Rachel Edwards

Parameters of Thromboelastography in Healthy Newborns

Thromboelastography (TEG) aids in monitoring a patients global hemostatic system by measuring the rate of clot formation, clot strength, and stability. The usefulness of TEG in pediatric settings, especially with neonates, is limited owing to a lack of neonatal reference values. In this study, neonatal TEG reference intervals were developed and results correlated with other coagulation test parameters. Samples were from women who delivered a neonate after at least 34 weeks of gestation in normal pregnancies. From the recovered placenta, cord blood from the umbilical vein or artery was collected within 30 minutes after delivery and tested. Neonatal TEG reaction time (time clot formation begins), clot firmness (shear elastic modulus strength), and platelet function analysis closure times were significantly lower than those in adult ranges (P< .001). When compared with the values for children, TEG reaction time, angle, coagulation index, clot firmness value, and clot kinetics (time from clot formation to time amplitude reaches 20 mm) were significantly different (P< .001) among neonates. TEG can be used to interpret the data for newborns by using reference values obtained in the present study.

Evaluation of Heparin Assay for Coagulation Management in Newborns Undergoing ECMO

The objective was to identify the usefulness of heparin level by anti-factor Xa (anti-Xa) assay vs activated partial thromboplastin time (PTT) or activated clotting time (ACT) in neonates undergoing extracorporeal membrane oxygenation (ECMO). A retrospective record review of 21 patients in the neonatal intensive care unit (mean ECMO initiation age, 2 days; range, 0-4 days; male/female ratio, 1:1) undergoing ECMO from 2006 to 2008 was performed. Linear regression correlations between anti-Xa, PTT, and ACT were determined by extrapolating PTT and ACT therapeutic ranges that corresponded with the ECMO heparin target range of 0.3 to 0.6 U/mL. Pearson correlation coefficients between heparin levels and PTT (-0.903 to 0.984), PTT less than 40 seconds after correction using PTT-heparinase (-0.903 to 1.000), and ACT (-0.951 to 0.891) in this patient population were widely variable. Inconsistency of PTT and ACT therapeutic ranges corresponding to heparin levels of 0.3 to 0.6 U/mL prompts a multifactorial approach to ECMO management because no single laboratory test can be used to determine appropriate anticoagulation management.

Bioengineered Factor IX Molecules with Increased Catalytic Activity Improve the Therapeutic Index of Gene Therapy Vectors for Hemophilia B

Although the desire to develop gene therapy for hemophilia B is high, safety remains a concern. Therefore, improving the therapeutic index of gene therapy vectors is an important goal. Thus, we evaluated the use of three bioengineered factor IX (FIX) variants with improved catalytic activity in the context of the helper-dependent adenoviral vector. The first vector expressed R338A-FIX, an FIX variant with the arginine at position 338 changed to an alanine, which resulted in a 2.9-fold higher specific activity (IU/mg) compared with the wild-type FIX. The second vector expressed FIX(VIIEGF1), a variant with the EGF-1 domain replaced with the EGF-1 domain from FVII, which resulted in a 3.4-fold increase in specific activity. The third expressed R338A + FIX(VIIEGF1), a novel variant containing both aforementioned modifications, which resulted in a 12.6-fold increase in specific activity. High-level, long-term, and stable expression of these three variants was observed in hemophilia B mice with no evidence of increased thrombogenicity compared with wild-type FIX. Thus, these bioengineered FIX variants can increase the therapeutic index of gene therapy vectors by permitting administration of lower doses to achieve the same therapeutic outcome. Furthermore, these variants may also be valuable for recombinant FIX protein replacement therapy.

A practical approach to pediatric patients referred with an abnormal coagulation profile.

CONTEXT Workup for prolonged prothrombin time (PT) and activated partial thromboplastin time (PTT) is a frequent referral to a Hematology and Coagulation Laboratory. Although the workup should be performed in a timely and cost-effective manner, the complete laboratory assessment of the coagulation state has not been standardized. OBJECTIVE To determine which clinical and laboratory data are most predictive of a coagulopathy and to formulate the most efficient strategy to reach a diagnosis in patients referred for abnormal coagulation profiles. DESIGN Retrospective case review. Medical records of 251 patients referred for prolonged PT and/or PTT to our Hematology Service between June 1995 and December 2002 were reviewed. RESULTS The study included 135 males and 116 females with a mean age of 7.0 years. A personal history of bleeding was reported in 137 patients, and a family history of bleeding was reported in 116 patients. Fifty-one patients (20%) had a coagulopathy (ie, a bleeding risk). Factors predictive of a bleeding risk were a positive family history of bleeding (P < .001) and a positive personal history of bleeding (P = .001). Of 170 patients with findings of normal PT and PTT values on repeat testing, 14 were subsequently diagnosed with a coagulopathy. Two of these patients reported no positive personal or family history of bleeding. CONCLUSIONS Coagulopathy was identified in 20% of the children referred for abnormal PT and/or PTT. In the absence of a personal or family history of bleeding, a normal PT and/or PTT on repeat testing has a negative predictive value of more than 95%.

