Char Witmer

Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007.

OBJECTIVES: The goals were to determine whether there has been an increase in the rate of venous thromboembolism (VTE) in pediatric tertiary care hospitals and to evaluate the use of anticoagulants in the treatment of hospitalized pediatric patients with VTE. METHODS: A retrospective cohort study of patients <18 years of age who were discharged from 35 to 40 childrens hospitals (depending on the year) across the United States in 2001–2007 was performed. By using the Pediatric Health Information System administrative database, cases were assessed for discharge diagnosis codes for VTE; the use of anticoagulants was assessed by using patient-specific pharmacy files. RESULTS: During the 7-year study period, in which 11337 hospitalized patients were diagnosed with VTE, the annual rate of VTE increased by 70%, from 34 to 58 cases per 10000 hospital admissions (P < .001). This increase was observed in neonates, infants, children, and adolescents. The majority (63%) of children with VTE had ≥1 coexisting chronic complex medical condition. Pediatric malignancy was the medical comorbid condition associated most strongly with recurrent VTE (P < .001). The proportion of children with VTE who were treated with enoxaparin increased from 29% to 49% during this time period (P < .001); the use of warfarin decreased slightly from 11.4% to 9.6% (P = .02). Increasing age was associated with increased likelihood of patients with VTE being treated with either enoxaparin or warfarin. CONCLUSION: This multicenter study demonstrates a dramatic increase in the diagnosis of VTE at childrens hospitals from 2001 to 2007.

Associations between intracranial haemorrhage and prescribed prophylaxis in a large cohort of haemophilia patients in the United States.

Intracranial haemorrhage (ICH) is the most serious type of bleeding for patients with haemophilia. Prior published reports regarding ICH predate the widespread provision of prophylaxis. Our study objectives were to determine risk factors for ICH and whether prophylaxis reduces ICH occurrence. We performed a nested case‐control study of persons with haemophilia, ≥2 years of age enrolled in the Centers for Disease Control and Prevention Universal Data Collection project. Of 10 262 patients 199 (1·9%) experienced an ICH for an incidence rate of 390/105 patient years. Head trauma was reported in 44% (88/199). ICH mortality was 19·6% (39/199). Significant risk factors for ICH included a high titre inhibitor [odds ratio (OR) = 4·01, 95% confidence interval (2·40–6·71)], prior ICH [OR = 3·62 (2·66–4·92)] and severe haemophilia [OR = 3·25 (2·01–5·25)]. Prophylaxis was associated with a significant risk reduction for ICH occurrence in patients with severe haemophilia who were negative for human immunodeficiency virus or an inhibitor, with an OR of 0·52 (0·34–0·81) and 0·50 (0·32–0·77) respectively. The most significant risk factors for ICH included the presence of an inhibitor, prior ICH, severity of haemophilia and reported head trauma. This is the first study to demonstrate that prescribed prophylaxis conferred a protective effect against ICH in patients with uncomplicated severe disease.

Factor VIII inhibitors in hemophilia A: rationale and latest evidence

Factor VIII (FVIII) replacement therapy is the foundation of treatment in hemophilia A and is effective unless a patient develops an alloantibody (inhibitor) against exogenous FVIII. Inhibitor development is currently the most significant treatment complication seen in patients with hemophilia and is associated with considerable morbidity and a decreased quality of life. The development of an inhibitor is the result of a complex interaction between a patient’s immune system and genetic and environmental risk factors. The mainstay of treatment is the eradication of the inhibitor through immune tolerance. This review summarizes the current evidence regarding inhibitor risk factors, eradication, and hemostatic bypassing agents.

Off-label recombinant factor VIIa use and thrombosis in children: a multi-center cohort study.

OBJECTIVE To describe the off-label use of recombinant factor VIIa (rFVIIa) in tertiary care pediatric hospitals across the United States and to assess thrombotic events. STUDY DESIGN A retrospective multi-center cohort study using the Pediatric Health Information System administrative database. Children 18 years of age or younger who received rFVIIa between 2000 and 2007 were included. A label admission was defined as an admission with an International Classification of Diseases diagnostic code for hemophilia or factor VII deficiency; admissions without these codes were classified as off-label. RESULTS There were 4942 rFVIIa admissions, representing 3764 individual subjects; 74% (3655) of the admissions were off-label. There was a 10-fold increase in the annual rate of off-label admissions from 2000 to 2007 (from 2 to 20.8 per 10 000 hospital admissions, P < .001). The mortality rate in the off-label group was 34% (1258/3655). Thrombotic events occurred in 10.9% (399/3655) of the off-label admissions. CONCLUSIONS The off-label use of rFVIIa in hospitalized children is increasing rapidly despite the absence of adequate clinical trials demonstrating safety and efficacy. Thrombotic events are common and mortality is high among patients receiving off-label rFVIIa. Further studies are warranted to determine whether these adverse events are attributable to rFVIIa.

Incidence of Bleeding Complications in Pediatric Patients with Type 1 von Willebrand Disease Undergoing Adenotonsillar Procedures

OBJECTIVE To review the incidence of postoperative bleeding in children with type 1 von Willebrand disease (VWD) who were treated with a single institution protocol. STUDY DESIGN We performed a retrospective study to determine the postoperative hemorrhage rate in pediatric patients with type 1 VWD who were treated via the Childrens Hospital of Philadelphia institutional protocol. This protocol utilizes intravenous desmopressin (DDAVP), oral aminocaproic acid, and overnight observation. RESULTS Between the years of 2000 to 2006, 41 children with type 1 VWD underwent an adenotonsillar procedure and were treated with this protocol. Seven patients (17%) experienced delayed (>24 hours after surgery) postoperative hemorrhage requiring intervention. Five of the 7 patients required cautery to control the bleeding, and the remaining 2 patients responded to DDAVP and aminocaproic acid alone. Older age and lower VW antigen levels were associated with postoperative hemorrhage (P = .05). CONCLUSIONS Despite therapeutic intervention to decrease the risk of postoperative hemorrhage, the incidence of hemorrhage was higher in pretreated patients with type 1 VWD than in children without bleeding disorders. Further prospective studies are necessary to determine the optimal treatment to reduce bleeding complications in these patients.

