleeding complications, most were considered to be related to an inadequate amount of rFVIIa. The cumulative experience presented here suggests that rFVIIa is safe and effective for providing adequate haemostatic cover for haemophilia patients with inhibitors undergoing orthopaedic surgery. The optimal dosing regimen and mode of administration has yet to be identified. Further controlled trials are needed to confirm these experiences.

The use of rFVIIa in non-haemophilia bleeding conditions in paediatrics A systematic review

From its original envisioned use in patients with hemophilia and inhibitors, recombinant factor VIIa has been increasingly used in a variety of non-hemophilia bleeding/hemorrhagic situations with great efficacy. Most of the reported work has been in adult patients. This paper sets out to review its use in the pediatric non-hemophilia patients and the varied conditions it has been tried and used. Most of the published literature has shown that this agent is efficacious, safe and can be used as an adjunctive measure in the achievement of hemostasis. However, most of the published work is mainly anecdotal, case reports or small series. Randomized trials in children are eagerly awaited.