Thrombotic microangiopathic hemolytic anemia with reduction of ADAMTS13 activity: initial manifestation of childhood-onset systemic lupus erythematosus.

Severe manifestations of systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and thrombotic thrombocytopenic purpura (TTP) are characterized by multiorgan thrombotic microangiopathy. We describe reduction of ADAMTS13 activity and the development of systemic autoimmunity in all 8 children initially diagnosed with acquired noncongenital TTP during an 8.5-year period. Median age at diagnosis was 12.0 years (range, 2.6-17.3 years). ADAMTS13 activity was absent (<5%) in 6 patients; 3 patients had a detected inhibitor. SLE was diagnosed concurrently in 3 patients, and 4 patients were diagnosed within 5 years. Six of the children diagnosed with SLE had absent ADAMTS13 activity at diagnosis. In 6 patients with SLE, immune-mediated nephritis developed by 46 months. All surviving patients with SLE developed antiphospholipid antibodies, including some with a lupus anticoagulant. Patients with SLE did not have TTP recurrences once daily immunosuppressive regimens were started. An evaluation for SLE/APS is warranted in children and adolescents with reduced ADAMTS13 activity and thrombotic microangiopathy.

Thromboelastographic and hemostatic characteristics in pediatric patients with sickle cell disease.

CONTEXT Patients with sickle cell disease suffer from a variety of vaso-occlusive events that may be related to activation of the hemostatic system. Thromboelastography assesses the functionality of this system from a global standpoint and has demonstrated some utility in detecting hypercoagulable states in varied clinical settings, but it has not been systematically evaluated in patients with sickle cell disease. OBJECTIVE To characterize the findings of thromboelastography in patients with sickle cell disease during periods of steady state and illness, to compare these results with those of healthy controls, and to correlate these profiles with other measured hemostatic parameters. DESIGN In this cross-sectional study, we obtained thromboelastographic and other hemostatic data on specimens from 46 patients with sickle cell disease (35 with hemoglobin SS, 7 with hemoglobin SC, and 4 with hemoglobin S-beta thalassemia) and 20 healthy race-matched controls. Data were obtained from patients with sickle cell disease at baseline conditions (n = 41) and in the setting of acute illness (n = 5). RESULTS Patients with hemoglobin SS had lower reaction time and higher angle, maximum amplitude, and coagulation index values on thromboelastography than the control group. Hemoglobin SC patients had higher angle, maximum amplitude, and coagulation index values than controls. Hemoglobin S-beta thalassemia patients showed no significant differences compared with controls. Five hemoglobin SS patients with recent or current illness demonstrated increased maximum amplitude and coagulation index compared with hemoglobin SS patients at baseline conditions. CONCLUSIONS Patients with sickle cell disease demonstrated a significant hypercoagulable state in thromboelastography profiles, with the degree of abnormality dependent on the type of sickle cell disease and perhaps the presence of acute illness. Continued follow-up of this patient cohort, as well as further study of larger and more homogeneous patient groups, is required to adequately assess the utility of thromboelastography in predicting complications of sickle cell disease.

Low prevalence and assay discordance of “aspirin resistance” in children

Although “aspirin resistance” (AR‐inadequate platelet inhibition as suggested by in vitro testing of aspirin‐treated patients) has been widely studied in adults and linked to increased risk of adverse outcomes, its prevalence and clinical significance are largely unknown in children.