Mycoplasma pneumoniae, Splenic Infarct, and Transient Antiphospholipid Antibodies: A New Association?

We report 2 children with Mycoplasma pneumoniae pulmonary infection with splenic infarcts and transient antiphospholipid antibodies. This association has not been reported previously.

Antithrombin Concentrate Use in Children: A Multicenter Cohort Study

OBJECTIVE To describe the off-label use of antithrombin concentrate in tertiary care pediatric hospitals across the US. STUDY DESIGN This is a retrospective, multicenter, cohort study of 4210 admissions of children younger than 18 years of age who received antithrombin concentrate between 2002 and 2011 within the Pediatric Health Information System administrative database. An on-label admission was defined as an admission with an International Classification of Diseases diagnostic code for a primary hypercoagulable state; admissions without this code were classified as off-label. RESULTS During the 10-year study period, off-label use of antithrombin concentrate increased 5-fold. Overall, 97% of study subjects received antithrombin off-label. Neonates younger than 30 days of age comprised the largest age group (45.7%) of use; 87% of patients had at least one complex chronic condition, with congenital heart/lung defects being the most prevalent primary diagnosis (36.3%). Extracorporeal membrane oxygenation was the most common procedure associated with antithrombin use (43.7%). CONCLUSIONS The off-label use of antithrombin concentrate is increasing rapidly, particularly in critically ill children receiving extracorporeal membrane oxygenation, with few parallel studies to substantiate its safety or efficacy. Further preclinical and controlled clinical studies are critical to expanding our knowledge of this drug. In the meantime, antithrombin concentrate should be used judiciously by clinicians and following guidelines instated by hospitals.

Utility of computed tomography of the head following head trauma in boys with haemophilia

Summary.  The most serious site of bleeding for patients with haemophilia is the central nervous system. Intracranial haemorrhage (ICH) in patients with haemophilia can occur spontaneously or following mild head trauma however no guidelines exist for the approach to these patients. The goal of this review was to determine the utility of screening computed tomography (CT) of the head for patients with haemophilia who experience head trauma and to determine if the use of clinical criteria could allow a selective approach to radiographic imaging. In a retrospective study we reviewed the management of head trauma in a cohort of paediatric patients with haemophilia in a single institution. The cohort included males, ages birth to 18 years with haemophilia A or B who were followed at the haemophilia treatment center at The Children’s Hospital of Philadelphia from 1994 to 2005. Between the years of 1994 and 2005, 97 patients were evaluated for head trauma for a total of 374 emergency department visits. There were 295 head CT scans performed to identify 9 (3%) episodes of intracranial bleeding. Fifty‐six per cent of the patients with intracranial bleeding had no clinical signs or symptoms. The clinical outcome was excellent in all cases with no deaths or reported morbidity. In this cohort, a lack of symptoms and a normal neurological exam did not exclude ICH, especially in patients with severe haemophilia who were evaluated soon after a mild head trauma event suggesting the utility of early head CT imaging.

Haemorrhagic stroke in term and late preterm neonates

Objective Few data regarding causes and outcomes of haemorrhagic stroke (HS) in term neonates are available. We characterised risk factors, mechanism and short-term outcomes in term and late preterm neonates with acute HS. Design Prospective cohort. Setting Single-centre tertiary care stroke registry. Subjects Term and late preterm neonates (≥34 weeks gestation), born 2004–2010, with acute HS ≤28 days of life were identified, and clinical information was abstracted. Short-term outcomes were assessed via standardised neurological exam and rated using the Paediatric Stroke Outcome Measure (PSOM). Results Among 42 neonates, median gestational age was 39.7 weeks (IQR 38–40.7 weeks). Diagnosis occurred at a median of 1 day (IQR 0–7 days) after delivery. Twenty-seven (64%) had intraparenchymal and intraventricular haemorrhage. Mechanism was haemorrhagic transformation of venous or arterial infarction in 22 (53%). Major risk factors included congenital heart disease (CHD), fetal distress and haemostatic abnormalities. Common presentations included seizure, apnoea, and poor feeding or vomiting. Acute hydrocephalus was common. Mortality was 12%. Follow-up occurred in 36/37 survivors at a median of 1 year (IQR 0.5–2.0 years). Among 17/36 survivors evaluated in stroke clinic, 47% demonstrated neurologic deficits. Deficits were mild (PSOM 0.5–1.5) in 9/36 (25%), and moderate-to-severe (PSOM ≥2.0) in 8/36 (22%). Conclusions In our cohort with acute HS, most presented with seizures, apnoea and/or poor feeding. Fetal distress and CHD were common. Nearly two-thirds had intraparenchymal with intraventricular haemorrhage. Over half were due to haemorrhagic transformation of infarction. Short-term neurologic deficits were present in 47% of survivors.

Multicenter Cohort Study Comparing U.S. Management of Inpatient Pediatric Immune Thrombocytopenia to Current Treatment Guidelines

Recent pediatric immune thrombocytopenia (ITP) guidelines have significantly altered and are encouraging an observational approach for patients without significant bleeding regardless of their platelet count.