Heparin versus 0.9% sodium chloride intermittent flushing for the prevention of occlusion in long term central venous catheters in infants and children: A systematic review

BACKGROUND Around the world, guidelines and clinical practice for the prevention of complications associated with central venous catheters (CVC) vary greatly. To prevent occlusion, most institutions recommend the use of heparin when the CVC is not in use. However, there is debate regarding the need for heparin and evidence to suggest normal saline may be as effective. The use of heparin is not without risk, may be unnecessary and is also associated with increased costs. OBJECTIVES To assess the clinical effects (benefits and harms) of heparin versus normal saline to prevent occlusion in long-term central venous catheters in infants, children and adolescents. DESIGN A Cochrane systematic review of randomised controlled trials was undertaken. DATA SOURCES The Cochrane Vascular Group Specialised Register (including MEDLINE, CINAHL, EMBASE and AMED) and the Cochrane Register of Studies were searched. Hand searching of relevant journals and reference lists of retrieved articles was also undertaken. REVIEW METHODS Data were extracted and appraisal undertaken. We included studies that compared the efficacy of normal saline with heparin to prevent occlusion. We excluded temporary CVCs and peripherally inserted central catheters. Rate ratios per 1000 catheter days were calculated for two outcomes, occlusion of the CVC, and CVC-associated blood stream infection. RESULTS Three trials with a total of 245 participants were included in this review. The three trials directly compared the use of normal saline and heparin. However, between studies, all used different protocols with various concentrations of heparin and frequency of flushes. The quality of the evidence ranged from low to very low. The estimated rate ratio for CVC occlusion per 1000 catheter days between the normal saline and heparin group was 0.75 (95% CI 0.10 to 5.51, two studies, 229 participants, very low quality evidence). The estimated rate ratio for CVC-associated blood stream infection was 1.48 (95% CI 0.24 to 9.37, two studies, 231 participants; low quality evidence). CONCLUSIONS It remains unclear whether heparin is necessary for CVC maintenance. More well-designed studies are required to understand this relatively simple, but clinically important question. Ultimately, if this evidence were available, the development of evidenced-based clinical practice guidelines and consistency of practice would be facilitated.

Assessment of liver function tests on Piccolo Xpress point of care chemistry analyzer in a pediatric hospital

Objectives Point of care testing (POCT) contributes to diagnosis and monitoring with fast testing time and easily performed assays. We evaluated the Abaxis Piccolo Xpress point of care chemistry analyzer using the Liver Panel Plus discs for our pediatric patient population at Texas Childrens Hospital. Design and methods Analytical performance was evaluated for precision and linearity using quality control materials and commercially available verification samples. Comparison studies were performed between Piccolo Xpress analyzer and Vitros 5600 analyzer using patient samples. Interference studies were carried out using nine different patient pool sera. Lipemia interference was removed using LipoClear for severely lipemic sample pools. Results Precision of all tests was excellent (CVs<5% for all measured analytes except TBIL). All assays were linear and accurate within the allowable total error. Comparison studies showed that three analytes (amylase, GGT and TBIL) had statistically significant bias. Interference study results did not exceed the total allowable error for hemoglobin (<150 mg/dL), bilirubin (<15 mg/dL) and lipemia (<400 mg/dL except ALT, GGT and TP). LipoClear treatment removed lipemia interference for all analytes except total protein. Conclusions The Piccolo Xpress chemistry analyzer showed an acceptable analytical performance for precision, linearity and interference from common substances. Increased bias for three analytes in comparison studies could be due to different methodologies.

Improving the central venous access devices maintenance process to reduce associated infections in paediatrics: evaluation of a practical, multi-faceted quality-improvement initiative

Abstract Introduction Central venous access devices (CVADs) provide essential and reliable vascular access, but infection is a common and serious complication with paediatric patients. CVAD bundles have been demonstrated to effectively reduce central line-associated bloodstream infections (CLABSI), but primarily during CVAD insertion. Another emerging strategy to encourage best practice is the use of a dedicated CVAD trolley for maintenance. Methods A quality-improvement initiative was undertaken to improve CVAD maintenance and to evaluate the effectiveness of the chosen interventions at the Royal Childrens Hospital, Brisbane. Nursing staff from four wards within the hospital elected to participate and the wards were allocated to receive either Intervention A (CVAD maintenance bundle only) or Intervention B (CVAD maintenance bundle and dedicated CVAD trolley). Effectiveness of the interventions was evaluated by: (i) rate of CLABSI per 1000 catheter-days; and (ii) audits of clinician compliance with evidence-based CVAD maintenance strategies. Results During the initiative, the hospital-wide CLABSI rate decreased from 9.07 to 1.05 episodes per 1000 catheter-days ( P = 0.01). The rate of CLABSI in Intervention A wards reduced from 7.6 to 2.2 episodes per 1000 catheter-days ( P (P 0.001). Hospital-wide audits of clinician compliance increased from 11.9% to 3 5% (P = 0.001) in the Intervention A wards and to 83% (P 0.001) in the Intervention B wards. Conclusion Implementation of CVAD maintenance bundles and a dedicated CVAD trolley successfully reduced CLABSI and improved audited compliance to evidence-based practices within our tertiary paediatric hospital.